Identification of Clinicopathological Spectrum, Platelet Glycoprotein IIb/IIIa complex and Platelet Antibodies in Egyptian Children with Glanzmann’s Thrombasthenia
Asmaa M. Zahran · Khaled Saad · Khalid I. Elsayh · Mohamd A. Alblihed · Mostafa Embaby
Abstract Glanzmann’s thrombasthenia (GT) is a rare genetic bleeding disorder. The aim of our study was to evaluate the clinicopathological spectrum of this syndrome and to study the platelet glycoprotein IIb/IIIa complex and platelet antibodies by flow cytometry in a cohort of children with GT in a tertiary care center in Upper Egypt. Forty children with GT were assessed for the expression of GPIIb-IIIa on the platelet surface and platelet antibodies by using flow cytometry, to determine the most common GT subtypes among Egyptian children. By analysis of platelet GP IIb-IIIa by flow cytometry the classification of patients with GT in our study was type I GT (47.5%), type II GT (32.5%) and type III GT (20%). In this study, we have delineated that type I is the most common type of GT in Upper Egypt. Our data suggested that there is a good correlation between quantitative changes in the surface expression of platelet membrane glycoproteins detected by flow cytometry and the clinical severity of bleeding. Therefore, classifying of severity of bleeding in patients with GT could possibly aid the pediatricians and hematologists in the implementation of ideal prophylactic measures.
Keywords Glanzmann’s thrombasthenia · Platelet glycoprotein GPIIb-IIIa complex · Flow cytometry · Children
Sildenafil, a Phosphodiesterase Type 5 Inhibitor, Downregulates Osteopontin in Human Peripheral Blood Mononuclear Cells
Beata Kaleta · Agnieszka Boguska
Abstract The aim of this study was to investigate the ability of sildenafil to regulate osteopontin (OPN) gene and protein in peripheral blood mononuclear cells (PBMCs) from healthy blood donors. OPN is expressed by a wide variety of cell types, including immune cells. OPN functions are linked to various physiological and pathological conditions. Sildenafil is a selective inhibitor of type 5 phosphodiesterase. Sildenafil has recently been found to have immunomodulatory effects in animal models and in studies performed in humans. PMA-stimulated and unstimulated PBMCs from 16 healthy blood donors (men) were cultured with sildenafil (at concentrations of 400 ng/ml and 4 μg/ml). OPN level in culture supernatants was measured by enzyme-linked immunosorbent assay. The analysis of OPN gene expression was performed by real-time PCR. Cell viability was assessed by trypan blue staining. PMA plus ionomycin stimulation of PBMCs resulted in a significant increase of OPN production and gene expression (p < 0.001). Sildenafil significantly decreased OPN secretion (p < 0.05) and gene expression (p < 0.05) in stimulated PBMCs; however, had no effect on OPN in unstimulated PBMCs. Sildenafil did not affect PBMCs viability. Sildenafil downregulates OPN in PBMCs from healthy men. Despite accumulating evidence for the immunomodulatory effects of sildenafil on human immune system cells, further studies are needed to determine if this drug affects the level of cGMP and NF-κB in PBMCs. In addition, it is needed to evaluate sildenafil’s activity in PBMCs from patients with elevated OPN levels.
Keywords Osteopontin · PDE5 inhibitor · Sildenafil · Immune response · Peripheral blood mononuclear cell
Neuronal Differentiation Capability of Nasal Polyps of Chronic
Rhinosinusitis
Michael Koennecke1 · Robert Böscke1 · Ann‑Christin Pfannerstill1 · Stefan Reers1 ·
Martina Elsner2 · Benjamin Fell2 · Anja Richter2 · Karl‑Ludwig Bruchhage1 ·
Sandra Schumann2 · Ralph Pries1 · Ludger Klimek3 · Barbara Wollenberg
Abstract Chronic rhinosinusitis with nasal polyps is con-
sidered a subgroup of chronic rhinosinusitis and a signifi-
cant health problem, but the pathogenesis remains unclear
to date. Therefore, we investigated the stemness to deter-
mine the role of stem cells in nasal polyps, with additional
analysis of the neuronal differentiation potential of nasal
polyp cells. We determined gene and protein expression
profiles of stem cells in nasal polyp tissues, using whole
genome microarray, quantitative real-time PCR (qPCR),
immunohistochemistry, and flow cytometry. To evaluate
the neuronal differentiation potential of nasal polyp cells,
we used an efficient xenogeneic co-culture model with
unsliced adult rat brain biopsies, followed by qPCR, immu-
nohistochemistry, and growth factor antibody arrays. Dur-
ing gene expression analysis and immunohistochemistry,
we were able to detect different stem cell markers, like Oct-
4, Sox2, Klf4, c-Myc, ABCG2, Nanog, CD133, and Nestin,
which confirmed the existence of stem cell like cells within
nasal polyps. In addition, co-culture experiments give evi-
dence for a guided differentiation into the neuronal lineage
by overexpression of Nestin, Neurofilament, and GM-CSF.
Our study demonstrated the expression of stem cell-related
markers in nasal polyps. Furthermore, we characterized,
for the first time, the stemness and neuronal differentiation
potential of nasal polyp cells. These results gave new
insights into the pathogenesis of nasal polyps and its thera-
peutic effectiveness could represent a promising strategy in
the future.
Keywords Chronic rhinosinusitis with nasal polyps ·
Nasal polyps · Stem cells · Neuronal differentiation
Pre-Pregnancy Levels of Peripheral Natural Killer Cells
as Markers for Immunomodulatory Treatment in Patients
with Recurrent Miscarriage
Ruben J. Kuon1 · Franziska Müller1 · Kilian Vomstein1 · Maja Weber2 ·
Hannes Hudalla3,4 · Sabine Rösner1 · Thomas Strowitzki1 · Udo Markert2 ·
Volker Daniel5 · Bettina Toth
Abstract Immunological risk factors in patients with
recurrent miscarriage (RM) are discussed controversially.
Abnormalities of natural killer cells (NK) have been
described in RM patients. Lipid infusions are known to
modulate lymphocyte subsets. The aim of this study was to
identify immune parameters that predict success of treat-
ment with lipid infusions in RM patients with elevated
NK. In sum, n = 341 couples with RM were screened for
established risk factors and peripheral lymphocyte sub-
populations as well as uterine NK cells. We identified
n = 136 patients with ≥ 2 consecutive RM and elevated
NK. So far, n = 40 RM patients with NK disorders were
treated with lipid infusions starting at positive pregnancy
test, every 2 weeks until 12 + 0 weeks of gestation (GW)
or miscarriage. The pre-pregnancy immune diagnostics
in idiopathic RM (iRM) patients with ongoing pregnancy
were compared to the group with miscarriages and healthy
controls (n = 15). Pre-pregnancy immune diagnostics dif-
fered significantly between the groups, with significant
higher levels of peripheral NK (% and /μL) in iRM patients
who miscarried again compared to controls (p = 0.0035
and p = 0.0019). Furthermore, iRM patients show lower
percentages of CD3+ lymphocytes than healthy controls
(p = 0.0049). In n = 22/40 (55%) patients, pregnancy is
ongoing >12 + 0 GW. RM patients with very high pre-preg-
nancy peripheral NK (pNK) lymphocytes might not benefit
from lipid infusions. Pre-pregnancy immunomodulatory
treatment in RM patients might be helpful to lower pNK
levels and establish an immune environment which is sup-
portive for fetal development.
Keywords Recurrent miscarriage · Natural killer cells ·
Lipid infusion · Immune diagnostics
Effects of IFN-β1a and IFN-β1b treatment on the expression
of cytokines, inducible NOS (NOS type II), and myelin proteins
in animal model of multiple sclerosis
Natalia Lubina-Dąbrowska1,5 · Adam Stepień1 · Grzegorz Sulkowski2 ·
Beata Dąbrowska-Bouta2 · Józef Langfort3,4 · Małgorzata Chalimoniuk5
Abstract The aim of this study was to investigate the
effects of interferon (IFN)-β1a and IFN-β1b treatment on
inflammatory factors and myelin protein levels in the brain
cortex of the Lewis rat experimental autoimmune encepha-
lomyelitis (EAE), animal model of multiple sclerosis. To
induce EAE, rat were immunized with inoculums contain-
ing spinal cord guinea pig homogenized in phosphate-buff-
ered saline and emulsified in Freund’s complete adjuvant
containing 110 μg of the appropriate antigen in 100 μl of
an emulsion and additionally 4-mg/ml Mycobacterium
tuberculosis (H37Ra). The rats were treated three times
per week with subcutaneous applications of 300,000 units
IFN-β1a or IFN-β1b. The treatments were started 8 days
prior to immunization and continued until day 14 after
immunization. The rats were killed on the 14th day of the
experiment. EAE induced dramatic increase in interleukin
(IL)-1β, IL-6, and tumor necrosis factor (TNF)-concentra-
tions and inducible nitric oxide synthase (iNOS) expression
in the brain, which closely corresponded to the course of
neurological symptoms and the loss of weight. Both IFN-
β1b and IFN-β1a treatments inhibited the pro-inflammatory
cytokines (IL-6, IL-1β, TNF-α and IFN-γ), decreased the
activation of astrocytes, increased the myelin protein level
in the brain cortex, and improved the neurological status of
EAE rats by different mechanisms; IFN-β1a reduced iNOS
expression, at least in part, by the enhancement of IL-10,
while IFN-β1b diminished IL-10 concentration and did not
decrease EAE-induced iNOS expression.
