Monocytes in Sterile Inflammation: Recruitment and Functional Consequences
Jessica H. Spahn • Daniel Kreisel
Abstract Monocytes play an important role in initiating innate immune responses. Three subsets of these cells have been defined in mice including classical, nonclassical and intermediate monocytes. Each of these cell types has been extensively studied for their role in infectious diseases. However, their role in sterile injury as occurs during ischemia–reperfusion injury, atherosclerosis, and trauma has only recently been the focus of investigations. Here, we review mechanisms of monocyte recruitment to sites of sterile injury, their modes of action, and their effect on disease outcome in murine models with some references to human studies. Therapeutic strategies to target these cells must be developed with caution since each monocyte subset is capable of mediating either anti- or pro-inflammatory effects depending on the setting.
Keywords Monocytes Sterile inflammation Recruitment Functional outcome
Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives
Emmanuel Somm
Abstract Nicotinic acetylcholine receptors (nAChRs) are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine or other biologic compounds including nicotine. Their roles in synaptic transmission in the central and peripheral nervous system as well as in the neuromuscular junction have been extensively studied. Recent implications of nAChRs in intracellular signaling and their detection in peripheral nonneural cells (including epithelial cells and immune cells) have renewed the interest for this class of ionotropic receptors. In the present review, we focus our attention on the potential use of nicotinic cholinergic signaling in the treatment of metabolic diseases (such as obesity and diabetes) in browsing functions of nAChRs in adipose tissue and pancreatic islet biology. In fact, different nAChR subunits can be detected in these metabolic tissues, as well as in immune cells interacting with them. Various rodent models of obesity and diabetes benefit from stimulation of the nicotinic cholinergic pathway, whereas mice deficient for some nAChRs, in particular the a7 nAChR subunit, harbor a worsened metabolic phenotype. In contrast to potential therapeutic applications in metabolic diseases, an overstimulation of this signaling pathway during the early stage of development (typically through nicotine exposure during fetal life) presents deleterious consequences on ontogeny and functionality of adipose tissue and the endocrine pancreas which persist throughout life.
Keywords Nicotine nAChR Islet Adipocyte Obesity Diabetes
Elastase, a1-Proteinase Inhibitor, and Interleukin-8 in Children
and Young Adults with End-Stage Kidney Disease Undergoing
Continuous Ambulatory Peritoneal Dialysis
Bo_zena Polan´ ska • Daria Augustyniak • Irena Makulska •
Maria Niemczuk • Adam Jankowski • Danuta Zwolin´ ska
Received: 28 March 2013 / Accepted: 14 November 2013 / Published online: 29 November 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Peritoneal dialysis is one of the main modality of
treatment in end-stage kidney diseases (ESKD) in children.
In our previous work in chronic kidney disease patients, in
pre-dialyzed period and on hemodialysis, the neutrophils
were highly activated. The aim of this study was to assess an
inflammatory condition and neutrophil activation in ESKD
patients undergoing continuous ambulatory peritoneal dial-
ysis (CAPD). Thirteen CAPD patients without infection,
both sexes, aged 2.5–24 years, and group of healthy subjects
(C) were studied. For comparative purposes the conserva-
tively treated (CT) group of ESKD patients was included.
Neutrophil elastase in complex with a1-proteinase inhibitor
(NE-a1PI; ELISA), a1-proteinase inhibitor (a1PI; radial
immunodiffusion) and interleukin-8 (IL-8; ELISA) were
measured in the blood samples from CAPD, CT, and C group
and in the peritoneal dialysate fluid (PDF) samples of
patients on CAPD. A significantly increased plasma NE-a1PI
levels (median 176.5 lg/L, range 85.2–373.2 lg/L;
p \ 0.00005), serum IL-8 (median 18.6 pg/mL, range
15.73–35.28 pg/mL; p \ 0.05), and slightly decreased
serum a1PI (median 1,540 mg/L, range 1,270–1,955;
p B 0.05) compared to the control groups were found. There
were no significant differences of analyzed parameters
between CAPD and CT patients. The concentration ratio of
NE-a1PI, a1PI and IL-8 in blood/PDF was 29.97, 8.24, and
4.48, respectively. There were significantly positive corre-
lations between serum and PDF concentration of a1PI and
IL-8 (r = 0.613, p \ 0.05; r = 0.59; p \ 0.005, respec-
tively). The results of our study demonstrate that neutrophils
are highly activated in non-infected CAPD patients. The
pivotal marker of this activation is NE-a1PI. It may con-
tribute to chronic inflammation and tissues injury.
Keywords Neutrophil elastase a1-Proteinase inhibitor
Interleukin-8 End-stage kidney diseases
Continuous ambulatory peritoneal dialysis
Sphingosine-1-Phosphate: a Master Regulator of Lymphocyte
Egress and Immunity
Szandor Simmons • Masaru Ishii
Received: 5 July 2013 / Accepted: 8 November 2013 / Published online: 26 November 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Sphingosine-1-phosphate (S1P) is a central
factor responsible for lymphocyte distribution in the body.
S1P is able to control the integrity of various effector cell
populations within many lymphoid tissues by directing
lymphocyte egress. In this review, we give an overview of
the generation and degradation of S1P in specific lymphoid
microenvironments. Furthermore, we discuss, sometimes
contradictory, the functions of the five S1P receptors on
different cells in diverse tissues and give an idea of addi-
tional counteracting chemotactic signals for lymphocyte
immigration and emigration. We focus special attention to
recent discoveries of S1P-specific transporters, like spin-
ster-homolog-2 and the active secretion of S1P by
endothelial cells, erythrocytes and platelets. In addition, we
describe the microanatomical structures as well as entry
and egress routes into lymphoid organs which lymphocytes
use for efficient trafficking. Finally, we give an overview of
open questions regarding the regulation of lymphocyte
homing from primary lymphoid organs to secondary lym-
phoid organs and back again.
Keywords Sphingosine-1-phosphate S1P receptors
Lymphocyte egress Spinster-homolog-2
The Role of Glycogen Synthase Kinase 3-b in Immunity and Cell
Cycle: Implications in Esophageal Cancer
Shegan Gao • Jonathan Brown • Huizhi Wang •
Xiaoshan Feng
Received: 31 December 2012 / Accepted: 6 November 2013 / Published online: 26 November 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Esophageal cancer (EC) is one of the most
aggressive gastrointestinal malignancies, possessing an
insidious onset and a poor prognosis. Numerous tran-
scription factors and inflammatory mediators have been
reported to play a pivotal role in the initiation and pro-
gression of this cancer. However, the specifics of the
signaling network responsible for said factors, especially
which elements are the critical regulators, are still being
elucidated. Glycogen synthesis kinases 3 (GSK3)b was
originally regarded as a kinase regulating glucose metab-
olism. Accumulating evidence demonstrated that it also
played an essential role in a variety of cellular processes
including proliferation, differentiation, inflammation,
motility, and survival by regulating various transcription
factors such as c-Jun, AP-1, b-catenin, CREB, and NF-jB.
Aberrant regulation of GSK3b has been shown to promote
cell growth in some cancers, while suppressing it in others,
and thus may play an important role in the development of
EC. This review will discuss our current understanding of
GSK3b signaling, and its control of the expression and
activation of various transcription factors that mediate the
inflammatory response. We will also explore some of the
known mediators of EC progression, and based on current
literature, elucidate the potential roles and implications of
GSK3 in this disease.
Keywords Esophageal cancer Inflammation
GSK3 PI3K Inflammatory cytokines
Intranasal Administration of Perillyl Alcohol Activates Peripheral
and Bronchus-Associated Immune System In Vivo
Marcela D’Alincourt Salazar • Rafael Ferreira da Silva •
Clovis Orlando Da Fonseca • Jussara Lagrota-Candido •
Thereza Quirico-Santos
Received: 7 December 2012 / Accepted: 5 November 2013 / Published online: 21 November 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Perillyl alcohol (POH) presents antitumoral
activity but clinical application is hampered by adverse
effects following oral administration. This work aimed to
verify the cytotoxic effect of intranasal POH administration
in the histology of lung, liver, brain; the cellularity and
function of peripheral and bronchoalveolar-associated
immune system. C57 adult mice received 1-min inhalation
with POH, vehicle 70 % ethanol or saline buffer, once
(84 lg/day) or twice (164 lg/day) during five consecutive
days, and were killed 72 h after treatment. Spleen, cervical
and mesenteric lymph nodes were removed for 3H-thymi-
dine proliferation assay, leukocyte cellularity and flow
cytometry analysis. Peripheral blood and bronchoalveolar
lavage cells were collected to assess cellularity and
immunoglobulin (IgA, IgM) levels. Intranasal POH did not
alter body weight or liver, brain and lung morphology, but
increased splenocyte and cervical lymph node cell prolif-
eration, and IgM production without altering peripheral
lymphocyte subsets. Treatment also increased the per-
centage of alveolar macrophages (83 %) and IgA-
producing lymphocytes (15 %), a pattern characteristic of
activated bronchoalveolar innate immune system. Intrana-
sal administration of POH activated peripheral immune
system and innate immunity of bronchus-associated lym-
phoid tissue, thus suggesting a possible role for POH as a
chemotherapeutic drug also in pathological processes
affecting the lung.
Keywords Perillyl alcohol Intranasal administration
Therapeutic strategy Immune system
Bronchoalveolar fluid
Etiopathogenesis of Recurrent Aphthous Stomatitis
and the Role of Immunologic Aspects: Literature Review
Zuzanna S´ lebioda • El_zbieta Szponar •
Anna Kowalska
Received: 31 May 2013 / Accepted: 28 October 2013 / Published online: 12 November 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Recurrent aphthous stomatitis (RAS; recurrent
aphthous ulcers; canker sores) belongs to the group of
chronic, inflammatory, ulcerative diseases of the oral
mucosa. Up to now, the etiopathogenesis of this condition
remains unclear; it is, however, considered to be multi-
factorial. The results of currently performed studies
indicate that genetically mediated disturbances of the
innate and acquired immunity play an important role in the
disease development. Factors that modify the immunologic
response in RAS include: food allergies, vitamin and
microelement deficiencies, hormonal and gastrointestinal
disorders (e.g., celiac disease, Crohn’s disease, ulcerative
colitis), some viral and bacterial infections, mechanical
injuries and stress. In this paper, we presented the main
etiopathogenetic factors of RAS with a special emphasis on
the mechanisms of the immune response modification.
