Revisiting the Natural History of Tuberculosis The Inclusion of Constant Reinfection, Host Tolerance, and Damage-Response Frameworks Leads to a Better Understanding of Latent Infection
and its Evolution towards Active Disease
Pere-Joan Cardona
Abstract Once Mycobacterium tuberculosis infects a person it can persist for a long time in a process calledlatent tuberculosis infection (LTBI). LTBI has traditionally been considered to involve the bacilli remaining in a nonreplicating state (dormant) in old lesions but still retaining their ability to induce reactivation and cause active tuberculosis (TB) once a disruption of the immune response takes place. The present review aims to challenge these concepts by including recent experimental data supporting LTBI as a constant endogenous reinfection process as well as the recently introduced concepts of damage-response and tolerance frameworks to explain TB induction. These frameworks highlight the key role of an exaggerated and intolerant host response against M. tuberculosis bacilli which induces the classical TB cavity in immunocompetent adults once the constant endogenous reinfection process has resulted in the presence of bacilli in the upper lobes, where they can grow faster and the immune response is delayed. This essay intends to provide new clues to understanding the induction of TB in non-immunosuppressed patients.
Keywords Mycobacterium tuberculosis Foamy macrophages Dynamic hypothesis Damage-framework response Tolerance theory
The Role of Heparanase in Diseases of the Glomeruli
Maciej Szymczak • Jakub Kuz´niar • Marian Klinger
Abstract The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves b 1,4 D-glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.
Keywords Heparanase Glomerular basement membrane Glomerulonephritis Proteinuria Heparan sulfate proteoglycans
Role of SLAM-Associated Protein in the Pathogenesis
of Autoimmune Diseases and Immunological Disorders
Hiroshi Furukawa • Shigeto Tohma •
Hiroshi Kitazawa • Hiroaki Komori •
Masato Nose • Masao Ono
Received: 11 March 2009 / Accepted: 2 June 2009 / Published online: 5 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009
Abstract Signaling lymphocytic activation molecule
(SLAM)-associated protein (SAP) is an adaptor molecule
containing a Src homology 2 (SH2) domain. SAP is
expressed in T cells and natural killer (NK) cells and binds
to the cytoplasmic domains of SLAM family receptors,
resulting in the subsequent recruitment of Fyn. The SAP
(SH2D1A) gene is located on the X chromosome and is
responsible for X-linked lymphoproliferative disease,
characterized by higher susceptibility to Epstein-Barr virus
infection. The SAP-mediated signal is not only essential for
the development of NKT cells, i.e. unconventional CD1d-
restricted T cells with invariant Va14 T cell receptors, but
also for the regulation of the function of NK cells and
conventional T cells. The role of SAP-mediated signaling
in the induction of autoimmune diseases has been analyzed
using animal models such as lupus, hepatitis, and graft-
versus-host disease and is considered important in their
pathogenesis in humans. In this review we highlight the
current findings on SAP-mediated signaling in hemato-
poietic cells and discuss its importance in autoimmune
diseases and immunological disorders.
Keywords SLAM SAP Autoimmune diseases
Different Facets of Competition in the Pharmaceutical Sector:
Preliminary Findings of the European Commission’s Sector
Inquiry into Pharmaceuticals
Filip Borkowski
Received: 18 May 2009 / Accepted: 10 June 2009 / Published online: 27 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2010
Abstract The pharmaceutical sector is a part of today’s
economy in which the relationship between patents and
competition has been receiving increasing attention. The
European Commission’s inquiry into this sector adds to the
ongoing debate. Its Preliminary Report, published in
November 2008, explains and quantifies a number of
practices adopted by individual companies operating in the
sector. The Report focuses on two strands of interplay
between pharmaceutical companies. The first focus is on
competition between originator and generic companies and
the second relates to competition among originators
themselves. The Report’s observations on the former pro-
vide us with some important insights into the potential
ways of raising barriers to the timely entry of cheaper, off-
patent products, while scrutiny of the latter adds to our
understanding of the current rate of introducing new
innovative products into the market. The study is com-
pleted by a number of observations on the sector’s
regulatory framework. The presentation below follows the
order of findings described in the Report.
Keywords Competition Patents Generic competition
European Commission
Immunotherapy of Rheumatoid Arthritis Targeting Inflammatory
Cytokines and Autoreactive T Cells
Guangjie Chen
Received: 27 February 2009 / Accepted: 6 July 2009 / Published online: 5 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009
Abstract Rheumatoid arthritis is a chronic disorder for
which there is no known cure. Concentrating on specific
elements of the abnormal immune response that charac-
terizes the disease, scientists are reaching into
biotechnology’s bag of tricks to develop immunothera-
peutic techniques. This paper will present some advances
in the immunotherapy of rheumatoid arthritis targeting
inflammatory cytokines and autoreactive T cells.
Keywords Rheumatoid arthritis Immunotherapy
Inflammatory cytokines Autoreactive T cells
Regulatory T cells Th17 cells
Cathelicidin LL-37: A Multitask Antimicrobial Peptide
Robert Bucki • Katarzyna Leszczyn´ ska •
Andrzej Namiot • Wojciech Sokołowski
Received: 12 February 2009 / Accepted: 30 April 2009 / Published online: 5 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009
Abstract The antimicrobial peptide LL-37 is the only
known member of the cathelicidin family of peptides
expressed in humans. LL-37 is a multifunctional host
defense molecule essential for normal immune responses to
infection and tissue injury. LL-37 peptide is a potent killer
of different microorganisms with the ability to prevent
immunostimulatory effects of bacterial wall molecules
such as lipopolysaccharide and can therefore protect
against lethal endotoxemia. Additional reported activities
of LL-37 include chemoattractant function, inhibition of
neutrophil apoptosis, and stimulation of angiogenesis, tis-
sue regeneration, and cytokine release (e.g. IL-8). Cellular
production of LL-37 is affected by multiple factors,
including bacterial products, host cytokines, availability of
oxygen, and sun exposure through the activation of CAP-
18 gene expression by vitamin D3. At infection sites, the
function of LL-37 can be inhibited by charge-driven
interactions with DNA and F-actin released from dead
neutrophils and other cells lysed as the result of inflam-
mation. A better understanding of LL-37’s biological
properties is necessary for its possible therapeutic appli-
cation for immunomodulatory purposes as well as in
treating bacterial infection.
Keywords Antibacterial agents Bacteria Infection
hCAP-18
The Enzymatic Activity of Type 1 Iodothyronine Deiodinase
(D1) is Low in Liver Hemangioma: A Preliminary Study
Oskar Kornasiewicz • Marcin Debski •
Marta Stepnowska • Anna Szałas •
Ewa Bar-Andziak • Marek Krawczyk
Received: 1 August 2008 / Accepted: 7 August 2009 / Published online: 5 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009
Abstract Type 1 iodothyronine deiodinase (D1) is a cru-
cial enzyme which converts the prohormone thyroxine (T4)
into active tri-iodothyronine (T3). There has been strong
evidence that the metabolism of thyroid hormones is dis-
turbed in some neoplastic tissues such as thyroid, renal, and
breast cancer. However, there are few available data about
D1 enzyme activity in benign tumors such as hemangioma,
which is the most common primary liver tumor. Hence this
study aimed to determine the enzymatic activity of D1 in
hemangiomas in relation to healthy liver tissue. Seven
tumors and healthy control tissues were obtained from
patients who had liver resection due to hemangioma. The
activity was assessed by measurement of radioactive iodine
released by deiodination catalyzed by D1. It was found that
D1 activity was significantly lower in the hemagiomas than
in the healthy surrounding tissue (p = 0.0017). The results
indicated that thyroid hormones play important roles not
only in the regulation of cell metabolism, but also in cell
growth, division, and apoptosis. The active form T3 acts
through its nuclear receptors and influences the up- and
down-regulation of target genes. Healthy liver tissue
expresses a high level of D1, but disturbed D1 activity may
result in changes in the local concentration of T3 which may
impair gene transcription. These finding demonstrate a low
enzymatic activity of D1 in liver hemangioma and suggest an
as yet unknown role of thyroid hormones in this type of
benign liver tumor.
Keywords Hemangioma Liver resection
Iodothyronine deiodinase (D1)
Serodiagnostic Efficacy of Mycobacterium tuberculosis 30/32-kDa
Mycolyl Transferase Complex, ESAT-6, and CFP-10 in Patients
with Active Tuberculosis
Gavish Kumar • Pradeep Kumar Dagur • Prashant Kumar Singh •
Hari Shankar • Virendra S. Yadav • Vishwa M. Katoch • Bharat Bajaj •
Rajesh Gupta • Utpal Sengupta • Beenu Joshi
Received: 29 January 2009 / Accepted: 2 June 2009 / Published online: 5 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2010
Abstract Elimination of tuberculosis (TB) largely
depends upon definitive rapid diagnosis and treatment.
Widely used diagnostic tests do not qualify for use in a
developing country due to lack of either desired accuracy
or their cost. In the present study an enzyme-linked
immunosorbent assay was used to evaluate the diagnostic
potential of an immuno-dominant 30/32-kDa mycolyl
transferase complex (Ag85 complex) and Mycobacterium
tuberculosis-specific proteins (ESAT-6 and CFP-10) of the
RD1 region. Higher sensitivity (84.1%) with Ag85 com-
plex was observed compared with ESAT-6 (64.9%) and
CFP-10 (66%), with almost similar specificity (Ag85:
85.2%, ESAT-6: 88.9%, CFP-10: 85.2%), whereas the
individual components of Ag85 complex, i.e. Ag85A,
Ag85B, and Ag85C, showed sensitivities of 44.6, 34, and
80.9% and specificities of 55.6, 74.1, and 40.7% respec-
tively. A cocktail of Ag85 complex, ESAT-6, CFP-10,
Ag85A, Ag85B, and Ag85C antigens also could not help in
increasing either sensitivity (51.1%) or specificity (85.2%).
Furthermore, immunoblot analysis using clinical isolates as
well as a standard strain (H37Rv) of M. tuberculosis also
showed strong reactivity of sera from TB patients to Ag85
complex and, to a lesser extent, also to ESAT-6. To
conclude, use of Ag85 complex along with ESAT-6 and
CFP-10 seems to be promising in minimizing the hetero-
geneous sero-responses of adult TB cases.
Keywords Secretory proteins
30/32-kDa Mycolyl transferase complex
ESAT-6/CFP-10 Serodiagnosis Tuberculosis
In Vitro Photodynamic Therapy with Chlorin e6 Leads
to Apoptosis of Human Vascular Smooth Muscle Cells
Magdalena Wawrzyn´ ska • Wojciech Kałas •
Dariusz Biały • Ewa Zioło • Jacek Arkowski •
Walentyna Mazurek • Leon Strza˛dała
Received: 30 October 2008 / Accepted: 15 July 2009 / Published online: 14 January 2010
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2010
Abstract Percutaneous coronary intervention has become
the most common and widely implemented method of heart
revascularization. However, the development of restenosis
remains the major limitation of this method. Photodynamic
therapy (PDT) recently emerged as a new and promising
method for the prevention of arterial restenosis. Here the
efficacy of chlorin e6 in PDT was investigated in vitro using
human vascular smooth muscle cells (TG/HA-VSMCs) as
one of the cell types crucial in the development of reste-
nosis. PDT-induced cell death was studied on many levels,
including annexin V staining, measurement of the genera-
tion reactive oxygen species (ROS) and caspase-3 activity,
and assessment of changes in mitochondrial membrane
potential and fragmentation of DNA. Photosensitization of
TG/HA-VSMCs with a 170 lM of chlorin e6 and sub-
sequent illumination with the light of a 672-nm diode laser
(2 J/cm2) resulted in the generation of ROS, a decrease in
cell membrane polarization, caspase-3 activation, as well as
DNA fragmentation. Interestingly, the latter two apoptotic
events could not be observed in photosensitized and illu-
minated NIH3T3 fibroblasts, suggesting different outcomes
of the model of PDT in various types of cells. The results
obtained with human VSMCs show that chlorin e6 may be
useful in the PDT of aerial restenosis, but its efficacy still
needs to be established in an animal model.