Keywords Interferon beta · Cytokines · Inducible nitric
oxide synthase · EAE
Perillyl alcohol, a pleiotropic natural compound suitable for brain
tumor therapy, targets free radicals
Aline C. Gomes1 · Angélica L. Mello1 · Manuel G. Ribeiro1 · Diogo G. Garcia2 ·
Clovis O. Da Fonseca3 · Marcela D’Alincourt Salazar4 · Axel H. Schönthal5 ·
Thereza Quirico‑Santos1
Abstract Monoterpenes such as limonene and perillyl
alcohol (POH) are promising natural compounds with pro-
oxidant properties partly due to endoplasmic reticulum
(ER) stress-induced cytotoxicity, and antioxidant activity
owing to their activity as free radical scavengers, inhibi-
tion of coenzyme Q synthesis, activation of antioxidant-
responsive elements (inducing detoxification enzymes) and
induction of apoptosis. Activation of ER-stress responses
generates reactive oxygen species (ROS), which are highly
reactive free radicals mainly produced during mitochon-
drial electron transfer for adenosine triphosphate (ATP)
synthesis. When cells are subjected to oxidative stress con-
ditions, there is an accumulation of ROS that can lead to
irreversible cell injury caused primarily by lipid peroxida-
tion, protein aggregation and/or DNA damage. Malignant
tumors, such as glioblastoma multiforme, display elevated
rates of oxygen consumption, necrosis and abnormal struc-
tural microvasculature. Alterations in the tumor microenvi-
ronment are tightly linked to tumor progression and occur
as a result of activation of complex signaling networks
involving inter-clonal cooperation, cell–matrix interactions
and an ongoing inflammatory response leading to genetic
and epigenetic alterations. This review will focus on the
pro- and anti-oxidant activities of POH, which are greatly
dependent on the respective ROS levels within the tumor
microenvironment and involve the ER stress response sys-
tem. As well, some critical aspects of tumor-associated
metabolic changes and the consequences of endogenous
ROS production for tumor progression will be discussed.
Keywords Reactive oxygen species · Hypoxia · Perillyl
alcohol · Tumor microenvironment
The transplantation of mesenchymal stem cells derived
from unconventional sources: an innovative approach to multiple
sclerosis therapy
Sabrina Giacoppo1 · Placido Bramanti1 · Emanuela Mazzon1
Abstract In recent years, in the effort to find a potential
innovative therapy for multiple sclerosis (MS), research-
ers focused on transplantation of mesenchymal stem cells
(MSCs) due to their well-recognized ability to suppress
inflammatory/autoimmune responses and exert neurore-
generative properties. MSCs are a heterogeneous subset
of pluripotent non-hematopoietic stromal cells that can be
isolated from many different adult tissues, characterized by
the capability to differentiate into various cell lineages, and
to translocate into damaged areas, providing immunomodu-
latory effects. To date, several encouraging results were
obtained mainly from the use of MSCs derived from the
bone marrow (BM-MSCs) in experimental models of MS
as well as in clinical trials. However, their use in clinic is
limited due to the invasive collecting procedure and the low
yield of viable stem cells. Consequently, these restrictions
have prompted researchers to look for alternative tissue
sources for stem cells such as adipose tissue, fetal annexes,
and dental tissues that could represent a novel therapeutic
option for MS treatment. Here, we provide an overview of
the current knowledge about the most explored BM-MSCs
in MS treatment in experimental and clinical studies. More-
over, we propose that unconventional sources of stem cells,
which show characteristics similar to that of BM-MSCs,
and being less invasive for removal, could be considered
an excellent alternative to BM-MSCs and thus could be a
promising innovative approach for MS treatment
Keywords Multiple sclerosis · Mesenchymal stem cells ·
Bone marrow · Adipose tissue · Fetal annexes · Dental
tissues
CD1: A Singed Cat of the Three Antigen Presentation Systems
Radoslaw Kaczmarek1 · Mariola Pasciak2 · Katarzyna Szymczak‑Kulus1 ·
Marcin Czerwinski1,3
Abstract Contrary to general view that the MHC Class I
and II are the kapellmeisters of recognition and response to
antigens, there is another big player in that part of immu-
nity, represented by CD1 glycoproteins. In contrast to
MHC Class I or II, which present peptides, CD1 molecules
present lipids. Humans express five CD1 proteins (CD1a-
e), four of which (CD1a-d) are trafficked to the cell surface,
where they may display lipid antigens to T-cell receptors.
This interaction may lead to both non-cognate and cognate
T cell help to B cells, the latter eliciting anti-lipid antibody
response. All CD1 proteins can bind a broad range of struc-
turally different exogenous and endogenous lipids, but each
shows a preference to one or more lipid classes. This unor-
thodox binding behavior is the result of elaborate architec-
tures of CD1 binding clefts and distinct intracellular traf-
ficking routes. Together, these features make CD1 system
a versatile player in immune response, sitting at the cross-
roads of innate and adaptive immunity. While CD1 system
may be involved in numerous infectious, inflammatory, and
autoimmune diseases, its involvement may lead to oppo-
site outcomes depending on different pathologies. Despite
these ambiguities and complexity, CD1 system draws
growing attention and continues to show glimmers of thera-
peutic potential. In this review, we summarize the current
knowledge about CD1 proteins, their structures, lipid-bind-
ing profiles, and roles in immunity, and evaluate the role of
CD1 proteins in eliciting humoral immune response.
Keywords CD1 proteins · Antigen presentation · iNKT
cells · Glycosphingolipids
Tumor-Associated Macrophages and Regulatory T Cells
Infiltration and the Clinical Outcome in Colorectal Cancer
Dariusz Waniczek1 · Zbigniew Lorenc2 · Mirosław Śnietura3 · Mariusz Wesecki2 ·
Agnieszka Kopec3 · Małgorzata Muc–Wierzgoń4
Abstract The aim of the study is the assessment of
the intensity of the infiltration of tumor-associated mac-
rophages (TAMs) CD68+/iNOS− and Tregs CD8+/FoxP3+
in colorectal cancer (CRC) patients as prognostic fac-
tors with respect to disease-free survival (DFS) and over-
all survival (OS). In this retrospective study, tissue sam-
ples were obtained from 89 patients undergoing resection
for CRC (stage IIA, pT3N0M0 and stages IIIB and IIIC,
pT3N1-2M0). Recurrence was observed in 45 patients at
the time of the follow-up (10 local recurrences, 35 distant
metastases). In patients with recurrence the following were
present: a tendency to an older average age at the time of
diagnosis (p = 0.07), higher nodal involvement (p = 0.002)
and more advanced clinical disease (p = 0.01). The analy-
sis of the clinical data and immunohistochemical studies
were performed with the methodology of identification of
TAM and Treg subsets in histological sections, with the
aim to use it in routine clinical management. Both DSF
and OS were the clinical parameters assessed in the study.
The presence of intense infiltration of TAMs in the tumor
stroma was related to shorter DFS (p = 0.005) and OS
(p = 0.006). The opposite tendency was observed in the
tumor front (p = 0.061). The relative risks of recurrence
and cancer-related death were more than twice higher in
the group of patients with intense infiltration of TAMs in
the tumor stroma (RR 2.05, 95% CI 1.33–3.14; p = 0.001
and RR 2.08, 95% CI 1.28–3.39; p = 0.003, respectively).
Intense infiltration of Tregs in the tumor stroma was related
to shorter DFS and OS (p < 0.0001). The relative risks of
recurrence and death in a group of patients with intense
infiltration of Tregs in the tumor stroma were more than 12
times higher than in patients with less intense infiltration
(RR 12.3, 95% CI 5.44–27.9; p < 0.0001 and RR 12.5, 95%
CI 4.9–32.4; p < 0.0001, respectively). Infiltration of TAMs
CD68+/iNOS− and Tregs CD8+/FoxP3+ in the tumor
stroma are negative prognostic factors with a positive cor-
relation between them. Tregs may constitute an independ-
ent prognostic factor in patients with CRC.
Keywords Tumor-associated macrophages · TAMs ·
Tregs · Regulatory lymphocytes · Colorectal cancer
Human Gyrovirus-Apoptin Interferes with the Cell Cycle
and Induces G2/M Arrest Prior to Apoptosis
Wiem Chaabane1 · Saeid Ghavami2,3 · Andrzej Małecki4 · Marek J. Łos5
Abstract The human gyrovirus-Apoptin (HGyv-Apoptin)
is a protein that gained attention because it is selectively
cytotoxic toward cancer cells. In this study, we have investi-
gated the effect of HGyv-Apoptin on cell cycle progression
of cancer cells. We also compared HGyv-Apoptin’s action
to its homologue chicken anemia virus Apoptin (CAV-
Apoptin). We show that HGyv-Apoptin induces G2/M
arrest in cancer cells. This is at least in part due to the fact
that HGyv-Apoptin induces an abnormal spindle formation
in mitotic cells that do not progress properly throughout the
cell cycle. HGyv-Apoptin most likely inhibits APC func-
tion leading to a sustained cyclin-B1-expression. These
results indicate that HGyv-Apoptin has a similar mecha-
nism of action as its homolog CAV-Apoptin and further
supports its cancer therapeutic potential.