Moreover, we discussed the crucial clinical symptoms and
types of RAS together with epidemiologic data based on
the current medical literature reports and our own
observations.
Keywords Recurrent aphthous stomatitis
Etiopathogenesis Immunologic factors Cytokines
Expression of Toll-Like Receptors on Human Rectal
Adenocarcinoma Cells
Marcin Tcho´rzewski • Przemysław Lewkowicz •
Adam Dziki • Henryk Tcho´rzewski
Received: 14 April 2013 / Accepted: 28 October 2013 / Published online: 5 January 2014
Ó The Author(s) 2014. This article is published with open access at Springerlink.com
Abstract The innate immune system uses Toll-like
receptors (TLR) to detect the presence of pathogen patterns
thus allowing for rapid host defense responses. Stimulation
of TLR results in inflammatory response and regulatory
cytokine production affecting acquired immunity. The aim
of the study was an evaluation of TLR2 and TLR4
expression on the surface of human colon cancer cells in
primary culture with or without autologous peripheral
blood mononuclear cells. Surgical specimens of colon
cancer were processed to obtain cancer cells. Cancer cells
separation was conducted first by mechanical tissue disin-
tegration and than by gradient centrifugation to obtain
95 % cell confluence. By staining the isolated cells the
pathologist determined them as adenocarcinoma. Colon
cancer cells were then co-cultured in 24 h culture alone or
together with autologous lymphocytes. Reverse-transcrip-
tion polymerase chain reaction was performed for detection
of TLR2 and TLR4 mRNA in colon cancer and normal
colon epithelial cells using commercially available prim-
ers. Resting as well as phytohemagglutinin or
lipopolysaccharide (LPS) stimulated cells were tested.
Receptor proteins on cancer cells were examined by
immunohistochemistry. TLR4 mRNA was detected in
cancer cells. Autologous lymphocytes do not exert any
effect on these receptors expression. TLR4 mRNA
expression was not observed in normal colon epithelial
cells. TLR2 mRNA was present on LPS stimulated cancer
cells as well as on resting and stimulated lymphocytes.
Expression of TLR2 and TLR4 receptor proteins on colon
cancer cells were confirmed by immunohistochemistry.
TLR4 may be responsible for uncontrolled tumor growth
under LPS stimulation in human colon environment.
Keywords Colon cancer Cell culture TLR2
TLR4 expression
Antitumor Effects of Recombinant Antivascular Protein
ABRaA-VEGF121 Combined with IL-12 Gene Therapy
Agnieszka Ciomber • Andrzej Smagur • Iwona Mitrus •
Tomasz Cichon´ • Ryszard Smolarczyk • Aleksander Sochanik •
Stanisław Szala • Magdalena Jarosz
Received: 29 March 2013 / Accepted: 26 October 2013 / Published online: 13 November 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Development and neoplastic progression
strongly rely on tumor microenvironment cells. Various
kinds of cells that form such tumor milieu play substantial
roles in angiogenesis and immunosuppression. Attempts to
inhibit tumor vascularization alter tumor milieu and
enhance immune response against the tumor. Anticancer
therapeutic strategy bringing together antiangiogenic and
immunostimulating agents has emerged as a promising
approach. We here investigated whether therapy directed
against preexisting vessels, combined with an immuno-
modulatory factor would be equally effective in arresting
tumor growth. To this goal, we investigated the effective-
ness of ABRaA–vascular endothelial growth factor isoform
121 (VEGF121), an antivascular drug constructed by us. It
is a fusion protein composed of VEGF121, and abrin A
chain (translation-inhibiting toxin). We used it in combi-
nation with interleukin (IL-12) gene therapy and tried to
inhibit B16-F10 melanoma tumor growth. ABRaA–
VEGF121 is a chimeric recombinant protein capable of
destroying tumor vasculature and triggering necrosis in the
vicinity of damaged vessels. IL-12 cytokine, in turn, acti-
vates both specific and non-specific immune responses.
Our results demonstrate that combination of ABRaA–
VEGF121 antivascular agent with immunostimulatory
cytokine IL-12 indeed inhibits tumor growth more effec-
tively than either agent alone, leading to complete cure of
ca. 20 % mice. Post-therapeutic analysis of tumors excised
from mice treated with combination therapy showed
decreased numbers of blood microvessels in the tumor
microenvironment, lowered numbers of regulatory T lym-
phocytes, as well as showed higher levels of CD4? and
CD8? as compared to control mice. It seems that bringing
together antivascular strategy and the action of immuno-
stimulating agents indeed inhibits growth of tumors.
Keywords Combined therapy Antivascular strategy
ABRaA–VEGF121 protein Immunostimulation
IL-12
Detection and Significance of Cytotoxic Cell Subsets in Biopsies
of HCV-Infected Human Livers
Iwona Mozer-Lisewska • Anna Mania •
Arleta Kowala-Piaskowska • Andrzej Kluk •
Husam Samara • Anna Pauli • Jan _Zeromski
Received: 14 January 2013 / Accepted: 25 October 2013 / Published online: 14 November 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Chronic viral hepatitis C still remains the clin-
ical challenge. Attempts of the immune system to cope with
this infection are unsatisfactory. There is a conviction that
the main site of interaction between virus (Hepatitis C virus,
HCV) and immune system is in situ, i.e., in liver. Natural
killer (NK) cells appeared relevant in the acute hepatitis.
Less is known about the immune response in the chronic
HCV infection. The aim of this study was to evaluate the
prevalence of various cytotoxic cell subsets in chronic
HCV? liver tissue and to seek links between them and
laboratory data of patients. Sections from paraffin blocks of
liver biopsy tissues of HCV? untreated patients were sub-
jected to the reaction with antibodies vs. cytotoxic cell
subsets and immunohistochemistry. Positive cells were
searched in cellular infiltrates in portal areas and in liver
parenchyma. They were classified on the ‘‘Yes’’ or ‘‘No’’
basis. Majority of liver biopsies exhibited cellular infiltrates
in portal spaces and as single cells in liver parenchyma.
Infiltrates consisted of CD8? T cells, CD56? NK ones,
including CD158i? and CD158b?. The latter were rarely
seen. There were also granzyme B? cells. The most abun-
dant were NKG2D? cells, much more common than NK
CD56? ones. It implied that NKG2D was also expressed on
T cells. Prevalence of NKG2D? cells correlated with high
activity of liver enzymes such as alanine aminotransferase,
aspartate aminotransferase and a greater histological
severity of liver injury. NKG2D? cells form the bulk of
cells infiltrating HCV-infected human liver. Correlation of
NKG2D? cells with some laboratory parameters of patients
suggests their role in hepatitis C pathogenesis.
Keywords HCV? liver biopsy NK cells
Cytotoxic T cells NKG2D receptor
Immunohistochemistry Patients data
Seronegative Hepatitis C Virus Infection
Justyna Kaz´mierczak • Agnieszka Pawełczyk •
Kamila Caraballo Cortes • Marek Radkowski
Received: 5 April 2013 / Accepted: 25 October 2013 / Published online: 9 November 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Hepatitis C virus (HCV) is a major cause of
liver disease worldwide. The routine diagnostics identify-
ing HCV infection include testing for specific anti-HCV
antibodies by enzyme-linked immnunosorbent assay and
viral genetic material in serum or plasma. However, a small
proportion of patients persistently infected with HCV, in
whom anti-HCV are undetectable, constitute a serious
diagnostic and possibly epidemiologic problem, as they
could facilitate pathogen spread in the population. This
type of infection is termed seronegative or serosilent.
Seronegative HCV infection is currently of great interest to
both scientists and physicians. The review presents epide-
miological data concerning the prevalence of seronegative
HCV infection in HIV/HCV co-infected individuals, he-
modialysis patients, and blood and organ donors. The
possible mechanisms behind this atypical course of infec-
tion are discussed. Furthermore, the differences between
seronegative and occult infections and prolonged sero-
conversion are explained.
Keywords HCV Anti-HCV HCV RNA
Seronegative infection Diagnostics
Dealing with Scientific Integrity Issues: the Spanish Experience
Pere Puigdome`nech
Published online: 15 October 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Integrity has been an important matter of con-
cern for the scientific community as it affects the basis of
its activities. Most countries having a significant scientific
activity have dealt with this problem by different means,
including drafting specific legal or soft law regulations and
the appointment of stable or ad hoc committees that take
care of these questions. This has also been the case in
Spain. After the period of transition between dictatorship to
a democratic regime, and, particularly, after the entrance in
the European Union, scientific activity has increased in the
country. As it could be expected, problems of misconduct
have appeared and different institutions have been dealing
with these matters. One of the best examples is that of
Consejo Superior de Investigaciones Cientificas (CSIC),
the largest institution devoted to scientific research
belonging to the Spanish Government. The experience of
the CSIC’s Ethics Committee in dealing with conflicts
related to scientific practices is discussed here.
Keywords Integrity Ethics Ethics committee
The Reverse-Direction Method Links Mass
Experimental Data to Human Diseases
Hideki Ogura • Toru Atsumi • Hidenori Bando • Lavannya Sabharwal •
Moe Yamada • Jing-Jing Jiang • Akihiro Nakamura • Yasunobu Arima •
Daisuke Kamimura • Masaaki Murakami
Received: 26 April 2013 / Accepted: 21 August 2013 / Published online: 31 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Genome-wide analyses such as DNA micro-
array, RNA sequencing and RNA interference-based high-
throughput screening are prevalent to decipher a biological
process of interest, and provide a large quantity of data to
be processed. An ultimate goal for researchers must be
extrapolation of their data to human diseases. We have
conducted functional genome-wide screenings to elucidate
molecular mechanisms of the inflammation amplifier, a
NFjB/STAT3-dependent machinery that potently drives
recruitment of immune cells to promote inflammation.
