Application of Genome Editing Techniques in Immunology
Agata O. Zych · Malgorzata Bajor · Radoslaw Zagozdzon
Abstract
The idea of using the effector immune cells to specifically fight cancer has recently evolved into an exciting concept of adoptive cell therapies. Indeed, genetically engineered T cells expressing on their surface recombinant, cancer-targeted receptors have been shown to induce promising response in oncological patients. However, in addition to exogenous expression of such receptors, there is also a need for disruption of certain genes in the immune cells to achieve more potent disease-targeted actions, to produce universal chimeric antigen receptor-based therapies or to study the signaling pathways in detail. In this review, we present novel genetic engineering methods, mainly TALEN and CRISPR/Cas9 systems, that can be used for such purposes. These unique techniques may contribute to creating more successful immune therapies against cancer or prospectively other diseases as well.
Keywords Adoptive therapy · Cancer · Viral diseases · Immunotherapy · TALEN · CRISPR/Cas9 · Genome editing
The Phenomenon of Neutrophil Extracellular Traps in Vascular Diseases
Dorota Dąbrowska · Ewa Jabłońska · Marzena Garley · Jolanta Sawicka‑Powierza · Karolina Nowak
Abstract
Vascular diseases constitute a global health issue due to the increasing number of cases of patients with these diseases. The pathogenesis of the majority of these diseases, including atherosclerosis and thrombosis, is complex and not yet fully understood. One of the major causes for their occurrence can be immune disorders resulting in the development of a chronic inflammation within the vessels. In recent years, studies have placed emphasis on the role of neutrophils in the development of these diseases, i.e., the discovery of neutrophil extracellular traps (NETs) demonstrated that the structures released by the cells may contribute to the enhancement of inflammatory reactions and cell damage. This article summarizes current knowledge on the role of NETs during atherosclerosis, thrombosis and small-vessel vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV).
Keywords Neutrophils · NETs · Atherosclerosis · Thrombosis · Small-vessel vasculitis · AAV
Humanized Mice as Unique Tools for Human-Specific Studies
Kylie Su Mei Yong1,2 · Zhisheng Her1 · Qingfeng Chen1,3,4
Received: 15 August 2017 / Accepted: 4 January 2018 / Published online: 7 February 2018
© The Author(s) 2018. This article is an open access publication
Abstract
With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized
mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis
and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted
with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements
on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in
humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant
promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This
review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform
as well as solutions to improve humanized mice for future clinical use.
Keywords Humanized mice · Human specificity · Precision therapy · Human diseases · Drug testing
Adverse Effects Associated with Clinical Applications of CAR
Engineered T Cells
Zohreh Sadat Badieyan1 · Sayed Shahabuddin Hoseini2
Received: 21 May 2017 / Accepted: 18 October 2017 / Published online: 9 February 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Cancer has been ranked as the second leading cause of death in the United States. To reduce cancer mortality, immunotherapy
is gaining momentum among other therapeutic modalities, due to its impressive results in clinical trials. The genetically
engineered T cells expressing chimeric antigen receptors (CARs) are emerging as a new approach in cancer immunotherapy,
with the most successful outcomes in the refractory/relapse hematologic malignancies. However, the widespread clinical
applications are limited by adverse effects some of which are life-threatening. Strategies to reduce the chance of side effects
as well as close monitoring, rapid diagnosis and proper treatment of side effects are necessary to take the most advantages
of this valuable therapy. Here we review the reported toxicities associated with CAR engineered T cells, the strategies to
ameliorate the toxicity, and further techniques and designs leading to a safer CAR T-cell therapy.
Keywords Engineered T cells · Chimeric antigen receptors (CARs) · Immunotherapy · Adverse effects
Intestinal Barrier Impairment and Immune Activation in HIV-Infected
Advanced Late Presenters are Not Dependent on CD4 Recovery
Kamila Wójcik‑Cichy1 · Anna Piekarska1 · Elżbieta Jabłonowska1
Received: 3 June 2017 / Accepted: 19 January 2018 / Published online: 21 February 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Damage of the mucosal barrier in HIV infection, microbial translocation, and immune activation can persist even in patients
on successful antiretroviral therapy (ART) especially advanced late presenters. The aim of this study was to find factors
that determine immune activation and bacterial translocation in HIV-infected advanced late presenters on suppressive ART.
Forty-three late presenters (CD4 < 200 cells/μl prior to ART) on successful ART (more than 2 years of ART) with optimal
and suboptimal CD4 recovery were enrolled into this study. The serum concentrations of intestinal fatty acid-binding peptide
(I-FABP), zonulin-1, programmed cell death-1 protein (PCDP-1), and soluble (s)CD14 were measured using the ELISA test.