Keywords Apoptin · PKTCs · Cell cycle · APC · Cyclin
B1
Evaluation of Endothelial Function by Flow-Mediated Dilation:
a Comprehensive Review in Rheumatic Disease
Luca Moroni1,2 · Carlo Selmi3,4 · Claudio Angelini5 · Pier Luigi Meroni4,6
Abstract Flow-mediated dilation (FMD) represents a
non-invasive marker of endothelial function to evaluate
vascular homeostasis, which reflects the effects of several
mechanisms, including vessel tone regulation, cell prolif-
eration, and inflammatory responses. Beyond classical ath-
erosclerotic risk factors such as arterial hypertension, dia-
betes mellitus, smoking, obesity, and dyslipidemia, chronic
inflammation contributes to the endothelial dysfunction
causing plaque formation and there is growing evidence
of a significantly higher cardiovascular morbidity associ-
ated with autoimmune diseases. The endothelium reacts
to several endogenous and exogenous stimuli, through
surface receptors and intracellular signalling, and releases
numerous vasoactive substances, including endothelins,
prostacyclins, and nitric oxide (NO). Chronic inflamma-
tory rheumatic diseases are commonly associated with
decreased endothelial NO production, vascular damage,
and premature atherosclerosis. Despite partially eclipsed by
pulse wave velocity measure in the modern scientific litera-
ture, we provide a comprehensive overview and critically
discuss the available data supporting FMD as a surrogate
marker of endothelial function and, therefore, its poten-
tial role in predicting early atherosclerosis in patients with
rheumatic diseases.
Keywords Cardiovascular risk · Chronic inflammation ·
Rheumatoid arthritis · Psoriatic arthritis · Connective tissue
disease · Autoantibody
Expanding Diversity and Common Goal of Regulatory T and B
Cells. I: Origin, Phenotype, Mechanisms
Katarzyna Bocian1 • Ewelina Kiernozek1 • Joanna Domagała-Kulawik2 •
Gra_zyna Korczak-Kowalska1,4 • Anna Stelmaszczyk-Emmel3 • Nadzieja Drela
Abstract Immunosuppressive activity of regulatory T and
B cells is critical to limit autoimmunity, excessive
inflammation, and pathological immune response to con-
ventional antigens or allergens. Both types of regulatory
cells are intensively investigated, however, their develop-
ment and mechanisms of action are still not completely
understood. Both T and B regulatory cells represent highly
differentiated populations in terms of phenotypes and ori-
gin, however, they use similar mechanisms of action. The
most investigated CD4?CD25? regulatory T cells are
characterized by the expression of Foxp3? transcription
factor, which is not sufficient to maintain their lineage
stability and suppressive function. Currently, it is consid-
ered that specific epigenetic changes are critical for
defining regulatory T cell stability in the context of their
suppressive function. It is not yet known if similar epige-
netic regulation determines development, lineage stability,
and function of regulatory B cells. Phenotype diversity,
confirmed or hypothetical developmental pathways, mul-
tiple mechanisms of action, and role of epigenetic changes
in these processes are the subject of this review.
Keywords Regulatory B cell Regulatory T cell
Immunosuppression Epigenetics
The Potential Role of Kru¨ ppel-Like Zinc-Finger Protein Glis3
in Genetic Diseases and Cancers
Chon-Kit Chou1,2 • Chin-Ju Tang2 • Han-Lin Chou2 • Chun-Yen Liu2 •
Ming-Chong Ng2 • Yu-Ting Chang2 • Shyng-Shiou F. Yuan4 • Eing-Mei Tsai5 •
Chien-Chih Chiu2,3,4,5
Abstract Gli-similar 3 (Glis3) belongs to a Glis subfamily
of Kru¨ppel-like zinc-finger transcription factors character-
ized to regulate a set of downstream targets essential for
cellular functions, including pancreatic development, b–
cell maturation and maintenance, and insulin production.
Examination of the DNA-binding domain of Glis3 reveals
that this domain contains a repeated cysteine 2/histidine 2
(Cys2/His2) zinc-finger motif in the central region where
the recognized DNA sequence binds. The loss of the pro-
duction of pancreatic hormones, such as insulin 1 and 2, is
linked to the down-regulation of b cells-related genes and
promotes the apoptotic death of b cells found in mutant
Glis3. Although accumulating studies converge on the
Glis3 functioning in b cells, recently, there have been
developments in the field of Glis3 using knockdown/mu-
tant mice to better understand the role of Glis3 in diseases.
The Glis3 mutant mice have been characterized for their
propensity to develop congenital hypothyroidism, poly-
cystic kidney disease, and some types of cancer. In this
review, we attempt to comprehensively summarize the
knowledge of Glis3, including its structure and general
function in cells. We also collected and organized the
academic achievements related to the possible mechanisms
of Glis3-related diseases.
Keywords Glis3 Diabetes mellitus
Cys2/His2 zinc-finger domains
Congenital hypothyroidism Polycystic kidney disease
Cancer
Expanding Diversity and Common Goal of Regulatory T and B
Cells. II: In Allergy, Malignancy, and Transplantation
Gra_zyna Korczak-Kowalska1,4 • Anna Stelmaszczyk-Emmel3 • Katarzyna Bocian1 •
Ewelina Kiernozek1 • Nadzieja Drela1 • Joanna Domagała-Kulawik2
Abstract Regulation of immune response was found to
play an important role in the course of many diseases such
as autoimmune diseases, allergy, malignancy, organ
transplantation. The studies on immune regulation focus on
the role of regulatory cells (Tregs, Bregs, regulatory
myeloid cells) in these disorders. The number and function
of Tregs may serve as a marker of disease activity. As in
allergy, the depletion of Tregs is observed and the results
of allergen-specific immunotherapy could be measured by
an increase in the population of IL-10? regulatory cells. On
the basis of the knowledge of anti-cancer immune response
regulation, new directions in therapy of tumors are intro-
duced. As the proportion of regulatory cells is increased in
the course of neoplasm, the therapeutic action is directed at
their inhibition. The depletion of Tregs may be also
achieved by an anti-check-point blockade, anti-CD25
agents, and inhibition of regulatory cell recruitment to the
tumor site by affecting chemokine pathways. However, the
possible favorable role of Tregs in cancer development is
considered and the plasticity of immune regulation should
be taken into account. The new promising direction of the
treatment based on regulatory cells is the prevention of
transplant rejection. A different way of production and
implementation of classic Tregs as well as other cell types
such as double-negative cells, Bregs, CD4? Tr1 cells are
tested in ongoing trials. On the basis of the results of
current studies, we could show in this review the signifi-
cance of therapies based on regulatory cells in different
disorders.
Keywords Regulatory T cell Regulatory B cell
Allergy Cancer Transplantology Myeloid cells
The Immune Response in Periodontal Tissues
Małgorzata Ne˛dzi-Go´ra1 • Jan Kowalski1 • Renata Go´rska1
Abstract The uniqueness of periodontal diseases is caused
by several factors. This group of diseases is caused by
numerous bacterial species formed in the dental biofilm,
and one cannot distinguish the specific pathogen that is
responsible for the disease initiation or progress (though
Gram-negative anaerobic rods are associated with the
advanced form of the disease). The disease is both infec-
tious and inflammatory in its nature, and in the state of
health there is always a subclinical level of inflammatory
response, caused by the so-called harmless bacteria. Neg-
ligence in oral hygiene may result in maturation of the
biofilm and trigger host response, manifesting clinically as
gingivitis or—later and in susceptible subjects—as peri-
odontitis. The article presents the contemporary knowledge
of the inflammatory reaction occurring in tissues sur-
rounding the tooth during periodontal inflammation. The
most important mechanisms are described, together with
implications for clinicists.
Keywords Periodontal diseases Inflammation
Non-specific immunity Mediators of inflammation
Acute Thymic Involution and Mechanisms for Recovery
Abdur Rahman Ansari1,2,3 · Huazhen Liu1
Abstract Acute thymic involution (ATI) is usually
regarded as a virulence trait. It is caused by several infec-
tious agents (bacteria, viruses, parasites, fungi) and other
factors, including stress, pregnancy, malnutrition and
chemotherapy. However, the complex mechanisms that
operate during ATI differ substantially from each other
depending on the causative agent. For instance, a transient
reduction in the size and weight of the thymus and deple-
tion of populations of T cell subsets are hallmarks of ATI
in many cases, whereas severe disruption of the anatomical
structure of the organ is also associated with some factors,
including fungal, parasitic and viral infections. However,
growing evidence shows that ATI may be therapeutically
halted or reversed. In this review, we highlight the current
progress in this field with respect to numerous pathologi-
cal factors and discuss the possible mechanisms. Moreover,
these new observations also show that ATI can be mecha-
nistically reversed.
Keywords Acute · Thymus · Atrophy · Thymic
involution · Mechanistic recovery
Myeloid-Derived Suppressor Cells in the Tumor
Microenvironment: Current Knowledge and Future Perspectives
Maria Ibáñez–Vea1 · Miren Zuazo1 · Maria Gato1 · Hugo Arasanz2 ·
Gonzalo Fernández–Hinojal2 · David Escors1 · Grazyna Kochan
Abstract The current knowledge on tumor-infiltrating
myeloid-derived suppressor cells (MDSCs) is based mainly
on the extensive work performed in murine models. Data
obtained for human counterparts are generated on the basis
of tumor analysis from patient samples. Both sources of
information led to determination of the main suppressive
mechanisms used by these cell subsets in tumor-bearing
hosts. As a result of the identification of protein targets
responsible for MDSCs suppressive activity, different ther-
apeutics agents have been used to eliminate/reduce their
adverse effect. In the present work, we review the current
knowledge on suppressive mechanisms of MDSCs and ther-
apeutic treatments that interfere with their differentiation,
expansion or activity. Based on the accumulation of new
evidences supporting their importance for tumor progression
and metastasis, the interest in these cell types is increasing.
We revise the methods of MDSC generation/differentiation
ex vivo that may help in overcoming problems associated
with limited numbers of cells available from animals and
patients for their study.
Keywords Myeloid-derived suppressor cells (MDSCs) ·
Immunosuppression · Myeloid regulatory cells · Tumor
progression · Metastasis · Immunotherapy
Are We Right to Consider Mesenchymal Stem Cells to Be a New
Perspective for Patients with Juvenile Idiopathic Arthritis?