Using a public database of genome-wide association
studies (GWAS), we recently reported the reverse-direction
method by which our mass screening data were success-
fully linked to many human diseases. As an example, the
epiregulin–epidermal growth factor receptor pathway was
identified as a regulator of the inflammation amplifier, and
associated with human diseases by GWAS. In fact, serum
epiregulin levels were higher in patients with chronic
inflammatory disorders. The reverse-direction method can
be a useful tool to narrow mass data down to focus on
human disease-related genes.
Keywords Inflammation amplifier IL-17 IL-6
NFjB STAT3 Chronic inflammation
Human diseases and disorders
The Complement Cascade and Renal Disease
Katarzyna Kos´cielska-Kasprzak • Dorota Bartoszek •
Marta Myszka • Marcelina _Zabin´ ska •
Marian Klinger
Received: 1 March 2013 / Accepted: 21 August 2013 / Published online: 13 September 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Serum complement cascade, a part of innate
immunity required for host protection against invading
pathogens, is also a mediator of various forms of disease and
injury. It is activated by classical, lectin, and alternative
pathways that lead to activation of C3 component by C3
convertases, release of C3b opsonin, C5 conversion and
eventually membrane attack complex formation. The tightly
regulated activation process yields also C3a and C5a ana-
phylatoxins, which target a broad spectrum of immune and
non-immune cells. The review discusses the involvement of
the complement cascade in kidney disease pathogenesis and
injury. The role of the complement pathways in autoantibody-
mediated forms of glomerulonephritis (lupus nephritis, anti-
glomerular basement membrane disease, anti-neutrophil
cytoplasmic autoantibody-induced or membranoproliferative
glomerulonephritis, membranous nephropathy), C3 glome-
rulopathy, atypical forms of hemolytic uremic syndrome,
ischemic-reperfusion injury of transplanted kidney, and anti-
body-mediated renal allograft rejection are discussed. The
disturbances in complement activation and regulation with
underlying genetics are presented and related to observed
pathology. Also promising strategies targeting the comple-
ment system in complement-related disorders are mentioned.
Keywords Complement cascade Renal disease
Kidney injury
Plant Polyisoprenoids and Control of Cholesterol Level
Alexander V. Pronin • Leonid L. Danilov •
Alexander N. Narovlyansky • Alexander V. Sanin
Received: 4 January 2013 / Accepted: 21 August 2013 / Published online: 31 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract The ability of plant polyisoprenoids (polypre-
nols and polyprenyl phosphates) to diminish the levels of
serum cholesterol affecting its biosynthetic pathway are
highlighted here. Possible mechanism of such process is
discussed. It is also noted that polyisoprenoids can prevent
toxic injuries of the liver and restore disturbed hepatic
functions. The possibility of polyprenyl phosphates to
reveal at the same time anti-inflammatory action sup-
pressing lipoxygenase activity and lowering the levels of
proinflammatory cytokines will be illustrated. Attention
will be focused on the potential usefulness of plant poly-
isoprenoids in the course of prevention and treatment of
hypercholesterolemia. High efficiency for combined use of
polyprenyl phosphate and b-sitosterol, which leads to
substantial enhancement of the ability to overcome
hypercholesterolemia versus the individual constituents
will be demonstrated.
Keywords Polyisoprenoids b-Sitosterol Sitopren
Cholesterol Atherosclerosis
Co-Infections with Cytomegalovirus and Human Herpesvirus
Type 7 in Adult Polish Allogeneic Haematopoietic Stem Cell
Transplant Recipients
Agnieszka Tomaszewska • Anna Krys´ko • Tomasz Dziecia˛tkowski • Maciej Przybylski • Grzegorz W. Basak •
Kazimierz Hałaburda • Karolina Piekarska • Agata Sulowska • Barbara Nasiłowska-Adamska •
Gra_zyna Młynarczyk • Wiesław W. Je˛drzejczak • Bo_zena Marian´ ska
Received: 11 February 2013 / Accepted: 5 August 2013 / Published online: 18 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Human herpesvirus 7 (HHV-7) is widespread
around the world and may also be a possible cofactor for
cytomegalovirus (CMV) infection in haematopoietic stem
cell transplant (HSCT) recipients. In case of viral dis-
eases where specific treatment is available, real-time
PCR assays constitute reliable diagnostic tools enabling
timely initiation of appropriate therapy and rapid
assessment of the efficacy of antiviral treatment strate-
gies. The presence of CMV and HHV-7 was confirmed
by the detection of viral DNA isolated from 1,027
plasma samples. A group of 69 allogeneic HSCT (allo-
HSCT) recipients was examined in early post-transplant
period using quantitative real-time PCR methods. Within
the study period, 62 % of patients had at least once
CMV DNA-emia, while HHV-7 DNA was found in
43 % of subjects. Co-infection between these b-herpe-
sviruses was detected in the plasma samples collected
from 18 patients (26 %). Patients with concomitant
HHV-7 DNA-emia had significantly higher number of
CMV DNA copies compared with those without HHV-7
infection (1986 vs. 432 copies/ml, p \ 0.001) but there
was no difference in duration of CMV DNA-emia
between these groups. On the other hand, while the load
of HHV-7 DNA was comparable between patients with
CMV DNA-emia and without CMV DNA-emia, the
duration of HHV-7 DNA-emia was significantly longer in
the first group (38.5 vs. 14 days, p \ 0.001). HHV-7
DNA-emia is very frequently detected in Polish allo-
HSCT recipients. In those, who have subsequent CMV
reactivation, the coexistence of the viruses may nega-
tively affect the kinetics of infection with either of them.
Therefore the investigation of concomitant HHV-7 DNA-
emia could affect the prognosis of post-transplant
patients suffering from CMV reactivation.
Keywords CMV HHV-7
Haematopoietic stem cell transplantation
Infectious complications Real-time PCR
Lobular Breast Cancer: Pathology, Biology, and Options
for Clinical Intervention
Eva Vlug • Cigdem Ercan • Elsken van der Wall •
Paul J. van Diest • Patrick W. B. Derksen
Received: 7 January 2013 / Accepted: 5 August 2013 / Published online: 20 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Lobular carcinoma is a breast cancer subtype
comprising approximately 15 % of all breast cancer cases.
Clinical diagnosis of this subtype is difficult due to a
characteristic growth pattern that inhibits detection using
palpation or standard X-ray mammography. While clinical
intervention based on hormone antagonists has proven an
effective strategy, hormone receptor negative or nonre-
sponsive disease cannot be treated successfully, indicating
the need for alternative curative approaches. In contrast to
its well-defined histopathological characteristics that were
first recognized a century ago, the surface of the underlying
biology has only recently been scratched. Progress was
made in understanding the biology of the disease, which
will hopefully have its impact on future treatment modal-
ities and initiate development of novel intervention
strategies. Here, we review the pathological and molecular
features of lobular breast cancer and report on the currently
known mechanisms that control disease development and
progression. Finally we will reflect on past, present, and
future treatment options.
Keywords Lobular breast cancer Pathological features
Clinical features Molecular features
Flow Cytometric Analysis of CD133- and EpCAM-Positive Cells
in the Peripheral Blood of Patients with Lung Cancer
Tomasz Skirecki • Gra_zyna Hoser • Jerzy Kawiak •
Dariusz Dziedzic • Joanna Domagała-Kulawik
Received: 21 November 2012 / Accepted: 5 August 2013 / Published online: 20 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Lung tumors are characterized by their high
metastatic potential, which is the main cause of therapeutic
failure. However, the exact cellular origin of metastasis
remains unknown. Since the introduction of the cancer
stem cell theory, lung cancer stem cells (LCSCs) have been
thought to represent metastasis-founding cells. The current
study aimed to evaluate whether LCSCs could be found in
the circulation. Expression of the stem cell markers CD133
and EpCAM was confirmed in tumor and normal lung
tissue by flow cytometry. Then, this technique was further
used to investigate the expression of CD133 and EpCAM
in the peripheral blood of 41 patients with primary lung
cancer. Putative LCSCs (CD133?EpCAM?) were present
in 6/7 tumor samples, and CD133?EpCAM? cells were
identified in the blood samples of 15 patients at a median
level of 40/ml of blood. EpCAM? cells were detected in
60 % of the patients, and the number of these cells was
higher in patients with adenocarcinoma than patients with
squamous cell carcinoma and was also higher in patients
with less advanced disease. Moreover, the frequency of this
subpopulation significantly correlated with the circulating
level of SSEA-4? cells. Additionally, CD133?EpCAM–
cells were found in 87 % of the patients, and the numbers
of these cells were significantly higher in patients with
distant metastases and correlated with disease stage. This
study confirmed the presence of an LCSC subpopulation
with a CD133?EpCAM? phenotype in the tumors and
blood of patients with lung cancer, and these results sug-
gest an important role for CD133 and EpCAM in lung
cancer progression and their potential application as novel
biomarkers of the disease.
Keywords Lung cancer Cancer stem cell (CSC)
CD133 EpCAM Metastases
Do Mesenchymal Stem Cells Modulate the Milieu
of Reconstructed Bladder Wall?