We found higher serum levels of I-FABP and sCD14 in successfully antiretroviral-treated advanced late presenters com-
pared to healthy subjects (p < 0.0001 and p = 0.0004). The serum concentration of PCDP-1 and zonulin-1 in HIV-infected
patients did not differ from healthy controls. The levels of microbial translocation and immune activation markers were not
associated with the degree of CD4 recovery. A serum concentration of I-FABP above 2.03 ng/ml was independently associ-
ated with a shorter ART (OR 0.78; p = 0.03). Older age was related to serum levels of sCD14 above 2.35 μg/ml (OR 1.1;
p = 0.01). Higher serum levels of I-FABP and sCD14 in successfully antiretroviral-treated advanced late presenters compared
to healthy subjects suggest an incomplete reconstruction of the intestinal barrier and sustained immune activation despite
good CD4 recovery. It was not the CD4 level, but the length of the suppressive ART that was found to be associated with
the restoration of the intestinal barrier.
Keywords HIV infection · Advanced late presenters · Microbial translocation and immune activation
Muscle Stem/Progenitor Cells and Mesenchymal Stem Cells of Bone
Marrow Origin for Skeletal Muscle Regeneration in Muscular
Dystrophies
Aleksandra Klimczak1,2 · Urszula Kozlowska1,2 · Maciej Kurpisz2
Received: 6 April 2017 / Accepted: 30 January 2018 / Published online: 13 March 2018
© The Author(s) 2018
Abstract
Muscular dystrophies represent a group of diseases which may develop in several forms, and severity of the disease is usu-
ally associated with gene mutations. In skeletal muscle regeneration and in muscular dystrophies, both innate and adaptive
immune responses are involved. The regenerative potential of mesenchymal stem/stromal cells (MSCs) of bone marrow
origin was confirmed by the ability to differentiate into diverse tissues and by their immunomodulatory and anti-inflammatory
properties by secretion of a variety of growth factors and anti-inflammatory cytokines. Skeletal muscle comprises different
types of stem/progenitor cells such as satellite cells and non-satellite stem cells including MSCs, interstitial stem cells positive
for stress mediator PW1 expression and negative for PAX7 called PICs (PW1+/PAX7− interstitial cells), fibro/adipogenic
progenitors/mesenchymal stem cells, muscle side population cells and muscle resident pericytes, and all of them actively
participate in the muscle regeneration process. In this review, we present biological properties of MSCs of bone marrow
origin and a heterogeneous population of muscle-resident stem/progenitor cells, their interaction with the inflammatory
environment of dystrophic muscle and potential implications for cellular therapies for muscle regeneration. Subsequently, we
propose—based on current research results, conclusions, and our own experience—hypothetical mechanisms for modulation
of the complete muscle regeneration process to treat muscular dystrophies.
Keywords Muscle stem/progenitor cells · Mesenchymal stem cells · Skeletal muscle regeneration · Muscular dystrophies
The Microbial Endocrinology of Pseudomonas aeruginosa:
Inflammatory and Immune Perspectives
Valerie F. L. Yong1 · Min Min Soh1 · Tavleen Kaur Jaggi1 · Micheál Mac Aogáin1 · Sanjay H. Chotirmall1
Received: 13 August 2017 / Accepted: 9 February 2018 / Published online: 14 March 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Pseudomonas aeruginosa is a major pathogen responsible for both acute and chronic infection. Known as a colonising
pathogen of the cystic fibrosis (CF) lung, it is implicated in other settings such as bronchiectasis. It has the ability to cause
acute disseminated or localised infection particularly in the immunocompromised. Human hormones have been highlighted
as potential regulators of bacterial virulence through crosstalk between analogous “quorum sensing” (QS) systems present in
the bacteria that respond to mammalian hormones. Pseudomonas aeruginosa is known to utilise interconnected QS systems
to coordinate its virulence and evade various aspects of the host immune system activated in response to infection. Several
human hormones demonstrate an influence on P. aeruginosa growth and virulence. This inter-kingdom signalling, termed
“microbial endocrinology” has important implications for host–microbe interaction during infection and, potentially opens
up novel avenues for therapeutic intervention. This phenomenon, supported by the existence of sexual dichotomies in both
microbial infection and chronic lung diseases such as CF is potentially explained by sex hormones and their influence on
the infective process. This review summarises our current understanding of the microbial endocrinology of P. aeruginosa,
including its endogenous QS systems and their intersection with human endocrinology, pathogenesis of infection and the
host immune system.