Krzysztof Orczyk1 · Elzbieta Smolewska1
Abstract Juvenile idiopathic arthritis (JIA) is the most
common cause of chronic arthritis in childhood. Up to 50%
of patients are resistant to standard therapy, which includes
non-steroid anti-inflammatory drugs, corticosteroids, dis-
ease-modifying anti-rheumatic drugs and biologic therapies.
Intra-articular injection of mesenchymal stem cells (MSCs)
is proposed as a new approach to JIA treatment. MSCs can
modulate inflammation via mechanisms of both adaptive and
innate immune response. They are able to inhibit T and B
cell proliferation, promote regulatory T cells, suppress the
maturation of dendritic cells, stimulate macrophage differen-
tiation into M2 phenotype and reduce effectiveness of natu-
ral killer cells. They also secrete plethora of soluble factors
which influence joint inflammation. Recent clinical stud-
ies reviewed in the article provide promising results which
may suggest including intra-articular injection of MSCs in
therapy of patients with oligoarticular JIA.
Keywords Mesenchymal stem cells · Juvenile idiopathic
arthritis · Pathogenesis
The Impact of Di(2-ethylhexyl)phthalate on Cancer Progression
Chon‑Kit Chou1,2 · Ya‑Ting Yang2 · Ho‑Chun Yang2 · Shih‑Shin Liang2,3 · Tsu‑Nai Wang3,4 · Po‑Lin Kuo5 ·
Hui‑Min David Wang6 · Eing‑Mei Tsai3,7,8 · Chien‑Chih Chiu2,3,9,10,11
Abstract
Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer, mainly serves as an additive to render polyvinyl chloride (PVC)
soft and flexible. PVC plastics have become ubiquitous in our modern society. Yet, the leaching of DEHP from PVC-based
consumables ultimately results in the deposition in certain tissues via inadvertent applications. Health risks for human popu-
lations exposed to DEHP has been assumed by studies on rodents and other species, including the DEHP-induced develop-
mental dysregulation, reproductive impairments, tumorigenesis, and diseases in a transgenerational manner. In this review,
we comprehensively summarize the accumulated literature regarding the multifaceted roles of DEHP in the activation of the
nuclear receptors, the alteration of the redox homeostasis, epigenetic modifications and the acquisition of chemoresistance.
Keywords DEHP · Tumorigenesis · Nuclear receptors · Redox homeostasis · Epigenetic modifications · Chemoresistance
Adaptive Immune Cell Dysregulation and Role in Acute Pancreatitis
Disease Progression and Treatment
Pascaline Fonteh1 · Martin Smith1 · Martin Brand1
Received: 24 April 2017 / Accepted: 31 August 2017 / Published online: 30 November 2017
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract
Acute pancreatitis (AP) is an inflammation of the pancreas caused by various stimuli including excessive alcohol consump-
tion, gallstone disease and certain viral infections. Managing specifically the severe form of AP is limited due to lack of an
understanding of the complex immune events that occur during AP involving immune cells and inflammatory molecules
such as cytokines. The relative abundance of various immune cells resulting from the immune dysregulation drives disease
progression. In this review, we examine the literature on the adaptive immune cells in AP, the prognostic value of these
cells in stratifying patients into appropriate care and treatment strategies based on cell frequency in different AP severities
are discussed.
Keywords Acute pancreatitis · Adaptive immune cells
Oxidative Stress in Kidney Diseases: The Cause or the Consequence?
Natalia Krata1 · Radosław Zagożdżon1,2,3 · Bartosz Foroncewicz1 · Krzysztof Mucha1,2
Received: 21 March 2017 / Accepted: 11 July 2017 / Published online: 6 December 2017
© The Author(s) 2017. This article is an open access publication
Abstract
Exaggerated oxidative stress (OS) is usually considered as a disturbance in regular function of an organism. The excessive
levels of OS mediators may lead to major damage within the organism’s cells and tissues. Therefore, the OS-associated bio-
markers may be considered as new diagnostic tools of various diseases. In nephrology, researchers are looking for alternative
methods replacing the renal biopsy in patients with suspicion of chronic kidney disease (CKD). Currently, CKD is a frequent
health problem in world population, which can lead to progressive loss of kidney function and eventually to end-stage renal
disease. The course of CKD depends on the primary disease. It is assumed that one of the factors influencing the course of
CKD might be OS. In the current work, we review whether monitoring the OS-associated biomarkers in nephrology patients
can support the decision-making process regarding diagnosis, prognostication and treatment initiation.
Keywords Oxidative stress · Biomarkers · Chronic kidney disease
Bindarit Attenuates Pain and Cancer-Related Inflammation
by Influencing Myeloid Cells in a Model of Bone Cancer
Shenghou Liu1 · Hongwei Gao2 · Chunzheng Gao3 · Wenguang Liu1 · Deguo Xing2
Received: 30 June 2017 / Accepted: 6 October 2017 / Published online: 12 December 2017
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract
C–C motif chemokine ligand 2 (CCL2) is a small cytokine that functions in inflammation and cancer development. Bindarit,
a CCL2 inhibitor, is a small anti-inflammatory molecule proven safe by phase II trials in type 2 diabetic nephropathy patients.
As cancer-related inflammation is a cause of pain, we investigated whether Bindarit suppresses cancer-related inflammation
and pain. We established a bone-cancer mouse model by inoculating cancer cells. After applying Bindarit, we preformed
pain sensitivity tests and checked cancer development by X-ray. Using flow cytometry and qRT-PCR assays, we assessed
the effect of Bindarit on peripheral blood monocyte mobilization and M2 macrophage polarization. We also investigated
the targets of Bindarit using western blotting and luciferase assay. Bindarit-treated mice performed better in pain sensitivity
tests compare to control mice. X-ray imaging showed that Bindarit-treated mice had fewer cancer cell colonies and smaller
overall tumor burden. Bindarit reduced the number of monocytes in peripheral blood and down-regulated the expression
of M2 macrophage polarization makers. Bindarit also inhibited IKKβ phosphorylation. Bindarit efficiently relieves cancer-
related pain and suppresses cancer development. Bindarit inhibits monocyte mobilization in peripheral blood as well as M2
macrophage polarization. IKKβ is identified as a target of Bindarit.
Keywords Bindarit · CCL2 · Cancer · Inflammation · Pain
Variation of Regulatory T Lymphocytes in the Peripheral Blood
of Children with Allergic Rhinitis
Khaled Saad1 · Asmaa M. Zahran2 · Khalid I. Elsayh1 · Abobakr Abdelmoghny3 · Mohamed Diab Aboul‑Khair4
Received: 10 October 2017 / Accepted: 23 November 2017 / Published online: 18 December 2017
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract
The studies of T-regulatory (Treg) cells in the pediatric allergic disorders, especially allergic rhinitis (AR), are very few and
still far from being elucidated. The aim of this study is to assess the frequencies of CD4+CD25+Foxp3+ (CD4+Tregs) and
CD8+CD25+highFoxp3+ (CD8+Tregs) regulatory T lymphocytes in the peripheral blood of children with AR. In fresh whole
blood of 60 children with AR and 40 healthy controls, the frequencies of CD4+Tregs and CD8+Tregs were examined by
flow cytometry. The total IgE concentration in the serum was measured. In AR children, the frequencies of CD4+Tregs and
CD8+Tregs were significantly reduced when compared to control group (p = 0.041, p = 0.011, respectively). Moreover, the
expressions of Foxp3+ in CD4+CD25+high and CD8+CD25+high cells were significantly lower in patient group than controls.
We found a significant negative correlation between the frequencies of CD4+Tregs and the total IgE concentration (p < 0.01).
In conclusion, the present study demonstrated that the percentages of CD8+Tregs and CD4+Tregs T cells were significantly
decreased in children with AR. This suggests that decreased Treg cells might represent a defect in the compartment of T-cell
population in children with AR. Further studies are warranted to fully appreciate the clinical relevance of Tregs in children
with AR.
Keywords Allergic rhinitis · CD4+Tregs, CD8+Tregs · Children · Regulatory T cells.
Soluble TREM-1 Serum Level can Early Predict Mortality of Patients
with Sepsis, Severe Sepsis and Septic Shock
Monika Jedynak1 · Andrzej Siemiatkowski1 · Barbara Mroczko2 · Magdalena Groblewska3 · Robert Milewski4 ·
Maciej Szmitkowski5
Received: 10 April 2017 / Accepted: 9 October 2017 / Published online: 27 December 2017
© The Author(s) 2017. This article is an open access publication
Abstract
Early prognostic prediction of sepsis is essential in adjusting therapeutic protocols to prevent deterioration and reduce mor-
tality. We compared the predictive value of the serum concentration of the soluble triggering receptor expressed on myeloid
cells 1 (sTREM-1) for 28-day mortality and for the development of severe sepsis or septic shock on the third day with the
levels of interleukin (IL)-6, C-reactive protein (CRP) and procalcitonin (PCT). The study was conducted on 85 patients
with sepsis. sTREM-1, CRP, PCT and IL-6 concentrations were measured upon study inclusion (day 0) and on days 1, 2, 3
and 5. APACHE II, SAPS II and SOFA scores were analyzed. The sTREM-1 levels (pg/ml) were higher in non-survivors
than in survivors at admission (773 vs. 391, p < 0.001) and on days 1, 2, 3 and 5. In predicting the development of severe
sepsis, the highest AUCs were found for PCT (0.744, 95% CI 0.638–0.85) and sTREM-1 (0.664, 95% CI 0.55–0.778); and in
septic shock prediction, for PCT (0.766, 95% CI 0.665–0.867) and IL-6 (0.707, 95% CI 0.595–0.819). sTREM-1 positively
correlated with APACHE II, SAPS II and SOFA scores. At inclusion, significant AUC for predicting 28-day mortality was
0.772 for the sTREM-1 (95% CI 0.672–0.871), 0.858 for APACHE II (95% CI 0.768–0.948), 0.847 for SAPS II (95% CI
0.733–0.96), 0.806 for SOFA score (95% CI 0.698–0.915). sTREM-1 can early predict the 28-day sepsis mortality, although
its effectiveness is lower in comparison with clinical severity scores.