Marta Pokrywczynska • Arkadiusz Jundzill • Magdalena Bodnar •
Jan Adamowicz • Jakub Tworkiewicz • Lukasz Szylberg • Robert Debski •
Andrzej Marszalek • Tomasz Drewa
Received: 5 July 2012 / Accepted: 5 August 2013 / Published online: 22 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract To evaluate the mesenchymal stem cells
(MSCs) influence on cytokines and matrix metallopro-
teinases (MMPs) expression in rat bladder wall
regeneration. MSCs cultures from the bone marrow were
established. Acellular matrices from the bladder submu-
cosa were prepared. Bladders were reconstructed using
cell-seeded (n = 5) and unseeded (n = 5) grafts. MSCs
were injected into the bladder wall (n = 5), bladders were
incised and MSCs were injected into the circulation
(n = 5) or were left intact (n = 5). Animals were killed
after 3 months. Bladder histology and immunohistochem-
ical staining of IL-2, IL-4, IL-6, IL-10, TNF-a, TGF-b1,
IFN-c, MMP-2, and MMP-9 were done. Bladders recon-
structed with cell-seeded grafts mimicked native tissue,
while unseeded grafts revealed shrinkage and morpholog-
ical irregularities. There were no morphological changes in
bladders of other groups. Different pattern of cytokine and
MMP expression was observed. Increased expression of
anti-inflammatory cytokines and MMPs in bladder pro-
motes detrusor regeneration.
Keywords Bladder regeneration Cytokines
Matrix metalloproteinases Mesenchymal stem cells
Tissue engineering
Functional Attributes of Responding T Cells in HCV Infection:
The Recent Advances in Engineering Functional Antiviral T Cells
Anna Pasetto • Soo Aleman • Margaret Chen
Received: 8 April 2013 / Accepted: 5 August 2013 / Published online: 18 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Hepatitis C virus (HCV) is one of the major
causes of hepatocellular carcinoma (HCC) around the
world. HCV promotes characteristics of cancer stem cells
and the infected cells are insensitive to apoptotic signals,
which lead to persistent antigen stimulation and T cell
exhaustion in the host. In spite of new effective antiviral
drugs, new challenges are around the corner as drug-
resistant viral strains and drug–drug interactions have
already been reported. Considering that there are few
effective treatments available for HCC, novel immuno-
therapies to prevent HCC and late stage HCV-related liver
diseases should be considered. Given that adoptive
immunotherapy with antigen-specific T lymphocytes has
emerged as an effective therapeutic strategy for combating
cancer, there is, therefore, reason to examine the possibility
of using highly functional HCV-reactive T cells in immu-
notherapy. This review aims to provide the current
understanding of natural HCV responding T cells in HCV
infection and to give an update on the novel approaches
that have the capacity to ex vivo generate functional T cells
for potential adoptive cell therapy. Approaches based on
the pMHC tetramer-associated magnetic enrichment,
exogenous HCV T cell receptor transfer, and induced
pluripotent stem cell technologies are described herein.
Their potentials as immunotherapeutic against HCV-rela-
ted diseases are discussed.
Keywords Virus Hepatitis Antiviral T cell receptor
Gene transfer Immunotherapy
Type 1 Diabetes: Prospective Cohort Studies for Identification
of the Environmental Trigger
Kjersti S. Rønningen
Received: 10 September 2012 / Accepted: 5 August 2013 / Published online: 18 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Type 1 diabetes (T1D) is one of the most
common chronic diseases with childhood onset, and the
disease incidence has increased two to fivefold over the
past half century by as yet unknown means. T1D occurs
when the body’s immune system turns against itself,
destroying in a very specific and targeted way—the pan-
creatic b-cells. T1D results from poorly defined
interactions between susceptibility genes and environ-
mental determinants. In contrast to the rapid progress in
finding T1D genes, identification and confirmation of
environmental determinants remain a formidable chal-
lenge. This review article will give an overview of ongoing
prospective cohort studies aiming to identify the environ-
mental trigger(s) causing T1D.
Keywords Autoimmunity Cohort studies
Environmental factors Genetic factors Type 1 diabetes
Interleukin-1 Gene Polymorphisms in Chronic Gastritis Patients
Infected with Helicobacter pylori as Risk Factors of Gastric
Cancer Development
Andrzej Hnatyszyn • Karolina Wielgus • Marta Kaczmarek-Rys •
Marzena Skrzypczak-Zielinska • Marlena Szalata • Joanna Mikolajczyk-Stecyna •
Jerzy Stanczyk • Ireneusz Dziuba • Adam Mikstacki • Ryszard Slomski
Received: 30 October 2012 / Accepted: 5 August 2013 / Published online: 31 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Epidemiological investigations indicated asso-
ciation of the Helicobacter pylori infections with the
occurrence of inflammatory conditions of the gastric
mucosa and development of chronic gastritis and intestinal
type of gastric cancer. IL1A and IL1B genes have been
proposed as key factors in determining risk of gastritis and
malignant transformation. The aim of this paper was to
evaluate association of interleukin-1 gene polymorphisms
with chronic gastritis, atrophy, intestinal metaplasia, dys-
plasia and intestinal type of gastric cancer in H. pylori-
infected patients. Patients subjected to analysis represent
group of 144 consecutive cases that suffered from dys-
pepsia with coexisting infection of H. pylori and chronic
gastritis, chronic atrophic gastritis, intestinal metaplasia,
dysplasia or gastric cancer. Molecular studies involved
analysis of –889C[T polymorphism of IL1A gene and
?3954C[T polymorphism of IL1B gene. Statistical anal-
ysis of association of polymorphism –889C[T of gene
IL1A with changes in gastric mucosa showed lack of sig-
nificance, whereas ?3954C[T polymorphism of IL1B
gene showed significant association. Frequency of allele T
of ?3954C[T polymorphism of IL1B gene was higher in
group of patients with chronic gastritis, atrophy, intestinal
metaplasia, dysplasia or intestinal type of gastric cancer
(32.1 %) as compared with population group (23 %),
v2 = 4.61 and p = 0.03. This corresponds to odds ratio:
1.58, 95 % CI: 1.04–2.4. Our results indicate that
?3954C[T polymorphism of IL1B gene increase suscep-
tibility to inflammatory response of gastric mucosa H.
pylori-infected patients and plays a significant role in the
development of chronic gastritis, atrophy, intestinal meta-
plasia, dysplasia and the initiation of carcinogenesis.
Keywords Helicobacter pylori Interleukin-1
Polymorphism Chronic gastritis Gastric cancer
T-Cell Subpopulations ab and cd in Cord Blood of Very Preterm
Infants: the Influence of Intrauterine Infection
Agata Serwatowska-Bargieł • Maria Wa˛sik •
Maria Katarzyna Kornacka • El_zbieta Go´rska •
Robert Kozarski
Received: 12 July 2012 / Accepted: 4 August 2013 / Published online: 20 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Preterm infants are very susceptible to infec-
tions. Immune response mechanisms in this group of
patients and factors that influence cord blood mononuclear
cell populations remain poorly understood and are con-
sidered insufficient. However, competent immune
functions of the cord blood mononuclear cells are also
described. The aim of this work was to evaluate the T-cell
population (CD3?) with its subpopulations bearing T-cell
receptor (TCR) ab or TCR cd in the cord blood of preterm
infants born before 32 weeks of gestation by mothers with
or without an intrauterine infection. Being a pilot study, it
also aimed at feasibility check and assessment of an
expected effect size. The cord blood samples of 46 infants
age were subjected to direct immunofluorescent staining
with monoclonal antibodies and then analyzed by flow
cytometry. The percentage of CD3? cells in neonates born
by mothers with diagnosis of intrauterine infection was
significantly lower than in neonates born by mothers
without infection (p = 0.005; Mann–Whitney U test). The
number of cells did not differ between groups. Infection
present in the mother did not have an influence on the TCR
ab or TCR cd subpopulations. Our study contributes to a
better understanding of preterm infants’ immune mecha-
nisms, and sets the stage for further investigations.
Keywords CD3? cells Gamma/delta T cells
Preterm newborn Intrauterine infection
Toll-Like Receptors’ Pathway Disturbances are Associated
with Increased Susceptibility to Infections in Humans
Josias Brito Fraza˜o • Paolo Ruggero Errante •
Antonio Condino-Neto
Received: 4 October 2012 / Accepted: 4 August 2013 / Published online: 22 September 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Toll-like receptors (TLRs) sense microbial
products and play an important role in innate immunity.
Currently, 11 members of TLRs have been identified in
humans, with important function in host defense in early
steps of the inflammatory response. TLRs are present in the
plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6) and
endosome (TLR3, TLR7, TLR8, TLR9) of leukocytes.
TLRs and IL-1R are a family of receptors related to the
innate immune response that contain an intracellular
domain known as the Toll-IL-1R (TIR) domain that
recruits the TIR-containing cytosolic adapters MyD88,
TRIF, TIRAP and TRAM. The classical pathway results in
the activation of both nuclear factor jB and MAPKs via the
IRAK complex, with two active kinases (IRAK-1 and
IRAK-4) and two non-catalytic subunits (IRAK-2 and
IRAK-3/M). The classical pro-inflammatory TLR signaling
pathway leads to the synthesis of inflammatory cytokines
and chemokines, such as IL-1b, IL-6, IL-8, IL-12 and TNF-
a. In humans, genetic defects have been identified that
impair signaling of the TLR pathway and this may result in
recurrent pyogenic infections, as well as virus and fungi
infections. In this review, we discuss the main mechanisms
of microbial recognition and the defects involving TLRs.
Keywords Toll-like receptors Immunodeficiencies
Recurrent infections NF-kappaB IRAK-4
The Virulence Factors of Bordetella pertussis: Talented
Modulators of Host Immune Response
Giorgio Fedele • Manuela Bianco • Clara Maria Ausiello
Received: 28 December 2012 / Accepted: 4 August 2013 / Published online: 18 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Approximately 40 million whooping cough
cases and between 200,000 and 400,000 pertussis-linked
deaths are recorded each year. Although several types of
vaccines are licensed and widely used, Bordetella pertussis
continues to circulate in populations with high vaccine
coverage of infants and children due to the waning of
protection induced by the vaccination. B. pertussis typi-
cally expresses a wide array of virulence factors which
promote bacterial adhesion and invasion by altering the
local environment, including pertussis toxin, tracheal
cytotoxin, adenylate cyclase toxin, filamentous hemagglu-
tinin, and the lipooligosaccharide. The virulence factors of
B. pertussis also possess immunomodulatory properties,
exerted through their enzymatic and receptor-binding
activities. Both pro- and anti-inflammatory effects are
mediated, that can subvert host innate and adaptive
immunity and favor the onset of a long-term infection. This
review describes the capacities of B. pertussis virulence
factors to modulate host immune responses and the
mechanisms employed, which have been the subject of
extensive research in the recent years, both in murine and
human experimental systems. Knowledge of these mech-
anisms is gaining increasing importance, since it could
provide in the near future the basis for the identification of
therapeutic agents for modulating the immune system as
well as novel molecular targets to treat pertussis.