Keywords Restenosis Photodynamic therapy
Cell death Chlorin Vascular smooth muscle cells
Resident peritoneal macrophages and mast cells
are important cellular sites of COX-1 and COX-2
activity during acute peritoneal inflammation
Elzbieta Kolaczkowska1, Anna Goldys1, Elzbieta Kozakiewicz1, Monika Lelito1,
Barbara Plytycz1, Nico van Rooijen2 and Bernd Arnold3
1 Department of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, Kraków, Poland
2 Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, the Netherlands
3 Laboratory for Molecular Immunology, German Cancer Research Center, Heidelberg, Germany
Received: 2008.10.07, Accepted: 2009.04.29
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Cyclooxygenases (COXs) play important roles during inflammation. While reports on COX-2 function in
inflammation preceded those on COX-1, it is now well established that both isoforms participate in this process. During
inflammation, COX expression was reported in inflammatory leukocytes, but much less is known about their presence in tis-
sue-resident leukocytes. The aim was thus to verify the expression and activity of the COX isoforms in resident peritoneal
mast cells and macrophages during acute peritonitis.
Materials and Methods: Zymosan peritoneal inflammation was induced in C57BL/6J mice and COX-1 and COX-2 expres-
sion was evaluated by RT-PCR (mRNA level) and immunocytochemistry (protein level). COX activity was assessed by a spe-
cific assay and prostaglandin production by ELISA. Furthermore, some mice were selectively depleted of either peritoneal
mast cells or macrophages and then COX activity was determined.
Results: The study revealed that both COXs are expressed/active at the peak of inflammation, but COX-2 predominates dur-
ing resolution. The expressions of the COXs were detectable in both populations of resident peritoneal leukocytes. In peri-
toneal macrophages both isoforms were active even during the late phases of peritonitis and the cells significantly con-
tributed to PGE2 and PGD2 synthesis. The most striking observation was that resident macrophages are critical for PGD2
production during the resolution of inflammation.
Conclusions: This study documents that both COX isoforms participate in all stages of acute inflammation and that tissue-
resident leukocytes, especially macrophages, are important sites of COX-1/COX-2 expression and prostaglandin synthesis.
Key words: cyclooxygenase, peritoneal inflammation, prostaglandins, resident peritoneal leukocytes.
Cellular glucose transport and glucotransporter 4
expression as a therapeutic target:
clinical and experimental studies
Anna Czech, Paweł Piątkiewicz and Jan Tatoń
Chair and Department of Internal Medicine, and Diabetology, Second Medical Faculty, Warsaw Medical University
(Brodnowski Hospital), Warsaw, Poland
Received: 2009.02.10, Accepted: 2009.04.29
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: The normalization of cellular glucose assimilation is the basic aim of metabolic therapy in type 2 diabetes mel-
litus (T2DM). It requires parallel changes in the process of cellular glucose transport (CGT). Therefore the level of CGT
could be regarded as a therapeutic target for oral hypoglycemic drugs in T2DM. To explore this hypothesis, CGT levels
before and after sulfonylurea therapy were investigated. Peripheral blood lymphocytes were used as a cell model for testing
CGT.
Materials and Methods: CGT was assessed by experimental in vitro tests allowing timed comparative observation of the
transport process during the incubation of lymphocytes with 2-[3H(G)] glucose under basal conditions and after the addition
of sulfonylurea or sulfonylurea plus insulin. The incubation tests were performed at baseline in 28 persons with newly diag-
nosed, therapy-naive T2DM and in 20 control subjects. In the diabetic patients the tests for CGT were repeated after 3
months of sulfonylurea therapy. The level of glucotransporter 4 (GLUT4) expression was also assessed by flow cytometry
before and after the therapy.
Results: Before treatment, CGT was significantly lower in the subjects with T2DM. The cells responded to the addition of
sulfonylurea by a moderate increase in CGT. This response was augmented by the addition of insulin to sulfonylurea in the
culture medium.
Conclusions: The three-month therapy with sulfonylurea resulted in a significant increase in CGT in all types of culture tests.
This sulfonylurea-related improvement in CGT was associated with a near normalization of GLUT4 expression in the cells.
Key words: sulfonylurea, cellular glucose transport, lymphocytes, GLUT4.
Cardiomyocyte death in doxorubicin-induced cardiotoxicity
Yi−Wei Zhang1, 2, Jianjian Shi1, 2, Yuan−Jian Li2 and Lei Wei1, 2
1 Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University, School of Medicine,
Indianapolis, IN, USA
2 Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, P.R.
China
Received: 2009.03.16, Accepted: 2009.05.20
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent
cardiac toxicity has been a major concern of oncologists in cancer therapeutic practice for decades. With the increasing pop-
ulation of cancer survivors, there is a growing need to develop preventive strategies and effective therapies against DOX-
-induced cardiotoxicity, in particular late-onset cardiomyopathy. Although intensive investigations on DOX-induced car-
diotoxicity have continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not
been completely elucidated. A rapidly expanding body of evidence supports the notion that cardiomyocyte death by apopto-
sis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and that other types of cell death, such as
autophagy and senescence/aging, may participate in this process. This review focuses on the current understanding of the
molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess
production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. The different
sensitivities to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed.
Key words: cardiomyocyte, doxorubicin, apoptosis, necrosis, autophagy.
Exploring the immune response
against
Mycobacterium tuberculosis
for a better diagnosis of the infection
Giovanni Ferrara1, Monica Losi2, 3, Leonardo M. Fabbri3, Giovanni B. Migliori4,
Luca Richeldi2, 3 and Lucio Casali1
1 Section of Respiratory Disease, Department of Internal Medicine, St. Maria Hospital, University of Perugia, Terni, Italy
2 Center for Rare Lung Diseases, University of Modena and Reggio Emilia, Modena, Italy
3 Sections of Respiratory Diseases, Department of Oncology and Hematology, University of Modena and Reggio Emilia,
Modena, Italy
4 WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy
Received: 2009.02.11, Accepted: 2009.04.29
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Tuberculosis (TB) still represents a monumental problem, with more than two million deaths every year worldwide. The cur-
rent diagnostics for TB offer sub-optimal accuracy both for the active and the latent form of infection and are often based
on technologies unaffordable in low-income settings. The tuberculin skin test was the first diagnostic based on an acquired
immune response towards Mycobacterium tuberculosis (MTB). Advances in molecular and cellular biology and the elucida-
tion of the mechanisms governing the relation between MTB and the human immune system form the basis for new and
more accurate assays, potentially able to fill the gaps and limits of classical diagnostics. However, the process of validating
new tests is still complex and hampered by specific questions regarding TB immunology and natural history. We present here
a summary of the current approaches to validate new diagnostics based on the detection of immunological biomarkers of TB
infection.
Key words: tuberculosis, acquired immune response, latent tuberculosis infection, diagnosis, new tools.
Recent advances in multivalent self adjuvanting
glycolipopeptide vaccine strategies against breast cancer
Aziz Alami Chentoufi1, Anthony B. Nesburn1 and Lbachir BenMohamed1, 2, 3
1 Laboratory of Cellular and Molecular Immunology, The Gavin S. Herbert Eye Institute, University of California Irvine,
School of Medicine, Irvine, CA, USA
2 Institute for Immunology, University of California Irvine, Irvine, CA, USA
3 Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
Received: 2009.02.17, Accepted: 2009.06.19
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Breast cancer (BrCa) is the second leading cause of cancer-related deaths for women worldwide. Evidence from both
patients and mouse cancer models suggests that the simultaneous induction of BrCa-specific CD4+ T cells, CD8+ cytotoxic
T cells, and antibodies is crucial for providing immune resistance. However, almost all current vaccines address only a single
arm of the immune system, which may explain their lack of efficacy. We believe that the correct response to monovalent vac-
cines’ “failure” is to increase our knowledge about antitumor protective immunity and to develop a multivalent vaccine mol-
ecule that can simultaneously induce multiple arms of the immune system. We highlight here recent advances in anti-BrCa
peptide-based vaccine strategies with an emphasis on the self adjuvanting multivalent glycolipopeptide vaccine strategy
recently developed in our laboratory and which showed promising results in both immunotherapeutic and immunoprophy-
lactic settings.
Key words: vaccine, glycolipopeptide, breast cancer, T-cell, epitopes, TLR.
CD40-activated B cells from patients with systemic lupus
erythematosus can be modulated by therapeutic
immunoglobulins
in vitro
Sonia Néron1, 2, Gilles Boire3, Nathalie Dussault1, Claudia Racine1,
Artur J. de Brum−Fernandes3, Serge Côté1, 2 and Annie Jacques1
1 Héma-Québec, Recherche et développement, Ingénierie cellulaire, Québec, Québec, Canada
2 Département de biochimie et microbiologie, Faculté des sciences et de génie, Université Laval, Québec, Québec, Canada
3 Service de rhumatologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke
et Centre hospitalier universitaire de Sherbrooke, Sherbrooke, Québec, Canada
Received: 2009.02.10, Accepted: 2009.04.29
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Aberrant signaling within and between B and T cells, considered to be central in systemic lupus erythemato-
sus (SLE), could depend on enhanced CD40-CD154 activation. As a result, autoreactive B cells, normally anergic, differen-
tiate and secrete antibodies attacking several normal tissues. Thus restorating B cell homeostasis might help control this dis-
ease. In this study, two facets of SLE B cells were investigated, namely their in vitro response to CD40-CD154 and the effect
of treatment with human immunoglobulins for intravenous use (IVIg).
Materials and Methods: Blood samples from SLE patients and healthy volunteers were obtained and used to isolate B cells,
which were activated through CD40 in the presence or absence of IVIg. The phenotype, proliferation, and differentiation of
the SLE B cells were determined and compared with those of control B cells using flow cytometry and standard ELISA.
Results: In this model, CD40-activated SLE B cells, as control B cells, proliferated and differentiated and were character-
ized by the emergence of CD19loCD38++CD138+CD27++ cells. IVIg treatment of the CD40-activated SLE B cells resulted
in higher differentiation, characterized by increased secretion rates of IgG and IgM, as reported previously for control
B cells.
Conclusions: Taken as a whole, such accelerated differentiation of CD40-activated B cells suggests that IVIg may participate
in re-equilibration of the antibody repertoire by replacing pathological antibodies by de novo harmless antibodies.
Key words: B cell, SLE; differentiation, intravenous immunoglobulins, IVIg
Complement: coming full circle
Gaëlle Le Friec and Claudia Kemper
King’s College London, MRC Centre for Transplantation, London SE1 9RT, UK
Received: 2009.02.18, Accepted: 2009.06.01
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The complement system has long been known to be a major element of innate immunity. Traditionally, it was regarded as
the first line of defense against invading pathogens, leading to opsonization and phagocytosis or the direct lysis of microbes.