Keywords Sepsis · Prognosis · Inflammation · sTREM-1
NK and NKT-Like Cells in Patients with Recurrent Furunculosis
Danuta Nowicka1 · Ewelina Grywalska2 · Elżbieta Fitas2 · Michał Mielnik2 · Jacek Roliński2
Received: 12 September 2017 / Accepted: 18 October 2017 / Published online: 13 December 2017
© The Author(s) 2017. This article is an open access publication
Abstract
To analyze changes in the number and percentage of NK and NKT-like cells in relation to other immune cells as well as
to examine associations between increased susceptibility to infections and NK and NKT-like status in patients with recur-
rent furunculosis (RF) and healthy controls. Thirty patients with RF and 20 healthy age- and sex-matched volunteers were
recruited. Blood samples were examined. Lymphocyte count and cytometric analyses were conducted. For statistical analysis,
the Student’s t test, F test, and Brown–Forsythe test were used for comparison between groups of variables. Associations were
assessed with Pearson coefficient. Patients with RF had lower lymphocyte count than controls. Additionally, they presented
with the following changes in the blood picture: a significant increase in the number of NK cells with a CD3+CD16+CD56+
phenotype; a proportional increase in the number and percentage of NKT-like cells with a CD3+CD16+CD56+ phenotype;
a significant decrease in the number and percentage of T CD3+ cells. The number of NK cells was strongly positively
correlated with the number of CD3 cells (r = 0.6162). The number of NKT cells was strongly positively correlated with
CD3 cells (r = 0.6885) and CD3CD8 cells (r = 0.5465). Periodic exacerbations in RF are associated with the development
of furuncles, which are a result of many already discovered as well as just being examined mechanisms. One of them is a
significant increase in the number and most likely activation of NK and NKT-like cells during the formation of the inflam-
matory process and furuncles.
Keywords NK cells · Staphylococcal infection · Staphylococcosis · Recurrent furunculosis · Immune response · Skin
infection · In vitro study
Allergen-Specific T Cells in IgE-Mediated Food Allergy
Aziza Saidova1,2 · Ahuva Magder Hershkop3 · Marta Ponce1 · Thomas Eiwegger3,4,5
Received: 27 June 2017 / Accepted: 23 November 2017 / Published online: 18 December 2017
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract
Food allergy is the major reason for severe anaphylaxis in childhood and adolescence. Currently, effective and safe treatments
for food allergy are unavailable. Allergen-specific CD4+ T cells have a pivotal role in causing and maintaining the allergic
response to food allergens. The purpose of this review is to provide an overview on the role of allergen-specific T cells in
food allergy during allergic sensitization, natural tolerance development and allergen immunotherapy. Allergen-specific T
cells in the context of food allergy are predominantly of a Th2 type with slightly different surface marker expression patterns
in different food allergies. During the process of reverting food allergy to a status of tolerance or sustained unresponsiveness
there is a loss of this Th2 committed compartment with an asymptotic approximation to a regulatory and Th0/Th1 dominated
compartment seen in non-allergic individuals. This process is accompanied by a significant reduction of absolute frequencies
of allergen-specific T cells. Particularly, regulatory T cells may provide significant help to achieve sustained control of the
effector cell populations via suppression of effector cell function and possibly induction of blocking antibodies.
Keywords Allergy · IgE-mediated food allergy · Helper T cells · Th2 cells · Regulatory T cells
Biomedical Research in Wrocław: A Combined Density-Equalizing
Mapping and Scientometric Analysis
David A. Groneberg1
Received: 10 July 2017 / Accepted: 4 September 2017 / Published online: 3 January 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
The aim of this study was to assess the evolution of biomedical scientific activities of Wrocław scientists in the post-war time
when this field of academics was rebuilt by the works of Ludwik Hirszfeld and colleagues. Using the NewQIS platform and
the Web of Science database, novel procedures such as density-equalizing mapping were combined to bibliometric tools to
visualize scientific progression. In total, 10,366 biomedical research articles originating from Wrocław were identified. Since
1972, there is a steady increase in research activity with the year 2015 holding the largest number of published items (895).
A total of 2934 published research cooperations with 104 different countries is present. This is a percentage of 28.3% of all
publications. In total, 101 research areas are present in Wrocław biomedical research with the highest number of articles
being published in the area of biochemistry/molecular biology (2140). Research in this field was cited 27,360 times. The
field of immunology has 1186 articles with 9247 citations. Density-equalizing mapping and network techniques revealed a
distinct global pattern of research collaborations with German, US and UK affiliations as the primary cooperating partners
of Wrocław. In summary, the present study supplies the first density-equalizing mapping approach that visualizes research
activity in Wrocław over the past decades.
Keywords Wrocław · Biomedical sciences · Scientometrics · Density-equalizing maps
Thymus Colonization: Who, How, How Many?
Andreas Krueger1
Received: 28 July 2017 / Accepted: 23 November 2017 / Published online: 29 December 2017
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract
De novo generation of T cells depends on continual colonization of the thymus by bone marrow-derived progenitors. Thymus
seeding progenitors (TSPs) constitute a heterogeneous population comprising multipotent and lineage-restricted cell types.
Entry into the thymic microenvironment is tightly controlled and recent quantitative studies have revealed that the adult
murine thymus only contains approximately 160 niches to accommodate TSPs. Of these niches only about 6% are open for
seeding on average at steady-state. Here, I review the state of understanding of colonization of the adult murine thymus with
a particular focus on past and current controversies in the field. Improving thymus colonization and/or maintaining intact
TSP niches during the course of pre-conditioning regimens are likely to be critical for efficient T-cell regeneration after
hematopoietic stem cell transplantation.
Keywords Thymus · T cells · Development · Migration · Hematopoietic stem cell transplantation
Interleukin (IL)-23 Receptor, IL-17A and IL-17F Gene
Polymorphisms in Brazilian Patients with Rheumatoid Arthritis
Isaura Isabelle Fonseca Gomes da Silva1 • Hildson Dornelas Angelo2 •
Eliezer Rushansky3 • Maria Helena Mariano3 • Maria de Mascena Diniz Maia4 •
Paulo Roberto Eleuterio de Souza
Abstract Rheumatoid arthritis (RA) is a progressive,
autoimmune disease for which the previous studies have
shown that some functional polymorphisms can influence
its etiology. Knowing this, the aim of this study was to
investigate the association of ?2199 A/C IL–23R
(rs10889677), –197 G/A IL–17A (rs2275913), and ?7488
A/G IL–17F (rs763780) gene polymorphisms with RA
susceptibility and clinical features in a Brazilian popula-
tion. A total of 127 RA patients and 134 healthy controls
were recruited for the analyses of polymorphic variants.
Genotyping was performed using RFLP-PCR. Logistic
regression was used to analyze the genotype distribution of
the polymorphisms. Individuals carrying the homozygous
CC genotype for the IL–23R polymorphism seem to be at
lower risk for RA development (OR 0.22; p = 0.004), as
well as those carrying the variant C allele (OR 0.56;
p = 0.002). For the –197 G/A IL–17A polymorphism, the
wild-type genotype (GG) was significantly associated with
a 3.18-fold (OR 3.18; p = 0.033) increased risk for RA. In
relation to the ?7488 A/G IL–17F polymorphism, no sig-
nificant difference was found between RA cases and
control subjects (p [ 0.05). Moreover, when investigating
the relationship between polymorphisms and clinical fea-
tures, no evidence of an association was found. Our
findings suggest that the variants ?2199 A/C IL–23R and
–197 G/A IL–17A could contribute to RA development in
the studied population. However, larger studies are needed
to fully understand this genetic predisposition.
Keywords Rheumatoid arthritis Cytokines
Th17 profile Polymorphisms
KIR, LILRB and their Ligands’ Genes as Potential Biomarkers
in Recurrent Implantation Failure
Izabela Nowak1 • Karolina Wilczyn´ ska1 • Jacek R. Wilczyn´ ski2 • Andrzej Malinowski3 •
Paweł Radwan4,5 • Michał Radwan4 • Piotr Kus´nierczyk1
Received: 1 February 2017 / Accepted: 3 April 2017 / Published online: 18 May 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Reproductive failure in humans is a very
important social and economic problem, because nowadays
women decide to conceive later in life and delay mother-
hood. Unfortunately, with increasing age they have less
chance for natural fertilization and maintenance of preg-
nancy. Many of them need assisted reproductive
technology. Approximately 10% of women after in vitro
fertilization-embryo transfers experience recurrent
implantation failure (RIF). Multiple factors may contribute
to RIF, including oocyte and sperm quality, parental
chromosomal anomalies, genetic or metabolic abnormali-
ties of the embryo, poor uterine receptivity, immunological
disturbances in the implantation site, and some gynecologic
pathologies such as endometriosis, uterine fibroids,
hydrosalpinx and endometrial polyps. Moreover, the pro-
cedure of in vitro fertilization itself could adversely
influence the implantation. Nowadays, many studies are
focused on the role of natural killer (NK) cells in normal
and pathologic pregnancy because NK cells constitute the
dominant cell population in the endometrium and they
come in close contact with the allogeneic extravillous
trophoblast cells in early pregnancy decidua. The majority
of these cells are of CD56bright phenotype. These cells can
express killer immunoglobulin-like receptors (KIRs),
which, upon recognition of HLA class I molecules (HLA-C
and HLA-G) on trophoblasts, may either stimulate or
inhibit NK cells to produce soluble factors, and display low
cytotoxicity necessary for maintenance of the allogeneic
embryo and fetus in the next steps of pregnancy. Moreover,
some members of the leukocyte immunoglobulin-like
receptor (LILR) family, also named ILT (immunoglobulin-
like transcript), are present in the human placenta. LILRB1
(ILT2) was described mainly on stromal cells, while
LILRB2 (ILT4), in addition to stromal cells, was also
found around vessels in the smooth muscle layer. In this
review we focus on the possible role of polymorphism of
KIR, LILRB and their ligands (HLA-C, HLA-G) in sus-
ceptibility to recurrent implantation failure, which could
serve as diagnostic biomarkers of this disease.