Keywords Bordetella pertussis Macrophages
Dendritic cells T cell response Cytokines
Airways epithelium
Blood of Patients with Various Autoimmune Diseases
after Autologous Hematopoietic Stem Cell Transplantations
and their Relations to the Survival Times
La´szlo´ Va´ro´czy • Ildiko´ Kova´cs • Sa´ndor Bara´th • Edit Gyimesi •
A´ rpa´d Ille´s • Margit Zeher • Sa´ndor Sipka
Received: 27 September 2012 / Accepted: 23 July 2013 / Published online: 10 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract The changes in the number of CD8? T lym-
phocytes were studied before (0 day) and then 30 days
after the autologous hematopoietic stem cell transplanta-
tions (AHSCT) in 14 therapy refractory patients with
autoimmune diseases. The years of survival and the clinical
states were also evaluated. The number of CD8? T cells
was determined by an hematologic automat and by flow
cytometry. Longer than 5-year survival times were found in
6 cases, whereas there was no progression (improvement)
in 2 cases, and 4 patients were lost. The increase in the
number of CD8? cytotoxic T cells was gradual in the first
2 months and reached the significantly highest values
among all subtypes of lymphocytes. It was of a special
interest that in all the 4 patients who died, the numbers of
CD8? T cells were less than 150/ll on the 30th day after
AHSCT, whereas all the 10 patients with a higher cell
number survived. These results suggest that the early
monitoring of the number (not only the ratio) of regener-
ating CD8? T cells in the peripheral blood can be a useful
and quantitative laboratory measurement after AHSCT,
and it has a significant relation also to the survival times of
transplanted patients.
Keywords Autoimmune diseases
Autologous stem cell transplantation CD8? T cells
The Immunomodulatory Activity of Staphylococcus aureus
Products Derived from Biofilm and Planktonic Cultures
Beata Sadowska • Marzena Wie˛ckowska-Szakiel •
Małgorzata Paszkiewicz • Barbara Ro´ _zalska
Received: 17 August 2012 / Accepted: 23 July 2013 / Published online: 8 August 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Biofilms are probably one of the most common
structures formed by microorganisms in various environ-
ments. The higher resistance of such microbial
communities to stress conditions, including antibiotics and
host immune response, is recently extensively studied.
However, the weak activity of phagocytic cells against
microbial biofilm is not yet fully understood and explained.
The aim of this study was: (1) a qualitative and quantitative
comparison of cell components/products released from
Staphylococcus aureus biofilm or planktonic cultures, (2)
evaluation of the influence of such cell components/prod-
ucts on murine leukocytes secretory function. For this,
mouse peritoneal leukocytes were stimulated with biofilm
or planktonic staphylococcal cultures or their acellular
filtrates, and then the production of cytokines (TNF-a, IL-
6, IL-10, MCP-1 and MIP-1a), hemolytic activity and
staphylokinase (SAK) production was determined. It was
found that similar staphylococcal components/products
possessing the immunomodulatory properties, were present
in both, biofilm and planktonic filtrates. Moreover, these
compounds were similarly active in the stimulation of
TNF-a and MCP-1 release from leukocytes. The hemolytic
activity and SAK release by planktonic and biofilm cul-
tures were also comparable. What is interesting, stronger
stimulatory activity of biofilm-derived components/prod-
ucts of clinical S. aureus strains in the case of MIP-1a, IL-6
and IL-10 was noticed. On the other hand, taking into
consideration the reference strains, MIP-1a production was
enhanced by ‘‘planktonic filtrates’’. Thus, in our study it
was proved, first of all, that biofilm is not a structure fully
separated from the external environment. Second, the
influence of these S. aureus constituents/metabolites on
leukocytes seems to be more strain-dependent than culture
phenotype-dependent. The lack of one common profile of
biofilm and planktonic S. aureus cultures/filtrates biologi-
cal activity indicates that the disturbances in cytokines’
production could not be the only reason for the so-called
‘‘frustrated phagocytosis’’, connected with enhanced bio-
film resistance.
Keywords Staphylococci Biofilm Modulins
Phagocytes Cytokines
Pro-inflammatory Cytokine Release in Rectal Surgery:
Comparison Between Laparoscopic and Open Surgical
Techniques
Andreas Kvarnstro¨m • Torbjo¨rn Swartling •
Go¨ran Kurlberg • Jan-Peter Bengtson •
Anders Bengtsson
Received: 22 April 2012 / Accepted: 23 July 2013 / Published online: 8 August 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract The objective of the present study was to
investigate whether laparoscopic rectal surgery causes a
less pronounced release of pro-inflammatory cytokines as
compared to open surgical technique. Twenty-four con-
secutive patients undergoing rectal surgery due to cancer
disease were included in a prospective and randomized
trial. The patients were randomized to laparoscopic
(n = 12) or open surgery (n = 12). Blood was sampled at
five occasions; after induction of anesthesia before start of
surgery, at 180, 360 min and 24 h after start of surgery and
the last sample was taken in the late post-operative period
3–5 days after surgery. The levels of interleukin (IL)-1a,
IL-6, IL-8, IL-10, tumor necrosis factor-a, C-reactive
protein (CRP), white blood cells, intracellular adhesion
molecule-1 and vascular cell adhesion molecule-1 were
analyzed using multiplex sandwich enzyme-linked immu-
nosorbent assay. There was a release of both pro- and anti-
inflammatory cytokines during colorectal surgery. The
release of IL-6, IL-10 and CRP was significantly lower in
the laparoscopic group. Rectal surgery causes release of
both pro- and anti-inflammatory cytokines. The inflam-
matory response is lower in laparoscopic rectal surgery as
compared to conventional open surgery. Less tissue trauma
in laparoscopic rectal surgery and/or less peri-operative
bleeding in the laparoscopic cases leads to a lower degree
of inflammatory response.
Keywords Anti-inflammatory cytokines Inflammation
Laparoscopy Pro-inflammatory cytokines Rectal surgery
Erratum to: Memory CD4 T Cell-Mediated Immunity against
Influenza A Virus: More than a Little Helpful
K. Kai McKinstry • Richard W. Dutton •
Susan L. Swain • Tara M. Strutt
Published online: 22 June 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Erratum to: Arch. Immunol. Ther. Exp.
DOI 10.1007/s00005-013-0236-z
In the original publication, the last name of the
corresponding author was inadvertently published as Kai
McKinstry in the affiliation part. The correct name should
read ‘‘K. K. McKinstry’’.
Blood Specimen Biomarkers of Inflammation, Matrix
Degradation, Angiogenesis, and Cardiac Involvement: a Future
Useful Tool in Assessing Clinical Outcomes of COPD Patients
in Clinical Practice?
Sabina Skrgat Kristan
Received: 4 August 2012 / Accepted: 13 May 2013 / Published online: 24 May 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Chronic obstructive pulmonary disease (COPD)
is characterized by airflow limitation that is not fully
reversible; this airflow limitation is both progressive and
associated with an abnormal inflammatory response of the
lung to noxious particles or gasses. COPD is undoubtedly an
umbrella term, and it seems unlikely that all patients with
COPD have the same underlying disease processes; thus,
there is a need for differential treatment of different sub-
groups. A potential solution is to find modifiable biomarkers
that can assist in drug development and distinguish sub-
groups of COPD. With the exception of lung function tests,
there are currently no well-validated biomarkers or surro-
gate endpoints that can be used to establish the efficacy of a
drug for COPD. This article discusses biomarkers of
inflammation (fibrinogen, C-reactive protein, pulmonary
and activation-regulated chemokine/CC-chemokine ligand-
18, serum surfactant protein D, interleukin (IL)-6, IL-8 and
tumor necrosis factor a, complement factor C5a), angio-
genesis factors as a part of the pathogenetic aspect in this
disease (vascular endothelial growth factor, angiogenin, and
IL-8), and matrix degradation biomarkers. Troponin and
natriuretic peptides are presented as biomarkers of cardiac
involvement in the light of COPD comorbidities. Trials
based on research on known clinical variables such as
FEV1, BODE, and 6MWT in combination with biomarkers
from lung and blood specimens will probably clarify part of
the prognosis and natural history of the disease. This will
also represent an additional step in COPD phenotyping and
new treatment possibilities.
Keywords Chronic obstructive pulmonary disease
Biomarkers Angiogenic factors Desmosine
Natriuretic peptides Troponin T Complement
Memory CD4 T Cell-Mediated Immunity against Influenza
A Virus: More than a Little Helpful
K. Kai McKinstry • Richard W. Dutton •
Susan L. Swain • Tara M. Strutt
Received: 1 November 2012 / Accepted: 13 May 2013 / Published online: 25 May 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Recent observations have uncovered multiple
pathways whereby CD4 T cells can contribute to protective
immune responses against microbial threats. Incorporating
the generation of memory CD4 T cells into vaccine strat-
egies thus presents an attractive approach toward
improving immunity against several important human
pathogens, especially those against which antibody
responses alone are inadequate to confer long-term
immunity. Here, we review how memory CD4 T cells
provide protection against influenza viruses. We discuss
the complexities of protective memory CD4 T cell
responses observed in animal models and the potential
challenges of translating these observations into the clinic.
Specifically, we concentrate on how better understanding
of organ-specific heterogeneity of responding cells and
defining multiple correlates of protection might improve
vaccine-generated memory CD4 T cells to better protect
against seasonal, and more importantly, pandemic
influenza.