Keywords Pseudomonas aeruginosa · Endocrinology · Sex hormones · Immunology · Quorum sensing
Role of Chicoric Acid and 13-Cis Retinoic Acid in Mycobacterium
tuberculosis Infection Control by Human U937 Macrophage
Bahareh Abd‑Nikfarjam1,2 · Marjan Nassiri‑Asl1,3 · Mehri Hajiaghayi1,2 · Taghi Naserpour Farivar1,4
Received: 2 October 2017 / Accepted: 22 February 2018 / Published online: 27 April 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Mycobacterium tuberculosis (Mtb) survives and proliferates within the main cells of the innate immune system, macrophages.
The goal of our study was to investigate the immunostimulatory effects of 13-cis retinoic acid (RA) and chicoric acid (CA)
in human U937 macrophages against H37Ra Mtb infection by evaluating its potential role in the cell surface expression of
HLA-DR, CD14 molecules as well as nitric oxide (NO) production and prevention of the Mtb growth within macrophages.
In this study, we investigated the effects of 13-cis RA and CA on Mtb-infected macrophages using flowcytometry and Griess
methods, respectively. Moreover, inhibitory effect of 13-cis RA and CA on Mtb growth within macrophages were assessed
using colony-forming unit. 13-Cis RA and CA enhanced the cell surface expression of HLA-DR and CD14 molecules on
U937 macrophages and prevented the growth of Mtb within macrophages. In addition, 13-cis RA and CA, have increased
NO generation compared to untreated control macrophages, significantly (p < 0.001). Both drugs have a significant inhibi-
tory effect on Mtb growth but CA at the highest concentration was more potent than 13-cis RA (p < 0.05). The results of
our study showed that infected U937 macrophages treated with 13-cis RA and CA represented significant increases in NO
production, CD14 and HLA-DR expression and also prevents intracellular survival of Mtb. Therefore, 13-cis RA and CA
may have a significant therapeutic approach in the control of Mtb infection.
Keywords Mycobacterium tuberculosis · 13-Cis retinoic acid · Chicoric acid · U937 macrophages
Detection of 16α-Hydroxyestrone-histone 1 Adduct as High-Affinity
Antigen for Rheumatoid Arthritis Autoantibodies
Wahid Ali Khan1 · Gaffar Sarwar Zaman2
Received: 22 November 2017 / Accepted: 12 April 2018 / Published online: 30 April 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Increased concentrations of 16α-hydroxyestrone (16α-OHE1) have been observed in rheumatoid arthritis (RA), but the
underlying mechanism of this remains elusive. Here we aimed to identify the role played by 16α-OHE1 in RA. In 40 RA
patients, the specificities of antibodies from the sera of these patients were checked by direct binding, inhibition ELISA,
and quantitative precipitation titration. Competition ELISA was also used for the estimation of 16α-OHE1 in the serum of
different RA patients. RA IgG from a patient’s sera showed strong recognition to 16α-OHE1-H1 (histone 1) adduct in com-
parison to control subjects (p < 0.001), as the formation of this adduct brings out various biochemical changes that might
generate neo-epitopes, which have been well-recognized by these antibodies. The affinity of RA antibodies for 16α-OHE1-H1
(1.10 × 10− 7 M) was high, as detected by the Langmuir plot. Comparing RA patients to the controls, no significant differences
were detected in the level of 16α-OHE1 or 2-hydroxyestrone/16α-OHE1 ratio. 16α-OHE1-H1 might have an antigenic role
and function as a high-affinity antigen for RA autoantibodies and, therefore, could be used as a biomarker for this disease.