Keywords Recurrent implantation failure
In vitro fertilization Polymorphism KIR LILRB
HLA
Ficolin-2 Gene rs7851696 Polymorphism is Associated
with Delayed Graft Function and Acute Rejection in Kidney
Allograft Recipients
Ewa Dabrowska-Zamojcin1 • Michal Czerewaty2 • Damian Malinowski1,2 •
Maciej Tarnowski2 • Sylwia Słuczanowska-Głabowska2 • Leszek Domanski3 •
Krzysztof Safranow4 • Andrzej Pawlik2
Received: 9 February 2017 / Accepted: 6 April 2017 / Published online: 23 May 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Ficolin-2 is an activator of the complement
system that acts via the lectin pathway. Complement acti-
vation plays a substantial role in the renal injury inherent to
kidney transplantation. In this study, we examined the
associations between ficolin-2 gene polymorphisms in exon
8 and kidney allograft function. This study comprised 270
Caucasian deceased-donor renal transplant recipients. The
following parameters were recorded in each case: delayed
graft function (DGF), acute rejection (AR), and chronic
allograft dysfunction. Among patients with DGF, we
observed a significantly increased frequency of rs7851696
GT and TT genotypes as well as T allele (TT ? GT vs GG
OR 1.98, 95% CI 1.12–3.48, p = 0.02; T vs G OR 2.08,
95% CI 1.27–3.41, p = 0.005). There was also an
increased frequency of rs4521835 GG and TG genotypes as
well as G alleles; however, these differences were on the
borderline of statistical significance (GG ? TG vs TT, OR
1.75, 95% CI 0.98–3.12, p = 0.07; G vs T OR 1.45, 95%
CI 1.00–2.09, p = 0.050). In addition, we observed an
increased frequency of acute allograft rejection in carriers
of ficolin-2 rs7851696 T alleles on the borderline of sta-
tistical significance (TT ? GT vs GG OR 1.75, 95% CI
0.97–3.16, p = 0.08), but the frequency of T allele was
significantly higher in patients with AR (T vs G OR 1.71,
95% CI 1.02–2.87, p = 0.048). The results of our study
suggest that ficolin-2 rs7851696 gene polymorphism
influences kidney allograft functions, with T allele
increasing the risk of DGF and AR.
Keywords Diabetes Transplantation
Single-nucleotide polymorphism Gene Polymorphisms
Heterogeneity Among Neutrophils
Marzena Garley1 • Ewa Jabłon´ ska1
Received: 13 September 2016 / Accepted: 3 April 2017 / Published online: 30 May 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Neutrophils (PMNs) play a key role in innate
defence mechanisms. Generally, PMNs were considered to
have a homogeneous population of mature and diversified
cells. It seems, however, that their pleiotropic action results
from the existence of different subpopulations in this group
of cells. There are data that confirm the involvement of
PMNs in the direct activation of other cells in non-specific
response, as well as specialised cells in specific response.
For example, there have been observations of PMNs with
different levels of activity in relation to lymphocytes, and a
population was identified which had characteristics similar
to those of cells which are capable of presenting antigens.
There are also reports of PMNs which demonstrate dif-
ferent survival time or capacity for chemotaxis. Other
studies suggest that the neutrophil response to Staphylo-
coccus aureus is diverse (not identical among all
neutrophil). There are also reports of PMNs with varying
activity during inflammation, which might explain many as
yet unknown pathophysiological aspects of their hyperre-
activity. The functional dualism of PMNs in the course of
neoplastic disorders raises a lot of controversy. This paper
presents the current state of knowledge of the heterogeneity
of PMNs and their potential roles in different stages of
disease.
Keywords Neutrophils PMNs Heterogeneity
Subpopulations Populations
Skin Immunity
Agata Matejuk1,2
Received: 14 November 2016 / Accepted: 20 March 2017 / Published online: 16 June 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Skin is the largest organ of the body with a
complex network of multitude of cell types that perform
plastic and dynamic cellular communication to maintain
several vital processes such as inflammation, immune
response including induction of tolerance and disease
prevention, wound healing, and angiogenesis. Of para-
mount importance are immunological functions of the skin
that protect from harmful exposure coming from external
and internal environments. Awareness of skin immunity
can provide a better comprehension of inflammation,
autoimmunity, cancer, graft-versus-host disease, vaccina-
tion, and immunotherapy approaches. This paper will
update on what we currently know about immune sentinels
contributing to skin immunity.
Keywords Immune response Skin Epidermis
Dermis Hypoxia
Exocrine Gland Morphogenesis: Insights into the Role
of Amphiregulin from Development to Disease
Margherita Sisto1 • Loredana Lorusso1 • Giuseppe Ingravallo2 • Sabrina Lisi1
Received: 17 November 2016 / Accepted: 2 June 2017 / Published online: 7 June 2017
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract Amphiregulin (AREG) is a well-characterized
member of the epidermal growth factor (EGF) family and
is one of the ligands of the EGF receptor (EGFR). AREG
plays a key role in mammalian development and in the
control of branching morphogenesis in various organs.
Furthermore, AREG participates in a wide range of phys-
iological and pathological processes activating the major
intracellular signalling cascades governing cell survival,
proliferation and motility. In this article, we review current
advances in exocrine glands morphogenesis, focusing on
the salivary gland, and discuss the essential aspects of
AREG structure, function and regulation, and its differen-
tial role within the EGFR family of ligands. Finally, we
identify emerging aspects in AREG research applied to
mammary gland development and the salivary gland
autoimmune disease, Sjo¨gren’s syndrome.
Keywords Morphogenesis Exocrine glands
Epidermal growth factor Amphiregulin Salivary gland
Sjo¨gren’s syndrome
Anti-GITR Antibody Treatment Increases TCR Repertoire
Diversity of Regulatory but not Effector T Cells Engaged
in the Immune Response Against B16 Melanoma
Bozena Scirka1 • Edyta Szurek3 • Maciej Pietrzak4 • Grzegorz Rempala4 •
Pawel Kisielow1 • Leszek Ignatowicz1,3 • Arkadiusz Miazek1,2
Received: 21 March 2017 / Accepted: 9 May 2017 / Published online: 21 June 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Crosslinking of glucocorticoid-induced TNF
family-related receptor (GITR) with agonist antibodies
restores cancer immunity by enhancing effector T cell
(Teff) responses while interfering with intra-tumor regu-
latory T cell (Treg) stability and/or accumulation.
However, how anti-GITR antibody infusion changes T cell
receptor (TCR) repertoire of Teffs and Tregs engaged in
anti-tumor immune response is unclear. Here, we used a
transgenic mouse model (TCRmini) where T cells express
naturally generated but limited TCR repertoire to trace the
fate of individual T cells recognizing B16 melanoma in
tumor-bearing mice, treated or non-treated with an anti-
GITR monoclonal antibody DTA-1. Analysis of TCRs of
CD4? T cells from these mice revealed that the TCR
repertoire of dominant tumor-reactive Teff clones
remained rather similar in treated and non-treated mice. In
contrast, both tumor-associated and peripheral TCR
repertoire of Tregs, which were mostly distinct from that of
Teffs, underwent DTA-1 mediated remodeling character-
ized by depletion of dominant clones and an emergence of
more diverse, low-frequency clones bearing increased
numbers of TCRs shared with Teffs. We conclude that the
DTA-1 infusion eliminates activated Tregs engaged in the
initial maintenance of tolerogenic niche for tumor growth,
but over time, it favors tumor replenishment by Tregs
expressing an array of TCRs able to compete with Teffs for
recognition of the same tumor antigens which may prevent
its complete eradication.
Keywords GITR DTA-1 TCR diversity
Immunotherapy T regulatory cells B16 melanoma
Tumor-Associated Macrophages as Target for Antitumor
Therapy
Katarzyna Sawa-Wejksza1 • Martyna Kandefer-Szerszen´ 1
Received: 30 September 2016 / Accepted: 15 May 2017 / Published online: 28 June 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract It is well known that the microenvironment of
solid tumors is rich in inflammatory cells that influence
tumor growth and development. Macrophages, called
tumor-associated macrophages (TAMs), are the most
abundant immune cell population present in tumor tissue.
Several studies have demonstrated that the density of
TAMs is associated with a poor prognosis and positively
correlates with tumor growth. Several studies have proved
that TAMs may activate and protect tumor stem cells,
stimulate their proliferation as well as promote angiogen-
esis and metastasis. Furthermore, TAMs-derived cytokines
and other proteins, such as CCL-17, CCL-22, TGF-b, IL-
10, arginase 1, and galectin-3, make a significant contri-
bution to immunosuppression. Since TAMs influence
various aspects of cancer progression, there are many
attempts to use them as a target for immunotherapy. The
numerous studies have shown that the primary tumor
growth and the number of metastatic sites can be signifi-
cantly decreased by decreasing the population of
macrophages in tumor tissue, for example, by blocking
recruitment of monocytes or eliminating TAMs already
present in the tumor tissue. Moreover, there are attempts at
reprogramming TAMs into proinflammatory M1 macro-
phages or neutralizing the protumoral products of TAMs.