Keywords Memory T cells Influenza vaccines
Neutralizing antibodies
Mitochondria as Oxidative Signaling Organelles in T-cell
Activation: Physiological Role and Pathological Implications
Marcin M. Kamin´ski • Daniel Ro¨th •
Peter H. Krammer • Karsten Gu¨ low
Received: 28 February 2013 / Accepted: 13 May 2013 / Published online: 9 June 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Early scientific reports limited the cell biological
role of reactive oxygen species (ROS) to the cause of
pathological damage. However, extensive research per-
formed over the last decade led to a wide recognition of
intracellular oxidative/redox signaling as a crucial mecha-
nism of homeostatic regulation. Amongst different cellular
processes known to be influenced by redox signaling, T-cell
activation is one of the most established. Numerous studies
reported an indispensible role for ROS as modulators of
T-cell receptor-induced transcription. Nevertheless, mecha-
nistic details regarding signaling pathways triggered by ROS
are far from being delineated. The nature and interplay
between enzymatic sources involved in the generation of
‘‘oxidative signals’’ are also a matter of ongoing research. In
particular, active participation of the mitochondrial respira-
tory chain as ROS producer constitutes an intriguing issue
with various implications for bioenergetics of activated T
cells as well as for T-cell-mediated pathologies. The aim of
the current review is to address these interesting concepts.
Keywords Reactive oxygen species (ROS)
Complex I (NADH:ubiquinone oxidoreductase)
T-cell receptor (TCR) NF-kappaB (NF-jB)
Glycerol-3-phosphate dehydrogenase (GPD2)
ADP-dependent glucokinase (ADPGK)
Thymoproteasome: Role in Thymic Selection and Clinical
Significance as a Diagnostic Marker for Thymic Epithelial
Tumors
Utano Tomaru • Masanori Kasahara
Received: 31 October 2012 / Accepted: 26 April 2013 / Published online: 7 May 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract The thymoproteasome is a specialized type of
proteasomes expressed exclusively in the thymic cortex. It
has a unique catalytic subunit b5t with unusual enzymatic
activity. The thymoproteasome exhibits lower chymotryp-
sin-like activity than other forms of proteasomes such as
constitutive proteasomes and immunoproteasomes. Its
cleavage specificity appears uniquely suited for the pro-
duction of peptides that mediate positive selection of CD8?
T cells. Similar to major histocompatibility complex mol-
ecules and T/B-cell receptors, the thymoproteasome occurs
only in jawed vertebrates, suggesting that it evolved con-
comitant with the cardinal elements of adaptive immunity.
b5t can be used as a marker in the differential diagnosis of
thymic tumors. It is expressed in most type B and some
type AB thymomas, but not in type A thymoma, thymic
carcinoma, or tumors of non-thymic epithelial origin.
Keywords Thymoproteasomes b5t Thymus
Positive selection Thymoma Thymic carcinoma
Fundamental Immunology of Skin Transplantation and Key
Strategies for Tolerance Induction
Junyi Zhou • Weifeng He • Gaoxing Luo •
Jun Wu
Received: 17 October 2012 / Accepted: 26 April 2013 / Published online: 18 May 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Transplantation of allogeneic or xenogeneic skin
grafts can evoke strong immune responses that lead to acute
rejection of the graft tissues. In this process, donor-derived
dendritic cells play crucial roles in the triggering of such
immune responses. Both the innate and acquired host immune
systems participate in graft rejection. At present, the rejection
of skin grafts cannot be well-controlled by ordinary systemic
immunosuppression therapy. Although several strategies for
the long-term survival of allogeneic or xenogeneic skin grafts
have been demonstrated in animal models, the induction of
long-term tolerance to skin grafts is still a great challenge in
clinical settings. In this article, we review the progress in the
understanding of immune responses to skin grafts and discuss
the possible methods that can decrease the immunogenicity of
graft tissues and improve the survival of skin grafts, especially
those included in preoperative pre-treatments.
Keywords Skin transplantation Immunology
Current Approaches for the Treatment of Autoimmune Hemolytic
Anemia
Jose´ Carlos Jaime-Pe´rez • Marisol Rodrı´guez-Martı´nez •
Andre´s Go´mez-de-Leo´n • Luz Tarı´n-Arzaga •
David Go´mez-Almaguer
Received: 28 September 2012 / Accepted: 26 April 2013 / Published online: 21 May 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Autoimmune hemolytic anemia (AIHA) is an
infrequent group of diseases defined by autoantibody
mediated red blood cell destruction. Correct diagnosis and
classification of this condition are essential to provide
appropriate treatment. AIHA is divided into warm and cold
types according to the characteristics of the autoantibody
involved and by the presence of an underlying or associated
disorder into primary and secondary AIHA. Due to its low
frequency, treatment for AIHA is largely based on small
prospective trials, case series, and empirical observations.
This review describes in detail the different treatment
approaches for autoimmune hemolytic anemia. Warm
antibody type AIHA should be treated with steroids, to
which most patients respond, although relapse can occur
and maintenance doses are frequently required. Splenec-
tomy is an effective second line treatment and can provide
long-term remission without medication. Rituximab is a
useful alternative for steroid refractory patients, those
requiring high maintenance doses and unfavorable candi-
dates for surgery. Promising therapeutic modifications with
this monoclonal antibody are emerging including drug
combinations, lower doses, and long-term use. Primary cold
agglutinin disease has been recognized as having a
lymphoproliferative monoclonal origin. It is unresponsive
to both steroids and splenectomy. Rituximab is currently the
best therapeutic alternative for this condition, and several
treatment regimens are available with variable responses.
Keywords Hemolytic anemia Autoimmune
Cold agglutinin disease Treatment Rituximab
MicroRNAs and Tumor Vasculature Normalization:
Impact on Anti-Tumor Immune Response
Agata Matejuk • Guillaume Collet •
Mahdi Nadim • Catherine Grillon • Claudine Kieda
Received: 20 July 2012 / Accepted: 15 January 2013 / Published online: 11 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Inefficient immune response is a major glitch
during tumor growth and progression. Chaotic and leaky
blood vessels created in the process of angiogenesis allow
tumor cells to escape and extricate anti-cancer immunity.
Proangiogenic characteristics of hypoxic tumor microen-
vironment maintained by low oxygen tension attract
endothelial progenitor cells, drive expansion of cancer stem
cells, and deviantly differentiate monocyte descendants.
Such cellular milieu further boosts immune tolerance and
eventually appoint immunity for cancer advantage. Blood
vessel normalization strategies that equilibrate oxygen
levels within tumor and fix abnormal vasculature bring
exciting promises to future anticancer therapies especially
when combined with conventional chemotherapy.
Recently, a new group of microRNAs (miRs) engaged in
angiogenesis, called angiomiRs and hypoxamiRs, emerged
as new therapeutic targets in cancer. Some of those miRs
were found to efficiently regulate cancer immunity and
their dysregulation efficiently programs aberrant angio-
genesis and cancer metastasis. The present review
highlights new findings in the field of miRs proficiency to
normalize aberrant angiogenesis and to restore anti-tumor
immune responses.
Keywords MicroRNAs regulation Hypoxia
Angiogenesis Cancer Vessels normalization
Tumor immune response
The Regulating Function of Heterotrimeric G Proteins
in the Immune System
Yantang Wang • Yan Li • Guixiu Shi
Received: 18 September 2012 / Accepted: 25 March 2013 / Published online: 7 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Heterotrimeric guanine nucleotide-binding
proteins (G proteins), which consist of an a-, a b– and a
c-subunit, have crucial roles as molecular switches in the
regulation of the downstream effector molecules of multi-
ple G protein-coupled receptor signalling pathways, such
as phospholipase C and adenylyl cyclase. According to the
structural and functional similarities of their a-subunits, G
proteins can be divided into four subfamilies: Gas, Gai/o,
Gaq/11 and Ga12/13. Most of the a– and the bc-subunits
are abundantly expressed on the surface of immune cells.
Recent studies have demonstrated that G proteins are a
group of important immunomodulatory factors that regu-
late the migration, activation, survival, proliferation,
differentiation and cytokine secretion of immune cells. In
this review, we summarise the recent findings on the
functions of G proteins in immune regulation and
autoimmunity.
Keywords G proteins Immune regulation
Lymphocyte development Autoimmune diseases
Structural and Functional Overview of the Lectin Complement
Pathway: Its Molecular Basis and Physiological Implication
Misao Matsushita • Yuichi Endo • Teizo Fujita
Received: 31 July 2012 / Accepted: 25 March 2013 / Published online: 7 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract The complement system is an effector mecha-
nism in immunity. It is activated in three ways, the
classical, alternative and lectin pathways. The lectin path-
way is initiated by the binding of mannose-binding lectin
(MBL) or ficolins to carbohydrates on the surfaces of
pathogens. In humans, MBL and three types of ficolins
(L-ficolin, H-ficolin, and M-ficolin) are present in plasma.
Of these lectins, at least, MBL, L-ficolin, and H-ficolin are
complexed with three types of MBL-associated serine
proteases (MASPs), MASP-1, MASP-2, and MASP-3 and
their truncated proteins (MAp44 and sMAP). In the lectin
pathway, the lectin–MASP complex (i.e., a complex of
lectin, MASPs and their truncated proteins) binds to
pathogens, resulting in the activation of C4 and C2 to
generate a C3 convertase capable of activating C3. MASP-
2 is involved in the activation of C4 and C2. MASP-1
activates C2 and MASP-2. The functions of MASP-3,
sMAP, and MAp44 in the lectin pathway remain unknown.
MASP-1 and MASP-3 also have a role in the alternative
pathway. MBL and ficolins are able to bind to a variety of
pathogens depending on their carbohydrate binding speci-
ficity, resulting in the activation of the lectin pathway.
Deficiencies of the components of the lectin pathway are
associated to susceptibility to infection, indicating an
important role of the lectin pathway in innate immunity.