However, from the second half of the twentieth century on, it became clear that complement is also intimately involved in
the induction and “fine tuning” of adaptive B- and T-cell responses as well as lineage commitment. This growing recognition
of the complement system’s multifunctional role in immunity is consistent with the recent paradigm that complement is also
necessary for the successful contraction of an adaptive immune response. This review aims at giving a condensed overview
of complement’s rise from a simple innate stop-and-go system to an essential and efficient participant in general immune
homeostasis and acquired immunity.
Key words: complement, innate immunity, adaptive immunity, immune regulation.
IRF4 selectively controls cytokine gene expression
in chronic intestinal inflammation
Jonas Mudter1, 2, 3, Jingling Yu2, Lioubov Amoussina2, Benno Weigmann2,
Arthur Hoffman3, Katrin Rücknagel3, Peter R. Galle3 and Markus F. Neurath1, 2, 3
1 1st Medical Clinic, University of Erlangen-Nürnberg, Germany
2 Institute for Molecular Medicine, University of Mainz, Germany
3 1st Medical Clinic, University of Mainz, Germany
Received: 2008.12.17, Accepted: 2009.03.06
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The authors previously showed that interferon regulatory factor (IRF)4 knockout mice are protected from experimental oxa-
zolone and TNBS colitis. Here the effect of IRF4 on the expression of pro- and anti-inflammatory cytokines in TNBS colitis
and long-term CD45RBhigh transfer colitis is examined. In TNBS colitis, no differences were found in interleukin (IL)-18 and
tumor necrosis factor (TNF)-α expression between IRF4 knockout and wild-type mice. However, significant differences were
detected in IL-6 and IL-17 production. Upon treatment with hyper-IL-6, IRF4–/– mice lost their protective properties towards
TNBS application. Hyper-IL-6 application induced IL-6 mRNA, but not IL-17 mRNA expression, suggesting that IL-6 defi-
ciency is not primarily responsible for the lack of IL-17 production. T-bet and GATA-3 mRNA expressions were not affected
upon IL-6 application. In transfer colitis, colonic cytokine mRNA analysis revealed a reduced production of IL-6 in IRF4–/–
reconstituted mice in the long-term course. In contrast, several other cytokines did not differ between the two groups (e.g.
TNF-α and IL-10). Measurement of supernatants from splenic mononuclear cells revealed a significant difference in IL-6 and
IL-17 production between the two groups. These findings suggest that IRF4 selectively regulates cytokine gene expression in
chronic inflammation. IRF4 therefore emerges as an attractive target for the therapy of chronic intestinal inflammation.
Blocking IRF4 might be an interesting option to modulate inflammation in the advanced state of inflammation.
Key words: IRF4, T cells, interferon regulatory factor, IL-6, IL-17
Reddish, scaly, and itchy: how proteases and their
inhibitors contribute to inflammatory skin diseases
Ulf Meyer−Hoffert
Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany
Received: 2009.01.16, Accepted: 2009.03.16
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The skin protects us from water loss and mechanical damage. The surface-exposed epidermis, a self-renewing stratified squa-
mous epithelium composed of several layers of keratinocytes, is most important in the barrier defense against these chal-
lenges. Endogenous and exogenous proteases such as kallikreins, matriptase, caspases, cathepsins, and proteases derived
from microorganisms are important in the desquamation process of the stratum corneum and are able to activate and inac-
tivate defense molecules in human epidermis. Protease inhibitors such as like LEKTI, elafin, SLPI, SERPINs, and cystatins
regulate their proteolytic activity and contribute to the integrity and protective barrier function of the skin. Changes in the
proteolytic balance of the skin can result in inflammation, which leads to the typical clinical signs of redness, scaling, and
itching. This review summarizes the current knowledge of how proteases, their inhibitors, and their target proteins, includ-
ing filaggrin, protease-activated receptors, and corneodesmosin, contribute to the pathophysiology of inflammation of the
skin and highlight their role in common inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis.
Key words: atopic dermatitis, proteases, epidermal barrier, innate immunity, protease inhibitors, psoriasis.
Fetal-cell microchimerism,
lymphopoiesis, and autoimmunity
Michele Leduc1, 2, Selim Aractingi1, 2, 3 and Kiarash Khosrotehrani1, 2, 3
1 Université Pierre et Marie Curie, Paris VI, Paris, France
2 Laboratoire des Cellules Souches Fetales, INSERM UMR_S938, Centre de Recherche Saint-Antoine, Paris France
3 Assistance Publique-Hôpitaux de Paris, Service de Dermatologie, Hôpital Tenon, Paris, France
Received: 2009.01.16, Accepted: 2009.03.16
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
During all human and murine pregnancies, fetal cells enter the maternal circulation and tissues and may persist there for
decades. The immune consequences of this phenomenon have been explored for many years as a potential origin of autoim-
munity or protection from cancer in women after pregnancy. The leading hypothesis, suggesting that semi-allogenic fetal
T cells may trigger a graft-versus-host type of disease, has been supported by several studies showing an increased frequen-
cy of fetal-cell microchimerism (FMc) in women affected with systemic sclerosis. However, a large proportion of healthy
women or women affected with non-immune disorders also display fetal T cells, challenging the direct pathogenic role of
such cells. In addition, recent evidence showing the transfer of various fetal progenitor cells to the mother during gestation
has shed new light on the interpretation of microchimerism in autoimmunity. This review discusses the functional capacity
of fetal hematopoietic progenitors to form T and B cells in maternal hematopoietic tissues, where they undergo an educa-
tional process probably resulting in tolerance to maternal antigens. Therefore, hypotheses other than the transfer of fetal
cells to the mother’s circulation should be considered in explaining the observed association of FMc and autoimmune dis-
orders.
Key words: microchimerism, pregnancy, fetal T cells, lymphopoiesis, auto-immunity, stem cells.
Human complement activation by smooth
and rough
Proteus mirabilis lipopolysaccharides
Wiesław Kaca1, 2, Michał Arabski2, Rafał Fudała2, Eva Holmström3, Anders Sjöholm3,
Andrej Weintraub1, Bożena Futoma−Kołoch4, Gabriela Bugla−Płoskońska4
and Włodzimierz Doroszkiewicz4
1 Division of Clinical Bacteriology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden
2 Department of Microbiology, Institute of Biology, Jan Kochanowski University, Kielce, Poland
3 Division of Microbiology, Immunology, and Glycobiology, Lund University, Lund, Sweden
4 Institute of Genetics and Microbiology, Wroc³aw University, Wroc³aw, Poland
Received: 2008.09.18, Accepted: 2009.03.31
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Proteus mirabilis bacilli play an important role in human urinary tract infections, bacteremia, and rheumatoid
arthritis. The authors previously studied human complement C3 conversion by smooth-form P. mirabilis O10, O23, O30, and
O43 lipopolysaccharides (LPSs) and showed that smooth Proteus LPSs fragmented C3 in a dose- and time-dependent man-
ner. In the present study, one smooth P. mirabilis S1959 and its two polysaccharide-truncated LPSs isolated from an R
mutant strain were used to study the C3 conversion.
Materials and Methods: The conversion of C3 to C3c by smooth and rough P. mirabilis LPSs was studied by capture ELISA
and crossed immunoelectrophoresis. Proteins isolated from the outer membrane were analyzed by discontinuous sodium
dodecyl sulfate gel electrophoresis.
Results: The smooth P. mirabilis S1959 (O3) strain was resistant to the bactericidal activity of human serum, in contrast to
the Ra and Re mutant strains. The presence of an exposed core oligosaccharide in R110 LPS was not sufficient to protect
the strain from serum-dependent killing. In addition to LPS structure, the outer-membrane proteins may also play roles in
protecting the smooth P. mirabilis S1959 (O3) strain from the bactericidal action of serum. It was shown that the Ra P.
mirabilis R110 and the Re P. mirabilis R45 mutants possess very different OMP compositions from that of the P. mirabilis S
1959 strain.
Conclusion: Regardless of the complement resistance of the P. mirabilis strains, the S1959, R110, and R45 LPSs fragment-
ed C3 and induced C3c neo-antigen exposure. The use of complement-deficient human serum allows the conclusion that the
Re-type P. mirabilis R45 LPS fragmented C3 by the antibody-independent classical pathway.
Key words: Proteus mirabilis, complement, lipopolysaccharide, outer-membrane protein.
Factors that deregulate the protective immune response
in tuberculosis
Rogelio Hernandez−Pando, Hector Orozco and Diana Aguilar
Experimental Pathology Section, Department of Pathology, National Institute of Medical Sciences and Nutrition, México
Received: 2009.02.02, Accepted: 2009.03.16
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Tuberculosis (TB) is a chronic infectious disease which essentially affects the lungs and produces profound abnormalities on
the immune system. Although most people infected by the tubercle bacillus (90%) do not develop the disease during their
lifetime, when there are alterations in the immune system, such as co-infection with HIV, malnutrition, or diabetes, the risk
of developing active disease increases considerably. Interestingly, during the course of active disease, even in the absence of
immunosuppressive conditions, there is a profound and prolonged suppression of Mycobacterium tuberculosis-specific pro-
tective immune responses. Several immune factors can contribute to downregulate the protective immunity, permitting di-
sease progression. In general, many of these factors are potent anti-inflammatory molecules that are probably overproduced
with the intention to protect against tissue damage, but the consequence of this response is a decline in protective immuni-
ty facilitating bacilli growth and disease progression. Here the most significant participants in protective immunity are revie-
wed, in particular the factors that deregulate protective immunity in TB. Their manipulation as novel forms of immunothe-
rapy are also briefly commented.
Growth inhibition of
Staphylococcus aureus
by chicken egg yolk antibodies
Marco Cesar Cunegundes Guimarães1, Lívia Gomes Amaral1,
Letícia Batista Azevedo Rangel1, Ian Victor Silva1, Claudia Gomes
Fernandes Matta1 and Marcos Fernando de Rezende Matta2
1 Laboratory of Cellular and Molecular Biology of Human Cancer, UFES, Vitória, ES, Brazil
2 Immunogenetics, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ, Brazil
Received: 2008.12.23, Accepted: 2009.05.20
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: The aim was to evaluate the ability of egg yolk antibody (IgY) in blocking Staphylococcus aureus growth in vitro.
Materials and Methods: Specific IgY was produced by immunizing hens with formalin-killed S. aureus (ATCC 33593).
Specific IgY against S. aureus was obtained from the yolks of their eggs with a carrageenan solution. IgY was identified by
SDS-PAGE and Western blot and its activity against S. aureus was tested by ELISA. A growth inhibition assay and protein
concentration determination were also conducted.
Results: ELISA indicated that the IgY was specific to the antigen; this activity was confirmed by Western blotting. The
growth of S. aureus was inhibited by the specific IgY at concentrations of 1–5 µg/ml The bacteriostatic function of IgY
appeared to result possibly from the interaction of IgY with surface components of S. aureus. In vitro experiments showed
that the immunoglobulin from egg yolk interfered with the culture growth of the S. aureus.
Conclusion: These findings indicate that eggs from hens immunized with appropriate antigens are a potentially useful source
of passive immunity.