Another approach uses TAMs for anticancer drug delivery
into the tumor environment. In this review, we would like
to summarize the clinical and preclinical trials that were
focused on macrophages as a target for anticancer
therapies.
Keywords Tumor-associated macrophages TAMs
Cancer therapies Immunotherapy Tumor
STING Signaling in Cancer Cells: Important or Not?
Olga Sokolowska1,2,3 • Dominika Nowis1,4,5
Received: 30 January 2017 / Accepted: 8 July 2017 / Published online: 26 July 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Stimulator of interferon genes (STING) is an
adaptor protein that plays an important role in the activa-
tion of type I interferons in response to cytosolic nucleic
acid ligands. Recent evidence indicates involvement of the
STING pathway in the induction of antitumor immune
response. Therefore, STING agonists are now being
extensively developed as a new class of cancer therapeu-
tics. However, little is known about the consequences of
activated STING-mediated signaling in cancer cells on the
efficacy of the antitumor treatment. It has been shown that
activation of the STING-dependent pathway in cancer cells
can result in tumor infiltration with immune cells and
modulation of the anticancer immune response. Under-
standing the function of STING pathway in cancer cells
might provide important insights into the development of
effective therapeutic strategies. This review focuses on the
role of STING pathway in cancer cells, the largely
unknown topic that has recently emerged to be important in
the context of STING-mediated antitumor responses.
Keywords STING Type I interferons Innate immunity
Cancer immunology Cyclic dinucleotides
Role of TGF-b in Self-Peptide Regulation of Autoimmunity
Bhagirath Singh1,2,3 • Michael D. Krawetz2 • Rachel M. De Lima2 •
Rinee Mukherjee2 • Pratibha Chaturvedi2 • Edwin Lee-Chan2 • Edward H. Leiter4 •
Kelly L. Summers1,2,5
Received: 29 March 2017 / Accepted: 19 June 2017 / Published online: 21 July 2017
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract Transforming growth factor (TGF)-b has been
implicated in regulation of the immune system, including
autoimmunity. We have found that TGF-b is readily pro-
duced by T cells following immunization with self-peptide
epitopes that downregulate autoimmune responses in type
1 diabetes (T1D) prone nonobese diabetic (NOD) mice.
These include multiple peptide epitopes derived from the
islet b-cell antigens GAD65 (GAD65 p202-221, GAD65
p217-236), GAD67 (GAD67 p210-229, GAD67 p225-
244), IGRP (IGRP p123-145, IGRP p195-214) and insulin
B-chain (Ins. B:9-23) that protected NOD mice from T1D.
Immunization of NOD mice with the self-MHC class II
I-Ag7 b-chain-derived peptide, I-Abg7 p54-76 also induced
large amounts of TGF-b and also protected these mice
from diabetes development. These results indicate that
peptides derived from disease related self-antigens and
MHC class II molecules primarily induce TGF-b producing
regulatory Th3 and Tr1-like cells. TGF-b produced by
these cells could enhance the differentiation of induced
regulatory iTreg and iTreg17 cells to prevent induction and
progression of autoimmune diseases. We therefore suggest
that peripheral immune tolerance could be induced and
maintained by immunization with self-peptides that induce
TGF-b producing T cells.
Keywords Auto-antigens NOD mice Peptide epitopes
Regulatory T cells TGF-beta Type 1 diabetes
Possible Immunomodulating Effect of Retinol on Cytokines
Secretion in Patients with Recurrent Furunculosis
Danuta Nowicka1 • Ewelina Grywalska2 • Anna Hymos3 • Michał Mielnik2 •
Jacek Rolin´ski2
Received: 11 April 2017 / Accepted: 19 June 2017 / Published online: 20 July 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Recurrent furunculosis is an infection of hair
follicles which results in formation of abscesses. Previous
studies showed that the pathogenesis of the disease may
include an immune-mediated component as the prolifera-
tive response of peripheral blood lymphocytes to
staphylococcal antigen is depressed. The aim of our study
was to evaluate cytokines concentration in the plasma of
patients with recurrent furunculosis and to determine
whether retinol affects the secretion of those cytokines in
patients with recurrent furunculosis and healthy subjects.
Blood samples were taken from 15 patients with recurrent
furunculosis and 15 age-matched healthy subjects. A
quantitative determination of selected cytokines (IL-17, 13,
2, 10, 4, IFN-c, TNF-a) was performed in the plasma at
baseline and after 72-h culture of peripheral blood
mononuclear cells with and without retinol in both groups.
In the plasma of patients with recurrent furunculosis,
concentration of IL-10, 2, and TNF-a was significantly
higher, whereas IL-13 significantly lower when compared
with healthy subjects. After retinol stimulation, the con-
centration of IL-17 and IFN-c increased significantly in
both groups. Secretion of anti-inflammatory cytokines,
especially IL-10 (p \ 0.002) and 13 (p \ 0.01), achieved
lower levels in recurrent furunculosis samples than in those
of healthy controls. Network of cytokines differs in patients
with recurrent furunculosis from healthy subjects. Retinol
stimulation affects secretion of both pro-inflammatory and
anti-inflammatory cytokines. Further studies are recom-
mended for better understanding the pathomechanism of
recurrent furunculosis and potential clinical use of retinol
in patients affected by recurrent furunculosis.
Keywords Retinol Recurrent furunculosis
Immune response Skin infection In vitro study
Comparative Assessment of Induced Immune Responses
Following Intramuscular Immunization with Fusion and Cocktail
of LeIF, LACK and TSA Genes Against Cutaneous Leishmaniasis
in BALB/c Mice
Nahid Maspi1,2 • Fatemeh Ghaffarifar1 • Zohreh Sharifi3 • Abdolhossein Dalimi1 •
Mohammad Saaid Dayer1
Received: 6 January 2017 / Accepted: 22 May 2017 / Published online: 4 August 2017
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract In the present study, we evaluated induced
immune responses following DNA vaccine containing
cocktail or fusion of LeIF, LACK and TSA genes or each
gene alone. Mice were injected with 100 lg of each plas-
mid containing the gene of insert, plasmid DNA alone as
the first control group or phosphate buffer saline as the
second control group. Then, cellular and humoral respon-
ses, lesion size were measured for all groups. All
vaccinated mice induced Th1 immune responses against
Leishmania characterized by higher IFN-c and IgG2a
levels compared with control groups (p \ 0.05). In addi-
tion, IFN-c levels increased in groups immunized with
fusion and cocktail vaccines in comparison with LACK
(p \ 0.001) and LeIF (p \ 0.01) groups after challenge. In
addition, fusion and cocktail groups produced higher IgG2a
values than groups vaccinated with a gene alone
(p \ 0.05). Lesion progression delayed for all immunized
groups compared with control groups from 5th week post-
infection (p \ 0.05). Mean lesion size decreased in
immunized mice with fusion DNA than three groups vac-
cinated with one gene alone (p \ 0.05). While, lesion size
decreased significantly in cocktail recipient group than
LeIF recipient group (p \ 0.05). There was no difference
in lesion size between fusion and cocktail groups. Overall,
immunized mice with cocktail and fusion vaccines showed
stronger Th1 response by production of higher IFN-c and
IgG2a and showed smaller mean lesion size. Therefore, use
of multiple antigens can improve induced immune
responses by DNA vaccination.
Keywords Leishmania Vaccine Immunization
Fusion Cocktail
The PD-1/PD-L1 Inhibitory Pathway is Altered in Primary
Glomerulonephritides
Ewelina Grywalska1 • Iwona Smarz-Widelska2 • Ewelina Krasowska-Zajac1 •
Izabela Korona-Glowniak3 • Karolina Zaluska-Patel4 • Michal Mielnik1 •
Martyna Podgajna1 • Anna Malm3 • Jacek Rolinski1 • Wojciech Zaluska2,5
Received: 12 March 2017 / Accepted: 19 July 2017 / Published online: 2 August 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract The pathogenesis of primary proliferative and
non-proliferative glomerulonephritides (PGN and NPGN)
is still not fully understood, however, current evidence
suggests that most cases of PGN and NPGN are the results
of immunologic response to different etiologic agents that
activates various biological processes leading to glomeru-
lar inflammation and injury. Programmed cell death protein
1 (PD-1) is the major inhibitory receptor regulating T cell
exhaustion. The aim of this study was to evaluate the fre-
quencies of PD-1-positive and PD-ligand 1 (PD-L1)-
positive T and B lymphocytes in patients with NPGN and
PGN in relation to clinical parameters for the first time.
The study included peripheral blood (PB) samples from 20
newly diagnosed PGN and NPGN patients. The control
group comprised of 20 healthy age- and sex-matched
subjects. The viable PB lymphocytes underwent labelling
with fluorochrome-conjugated monoclonal antibodies anti-
PD-1 and anti-PD-L1, and were analyzed using a flow
cytometer. The frequencies of CD4?/PD1? T lymphocytes,
CD8?/PD1? T lymphocytes, and CD19?/PD-1? B lym-
phocytes in the PGN group exceeded values obtained both
in the NPGN group, and the control group. Alteration of
PD-1/PD-L1 pathway may be involved in poorer prognosis,
as patients with PGN are characterized by higher fre-
quencies of PD-1-positive and PD-L1-positive T and B
lymphocytes than patients with NPGN. Our results suggest
that deregulation of PD-1/PD-L1 axis may contribute to the
PGN and NPGN pathogenesis. High percentages of lym-
phocytes with PD-1 and PD-L1 expression may be related
to the continuous T-cell activation and development of
glomerular inflammation and injury.