The lectin-MASP complex is also involved in innate
immunity by activating the coagulation system. Recent
findings suggest a crucial role of MASP-3 in development.
Keywords Complement Lectin pathway
Mannose-binding lectin (MBL)-associated serine protease
(MASP) Ficolin
Inflammatory Markers in Patients after Hematopoietic Stem Cell
Transplantation
Camilla Sjøqvist • Emilian Snarski
Received: 19 June 2012 / Accepted: 25 March 2013 / Published online: 7 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Infections are one of the most common com-
plications after hematopoietic stem cell transplantation
(HSCT). Diagnosis is established by analysis of clinical
symptoms and results of diagnostic tests such as bio-
chemical panels, microbiological cultures, and visual
diagnostics. As the microbiological cultures yield positive
results in only some patients and visual diagnostics might
miss the infectious source, the diagnosis and proper treat-
ment often depends on clinical assessment supported by
laboratory test results. The most commonly used makers of
inflammation include C-reactive protein and procalcitonin.
However, these tests have serious limitations when used in
patients after HSCT. The drugs used in conditioning,
neutropenia, and graft-versus-host disease might influence
the results of the tests and misguide the physician. In this
review, we summarize the current knowledge on profiles of
expression of basic markers of inflammation used in clin-
ical practice in patients after HSCT.
Keywords C-reactive protein Procalcitonin
Hematopoietic stem cell transplantation Infection
Application of Aptamers for Targeted Therapeutics
Partha Ray • Kristi D. Viles • Erin E. Soule •
Rebecca Smock Woodruff
Received: 18 September 2012 / Accepted: 25 March 2013 / Published online: 7 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Aptamers are short, single-stranded oligonu-
cleotides that are isolated through a process termed
systematic evolution of ligands by exponential enrichment.
With the advent of cell-based selection technology, apta-
mers can be selected to bind protein targets that are
expressed on the cell surface. These aptamers demonstrate
excellent specificity and high affinity toward their target
proteins and are often internalized upon binding to their
targets. This has opened up the possibility of using apta-
mers for cell-specific targeted drug delivery. In this review,
we will discuss cell-surface protein targets, the aptamers
that bind them, and their applications for targeted
therapeutics.
Keywords Systematic evolution of ligands by
exponential enrichment (SELEX) Aptamers
Targeted therapy
Radiofrequency Ablation Does Not Induce the Significant Increase
of CD4+CD25+Foxp3+ Regulatory T Cells Compared
with Surgical Resection in Hepal-6 Tumor Model
Heng-Jun Gao • Yao-Jun Zhang • Hui-Hong Liang •
Peng Li • Zhen-Wei Peng • Xiong-Hao Pang •
Min-Shan Chen
Received: 18 August 2012 / Accepted: 25 March 2013 / Published online: 18 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Surgical resection (SR) and radiofrequency
ablation (RFA) are all currently recognized as important
and effective treatment in solid tumors. This study aimed to
investigate change in level of CD4?CD25?Foxp3? regu-
latory T (Treg) cells in tumor-bearing mice after SR vs.
RFA and the relationship of this level with tumor pro-
gression. Hepa1-6 tumor cells were inoculated
subcutaneously into C57BL/6J mice. The population of
Treg cells was measured by flow cytometry at selected
post-SR or post-RFA times. Tumor growth was measured
by rechallenge in the contralateral flank. The tumor volume
was calculated and compared with that of a control group.
The correlation between the population of Treg cells and
tumor volume was analyzed. A significant increase in Treg
cells was observed after SR compared with the preopera-
tive level, while the level after RFA was relatively stable.
A significant difference in tumor growth between the SR
and RFA groups was observed in the initial postoperative
phase but not in the later phase. A correlation was found
between tumor volume and level of Treg cells. Our study
revealed that RFA stabilizes the level of Treg during
postoperative recovery, whereas SR activates the
immunosuppressive reaction by upregulating the level of
such cells, promoting tumor growth.
Keywords Radiofrequency ablation Surgical resection
Tumor progression CD4?CD25?Foxp3? regulatory
T cells Animal model
Are Killer Cell Immunoglobulin-Like Receptor Genes Important
for the Prediction of Kidney Graft Rejection?
Piotr Kus´nierczyk
Received: 29 October 2012 / Accepted: 25 March 2013 / Published online: 4 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Killer cell immunoglobulin-like receptors
(KIRs) are expressed on natural killer cells and minor
subpopulations of thymus-derived (T) lymphocytes. KIRs
may have a long cytoplasmic tail and inhibit cell activation
upon ligand (HLA class I) binding, or they may have a
short cytoplasmic tail and activate a cell after ligand
binding. They are encoded by up to 14 genes present in
different individuals in different combinations, whence
their associations with several human diseases. KIR
involvement in the fate of kidney allograft has not been
extensively studied; nevertheless some associations had
already been noticed. Their results are not concordant:
some authors found no effect of KIR genotype, whereas
others detected protective effect of KIR2DL2/KIR2DS2 or
KIR–KIR ligand mismatch. We found an association of
KIR2DS4 gene with acute rejection and a protective effect
of KIR2DS5 gene. Interestingly, in patients, whose end-
stage renal disease was caused by glomerulonephritis, the
effect of KIR2DS4 was stronger than HLA mismatch,
whereas opposite was true for recipients with other causes
of renal failure.
Keywords Killer immunoglobulin-like receptor
HLA Genetics Kidney graft acute rejection
Glomerulonephritis
Increased cys-Leukotrienes in Exhaled Breath Condensate
and Decrease of PNIF after Intranasal Allergen Challenge
Support the Recognition of Allergic Rhinitis in Children
Wioletta Zago´rska • Katarzyna Grzela •
Marek Kulus • Maciej Sobczyn´ ski • Tomasz Grzela
Received: 20 July 2012 / Accepted: 25 March 2013 / Published online: 7 April 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Exhaled breath condensate (EBC) contains
various mediators of inflammation. Since their concentra-
tions correlate with severity of inflammatory response,
EBC assessment allows non-invasive detection of various
respiratory tract diseases and enables monitoring of their
progression or treatment effectiveness. In this study,
authors evaluate the usefulness of cysteinyl leukotrienes
(cysLT) measurement in EBC, as non-invasive diagnostic
markers of allergic rhinitis in children. It has been found
that the assessment of cysLT in EBC, when performed out
of the natural allergen exposure, can discriminate between
healthy and allergic rhinitis individuals, with sensitivity
87.8 % and specificity 76.4 %, at the threshold level
39.05 pg/ml. The change of peak nasal inspiratory flow
(DPNIF), measured before and after intranasal allergen
challenge allowed recognition of healthy/allergic rhinitis-
suffering individuals with sensitivity 76.8 % and specific-
ity 78.6 %, at the threshold level of –3.2 l/min. When
DPNIF assessment was combined with the measurement of
cysLT in EBC, the sensitivity of such diagnostic approach
reached 100 % and its specificity increased up to 84.6 %.
The proposed algorithm was found to sufficiently dis-
criminate between allergic rhinitis-suffering and healthy
children, however, its clinical usefulness especially in
young children requires further studies.
Keywords Allergic rhinitis Cysteinyl leukotrienes
Exhaled breath condensate Peak nasal inspiratory
flow (PNIF)
Anti-CCL25 Antibody Prolongs Skin Allograft Survival
by Blocking CCR9 Expression and Impairing Splenic
T-Cell Function
Jie Li • Tao Xiong • Ruijing Xiao • Ali Xiong •
Jie Chen • Ehtisham Altaf • Yingcheng Zheng •
Guoguo Zhu • Yuling He • Jinquan Tan
Received: 26 June 2012 / Accepted: 22 February 2013 / Published online: 2 March 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Chemokines, by virtue of their ability to recruit
immune cells into allografts, play critical roles in acute
transplantation rejection. CCR9 and its ligand, CCL25, is
one of the key regulators of thymocyte migration and
maturation in normal and inflammatory conditions. More-
over, several studies have revealed that high expression of
CCR9 and CCL25 participated in many kinds of diseases.
However, the role of CCR9 in allograft rejection is still
unclear. In this study, we established a murine skin trans-
plantation model of acute rejection. Our findings showed
that the proportion of CCR9-expressing T cells was sig-
nificantly increased in the spleen of allotransplanted mice
compared with syngeneic transplantation. Furthermore,
expression of CCL25 in allograft was similarly increased.
Neutralization of CCL25 by intravenous injection of anti-
CCL25 monoclonal antibody significantly prolonged skin
allograft survival, decreased the number of infiltrating
cells, and simultaneously suppressed the chemotactic
ability and the proliferation of the splenic T cells in
response to allogeneic antigens. Finally, blockade of
CCL25 also diminished the secretion of IFN-c by splenic
T cells. These studies indicated that CCR9/CCL25 was
involved in acute transplantation rejection and anti-CCL25
strategies might be useful in preventing acute rejection.