Key words: inhibition of bacterial growth, chicken egg yolk antibody, ELISA and Staphylococcus aureus
Fc receptor-targeted mucosal vaccination
as a novel strategy for the generation of enhanced
immunity against mucosal and non-mucosal pathogens
Edmund J. Gosselin, Constantine Bitsaktsis, Ying Li and Bibiana V. Iglesias
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
Received: 2009.01.15, Accepted: 2009.03.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Numerous studies have demonstrated that targeting immunogens to Fcγ receptors (FcγR) on antigen (Ag)-presenting cells
(APC) can enhance humoral and cellular immunity in vitro and in vivo. FcγR are classified based on their molecular weight,
IgG-Fc binding affinities, IgG subclass binding specificity, and cellular distribution and they consist of activating and inhibito-
ry receptors. However, despite the potential advantages of targeting Ag to FcR at mucosal sites, very little is known regarding
the role of FcR in mucosal immunity or the efficacy of FcR-targeted mucosal vaccines. In addition, recent work has suggest-
ed that FcRn is present in the lungs of adult mice and humans and can transport FcRn-targeted Ag to FcγR-bearing APC
within mucosal lymphoid tissue. In this review we will discuss the need for new vaccine strategies, the potential for FcR-tar-
geted vaccines to fill this need, the impact of activating versus inhibitory FcγR on FcR-targeted vaccination, the significance
of focusing on mucosal immunity, as well as caveats that could impact the use of FcR targeting as a mucosal vaccine strategy.
Key words: vaccine, mucosal immunity, Fc receptors.
Immunopathogenesis of bronchial asthma
Milan Buc1, Martin Dzurilla1, Mojmir Vrlik2 and Maria Bucova1
1 Department of Immunology, Comenius University School of Medicine, Bratislava, Slovakia
2 Martin Immunology Centre, Martin, Slovakia
Received: 2009.01.15, Accepted: 2009.04.16
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Bronchial asthma is a common immune-mediated disorder characterized by reversible airway inflammation, mucus produc-
tion, and variable airflow obstruction with airway hyperresponsiveness. Allergen exposure results in the activation of numer-
ous cells of the immune system, of which dendritic cells (DCs) and Th2 lymphocytes are of paramount importance. Although
the epithelium was initially considered to function solely as a physical barrier, it is now evident that it plays a central role in
the Th2-cell sensitization process due to its ability to activate DCs. Cytokines are inevitable factors in driving immune
responses. To the list of numerous cytokines already known to be involved in the regulation of allergic reactions, new
cytokines were added, such as TSLP, IL-25, and IL-33. IgE is also a central player in the allergic response. The activity of
IgE is associated with a network of proteins, especially with its high- and low-affinity Fc receptors. Understanding the cellu-
lar and molecular mechanisms of allergic reactions helps us not only to understand the mechanisms of current treatments,
but is also important for the identification of new targets for biological intervention. An IgE-specific monoclonal antibody,
omalizumab, has already reached the clinic and similar biological agents will surely follow.
Key words: bronchial asthma, cytokines, dendritic cells, IgE, Th2 lymphocytes, corticosteroids, anti-IgE monoclonal anti-
bodies.
Immunomodulation by statins: mechanisms
and potential impact on autoimmune diseases
Sek C. Chow
School of Science, Monash University Sunway Campus, Selangor Darul Ehsan, Malaysia
Received: 2008.12.29, Accepted: 2009.03.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Statins are inhibitors of the enzyme 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) and they are the most effective
agents for lowering cholesterol in clinical practice for the treatment of cardiovascular diseases. However, it has become clear
that statins also have pleiotropic immunomodulatory effects in addition to their lipid-lowering properties. As a result, much
attention has been focused on their potential as therapeutic agents for the treatment of inflammatory autoimmune diseases.
In this review the effect of statins on the expression and function of a variety of immune-relevant molecules will be discussed
alongside the underlying mechanisms that contribute to the immunomodulatory effects of statins.
Key words: statins, cardiovascular diseases, autoimmune diseases.
Innate immunity: a key player in the mobilization
of hematopoietic stem/progenitor cells
HakMo Lee1 and Mariusz Z. Ratajczak1, 2
1 Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
2 Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland
Received: 2009.01.28, Accepted: 2009.03.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The mobilization of hematopoietic stem/progenitor cells (HSPCs) from bone marrow into peripheral blood (PB) is still not
fully understood. Different chemokines, cytokines, growth factors, and neurotransmitters have been described that facilitate
this process. However, mounting evidence suggests that mobilization of HSPCs is a part of the immune response and is medi-
ated by innate immunity. We discuss evidence showing that complement system cleavage fragments play a crucial role in both
the retention and mobilization of HSPCs by modulating their responsiveness to stromal-derived growth factor-1 (SDF-1)
gradient (by C3-derived anaphylatoxins) and by modulating the release of granulocytes into PB that subsequently facilitate
the egress of HSPCs (by C5-derived anaphylatoxins).
Key words: complement, stem cell mobilization, CXCR4, SDF-1.
Interleukin 7 receptor αα as a potential
therapeutic target in transplantation
Maud Racapé1, 3, Bernard Vanhove1, 3, Jean−Paul Soulillou1, 2, 3, 4 and Sophie Brouard1, 3
1 Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 643, Nantes, France
2 Centre Hospitalier Universitaire de Nantes, France
3 Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes, France
4 Université de Nantes, Faculté de Médecine, Nantes, France
Received: 2008.11.08, Accepted: 2009.04.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Drugs targeting memory lymphocytes may allow for a better control of rejection in transplantation, particularly in immunized
patients. In this article the rationale of targeting interleukin 7 receptor α (IL-7Rα), a molecule expressed by both memory
and naive T cells, is reviewed in the context of transplantation. Whereas naive T cells are partly responsible for acute rejec-
tion and are targeted by current immunosuppressive drugs that block costimulatory signals (cyclosporine A, anti-CD3 anti-
body, anti-CD52 antibody, anti-thymocyte globulin, etc.), memory T cells are resistant to costimulation blockade. As such,
memory cells are an obstacle to experimental tolerance induction and may be involved in chronic rejection. There is thus
much scientific interest in developing molecules able to target these cells. The role of the IL-7/IL-7Rα pathway in trans-
plantation rejection has been suggested by the effect of an anti-IL-7 monoclonal antibody which, when associated with cos-
timulation blockade, prolonged heart allograft survival in mice. Here the hypothesis that targeting IL-7Rα would preserve
effector T cells that are less dependent on IL-7 for survival while sparing regulatory CD4+ CD25high IL-7Rαlow T cells is dis-
cussed. An anti-IL-7Rα antibody could also help achieve allograft tolerance by reducing alloreactive cells.
Key words: interleukin 7 receptor alpha, memory cells, TCR signaling, allograft tolerance.
Pathogenicity of the family
Legionellaceae
Marta Palusińska−Szysz1 and Monika Cendrowska−Pinkosz2
1 Department of Genetics and Microbiology, Maria Curie-Sk³odowska University, Lublin, Poland
2 Department of Anatomy, Department of Allergology, Medical University, Lublin, Poland
Received: 2008.10.27, Accepted: 2009.01.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The Legionellae are Gram-negative bacteria able to survive and replicate in a wide range of protozoan hosts in natural envi-
ronments, but they also occur in man-made aquatic systems, which are the major source of infection. After transmission to
humans via aerosols, Legionella spp. can cause pneumonia (Legionnaires’ disease) or influenza-like respiratory infections
(Pontiac fever). In children, Legionnaires’ disease is uncommon and is mainly diagnosed in children with immunosuppres-
sion. The clinical picture of Legionella pneumonia does not allow differentiation from pneumonia caused by others
pathogens. The key to diagnosis is performing appropriate microbiological testing. The clinical presentation and the natur-
al course of Legionnaires’ disease in children are not clear due to an insufficient number of samples, but morbidity and mor-
tality caused by this infection are extremely high. The mortality rate for legionellosis depends on the promptness of an appro-
priate antibiotic therapy. Fluoroquinolones are the most efficacious drugs against Legionella. A combination of these drugs
with macrolides seems to be promising in the treatment of immunosuppressed patients and individuals with severe legionel-
losis. Although all Legionella species are considered potentially pathogenic for humans, Legionella pneumophila is the etio-
logical agent responsible for most reported cases of community-acquired and nosocomial legionellosis.
Key words: Legionnaires’ disease, Pontiac fever.
Serological characterization of the core region
of lipopolysaccharides of rough
Proteus sp. strains
Agata Palusiak and Zygmunt Sidorczyk
Department of General Microbiology, Institute of Microbiology, Biotechnology and Immunology, University of £ódŸ, Poland
Received: 2008.02.22, Accepted: 2008.10.29
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Both smooth and rough Proteus sp. strains can be found. The latter are characterized by their lack of an O-
-polysaccharide chain in the lipopolysaccharide (LPS) molecule, which makes them suitable for obtaining anti-core sera.
Using this kind of material enables identifying fragments of the Proteus LPS core region that might be involved in cross-reac-
tions. To date only a few similar epitopes have been established for the genus Proteus.
Materials and Methods: Polyclonal rabbit antisera directed against three rough strains of Proteus sp. were tested by enzyme-
linked immunosorbent assay (ELISA) with a set of LPSs. The reactivity of the selected cross-reactive and homologous sys-
tems was checked by the Western blot technique and by a passive immunohemolysis assay preceded by the absorption of each
antiserum with appropriate cross-reactive and homologous alkalized LPSs.
Results: On the basis of the ELISA results, 19 cross-reactive antigens were selected among which both smooth and rough
LPS forms were found. All the observed reactions involved the core region of the LPS. Using the antisera absorbed with the
appropriate LPSs allowed identification of four groups of antigens with serologically identical core regions.
Conclusions: Comparing the results of the serological studies with the known chemical structures of the core regions of the
LPSs used enabled the identification of a few core oligosaccharide fragments probably involved in the observed cross-reac-
tions. All were located in the most distal part of LPS core region, which made them more easily recognized by specific anti-
bodies.
Key words: Proteus, lipopolysaccharide, core region, rough strains.
Immunohistochemical localization of metallothionein
and p53 protein in pancreatic serous cystadenomas
Mariola Śliwińska−Mossoń1, Halina Milnerowicz1, Jerzy Rabczyński2
and Stanisław Milnerowicz3
1 Department of Biomedical and Environmental Analyses, Wroc³aw Medical University, Wroc³aw, Poland
2 Department of Pathological Anatomy, Wroc³aw Medical University, Wroc³aw, Poland
3 Department and Clinic of Gastrointestinal and General Surgery, Wroc³aw Medical University, Wroc³aw, Poland
Received: 2008.08.14, Accepted: 2009.01.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: The objective of this study was to determine the expression levels of metallothionein (MT) and p53 protein,
recognized neoplastic transformation markers, in pancreatic serous cystadenomas (SCA) and adenomocarcinomas.
Materials and Methods: Neoplastic pancreatic tissue was taken from 20 patients with diagnosed benign (SCA: 5 cases) or
malignant tumors (adenomocarcinomas: 15 cases) and control pancreatic tissue from healthy persons who had died in car
accidents. Sections were stained with hematoxylin-eosin. Immunohistochemical localization of MT and p53 protein was car-
ried out by LSAB2-HRP using specific antibodies against MT and p53.
Results: Metallothionein expression was observed only in the epithelial cells of the neoplastic tissue of SCAs. MT expression
in the cystadenomas was weaker than in the healthy pancreatic tissue. No tissue was found with p53 protein expression. In
the adenomocarcinomas, positive staining for MT was observed in 67% and p53 was positive in the carcinoma cells.
Conclusion: The weak MT expression and lack of p53 protein expression in pancreatic SCAs confirms the lack of local inva-
sive potential of the neoplastic lesion. Increased expressions of MT and p53 were observed in the less differentiated tumors.
Thus the expression of MT may be a potential prognostic marker for tumors.
Key words: serous cystadenoma, adenomocarcinoma, pancreas, immunochemistry, metallothionein, p53 protein.