Keywords 16α-Hydroxyestrone · Histone · Rheumatoid arthritis · Antibodies · ELISA
Changes in MiRNA-5196 Expression as a Potential Biomarker of Anti-
TNF-α Therapy in Rheumatoid Arthritis and Ankylosing Spondylitis
Patients
Marzena Ciechomska1,2 · Krzysztof Bonek3 · Michal Merdas2 · Patryk Zarecki2 · Jerzy Swierkot4 · Piotr Gluszko3 ·
Katarzyna Bogunia‑Kubik2,5 · Wlodzimierz Maslinski1
Received: 6 November 2017 / Accepted: 10 April 2018 / Published online: 9 May 2018
© The Author(s) 2018
Abstract
In this study, we analysed the expression level of sera circulating miRNA-5196 in rheumatoid arthritis (RA) and ankylosing
spondylitis (AS) patients before and after tumor necrosis factor (TNF)-α therapy as biomarkers predicting positive treatment
outcome. We enrolled 10 RA patients, 13 AS patients, and 12 healthy individuals in the study. The expression of miRNA-
5196 was measured by real-time polymerase chain reaction before and after anti-TNF-α therapy. Disease activity of RA
patients was assessed using disease activity score 28 (DAS28), whereas ankylosing spondylitis DAS (ASDAS) was used in
AS patients. MiRNA-5196 expression was significantly higher in patients with RA and AS before TNF-α therapy than in
those following anti-TNF-α therapy and healthy controls. Changes in miRNA-5196 expression positively correlated with delta
DAS28 or delta ASDAS, respectively, following TNF-α therapy. In contrast, changes in C-reactive protein (CRP) levels in
RA and AS patients did not positively correlate with DAS28 or ASDAS changes. Receiver-operating characteristic analysis
showed better diagnostic accuracy of miRNA-5196 expression both in RA (area under curve (AUC) = 0.87, p = 0.055) and
AS patients (AUC = 0.90, p = 0.050) compared to CRP levels in RA (AUC = 0.75, p = 0.201) and AS patients (AUC = 0.85,
p = 0.086) upon biologic therapy treatment. Finding novel biomarkers, including miRNA-5196 which allow to predict and
monitor anti-TNF-α response, would be of clinical value especially during the early phase of RA or AS development.
Keywords MiRNA · Biomarker · Rheumatoid arthritis · Ankylosing spondylitis · Anti-TNF-α · Biologic therapy
Differences in the Expression of TLR-2, NOD2, and NF-κB in Placenta
Between Twins
Łukasz Szylberg1,4,5 · Magdalena Bodnar1 · Anna Lebioda2 · Patrycja Krepska3 · Adam Kowalewski1 ·
Grzegorz Bręborowicz2 · Andrzej Marszałek4
Received: 2 December 2017 / Accepted: 8 May 2018 / Published online: 23 May 2018
© The Author(s) 2018
Abstract
Dizygotic twins share the same type of genetic relationship as non-twin siblings. Whereas monozygotic (MZ) twins are
considered to have identical genetic material, they still differ. There is a number of reasons for early MZ twin discordance,
including differences in the in utero environment, stochasticity, genetic mosaicism, and epigenetic factors. During gesta-
tion, the efficient innate immune system is of utmost importance. Our study was based on immunohistochemical evaluation
of the differences in innate immune protein expression (TLR-2, NOD2, and NF-κB) in the 95 placentas between twins.
Our study revealed statistical significant differences between diamniotic–dichorionic and monoamniotic–dichorionic twins.
Monoamniotic–monochorionic twins exhibited no significant differences in protein expressions. To identify epigenetic fac-
tors causing the differences between twins, we made a series of comparisons with clinical data. The study revealed more
cases with infections, miscarriages, in vitro fertilization, and premature rupture of membranes within the group with higher
differences level of NF-κB, NOD2 and TLR-2 between twins. In case of twin-to-twin transfusion syndrome, there were no
significant differences in innate immune protein expressions between twins. These results show that dissimilar genetic mate-
rial and separate in utero environment promote discordance in innate immune protein expressions between twins. Moreover,
additional blood flow between twins may be favorable in life-threatening conditions ensuring similar microenvironment.
Keywords Placenta · Immunology · Twins · NOD2 · TLR-2 · NF-κB
Deviations in Peripheral Blood Cell Populations are Associated
with the Stage of Primary Biliary Cholangitis and Presence of Itching
Halina Cichoż‑Lach1 · Ewelina Grywalska2 · Agata Michalak1 · Agnieszka Kowalik1 · Michał Mielnik2 ·
Jacek Roliński2
Received: 4 March 2018 / Accepted: 29 May 2018 / Published online: 27 June 2018
© The Author(s) 2018
Abstract
To evaluate the role of Th17, Treg cells, activated T CD3+ and B CD19+ lymphocytes in primary biliary cholangitis (PBC)
patients. 40 female patients with PBC and 20 healthy donors were enrolled in this study. The percentages and absolute counts
of Th17, Treg, activated T CD3+, B CD19+, NK, NKT-like lymphocytes were measured by flow cytometry. Our research
revealed significantly lower frequencies and absolute counts of CD4+CD25+FOXP3+ Treg cells (p < 0.0001), higher percent-
ages and absolute counts of Th17 cells (IL-17A+CD3+CD4+; p < 0.0001 and p = 0.009, respectively), CD3−/CD16+CD56+
NK cells (p < 0.0001 and p = 0.039, respectively), CD3+/CD16+CD56+ NKT-like cells (p < 0.0001 and p = 0.048, respec-
tively). There were also higher percentages and numbers of B CD19+ lymphocytes (p = 0.002 and p = 0.001, respectively)
and higher percentages and absolute counts of activated B CD19+CD25+ cells (p = 0.007 and p = 0.002, respectively).