Keywords Glomerulonephritis Immunology
IgA nephropathy Immunosuppression
Membranoproliferative glomerulonephritis
Minimal change diseas
Biological and Pro-Angiogenic Properties of Genetically Modified
Human Primary Myoblasts Overexpressing Placental Growth
Factor in In Vitro and In Vivo Studies
Agnieszka Zimna1 • Bartosz Wiernicki1 • Tomasz Kolanowski1 • Natalia Rozwadowska1 •
Agnieszka Malcher1 • Wojciech Labedz2 • Tomasz Trzeciak2 • Katarzyna Chojnacka3 •
Katarzyna Bednarek-Rajewska3 • Przemyslaw Majewski3 • Maciej Kurpisz1
Received: 9 March 2016 / Accepted: 11 July 2017 / Published online: 26 September 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Cardiovascular diseases are a growing problem
in developing countries; therefore, there is an ongoing
intensive search for new approaches to treat these disor-
ders. Currently, cellular therapies are focused on healing
the damaged heart by implanting stem cells modified with
pro-angiogenic factors. This approach ensures that the
introduced cells are capable of fulfilling the complex
requirements of the environment, including the replace-
ment of the post-infarction scar with cells that are able to
contract and promote the formation of new blood vessels
that can supply the ischaemic region with nutrients and
oxygen. This study focused on the genetic modification of
human skeletal muscle cells (SkMCs). We chose myoblast
cells due to their close biological resemblance to car-
diomyocytes and the placental growth factor (PlGF) gene
due to its pro-angiogenic potential. In our in vitro studies,
we transfected SkMCs with the PlGF gene using electro-
poration, which has previously been proven to be efficient
and generate robust overexpression of the PlGF gene and
elevate PlGF protein secretion. Moreover, the functionality
of the secreted pro-angiogenic proteins was confirmed
using an in vitro capillary development assay. We have
also examined the influence of PlGF overexpression on
VEGF–A and VEGF–B, which are well-known factors
described in the literature as the most potent activators of
blood vessel formation. We were able to confirm the
overexpression of VEGF–A in myoblasts transfected with
the PlGF gene. The results obtained in this study were
further verified in an animal model. These data were able to
confirm the potential therapeutic effects of the applied
treatments.
Keywords Regenerative medicine Stem cell therapy
Myocardial infarction Human skeletal myoblasts
Placental growth factor
Novel Therapeutic Approaches to Atopic Dermatitis
Katarzyna Osinka1 • Karolina Dumycz1 • Bartłomiej Kwiek2 • Wojciech Feleszko1
Received: 2 February 2017 / Accepted: 11 July 2017 / Published online: 31 August 2017
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract Atopic dermatitis (AD) is one of the most
common inflammatory skin diseases. The number of peo-
ple affected by AD is relatively high and seems to be
rising. Although mild and moderate forms of the disease
can be well controlled by the use of emollients, topical
corticosteroids, and topical calcineurin inhibitors, treat-
ment of severe is still a huge challenge. The new hope is
biologic drugs, magic bullets in allergy, targeted at dif-
ferent points of the complex pathomechanism of
inflammation in AD. In this review, novel biologic thera-
pies are discussed, including recombinant monoclonal
antibodies directed against various interleukin pathways
(such as IL-4, IL-13, TSLP, IL-31, and IL-12/23), on
immunoglobulin E, molecules acting as T cells, B cells,
etc. Of biological drugs, the most promising seems to be
anti-IL-4/IL-13 therapy (dupilumab—the biological agent)
and phosphodiesterase-4 inhibitor (crisaborole—a small
molecule). A deep understanding of the AD pathomecha-
nism provides a new perspective for tailor-made treatment
of severe atopic dermatitis.
Keywords Atopic dermatitis Immunology Skin barrier
Biological treatment Antihistamine
Natural Agents-Mediated Targeting of Histone Deacetylases
Ammad Ahmad Farooqi1 • Syed Kamran-ul-Hassan Naqvi2 • Aliye Aras Perk3 •
Onur Yanar3 • Sobia Tabassum4 • Muhammad Sheeraz Ahmad5 • Qaisar Mansoor1 •
Mohamed S. Ashry9 • Muhammad Ismail1 • George E. Naoum6,7 • Waleed O. Arafat8
Received: 14 January 2017 / Accepted: 3 March 2017 / Published online: 30 August 2017
Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Abstract In the past few years, basic and clinical scientists
have witnessed landmark achievements in many research
projects, such as those conducted by the US National Institutes
of Health Roadmap Epigenomics Mapping Consortium, the
International Human Epigenome Consortium, The Cancer
Genome Atlas Network and the International Cancer Genome
Consortium, which have provided near-complete resolution
of epigenetic landscape in different diseases. Furthermore,
genome sequencing of tumors has provided compelling evi-
dence related to frequent existence of mutations in readers,
erasers and writers of epigenome in different cancers. Histone
acetylation is an intricate mechanism modulated by two
opposing sets of enzymes and deeply studied as a key
biological phenomenon in 1964 by Vincent Allfrey and col-
leagues. The research group suggested that this protein
modification contributed substantially in transcriptional reg-
ulation. Subsequently, histone deacetylases (HDACs), histone
acetyltransferases and acetyl-Lys-binding proteins were
identified as transcriptional mediators, which further
deepened our comprehension regarding biochemical modifi-
cations. Overwhelmingly increasing high-impact research is
improving our understanding of this molecularly controlled
mechanism; moreover, quantification and identification of
lysine acetylation by mass spectrometry has added new layers
of information. We partition this multi-component review into
how both activity and expression of HDAC are targeted using
natural agents. We also set spotlight on how oncogenic fusion
proteins tactfully utilize HDAC-associated nano-machinery
to modulate expression of different genes and how HDAC
inhibitors regulate TRAIL-induced apoptosis in cancer cells.
HDAC inhibitors have been reported to upregulate expression
of TRAIL receptors and protect TRAIL from proteasomal
degradation. Deeper understanding of HDAC biology will be
useful for stratification and selection of patients who are
responders, non-responders and poor-responders for HDACi
therapy, and for the rational design of combination studies
using HDACi.
Keywords Histone deacetylase (HDAC)
Transcription regulation TRAIL Natural agents
Cancer
The Effects of Intestinal Nematode L4 Stage on Mouse
Experimental Autoimmune Encephalomyelitis
Katarzyna Donskow‑Łysoniewska1,3 · Katarzyna Krawczak1 · Katarzyna Bocian2 ·
Maria Doligalska1
Abstract Helminths use various immunomodulatory and
anti-inflammatory strategies to evade immune attack by
the host. During pathological conditions, these strategies
alter the course of disease by reducing immune-mediated
pathology. The study examines the therapeutic effect of the
nematode L4 stage based on an in vivo model of multiple
sclerosis, monophasic encephalomyelitis (EAE), induced
by sensitization with MOG35–55 peptide in C57BL/6 female
mice infected with the intestinal nematode Heligmosomoides
polygyrus. The EAE remission was correlated with altered
leukocyte number identified in the central nervous system
(CNS), and temporary permeability of the blood–brain
barrier at the histotrophic phase of infection. At 6 days
post-infection, when the L4 stage had almost completely
attenuated the clinical severity and pathological signs of
EAE, CD25+ cell numbers expanded significantly, with
parallel growth of CD8+ and CD4+, both CD25+Foxp3+
and CD25+Foxp3− subsets and alternatively activated
macrophages. The phenotypic changes in distinct subsets
of cerebrospinal fluid cells were correlated with an inhib-
ited proliferative response of encephalitogenic T cells and
elevated levels of nerve growth factor and TGF-β. These
results enhance our understanding of mechanisms involved
in the inhibition of immune responses in the CNS during
nematode infection.
Keywords Helminth therapy · Nematodes · EAE ·
Immunomodulation
Correction to: Expanding Diversity and Common Goal
of Regulatory T and B Cells. I: Origin, Phenotype, Mechanisms
Katarzyna Bocian1 · Ewelina Kiernozek1 · Joanna Domagała‑Kulawik2 ·
Grażyna Korczak‑Kowalska1,4 · Anna Stelmaszczyk‑Emmel3 · Nadzieja Drela1
Published online: 10 October 2017
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017
Erratum to: Arch. Immunol. Ther. Exp.
DOI 10.1007/s00005‑017‑0469‑3
The original article has been published without acknowledg-
ment section. The acknowledgement section is given below
for your reading.
Acknowledgements This work was supported by Grant no.
STRATAGMED2/267976/13/NCBR/2015.
Immunotherapy as an Option for Cancer Treatment
Tillmann Rusch1 · Jagadeesh Bayry2 · Jens Werner1,3 · Ivan Shevchenko4 ·
Alexandr V. Bazhin1,
Abstract The progress in melanoma immunotherapy high-
lights the importance of immunotherapy for cancer treat-
ment. Although the concept of immunotherapy emerged
in the beginning of the twentieth century, the end of the
century signaled the start of modern immunotherapy, which
has recently allowed a staggering progress in the field of
cancer immunotherapy. Currently, there is a wide variety of
immunotherapeutic approaches and critical improvements
are continually being made. Among different immunothera-
peutic strategies, therapies based on the blockade of immune
checkpoint molecules have shown unparalleled efficacy in
late-stage cancer patients. Pre-clinical research using ex vivo
and in vivo approaches demonstrates the promise of numer-
ous novel strategies for the immunotherapy of cancer.
Keywords Immunotherapy · Immune editing · Cancer
vaccine · Adoptive cell transfer · Monoclonal antibody ·
Adjuvants · Checkpoint inhibitors · Cytokines