Platelet influence on T- and B-cell responses
Jennifer M. Sowa1, Scott A. Crist1, Timothy L. Ratliff1, 2 and Bennett D. Elzey1, 3
1 Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
2 Purdue Cancer Center, Purdue University, West Lafayette, IN, USA
3 Department of Urology, Indiana University, Indianapolis, IN, USA
Received: 2008.12.29, Accepted: 2009.04.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Understanding the adaptive immune response is an area of research critically important in medicine. Several positive regu-
lators of B- and T-cell activation exist to eliminate pathogens, in which CD40 ligand (CD154) plays a fundamental role. It is
well documented that CD154 expressed by CD4 T helper cells can be critical in the proper activation of dendritic cells for
the productive stimulation of CD8 T cells and is required for proper T-dependent B-cell immunity. However, platelets are
an abundant and systemic source of CD154. While classically known to be important for hemostasis and inflammation, sev-
eral lines of evidence suggest that platelet-derived ligands can modulate the adaptive immune compartment.
Key words: platelets, CD154, T cells, B cells.
Proinflammatory cytokines and IL-10 in inflammatory
bowel disease and colorectal cancer patients
Andrzej Szkaradkiewicz1, Ryszard Marciniak2, Izabela Chudzicka−Strugała1,
Agnieszka Wasilewska2, Michał Drews2, Przemysław Majewski3, Tomasz Karpiński1
and Barbara Zwoździak1
1 Department of Medical Microbiology, University of Medical Sciences, Poznañ, Poland,
2 Department of General, Gastroenterological, and Endocrinological Surgery, University of Medical Sciences, Poznañ,
Poland
3 Department of Clinical Pathomorphology, University of Medical Sciences, Poznañ, Poland
Received: 2008.08.18, Accepted: 2009.01.10
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: The aim of the study was to describe the levels of circulating monocyte/macrophage pro-inflammatory
cytokines (TNF-α, IL-1β, IL-6, and IL-8) and an anti-inflammatory cytokine (IL-10) in inflammatory bowel disease (IBD)
and colorectal cancer (CRC) patients and healthy controls.
Materials and Methods: The study was conducted on 15 healthy individuals, 20 patients with ulcerative colitis (UC), 12 with
Crohn’s disease (CD), and 15 with CRC (Dukes’ stage B). Blood serum cytokine levels were measured by ELISA.
Results: The patients with UC had significantly higher levels of the pro-inflammatory cytokines and of circulating IL-10 than
the healthy controls. The patients with CD and CRC had the same specific pattern of serum cytokines of significantly ele-
vated levels of the pro-inflammatory cytokines, but the IL-10 levels were within the range found in the healthy individuals.
Conclusions: Thus our results demonstrate that both IBD and CRC are linked with an intensified production of a wide array
of monocyte/macrophage pro-inflammatory cytokines which is not accompanied by elevated levels of circulating IL-10,
except for its insufficiently inhibitory elevation in UC patients.
Key words: cytokines, inflammation, Crohn’s disease, ulcerative colitis, colorectal cancer.
Role of ocular pigment epithelial cells
in immune privilege
Sunao Sugita
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine,
Tokyo, Japan
Received: 2009.01.09, Accepted: 2009.03.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The ocular microenvironment is both immunosuppressive and anti-inflammatory in nature. Pigment epithelial (PE) cells iso-
lated from the eye possess the ability to suppress the T cell receptor-dependent activation of T cells and the induction of reg-
ulatory T cells in vitro. This property is dependent on the cells’ capacity to produce cell-surface and soluble inhibitory mole-
cules, for example CD86 (B7-2), transforming growth factor (TGF)-β, thrombospondin-1, programmed cell death 1 ligand 1
(PD-L1/B7-H1), and cytotoxic T lymphocyte-associated antigen 2α. Cultured ocular PE cells from the iris, ciliary body, and
retina can individually suppress T-cell activation via mechanisms that partially overlap. Moreover, PE-derived regulatory
T cells acquire functions that play a role in establishing immune regulation in the eye. Multiple strategies are employed with-
in the eye to control immune-mediated inflammation. This phenomenon is known as immune privilege and is instrumental
in helping to prevent extensive damage to bystander cells that would otherwise lead to blindness. This review focuses on the
immunosuppressive property and role of ocular PE cells in immune privileged sites.
Key words: pigment epithelium, immune privilege, eye, suppression, T regulatory cells.
Evaluation of lectin pathway activity and mannan-binding
lectin levels in the course of pregnancy complicated
by diabetes type 1, based on the genetic background
Magdalena Pertyńska−Marczewska1, Maciej Cedzyński2, Anna Świerzko2,
Agnieszka Szala2, Małgorzata Sobczak3, Katarzyna Cypryk4 and Jan Wilczyński1
1 Department of Fetal-Maternal Medicine and Gynecology, Research Institute Polish Mother’s Memorial Hospital, £ódŸ,
Poland
2 Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, £ódŸ, Poland
3 Specialized Outpatient Clinic, Department of Fetal-Maternal Medicine and Gynecology, Research Institute Polish
Mother’s Memorial Hospital, £ódŸ, Poland
4 Department of Diabetology and Metabolic Diseases, Medical University of £ódŸ, £ódŸ, Poland
Received: 2008.06.09, Accepted: 2008.11.10
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: There are numerous indications that either mannan-binding lectin (MBL) deficiency or its excessive activity
are associated with adverse pregnancy outcomes. High MBL concentrations and corresponding MBL2 genotypes were shown
to be associated with microvascular complications in type 1 diabetes. The aim of this study was to evaluate levels of MBL
and MBL-dependent activity of the lectin pathway (LP) of complement in the course of pregnancy in diabetic mothers, based
on genetic background.
Materials and Methods: These parameters were determined in samples from healthy non-pregnant (control), diabetic non-
-pregnant, healthy pregnant, and pregnant diabetic women.
Results: No significant differences in median MBL levels or LP activities were found in any study group compared to the con-
trol. However, statistically significant differences in MBL levels were noted during pregnancy between the 1st and 3rd trimesters
in both healthy controls and pregnant diabetics. With regard to LP values, similar trends were evident, but statistically signifi-
cant results were obtained only in the healthy pregnant group. When data analysis was confined to patients carrying the
A/A (wild-type) MBL2 genotype, an increase in MBL level during pregnancy (in both healthy and diabetic pregnant women)
was still observed. Similarly, LP activity increased during both healthy and diabetic pregnancies, significantly so for the former.
Conclusions: Diabetes, an autoimmune disease, is a serious complication of pregnancy. Therefore, determination of MBL
status might be beneficial in identifying type 1 diabetic patients who are at increased risk of developing both vascular com-
plications and poor pregnancy outcomes.
Key words: mannan-binding lectin, lectin pathway activity, diabetes, pregnancy.
Dual use of biological research
and the role of the scientific unions
Angelo Azzi
Clinical and research ethics as moral strangers
Michael H. Kottow
Universidad Diego Portales, Santiago, Chile
Received: 2008.04.10, Accepted: 2008.11.10
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
This article takes issue with those who defend a brand of clinical research ethics that tends to substitute the ethics of clinical
care of patients being recruited as trial subjects. The distinction between therapeutic and non-therapeutic studies is being
disregarded by arguing that research is concerned with the pursuit of knowledge rather than with the medical benefits for
patients. Non-competent patients may therefore be recruited for studies that will offer them no medical benefits in spite of
involving them in the inherent risks of any biomedical trial. Supported by the World Medical Association, clinicians tend to
shun the use of placebos in randomized trials, because of the therapeutic void created in the control group. Nevertheless,
investigators continue to consider that scientific purity demands the use of placebos as the most appropriate comparator,
even if risks to patient-subjects are increased. Equipoise and clinical equipoise have been suggested as adequate criteria to
evaluate the need for a clinical trial, when genuine uncertainty about the equivalence of medical measures requires clarifi-
cation. If equipoise is understood as a balanced situation where alternatives are equivalent and exchangeable in the view of
experienced and current medical thought, no comparison seems warranted until a substantiated doubt about their true equiv-
alence appears. Whereas respecting equipoise is an important measure to curb redundant research, new trials become
mandatory if equivalence is reliably questioned. In the best interests of patients being recruited for clinical trials, they should
continue to be the full beneficiaries of clinical ethics, in addition to receiving the protection of research ethics. Placebos and
sub-medication for control groups are to be used sparingly, and best existing therapy should be employed as control when
new and promising agents are developed.
Key words: clinical research, ethics, placebo in clinical trials
Increased salivary level of 8-hydroxydeoxyguanosine
is a marker of premature oxidative mitochondrial DNA
damage in gingival tissue of patients with periodontitis
Cenk Fatih Çanakçi1, Varol Çanakçi1, Abdulgani Tatar2, Abubekir Eltas1, Ufuk Sezer3,
Yasin Çiçek1 and Sitki Oztas2
1 Department of Periodontology, Ataturk University, Faculty of Dentistry, Erzurum, Turkey
2 Department of Genetics, Faculty of Medicine, Ataturk University, Erzurum, Turkey
3 Department of Periodontology, Karadeniz Technical University, Faculty of Dentistry, Trabzon, Turkey
Received: 2008.10.19, Accepted: 2009.01.28
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
Introduction: Oxidative stress may contribute to the pathogenesis of periodontitis. However, the detailed molecular mecha-
nism remains unclear. Both 8-hydroxydeoxyguanosine (8-OHdG) and mitochondrial DNA (mtDNA) deletion have been
reported as early oxidative DNA damage markers. In this study, 8-OHdG levels in saliva and mtDNA deletions in gingival
tissue of patients with chronic periodontitis (CP) were evaluated.
Materials and Methods: Gingival tissue and whole saliva samples were collected from 32 patients with CP and 32 healthy
control subjects. To determine the clinical condition of each subject, the plaque index, gingival index, clinical attachment
level (CAL), and probing depth (PD) were measured. Using the ELISA and polymerase chain reaction methods, the sali-
vary 8-OHdG levels and the 7.4-kbp and 5-kbp mtDNA deletions were examined.
Results: The 5-kbp mtDNA deletion was detected in 20 of the 32 periodontitis patients (62.5%), but was not detected in the
healthy controls. The mean value of 8-OHdG in the saliva of the periodontitis patients with deleted mtDNA was significantly
higher than in the patients with non-deleted mtDNA (p<0.01). Also, significant correlation was found between the occur-
rence of the 5-kbp mtDNA deletion and salivary 8-OHdG levels (p<0.01). Similar correlations were detected between sali-
vary 8-OHdG levels and age, PD, and CAL (p<0.01, p<0.05).
Conclusion: Increased oxidative stress may lead to premature oxidative DNA damage in the gingival tissue of periodontitis
patients and the salivary 8-OHdG level may signify premature oxidative mtDNA damage in diseased gingival tissue.
Key words: periodontitis, gingiva, saliva, 8-hydroxyguanosine, mitochondrial DNA deletion, oxidative DNA damage.