Moreover, we observed a statistically significant correlation between the presence of itching and particular peripheral blood
subpopulations in PBC patients. Absolute counts of both CD4+CD3+ cells (p = 0.0119) and CD3+CD25+ cells (p = 0.0329)
were lower in patients with pruritus. A similar dependency was noted in reference to percentages of NKT-like cells (CD3+/
CD16+CD56+; p = 0.0359) and (CD3+) T lymphocytes (p = 0.0302). Th17 and Treg cells are involved in the course of PBC.
There is also the association between the pruritus and peripheral blood subpopulations.
Keywords Primary biliary cholangitis · Immune dysfunction · Pruritus
Analysis of Polymorphisms in the Mediator Complex Subunit 13-like
(Med13L) Gene in the Context of Immune Function and Development
of Experimental Arthritis
Samra Sardar1,2 · Katrine Kanne1,3 · Åsa Andersson1,4
Received: 15 February 2018 / Accepted: 15 May 2018 / Published online: 27 June 2018
© The Author(s) 2018
Abstract
The Mediator complex subunit 13-like (MED13L) protein is part of the multi-protein mediator complex and plays an
important role in gene transcription. Polymorphisms in the MED13L gene have been linked to congenital heart anomalies
and intellectual disabilities. Despite recent evidence of indirect links of MED13L to cytokine release and inflammation,
impact of genetic variations in MED13L on immune cells remains unexplored. The B10.RIII and RIIIS/J mouse strains vary
in susceptibility to induced experimental autoimmune disease models. From sequencing data of the two mouse strains, we
identified six polymorphisms in the coding regions of Med13L. Using congenic mice, we studied the effect of these polymor-
phisms on immune cell development and function along with susceptibility to collagen-induced arthritis, an animal model
for rheumatoid arthritis. Combining in vivo disease data, in vitro functional data, and computational analysis of the reported
non-synonymous polymorphisms, we report that genetic polymorphisms in Med13L do not affect the immune phenotype in
these mice and are predicted to be non-disease associated.
Keywords MED13L · THRAP2 · Mediator complex · Collagen-induced arthritis · Rheumatoid arthritis · Congenic mice
Transplant Tolerance: Current Insights and Strategies for Long-Term
Survival of Xenografts
Lu Liu1,2 · Chen He3 · Jintao Liu2 · Zhiwu Lv2 · Ganlu Wang2 · Hanchao Gao1 · Yifan Dai4 · David K. C. Cooper5 ·
Zhiming Cai1 · Lisha Mou1
Received: 15 March 2018 / Accepted: 18 June 2018 / Published online: 10 July 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Xenotransplantation is an attractive solution to the problem of allograft shortage. However, transplants across discordant
species barriers are subject to vigorous immunologic and pathobiologic hurdles, some of which might be overcome with
the induction of immunologic tolerance. Several strategies have been designed to induce tolerance to a xenograft at both the
central (including induction of mixed chimerism and thymic transplantation) and peripheral (including adoptive transfer of
regulatory cells and blocking T cell costimulation) levels. Currently, xenograft tolerance has been well-established in rodent
models, but these protocols have not yet achieved similar success in nonhuman primates. This review will discuss the major
barriers that impede the establishment of immunological tolerance across xenogeneic barriers and the potential solution to
these challenges, and provide a perspective on the future of the development of novel tolerance-inducing strategies.
Keywords Costimulation blockade · Immunological tolerance · Mixed chimerism · Thymic transplantation ·
Xenotransplantation
Baicalin Attenuates Joint Pain and Muscle Dysfunction by Inhibiting
Muscular Oxidative Stress in an Experimental Osteoarthritis Rat Model
De‑sheng Chen1 · Jian‑gang Cao1 · Bo Zhu1 · Zeng‑liang Wang1 · Tong‑fu Wang1 · Jian‑jun Tang1
Received: 22 December 2017 / Accepted: 4 June 2018 / Published online: 3 August 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Osteoarthritis (OA) is the most common degenerative joint disease, and causes major pain and disability in adults. It has
been reported that muscle weakness and inflammation contribute to osteoarthritis development and progression. Oxidative
stress plays important roles in muscle dysfunction and inflammation in osteomyelitis. Baicalin, the major active constituent
of the isolated root of Scutellarialateriflora Georgi, has been shown to have anti-oxidative and anti-inflammatory effects.