Keywords CCR9 CCL25 Transplantation
Rejection
The Dysfunction of NK Cells in Patients with Type 2 Diabetes
and Colon Cancer
Paweł Pia˛tkiewicz • Tomasz Miłek •
Małgorzata Bernat-Karpin´ ska • Monika Ohams •
Anna Czech • Piotr Ciostek
Received: 6 July 2012 / Accepted: 13 February 2013 / Published online: 2 March 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Glucose metabolism disorders influence anti-
carcinogenic function of natural killer (NK) cells. The aim
of this study was to evaluate the number and cytotoxic
activity of NK cells in type 2 diabetic (T2D) patients with
negative family history of cancer, type 2 diabetic subjects
with newly diagnosed untreated colon cancer (T2DCC) and
patients without type 2 diabetes with newly diagnosed,
untreated colon cancer (CC). Incubation tests were per-
formed in 18 T2D patients, treated with diet and oral
antidiabetic agents, 16 T2DCC; cT1-4N0M0 (c-clinical
diagnosis based on computed tomography, colonoscopy
and histopathology) treated with diet and oral antidiabetic
agents and 16 normoglycemic CC; cT1-4N0M0. Control
group included 18 metabolically healthy (with normal
fasting glucose and normal glucose tolerance) subjects
(HS) with negative family history of cancer, matched by
age, BMI and waist circumference. Peripheral blood
mononuclear cells were isolated by means of gradient
centrifugation. The K562 human erythroleukemia cell line
served as the standard target for human NK cytotoxicity
assay. The T2D revealed an increased number of NK cells
(13.56 ± 5.9 vs 9.50 ± 4.8 %; p \ 0.05) when compared
with HS, yet these cells had a decreased activity (3.3 ± 2.5
vs 9.4 ± 3.6 %; p \ 0.01). The CC demonstrated a
decreased activity (2.9 ± 1.8 %; p \ 0.01) but a similar
number (8.82 ± 3.7 %; not significant) of NK cells when
compared to HS. The T2DCC NK cells were characterized
by trace cytotoxic activity (1.1 ± 0.7 %; p \ 0.01) and
nearly three times greater amount (21.24 ± 7.5 %;
p \ 0.01) when compared to T2D. Type 2 diabetes and CC
are associated with disadvantageous alterations of NK
cells, leading to impairment in their cytotoxic activity. The
impaired activity of NK cells in T2D can be involved in the
increased carcinogenic risk and can promote a higher
incidence of CC.
Keywords NK cells Diabetes Colon cancer
GSL-Enriched Membrane Microdomains in Innate Immune
Responses
Hitoshi Nakayama • Hideoki Ogawa •
Kenji Takamori • Kazuhisa Iwabuchi
Received: 10 July 2012 / Accepted: 13 February 2013 / Published online: 28 February 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Many pathogens target glycosphingolipids
(GSLs), which, together with cholesterol, GPI-anchored
proteins, and various signaling molecules, cluster on host
cell membranes to form GSL-enriched membrane micro-
domains (lipid rafts). These GSL-enriched membrane
microdomains may therefore be involved in host–pathogen
interactions. Innate immune responses are triggered by the
association of pathogens with phagocytes, such as neutro-
phils, macrophages and dendritic cells. Phagocytes express
a diverse array of pattern-recognition receptors (PRRs),
which sense invading microorganisms and trigger patho-
gen-specific signaling. PRRs can recognize highly
conserved pathogen-associated molecular patterns expres-
sed on microorganisms. The GSL lactosylceramide
(LacCer, CDw17), which binds to various microorganisms,
including Candida albicans, is expressed predominantly on
the plasma membranes of human mature neutrophils and
forms membrane microdomains together with the Src
family tyrosine kinase Lyn. These LacCer-enriched mem-
brane microdomains can mediate superoxide generation,
migration, and phagocytosis, indicating that LacCer func-
tions as a PRR in innate immunity. Moreover, the
interactions of GSL-enriched membrane microdomains
with membrane proteins, such as growth factor receptors,
are important in mediating the physiological properties of
these proteins. Similarly, we recently found that interac-
tions between LacCer-enriched membrane microdomains
and CD11b/CD18 (Mac-1, CR3, or aMb2-integrin) are
significant for neutrophil phagocytosis of non-opsonized
microorganisms. This review describes the functional role
of LacCer-enriched membrane microdomains and their
interactions with CD11b/CD18.
Keywords Membrane microdomain Lactosylceramide
Innate immunity Integrin Src family kinase
Toll-Like Receptors in Human Papillomavirus Infection
Qiang Zhou • Kejian Zhu • Hao Cheng
Received: 18 April 2012 / Accepted: 13 February 2013 / Published online: 24 February 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Infection with human papillomaviruses (HPVs)
often causes cutaneous benign lesions, cervical cancer, and
a number of other tumors. The mechanisms of host immune
system to prevent and control HPV infection still remain
poorly understood. Toll-like receptors (TLRs) are specific
pattern recognition molecules that bind to microbial com-
ponents to trigger innate immunity and direct adaptive
immunity in the face of immunological danger. TLRs have
been established to play an essential role in sensing and
initiating antiviral immune responses. Recent accumulating
evidence demonstrated that HPVs modulate TLR expres-
sion and interfere with TLR signaling pathways, leading to
persistent viral infection and carcinogenesis. This review
summarizes current knowledge on the roles of TLR during
HPV infection, focusing on TLR recognition, modulation
of TLR expression and signaling, regulatory receptors
involved in TLR signaling, and cross-talk of TLRs with
antimicrobial peptides. Immunotherapeutic strategies based
on TLR agonists have emerged to be one of the novel
promising avenues in treatment of HPV-associated diseases
in the future.
Keywords TLR HPV Innate immunity
Adaptive immunity TLR agonist
Immune Exhaustion and Immune Senescence: Two Distinct
Pathways for HBV Vaccine Failure During HCV and/or HIV
Infection
Zhi Q. Yao • Jonathan P. Moorman
Received: 25 September 2012 / Accepted: 1 February 2013 / Published online: 12 February 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Given the shared risk factors for transmission,
co-infection of hepatitis B virus (HBV) with hepatitis C
virus (HCV) and/or human immunodeficiency virus (HIV)
is quite common, and may lead to increases in morbidity
and mortality. As such, HBV vaccine is recommended as
the primary means to prevent HBV super-infection in
HCV- and/or HIV-infected individuals. However, vaccine
response (sero-conversion with a hepatitis B surface anti-
body titer [10 IU/L) in this setting is often blunted, with
poor response rates to standard HBV vaccinations in virally
infected individuals when compared with the healthy sub-
jects. This phenomenon also occurs to other vaccines in
adults, such as pneumococcal and influenza vaccines, in
other immunocompromised hosts who are really at risk for
opportunistic infections, such as individuals with hemodi-
alysis, transplant, and malignancy. In this review, we
summarize the underlying mechanisms involving vaccine
failure in these conditions, focusing on immune exhaustion
and immune senescence—two distinct signaling pathways
regulating cell function and fate. We raise the possibility
that blocking these negative signaling pathways might
improve success rates of immunizations in the setting of
chronic viral infection.
Keywords Immune exhaustion Immune senescence
HCV HIV HBV vaccine response
The Novel Roles of Neutrophils Via Opioid Peptides: Regulation
of the Estrous Cycle and Pain
Yoshiro Kobayashi
Received: 21 August 2012 / Accepted: 1 February 2013 / Published online: 12 February 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Neutrophils are excreted into the vaginal vault
at metestrus during the estrous cycle, and this phenomenon
has long been used to determine the phase of the estrous
cycle. A much smaller number of neutrophils are also
detected in the uterus and the ovary. Recently, we provided
several lines of evidence supporting the notion that neu-
trophils infiltrate into the ovary to regulate the estrous cycle
by opioid peptides. Upon inflammation, on the other hand,
neutrophils infiltrate into the site of infection to suppress
pain by opioid peptides. Thus, opioid peptides are key
molecules by which neutrophils play a novel role in reg-
ulation of the pain and estrous cycle. In both cases, opioid
peptides appear to be secreted by neutrophils stimulated
with chemokines, such as MIP-2 and KC in mouse, corti-
cotropin-releasing hormone and IL-1.
Keywords Neutrophils Opioid peptides Estrous cycle
Pain
Human T Regulatory Cells: On the Way to Cognition
Maciej Kaczorowski • Marek Jutel
Received: 25 July 2012 / Accepted: 1 February 2013 / Published online: 28 March 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Forkhead box P3 (Foxp3)? T regulatory (Treg)
cells are powerful controllers of the immune response and
their role in the human immune system is indispensable.
Since a number of revolutionary and very convincing
results were brought to light, Foxp3 has unquestionably
been thought to be the ‘‘master regulator’’ of Treg lineage
commitment. Herein, we depict the revised view on the
role of Foxp3 transcription factor, challenging this theory,
as well as the growing significance of Runt-related tran-
scription factor (RUNX) family proteins for Treg lineage.
The review presents the current notion of Treg cell heter-
ogeneity, molecular characteristics and their mechanisms
of action.
Keywords T regulatory cells Foxp3
Treg immunophenotype RUNX
Impact of Microbes on Autoimmune Diseases
Claudia Danzer • Jochen Mattner
Received: 11 July 2012 / Accepted: 1 February 2013 / Published online: 16 February 2013
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract Autoimmune and autoinflammatory diseases arise
as a consequence of complex interactions of environmental
factors with genetic traits. Although specific allelic variations
cluster in predisposed individuals and promote the generation
and/or expansion of autoreactive T and B lymphocytes, auto-
immunity appears in various disease phenotypes and localizes to
diverging tissues. Furthermore, the discovery that allelic varia-
tions within genes encoding components of the innate immune
system drive self-reactive immune responses as well, led to the
distinction of immune responses against host tissues into auto-
immune and autoinflammatory diseases. In both categories of
disorders, different pathogenic mechanisms and/or subsequent
orders of tissue assaults may underlie the target cell specificity of
the respective autoimmune attack. Furthermore, the transition
from the initial tissue assault to the development of full-blown
disease is likely driven by several factors. Thus, the develop-
ment of specific forms of autoimmunity and autoinflammation
reflects a multi-factorial process. The delineation of the specific
factors involved in the pathogenic process is hampered by the
fact that certain symptoms are assembled under the umbrella of a
specific disease, although they might originate from diverging
pathogenic pathways. These multi-factorial triggers and patho-
genic pathways may also explain the inter-individual divergent
courses and outcomes of diseases among humans. Here, we will
discuss the impact of different environmental factors in general
and microbial pathogens in particular on the regulation/
expression of genes encoded within susceptibility alleles, and its
consequences on subsequent autoimmune and/or autoinflam-
matory tissue damage utilizing primarily the chronic cholestatic
liver disease primary biliary cirrhosis as model.
Keywords Autoimmunity Autoinflammation
Genetic susceptibility Infection
Host–pathogen interactions