Dendritic cell-based cancer immunotherapies
Shin−ichiro Fujii1, Takuya Takayama2, Miki Asakura1, Kaori Aki1, Koji Fujimoto3
and Kanako Shimizu1, 4
1Research Unit for Cellular Immunotherapy, Research Center for Allergy and Immunology (RCAI), Institute of Physical
and Chemical Research (RIKEN), Yokohama, Kanagawa, Japan
2Division of Cancer Genomics, Cancer Institute (Japanese Foundation for Cancer Research), Koto-ku, Tokyo, Japan
3NTT West Kyushu Hospital, Kumamoto, Kumamoto, Japan
4Research Unit for Therapeutic Model, Research Center for Allergy and Immunology (RCAI), Institute of Physical and
Chemical Research (RIKEN), Yokohama, Kanagawa, Japan
Received: 2008.12.17, Accepted: 2009.03.27
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
Because of their unique role in linking the innate and adaptive immune systems, dendritic cells (DCs) have been a logical
focus for novel immunotherapies. However, strategies employing active immunization with ex vivo generated and antigen-
-pulsed DCs have shown limited efficacy in clinical trials. These past approaches did not take into account the complex inter-
actions between cells of the innate immune system and DCs during DC maturation, antigen processing, and presentation to
naïve T cells. By better understanding the natural sequence of events occurring in vivo during an effective immune response,
we can tailor antitumor immunotherapeutic strategies to augment aspects of this response from the activation of innate
immune cells to antigen uptake and DC maturation to priming of naïve T cells and, ultimately, to the establishment of anti-
tumor immunity. Current DC vaccination strategies utilize a number of methods to recapitulate the cascade of events that
culminate in a protective antitumor immune response.
Key words: dendritic cells (DCs), adjuvant, ex vivo DC therapy, in vivo DC therapy, immunotherapy
The role of IL-1 in the pathogenesis of heart disease
Marcin Bujak and Nikolaos G. Frangogiannis
Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Received: 2008.11.17, Accepted: 2009.01.28
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
Interleukin (IL)-1 consists of two distinct ligands, IL-1α and IL-1β, with indistinguishable biological activities that signal
through the IL-1 type I receptor (IL-1RI). A naturally occurring IL-1 receptor antagonist (IL-1Ra) binds to IL-1RI without
initiating signal transduction and prevents IL-1 signaling, competitively inhibiting IL-1-mediated responses. Emerging evi-
dence suggests that the balance between IL-1 agonists and antagonists plays an essential role in a variety of cardiovascular
conditions. IL-1 may play a role in atherothrombotic disease by promoting the formation of atheromatous lesions, enhanc-
ing vascular inflammation, and triggering plaque destabilization. Following myocardial infarction, IL-1 critically regulates
the inflammatory response and is involved in the development of adverse remodeling by enhancing expression of matrix met-
alloproteinases. IL-1 signaling may also be an essential mediator in the pathogenesis of heart failure by suppressing cardiac
contractility, promoting myocardial hypertrophy, and inducing cardiomyocyte apoptosis. The present review summarizes cur-
rent available data showing the significant role of IL-1 signaling in heart disease and raising the possibility that IL-1 inhibitors
(such as anakinra, a nonglycosylated recombinant human IL-1Ra) may be clinically useful agents in patients with certain car-
diovascular conditions.
Key words: interleukin-1, myocardial ischemia, cardiac fibrosis, hypertrophy, remodeling, inflammation
The expressions of intrinsic and extrinsic apoptotic path-
way proteins in neutrophils of oral cavity cancer patients:
a preliminary study
Ewa Jabłońska1, Marzena Garley1 and Jakub Jabłoński2
1 Department of Immunology, Medical University of Bia³ystok, Poland
2 Department of Toxicology, Medical University of Bia³ystok, Poland
Received: 2008.05.06, Accepted: 2008.12.03
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
Introduction: The biological availability and activity of polymorphonuclear neutrophils (PMNs) are regulated by their short
life span, which can be additionally shortened by a malignant process. The signaling pathways leading to apoptotic PMN
death are classified in two categories: the intrinsic and the extrinsic. In the present study the expressions of proteins partici-
pating in the extrinsic apoptotic pathway (DR5, FADD, caspase-8 activity) and the intensity of apoptosis of PMNs from
patients with cancer of the oral cavity were examined. The expression of proteins participating in the intrinsic pathway (Bax
and Mcl-1) were also examined in these cells. The results can be helpful in explaining the reasons for the decreased activity
of these cells in oral cavity cancer patients.
Materials and Methods: The examinations were carried out in patients with squamous cell carcinoma of the oral cavity before
and after treatment. The expressions of all the proteins were measured in neutrophils and, for comparison, in autologous
peripheral blood mononuclear cells (PBMCs). Western blot analysis was used to assay the expressions of DR5, FADD, Bax,
and Mcl-1 in cell lysates. The apoptosis level was determined by flow cytometry and caspase-8 activity by colorimetric assay.
Results: A lack of changes in DR5 expression associated with increased FADD protein expression and caspase-8 activity
accompanied the accelerated apoptosis rates in the PMNs of the patients before treatment. Decreased expression of anti-
-apoptotic Mcl-1 protein was associated with an unchanged expression of pro-apoptotic Bax protein. There were no such
changes in the patients PBMCs. Increased expression of Mcl-1 in the PMNs of the patients following surgical treatment was
found.
Conclusion: The acceleration of the apoptosis of PMNs of oral cavity cancer patients before treatment is dependent on both
the intrinsic and extrinsic pathways.
Key words: polymorphonuclear neutrophils, mononuclear cells, apoptosis, oral cavity carcinoma.
Detection of a CD4+CD8–CD3– cell subpopulation
during the differentiation of cord blood CD34+ cells
into T cells
in vitro
Jian Gang Jin, Bao Jun Bai, Zhi Juan Yao, Ren Na Wu, Kai Feng, Jiang Wei Hu,
Liang Ding Hu, Min Jiang, Lianming Liao and Hu Chen
Hematopoietic Stem Cell Transplant Center, Bei Tai Ping Lu Hospital, Bei Jing, P.R. China, 100039
Received: 2008.08.04, Accepted: 2008.12.19
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
Introduction: Umbilical cord blood contains relatively abundant primitive CD34+ hematopoietic progenitor cells which can
differentiate into T lymphocytes ex vivo.
Materials and Methods: In this study, thymic stromal cells (TSCs) were isolated from aborted fetuses and a monolayer cul-
ture system was established. Highly-purified CD34+ cells from umbilical cord blood were cultured on the TSCs after limit-
ing-dilution. The cells were then harvested and evaluated for CD4, CD8, and CD3 expression at different time points.
CD4+CD8–CD3– lymphoid progenitor cells that could differentiate into mature T lymphocytes were observed after 15 days
when a cocktail of cytokines, including Flt-3 ligand, stem cell factor, interleukin (IL)-12, and IL-2, was added.
Results: These results thus show that CD4+CD8–CD3– cells can be derived from CD34+ cells in vitro when cultured on TSCs.
Conclusions: We showed that CD4+CD8–CD3– cells can be derived from highly purified CD34+ cells on TSCs during T-cell
lymphopoiesis in vitro.
Key words: thymus, cell differentiation, stromal cells, T cells.
Expanding and converting regulatory T cells:
a horizon for immunotherapy
Mithun Khattar, Wenhao Chen and Stanislaw M. Stepkowski
Department of Medical Microbiology and Immunology, University of Toledo, College of Medicine,
Toledo, OH 43614, USA
Received: 2008.11.26, Accepted: 2009.01.28
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
The human immune system is a myriad of diverse cellular populations, each contributing to maintaining an effective and
optimal immune response against infectious agents. It is important to maintain a “self-check” in the immune system so that
responses do not go haywire, leading to the development of autoimmune diseases. Regulatory/suppressor T (Treg) cells are
a specialized subpopulation of T cells that suppress the activation, expansion, and function of other T cells, thereby main-
taining homeostasis through a fine balance between reactivity to foreign and self antigens. Tregs are characterized by sur-
face expression of interleukin (IL)-2 receptor α chain (CD25) and intracellular expression of forkhead box protein P3
(FoxP3). There are at least two important functional populations of Treg cells, namely natural Treg (nTreg), which are con-
tinuously derived from the thymus, and induced Treg (iTreg), which are converted from naive T cells. The development and
function of both nTreg and iTreg cells are regulated by several factors, such as antigen T-cell receptor, co-stimulatory recep-
tors (i.e., cytotoxic T lymphocyte-associated antigen, or CTLA-4), and cytokines (IL-2, IL-10, and tumor growth factor-β, or
TGF-β). In addition, the TGF-β inhibitor ALK5, retinoid acid, and rapamycin influence the expansion of nTreg cells and the
conversion of iTreg cells in vitro and in vivo. The heightening of Treg expansion may be harnessed to therapeutic methods
for the treatment of autoimmune diseases and the induction of transplantation tolerance.
Key words: nTreg, iTreg, FoxP3, expansion, conversion.
Role of ubiquitin ligases in neural stem
and progenitor cells
Cord Naujokat
Institute of Immunology, University of Heidelberg, Heidelberg, Germany
Received: 2008.11.26, Accepted: 2009.01.30
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland 2009
Abstract
Ubiquitin ligases are central components of the ubiquitin-proteasome system (UPS), the major machinery for regulated pro-
teolysis in eukaryotic cells. Proteins essential for regulating development, differentiation, proliferation, cell cycling, apopto-
sis, gene transcription, and signal transduction undergo posttranslational processing via selection by ubiquitin ligases and
subsequent controlled proteolysis by the 26S proteasome, the proteolytic unit of the UPS. Neural stem cells (NSCs) are self-
-renewing multipotent cells of the embryonic and adult mammalian central nervous system. In the last few years, NSCs have
generated considerable interest because of their potential to repair neurological damage in preclinical models of stroke,
spinal cord injury, and neurodegenerative disease. Recent evidence reveals a central role of ubiquitin ligases in controlling
the development, survival, differentiation, and programming of neural stem and progenitor cells. Here the current knowl-
edge of the role and function of ubiquitin ligases in neural stem and progenitor cells is reviewed and insight into an impor-
tant mechanism of NSC homeostasis by regulated proteolysis is provided.
Key words: ubiquitin ligase, ubiquitin-proteasome system, regulated proteolysis, neural stem cells, neural progenitor cells,
neurogenesis.
ECA-immunogenicity of
Proteus mirabilis strains
Katarzyna Anna Duda1, Katarzyna Teresa Duda1, Agnieszka Beczała1,
Katarzyna Kasperkiewicz1, Joanna Radziejewska−Lebrecht1 and Mikael Skurnik2
1 Department of Microbiology, Faculty of Biology and Environment Protection, University of Silesia, Katowice, Poland
2 The Haartman Institute, University of Helsinki and Helsinki University Central Hospital Laboratory Diagnostics,
Helsinki, Finland
Received: 2008.05.21, Accepted: 2008.12.19
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Bacteria of the genus Proteus are opportunistic pathogens and cause mainly urinary tract infections. They also
play a role in the pathogenesis of reactive arthritis (RA). Patients suffering from Yersinia-triggered RA often carry high titers
of antibodies specific to enterobacterial common antigen (ECA). The immunogenicity of ECA has not received much atten-
tion thus far and studies have focused mainly on the ECA of Escherichia coli and Yersinia enterocolitica. In this paper the
ECA-immunogenicity of Proteus mirabilis is elucidated using two wild-type strains (S1959 and O28) as well as their rough
(R) derivative strains R110/1959, which expresses lipopolysaccharide (LPS) with a full core, and R4/O28, which expresses
LPS with only an inner core.
Materials and Methods: Rabbit polyclonal antisera were produced by immunization with boiled suspensions of the four P.
mirabilis strains. The antisera were tested for the presence of antibodies specific to ECA by Western blotting using glyc-
erophospholipid-linked ECA (ECAPG) of Salmonella montevideo as antigen. Lipopolysaccharide (LPS) was isolated from the
four strains by the hot phenol/water procedure in which ECAPG is co-extracted with LPS and by the
phenol/chloroform/petroleum ether extraction that results in the isolation of LPS and/or LPS-linked ECA (ECALPS) free of
ECAPG. The LPS preparations were tested for the presence of ECA by Western blotting using ECA-specific antibodies.