In this study, we evaluated the potential effects of baicalin on osteoarthritis. We established experimental osteoarthritis rat
model, applied baicalin to the rats, and then explored the potential protective effect of baicalin on osteoarthritis severity,
muscle dysfunction, and oxidative stress. Baicalin alleviated severity of OA in rats. Baicalin application attenuated muscle
dysfunction in OA rats by increasing citrate synthase activity, myosin heavy chain IIa expression, and decreasing interleukin
6 production. Baicalin decreased muscular reactive oxygen species generation in OA rats. Baicalin inhibited nuclear fac-
tor erythroid-derived 2-like 2 expression in OA rats. Baicalin attenuated osteoarthritis in rat by inhibiting oxidative stress.
Keywords Baicalin · Osteoarthritis · Joint pain · Muscle · Oxidative stress
Innate Lymphoid Cells in Inflammatory Bowel Disease
Jian Li1 · Sarah C. Glover1
Received: 5 October 2017 / Accepted: 18 May 2018 / Published online: 29 August 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a complex chronic inflammatory condi-
tion of the human gut of unknown causes. Traditionally, dysregulated adaptive immune responses are thought to play a major
role; however, accumulating evidence suggests that innate immunity also contributes to this process. Innate lymphoid cells
(ILCs) are recently identified important components of innate immunity. They have critical roles in immunity, tissue develop-
ment and remodeling. Numerous researchers have linked ILCs to the pathogenesis of IBD. In this review, we describe recent
progress in our understanding about the phenotype and function alterations of ILCs as well as its interactions with other key
mucosal cells in the gut of IBD patients. A better delineation of the ILCs’ behavior in the human intestine will contribute to
our understanding of ILCs biology and provide valuable insights for potential therapeutic target selection for IBD patients.
Keywords Innate lymphoid cells · Inflammatory bowel disease · Mucosal homeostasis · T-cells
Celiac Disease Autoimmunity
Miguel Ángel López Casado1 · Pedro Lorite2 · Candelaria Ponce de León2 · Teresa Palomeque2 ·
Maria Isabel Torres2
Received: 17 October 2017 / Accepted: 6 July 2018 / Published online: 25 August 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Celiac disease is an autoimmune condition triggered by the ingestion of gluten, the protein fraction of wheat, barley and rye. It
is not simply an intestinal disease; it is multifactorial caused by many different genetic factors acting together with non-genetic
causes. Similar to other autoimmune diseases, celiac disease is a polygenic disorder for which the major histocompatibility
complex locus is the most important genetic factor, and is the result of an immune response to self-antigens leading to tissue
destruction and the autoantibodies production. Celiac disease exemplifies how an illness can have autoimmune-like features
having to be driven by exogenous antigen and how can be reasonably considered as a model of organ-specific autoimmunity.
Keywords Celiac disease · Autoimmunity · Immune tolerance · Autoantibodies
Systemic Treatment for Severe Atopic Dermatitis
Mara Giavina‑Bianchi1 · Pedro Giavina‑Bianchi1
Received: 16 April 2018 / Accepted: 10 August 2018 / Published online: 22 August 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Atopic dermatitis (AD) is a chronic inflammatory, relapsing disease of the skin, characterized by intense pruritus, maculo-
papular or vesicular erythematous lesions and scaling, sometimes accompanied by oozing, crusts and/or lichenification that
has a negative impact on patients’ quality of life. Prevalence is higher in children, around 15%, and approximately 5% in
adults. Before introducing systemic therapy, it is mandatory to review patients’ adherence to the correct use of topical treat-
ments (corticosteroids, calcineurin inhibitors or cresoborole) and/or phototherapy. Ensure that environmental measures are
being taken care of, irritant or proven allergic substances are not in use and even if the diagnostic is correct. If all is being
done and topical treatment with corticosteroid, emollients and phototherapy have not been sufficient to achieve a good con-
trol in AD of adults or children patients, it is time to consider systemic agents. Up to now, most of systemic treatments were
based on immunosuppressive therapies, being cyclosporine A, the usually first choice for moderate-to-severe AD. Recently,
biologic drugs have been developed and approved for AD, as dupilumab, and a whole new group of drugs is giving much
hope for patients to have a better control of the disease with less side effects.
Keywords Systemic treatment · Atopic dermatitis · Review · Immunosuppressive agents · Biologic agents
Manipulation of Non-canonical NF-κB Signaling by Non-oncogenic
Viruses
Justyna Struzik1 · Lidia Szulc‑Dąbrowska1
Received: 22 March 2018 / Accepted: 19 June 2018 / Published online: 8 September 2018
© The Author(s) 2018
Abstract
Nuclear factor (NF)-κB is a major regulator of antiviral response. Viral pathogens exploit NF-κB activation pathways to avoid
cellular mechanisms that eliminate the infection. Canonical (classical) NF-κB signaling, which regulates innate immune
response, cell survival and inflammation, is often manipulated by viral pathogens that can counteract antiviral response.