Results: The results demonstrated that all four P. mirabilis strains were ECA immunogenic. The rabbit antisera immunized
by the four strains all contained ECA-specific antibodies. Analysis of the LPS preparations demonstrated that the P. mirabilis
wild-type strains O28 and S1959 and the Ra mutant strain R110/1959 expressed ECALPS, suggesting that it induced the anti-
ECA antibody responses. Only the presence of ECAPG could be demonstrated in the Rc mutant strain R4/O28.
Conclusions: These results therefore suggest that, similar to E. coli, LPS with a full core is also required as the acceptor of
ECA for P. mirabilis strains to produce ECALPS. Since ECAPG is not immunogenic unless combined with some proteins, it is
likely that ECAPG-protein complexes formed during the intravenous immunization with the Rc mutant strain R4/O28.
Key words: Proteus mirabilis, S and R strains, enterobacterial common antigen, lipopolysaccharide, ECA immunogenicity.
Antigen-restricted γγδ T-cell receptors?
Willi K. Born1, 2 and Rebecca L. O’Brien1, 2
1 Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA
2 University of Colorado at Denver, Aurora, CO 80262, USA
Received: 2008.12.23, Accepted: 2009.02.03
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
After more than two decades of investigation, the biological role of the γδ T-cell receptors (TCRs) remains elusive. In fact,
a theory of ligand recognition is still lacking that accounts for their adaptable structure, their peripheral selection, and the
observed responses of γδ T cells, which do not require immunization but only include cells sharing germline-encoded com-
ponents of the TCR. Assuming that all γδ T cells recognize ligands by a common mechanism, we now propose that germline-
-encoded components of the γδ TCRs provide for the specific recognition of a select set of antigenic determinants (Ags)
which appear on the cell surface in various molecular associations. Furthermore, we hypothesize that the adaptivity of the γδ
TCRs serves to increase affinity for the molecules with which these Ags associate rather than for the Ags themselves. Here
we outline this hypothetical mechanism and discuss its possible implications for thymic selection and potential for comple-
menting known innate and adaptive mechanisms of immune defense.
Key words: T lymphocyte, T-cell receptor, ligand, antigen recognition
A reflection on open-access, citation counts,
and the future of scientific publishing
Xavier Bosch
Prophylaxis with α-lipoic acid against
lipopolysaccharide-induced brain injury in rats
Anna Gorąca and Katarzyna Asłanowicz−Antkowiak
Chair of Experimental and Clinical Physiology, Department of Cardiovascular Physiology, Medical University of £ódŸ,
£ódŸ, Poland
Received: 2008.02.25, Accepted: 2008.10.09
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Lipopolysaccharide (LPS) stimulates the synthesis and release of reactive oxygen species that play an impor-
tant role in the pathogenesis of tissue injuries. In this study the effect of early administration of the antioxidant α-lipoic acid
(α-LA) on brain lipid peroxidation, brain hydrogen peroxide (H2O2) concentration, and brain total sulfhydryl group (-SH
group) content was evaluated in rats with endotoxic shock induced by administration of LPS (Escherichia coli 026:B6, 30
mg/kg i.v.)
Materials and Methods: Rats were treated intravenously with normal saline or α-LA (60 mg/kg) 30 min after LPS injection.
After 5 h of observation, the animals were killed and their brains were isolated for the measurements.
Results: Injection of LPS alone resulted in the development of shock and oxidative stress, the latter indicated by a signifi-
cant increase in brain concentrations of thiobarbituric acid-reacting substances (TBARS) and H2O2 and a decrease in total
brain -SH group content. Administration of α-LA after the LPS challenge resulted in an increase in total -SH group content
and a decrease in TBARS and H2O2 concentration in the brain tissue compared with the LPS group.
Conclusion: The results indicate that α-LA treatment effectively protected the brain tissue against endotoxin-induced oxida-
tive stress. Administration of LA could be a useful adjunct to clinical application in the management of septic shock.
Key words: lipopolysaccharide, alpha-lipoic acid, oxidative stress.
On the fairness of using relative indicators for comparing
citation performance in different disciplines
Claudio Castellano1 and Filippo Radicchi2
1SMC, INFM-CNR and Dipartimento di Fisica, “Sapienza” Universita’ di Roma, Roma, Italy
2Complex Networks Lagrange Laboratory, Institute for Scientific Interchange Foundation, Torino, Italy
Received: 2009.03.04, Accepted: 2009.03.11
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Relative indicators are commonly used to remove biases due to different citation practices in various scientific fields. Here
we extend our recent investigation on the viability of the use of relative indicators for comparing article impact in different
disciplines. We consider citation distributions for papers published in 14 of the 172 disciplines categorized by the Journal
Citation Reports. The distribution of the number of citations received by publications in a certain discipline divided by the
average number for the discipline is a universal function. Based on it, we compute the relative number of citations needed
to be among the q percent most-cited publications in a discipline. The effect of finite samples is also discussed. The average
number of citations is shown to be strongly correlated with the impact factor, but fluctuations are quite large. A similar uni-
versal distribution is found (with exceptions) when citation distributions restricted to papers published in a single journal are
considered.
Key words: citation analysis, relative indicators, impact factor, universality
Autoimmunity and heart diseases:
pathogenesis and diagnostic criteria
Udi Nussinovitch1 and Yehuda Shoenfeld1,2
1 Department of Medicine 'B’, Chaim Sheba Medical Center, Tel-Hashomer, Israel
2 Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Tel-Aviv,
Israel
Received: 2008.11.12, Accepted: 2008.12.05
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Autoimmunity may evolve in predisposed individuals following an exogenous trigger. Autoimmunity is affected by genetic,
immune, hormonal, and environmental factors. Immune mechanisms in heart diseases are complex and often not complete-
ly understood. Several cardiac disorders are believed to be mediated by an immune reaction. Both humoral and cellular
immunity are associated with the development of myocarditis, dilated cardiomyopathy, heart failure, rheumatic fever, and
atherosclerosis. Here the diagnostic criteria and autoimmune aspects of autoimmune-mediated cardiac disorders are
reviewed. New diagnostic criteria for “autoimmune dilated cardiomyopathy” were recently suggested by the authors. They
presume that establishing a dominant autoimmune etiology in some patients will have clinical significance because these
patients will potentially gain the greatest benefit from immunosuppressive and immunomodulating treatments.
Key words: autoantibodies, myocarditis, autoimmune dilated cardiomypathy, atherosclerosis, rheumatic fever
Revealing the faults in medical journals*
Thomas J. Liesegang
Mayo Clinic, Jacksonville, FL 32224, USA
Received: 2009.03.02, Accepted: 2009.03.11
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Medical journals hold an exalted position in medicine, but have many shortcomings. This perspective reviews some of the
shortcomings of medical journals which are primarily related to inexperience, bias, and commercialism. The issues discussed
include the uncertain mission of the traditional medical journal in the modern digital age, the inherent inexperience of vol-
untary editorial boards, the weaknesses and capricious nature of decisions made by the peer-review process, the uneven value
of most journal articles, the bias in what gets submitted and published in journals, the misunderstanding about the criteria
for authorship, the misunderstanding of the need for ethical review board approval of studies, the misunderstanding of the
need for informed consent for research from patients and ethical review boards, the various sources of assistance to editors
and authors in dealing with the many ethical issues arising in the publication process, the commercialization and manipula-
tion of medical journals by industry, the prevalent and complex financial entanglements of authors with industry, and the
imperfect impact factor, which has the potential to be abused. The perspective concludes with theorization of the role of
medical journals in the future. Readers need to scrutinize data in the literature carefully and interpret the discussions and
conclusions critically, as there are biases in what is published in medical journals.
Key words: medical journals, commercialism, bias, scientific merit.
The roles of the RAG1 and RAG2 “non-core” regions
in V(D)J recombination and lymphocyte development
Jessica M. Jones and Carrie Simkus
Department of Biochemistry and Molecular and Cellular Sciences, Georgetown University Medical Center, Washington,
DC 20007, USA
Received: 2008.12.05, Accepted: 2009.01.28
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The enormous repertoire of the vertebrate specific immune system relies on the rearrangement of discrete gene segments
into intact antigen receptor genes during the early stages of B- and T-cell development. This V(D)J recombination is initi-
ated by a lymphoid-specific recombinase comprising the RAG1 and RAG2 proteins, which introduces double-strand breaks
in the DNA adjacent to the coding segments. Much of the biochemical research into V(D)J recombination has focused on
truncated or “core” fragments of RAG1 and RAG2, which lack approximately one third of the amino acids from each.
However, genetic analyses of SCID and Omenn syndrome patients indicate that residues outside the cores are essential to
normal immune development. This is in agreement with the striking degree of conservation across all vertebrate classes in
certain non-core domains. Work from multiple laboratories has shed light on activities resident within these domains, includ-
ing ubiquitin ligase activity and KPNA1 binding by the RING finger domain of RAG1 and the recognition of specific chro-
matin modifications as well as phosphoinositide binding by the PHD module of RAG2. In addition, elements outside of the
cores are necessary for regulated protein expression and turnover. Here the current state of knowledge is reviewed regard-
ing the non-core regions of RAG1 and RAG2 and how these findings contribute to our broader understanding of recombi-
nation.
Key words: V(D)J recombination, RAG1, RAG2, RING finger, PHD domain/plant homeodomain.
TNF-α and sICAM-1 in intracranial aneurismal rupture
Anna Maria Witkowska1, Maria Halina Borawska2, Katarzyna Socha2,
Jan Kochanowicz3, Zenon Mariak3 and Maria Konopka2
1 Department of Food Commodities Science and Technology, Medical University, Bia³ystok, Poland
2 Department of Bromatology, Medical University, Bia³ystok, Poland
3 Department of Neurosurgery, Medical University, Bia³ystok, Poland
Received: 2008.07.03, Accepted: 2008.12.09
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Subarachnoidal hemorrhage (SAH) occurring after aneurismal rupture produces an inflammatory response in
the cerebral circulation. Tumor necrosis factor (TNF)-α is a major cytokine in this process. Adhesion molecules provide
information on inflammatory reactions taking place in the walls of blood vessels. Clinical evidence suggests a role of soluble
intercellular adhesion molecule (sICAM)-1 in early hemorrhagic events. This study aimed to evaluate the implementation
of early TNF-α and sICAM-1 serum measurement for the prognosis of patient outcome after intracranial aneurismal
rupture.
Materials and Methods: The study consisted of 27 patients with a diagnosis of intracranial aneurysm. SAH was evaluated on
admission according to the Fisher scale, patients’ consciousness with the Glasgow Coma Scale, clinical grading with the Hunt
and Hess scale, and clinical outcome with the Glasgow Outcome Scale (GOS). Blood samples were drawn within 72 h after
arrival at the emergency room. Serum concentrations of TNF-α and sICAM-1 were assayed with the ELISA method.
Results: The initial serum TNF-α concentration in the aneurismal patients was low and did not correlate with radiological
and clinical scores. The serum sICAM-1 level positively correlated with the severity of bleeding assessed by the Fisher scale
and negatively with the patient’s scoring in the GOS.