Oncogenic viruses can modulate not only canonical, but also non-canonical (alternative) NF-κB activation pathways. The
non-canonical NF-κB signaling is responsible for adaptive immunity and plays a role in lymphoid organogenesis, B cell
development, as well as bone metabolism. Thus, non-canonical NF-κB activation has been linked to lymphoid malignan-
cies. However, some data strongly suggest that the non-canonical NF-κB activation pathway may also function in innate
immunity and is modulated by certain non-oncogenic viruses. Collectively, these findings show the importance of studying
the impact of different groups of viral pathogens on alternative NF-κB activation. This mini-review focuses on the influence
of non-oncogenic viruses on the components of non-canonical NF-κB signaling.
Keywords Antiviral immunity · Non-canonical NF-κB signaling · Non-oncogenic viruses
TLR2 Expression on Leukemic B Cells from Patients with Chronic
Lymphocytic Leukemia
Agata Szymańska1 · Agnieszka Bojarska‑Junak2 · Arkadiusz Drobiecki3 · Waldemar Tomczak4 · Jacek Roliński2 ·
Marek Hus4 · Iwona Hus1
Received: 9 January 2018 / Accepted: 6 July 2018 / Published online: 8 September 2018
© The Author(s) 2018
Abstract
Antigenic stimulation is considered as a possible trigger of neoplastic transformation in chronic lymphocytic leukemia (CLL).
B-cell receptor plays a key role in the interactions between the microenvironment and leukemic cells; however, an important
role has also been attributed to Toll-like receptors (TLRs). It is believed that disorders of TLR expression may play a part
in the pathogenesis of CLL. In this study, we investigated the potential role of TLR2 in CLL by analyzing its expression on
leukemic B cells in correlation with clinical and laboratory parameters characterizing disease activity and patients’ immune
status. We assessed the frequencies of TLR2+/CD19+ cells by the flow cytometry method in peripheral blood of 119 patients
with CLL. The percentage of TLR2+/CD19+ cells was significantly lower in patients with CLL as compared to the healthy
volunteers. There was also a lower percentage of TLR2+/CD19+ cells in CLL patients with poor prognostic factors, such
as ZAP70 and/or CD38 expression, 17p and/or 11q deletion. On the other hand, among patients with del(13q14) associ-
ated with favorable prognosis, the percentage of TLR2+/CD19+ cells was higher than among those with del(11q22) and/or
del(17p13) as well as in the control group. We found an association between low percentage of CD19+/CD5+/TLR2+ cells
and shorter time to treatment. We also demonstrated the relationship between low percentage of CD19+/CD5+ TLR2-positive
and overall survival (OS) of CLL patients. CLL patients with a proportion of 1.6% TLR2-positive B CD5+ cells (according
to the receiver operating characteristic curve analysis) or more had a longer time to treatment and longer OS than the group
with a lower percentage of TLR2 positive cells. To sum up, the results of the study suggest that low TLR2 expression is
associated with poor prognosis in CLL patients. The monitoring of CD19+/CD5+/TLR2+ cells number may provide useful
information on disease activity. Level of TLR2 expression on leukemic B cells may be an important factor of immunologi-
cal dysfunction for patients with CLL. Our study suggests that TLR2 could becomes potential biological markers for the
clinical outcome in patients with CLL.
Keywords Chronic lymphocytic leukemia · Toll-like receptors · TLR2 expression · Prognostic factors
Cellular Interactions in the Intestinal Stem Cell Niche
Agnieszka Pastuła1,3,4,5,6 · Janusz Marcinkiewicz2
Received: 24 April 2018 / Accepted: 6 July 2018 / Published online: 21 September 2018
© The Author(s) 2018
Abstract
Epithelial cells are one of the most actively cycling cells in a mammalian organism and therefore are prone to malignant
transformation. Already during organogenesis, the connective tissue (mesenchyme) provides instructive signals for the
epithelium. In an adult organism, the mesenchyme is believed to provide crucial regulatory signals for the maintenance
and regeneration of epithelial cells. Here, we discuss the role of intestinal myofibroblasts, α-smooth muscle actin-positive
stromal (mesenchymal) cells, as an important regulatory part of the intestinal stem cell niche. Better understanding of the
cross-talk between myofibroblasts and the epithelium in the intestine has implications for advances in regenerative medicine,
and improved therapeutic strategies for inflammatory bowel disease, intestinal fibrosis and colorectal cancer.