Conclusions: This study demonstrated the absence of a systemic TNF-α-mediated inflammatory response at the onset of sub-
arachnoid hemorrhage. Early measurement of serum sICAM-1 levels offers a potential prognostic value in the assessment
of patients’ outcome after brain aneurismal rupture.
Key words: TNF-α, sICAM-1, brain, aneurismal rupture.
NKT cells: from totipotency to regenerative medicine
Hiroshi Wakao
Environmental Biology, School of Medicine, Hokkaido University, Sapporo, Japan
Received: 2008.11.12, Accepted: 2009.01.05
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The recent discovery that natural killer T (NKT) cell nuclei are totipotent opens a novel avenue for further understanding
NKT cell function in normal and diseased states. The progeny of a cloned mouse harboring the in-frame rearranged Vα14-
-Jα18 T cell receptor in one allele showed a significant increase in NKT cell number compared with wild-type or littermate
control mice that possessed a different TCR. Importantly, NKT cells from such progeny produced both interferon-γ and in-
terleukin-4, a hallmark of NKT cells. In these progeny, NKT cell development appeared to be instructively, rather than per-
missively, determined. Using embryonic stem cells prepared via the somatic cell nuclear transfer of NKT nuclei, relatively
mature NKT cells were induced under conditions permissible for T cell induction. Furthermore, these NKT cells matured
autonomously upon injection into mice, resulting in an antigen-specific adjuvant effect.
Key words: NKT cell, totipotency, embryonic stem cell, instructive, permissive, differentiation.
The use and misuse of journal metrics
and other citation indicators
David A. Pendlebury
Thomson Reuters, Philadelphia, PA, USA
Received: 2008.12.05, Accepted: 2008.12.17
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
This article reviews the nature and use of the journal impact factor and other common bibliometric measures for assessing
research in the sciences and social sciences based on data compiled by Thomson Reuters. Journal impact factors are fre-
quently misused to assess the influence of individual papers and authors, but such uses were never intended. Thomson
Reuters also employs other measures of journal influence, which are contrasted with the impact factor. Finally, the author
comments on the proper use of citation data in general, often as a supplement to peer review. This review may help gov-
ernment policymakers, university administrators, and individual researchers become better acquainted with the potential
benefits and limitations of bibliometrics in the evaluation of research.
Key words: impact factor, bibliometric indicators, peer review, citation analysis.
Virulence factor genotypes of
Helicobacter pylori
affect cure rates of eradication therapy
Mitsushige Sugimoto and Yoshio Yamaoka
Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine,
Houston, TX, USA
Received: 2008.07.07, Accepted: 2008.10.20
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
The cure rates of Helicobacter pylori infection by using a combination of a proton pump inhibitor (PPI) and antimicrobial
agents are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of acid inhibition during
the treatment. Currently used empirical triple therapies do not reliably produce a ≥80% cure rate on an intention-to-treat
basis. Therefore, tailored regimens based on relevant microbiological findings and pharmacogenomics are recommended for
attaining an acceptable ≥95% cure rate. Recently, virulence factors of H. pylori, such as cagA and vacA, are reported to be
major factors determining the cure rates. Individuals infected with strains with cagA-negative and vacA s2 genotypes have
significantly increased risk of eradication failure of H. pylori infection. These virulence factors enhance gastric mucosal
inflammation and are associated with the development of peptic ulcer and gastric cancer. H. pylori virulence factors induce
proinflammatory cytokines, such as interleukin (IL)-1, IL-8, and tumor necrosis factor (TNF)-α, which influence mucosal
inflammation and/or gastric acid secretion. When physicians select an H. pylori eradication regimen with an acceptable cure
rate, they might need to consider H. pylori virulence factors, especially cagA and vacA.
Key words: Helicobacter pylori, eradication therapy, virulence factor, cagA, vacA, tailored regimen.
Rank-normalized journal impact factor
as a predictive tool*
Grzegorz Racki
Institute of Paleobiology, Polish Academy of Sciences, Warszawa, Poland
Received: 2008.11.25, Accepted: 2008.12.12
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Citation data accumulated on articles from the top and bottom 25% of impact factor (IF)-ranked international journals are com-
pared using 59 international geoscience journals from 1998 and 378 Polish geological papers from 1989–1994. There is a minor risk
of being uncited when results are published in high-IF periodicals as the average non-citation rate is 0.88% over a10-year period
in this not very rapidly developing scientific discipline. Similarly, the established error levels in the prognosis of expected citation
success versus failure based on the extreme IF quartiles as an evaluation tool is low (at most 12.5%). Thus the application of the
rank-normalized journal IF as a proxy of real citation frequency and, accordingly, as a predictive tool in the a priori qualification
of recently published publications is a rational time- and cost-saving alternative (or at least a significant supplement) to tradition-
al informed peer review. Blanket criticism of using IF for decisions in research funding is therefore at least partly exaggerated.
Key words: impact factor, citation, scientific quality, research funding
Biological activity of dendritic cells generated
from cord blood CD34+ hematopoietic progenitors
in IL-7- and IL-13-conditioned cultures
Bożenna Mytar, Małgorzata Stec, Kazimierz Węglarczyk and Marek Zembala
Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College,
Cracow, Poland
Received: 2008.02.11, Accepted: 2008.12.19
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Introduction: Dendritic cells (DCs) are required for initiation of the immune response and may therefore be used for the pro-
duction of cancer vaccines. As mature DCs (mDCs) are the most potent antigen-presenting cells, there is increasing interest
in generating them ex vivo. The present study was designed to obtain mDCs from CD34+ hematopoietic progenitors by cul-
turing them in different media.
Materials and Methods: Cord blood CD34+ hematopoietic progenitors were expanded for 7 days in FST medium containing
fms-related tyrosine kinase 3 ligand (Flt3-L), stem cell factor (SCF), and thrombopoietin (TPO). Then the cells were divid-
ed into three parts and cultured for 21 days in different media: FST medium or FST enriched in interleukin (IL)-3 (FST3
medium) or supplemented with IL-7 and IL-13 (FST713 medium). At the end of culture part of the cells was harvested,
counted, and analyzed while the other part was matured with proinflammatory cytokines for 2 days. The cells’ phenotypes,
ability to induce proliferation of allogeneic lymphocytes in the mixed lymphocyte reaction (allo-MLR), chemotaxis, phago-
cytosis, and O2– production were determined.
Results: The average fold increase of DCs at the end of culture in FST medium was 127, in FST3 1043, and in FST713 71. In
comparison with the other media, FST713 medium supported the generation of mDCs that were characterized by higher
expression of CD83, costimulatory molecules, and HLA-DR, enhanced ability to induce allo-MLR and migration to
macrophage inflammatory protein (MIP) 3β, poor phagocytosis, and O2– production.
Conclusions: This study indicates that FST713 medium allows the generation of limited numbers of more mature DCs, while
FST3 medium leads to the production of immature DCs in high numbers.
Key words: allo-MLR, CD34+ cells, chemotaxis, dendritic cells, immunophenotype, phagocytosis.
The use of bibliometric indicators
to help peer-review assessment
Nicole Haeffner−Cavaillon and Claude Graillot−Gak
Département d’Evaluation Scientifique INSERM, Paris Cedex 13, France
Received: 2008.10.28, Accepted: 2008.11.27
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Inserm is the only French public research institution entirely dedicated to human health. Inserm supports research across
the biomedical spectrum in all major disease areas, from fundamental lab-based science to clinical trials. To translate its sci-
entists’ findings into tangible health benefits, Inserm has its own affiliated company, Inserm Transfert, which works with
industry. Since 2001, Inserm has been setting up on-line file management software for the evaluation of researchers and lab-
oratories, called EVA (www.eva.inserm.fr). EVA includes all grant applications, assessment reports, evaluation grading eval-
uation forms and includes automated bibliometric indicator software that enables calculating, for example, the number of
publications, journal impact factors, number of citations, citation index, and number of the Top 1% publications for each
researcher of the teams. The indicators take into account research fields, the year of publications, and the author’s position
among the participants. Bibliometrics is now considered a tool for science policy providing indicators to measure productiv-
ity and scientific quality, thereby supplying a basis for evaluating and orienting R&D. It is also a potential tool for evalua-
tion. It is neutral, allows comparative (national and international) assessment, and may select papers in the forefront in all
fields. For each team, bibliometric indicators are calculated for all researchers with permanent or long-term positions (3–5
years). The use of bibliometric indicators requires great vigilance, but according to our experience they enrich the commit-
tee’s debates without any doubt. We present an analysis of the data of 600 research teams evaluated in 2007–2008.
Key words: peer review, impact factor, bibliometric indicators.
The use of bibliometrics to measure research quality
in UK higher education institutions
Jonathan Adams
Evidence Ltd, Leeds, UK
Received: 2008.12.10, Accepted: 2008.12.17
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Research assessment in the UK has evolved over a quarter of a century from a loosely structured, peer-review based process
to one with a well understood data portfolio and assessment methodology. After 2008, the assessment process will shift again,
to the use of indicators based largely on publication and citation data. These indicators will in part follow the format intro-
duced in 2008, with a profiling of assessment outcomes at national and international levels. However, the shift from peer
assessment to a quantitative methodology raises critical issues about which metrics are appropriate and informative and how
such metrics should be managed to produce weighting factors for funding formulae. The link between publication metrics
and other perceptions of research quality needs to be thoroughly tested and reviewed, and may be variable between disci-
plines. Many of the indicators that drop out of publication data are poorly linked to quality and should not be used at all.
There are also issues about which publications are the correct base for assessment, which staff should be included in a review,
how subjects should be structured and how the citation data should be normalised to account for discipline-dependent vari-
ables. Finally, it is vital to consider the effect that any assessment process will have on the behaviour of those to be assessed.
Key words: assessment, indicators, profiling, peer review.
Sjögren’s syndrome: An old tale with a new twist
Byung Ha Lee, Mauro A. Tudares and Cuong Q. Nguyen
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
Received: 2008.11.24, Accepted: 2008.12.08
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
Sjögren’s syndrome (SjS) is chronic autoimmune disease manifested by the loss of saliva and/or tear secretion by salivary
and/or lacrimal glands, respectively. The pathogenesis of the disease remains elusive, perhaps due to the multiple triggers of
the disease. However, substantial advances have been made in attempting to resolve the complexity of SjS using both animal
models and human subjects. The primary objectives of this review are to provide a better understanding of the disease process-
es with major emphasis on the use of mouse models, how genetic predisposition plays a role in the natural history of the dis-
ease, as well as a presentation of new findings pertaining to the role of TH1, TH2, and TH17 cells in the pathogenesis of SjS.
Key words: Sjögren’s syndrome, animal models, genetics, TH1 cells, TH2 cells, TH17 cells.
New developments in the use of citation analysis
in research evaluation
Henk F. Moed
Center for Science and Technology Studies, Leiden University, the Netherlands
Received: 2008.12.01, Accepted: 2008.12.22
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroc³aw, Poland
Abstract
This paper presents an overview of research assessment methodologies developed in the field of evaluative bibliometrics,
a subfield of quantitative science and technology studies, aimed to construct indicators of research performance from a quan-
titative statistical analysis of scientific-scholarly documents. Citation analysis is one of its key methodologies. The paper illus-
trates the potentialities and limitations of the use of bibliometric indicators in research assessment. It discusses the relation-
ship between metrics and peer review; databases used as sources of bibliometric analysis; the pros and cons of indicators
often applied, including journal impact factors, Hirsch indices, and normalized indicators of citation impact; and approach-
es to the bibliometric measurement of institutional research performance.
Key words: impact factor, Hirsch index, citation analysis.