Keywords Mesenchymal–epithelial cross-talk · Inflammatory bowel disease · Myofibroblasts · Intestinal stem cells · Stem
cell niche
Role of Monocytes in the Pathogenesis of Dengue
Jorge Andrés Castillo1 · Juan Sebastián Naranjo2 · Mauricio Rojas2,3 · Diana Castaño2 · Paula Andrea Velilla1
Received: 30 May 2017 / Accepted: 3 September 2018 / Published online: 20 September 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Diseases caused by dengue virus (DENV) are a major public health problem worldwide, considered one of the infections
with more prevalence in tropical and subtropical zones of the world. Despite the intense research in the pathogenesis of
DENV, this feature is not well understood. One of the main target cells for DENV infection is monocytes; these phagocytes
can play a dual role, since they are essential to control viremia, but they also participate in the induction of tissue damage
during DENV infection. Monocytes produce different pro-inflammatory cytokines and chemokines in response to infection,
and also mediate endothelial damage. In peripheral blood, monocytes can be divided into three different subpopulations,
namely classical, intermediate and non-classical, which differ in frequency, cytokine production, among others. Studies in
the last years suggest that non-classical monocytes have higher affinity for microvasculature endothelium compared to other
type of monocytes, which implies that they could be more involved in the increase of endothelial permeability observed
during DENV infection. This review provides a general view of the role of monocytes and their subpopulations in DENV
pathogenesis and its effect in viral replication. Finally, the potential contribution of these phagocytes in the alterations of
endothelial permeability is discussed.
Keywords Dengue virus · Monocytes · Monocyte subpopulations · Endothelial permeability · Dengue virus pathogenesis
Precision/Personalized Medicine in Allergic Diseases and Asthma
Umut Can Kucuksezer1 · Cevdet Ozdemir2 · Mubeccel Akdis3,4 · Cezmi A. Akdis3,4
Received: 24 September 2017 / Accepted: 16 September 2018 / Published online: 24 September 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Like many other chronic diseases, every allergic patient has different characteristics based on clinical course, treatment
responsiveness and disease outcomes, which are associated with the genetic and epigenetic control of molecular mechanisms
and environment. This variability necessitates the establishment of patient-tailored and precision approaches in handling
allergic disorders. Better understanding of the underlying pathophysiological mechanisms for the development of allergic
disorders will provide more rationale strategies based on individual cases in controlling and treating these disorders. Endotyp-
ing, phenotyping, genotyping and theratyping, and biomarkers are keywords in this area and have been gaining lots of atten-
tion in the field of precision medicine, which aims to revolutionize patient care and develop better prevention and treatment
strategies. In addition, precision health is a new concept that brings precise approaches to the scene for being healthy and
prevention of allergic disease and asthma. The specialty of allergy has a leading role in the field, because allergen-specific
immunotherapy started 105 years ago, and is historically a leading personalized/precision medicine approach in all medicine
disciplines providing the possibility of cure in an individualized manner instead of conventional symptomatic treatments.
Keywords Allergy · Asthma · Biomarker · Endotype · Phenotype · Theratype · Genotype · Cytokines · Precision medicine ·
Personalized medicine
Interleukin-22 and Its Correlation with Disease Activity in Plaque
Psoriasis
Bartłomiej Wawrzycki1 · Aldona Pietrzak1 · Ewelina Grywalska2 · Dorota Krasowska1 · Grażyna Chodorowska1 ·
Jacek Roliński2
Received: 18 July 2018 / Accepted: 17 September 2018 / Published online: 5 October 2018
© The Author(s) 2018
Abstract
Psoriasis is a chronic debilitating skin disease with an estimated prevalence reaching 2% of the worldwide population.
Psoriatic disease is driven by a network of complicated reciprocal interactions among innate and adaptive mechanisms of
immune system with structural components of the skin. Interleukin (IL)-22 mediates keratinocyte proliferation and epider-
mal hyperplasia, inhibits terminal differentiation of keratinocytes, and induces the production of antimicrobial proteins.
The aim of this study was the assessment of IL-22 levels and its correlation with disease activity in plaque psoriasis. The
study group included 64 patients with mild, moderate and severe psoriasis. Control group was composed of 24 sex- and age-
matched healthy volunteers. IL-22 concentration was assessed in supernatants of T-cell cultures as well as in the plasma of
study and control group with the use of ELISA method. Statistical analysis showed that concentration of IL-22 in cultures
exposed to staphylococcal enterotoxin B was significantly higher than in control samples (p = 0.005) and cultures treated
with IL-12 (p = 0.005). Patients with psoriasis presented significantly higher concentrations of IL-22 than healthy individuals
(p = 0.0000001). In conclusion, IL-22 may collaborate with other soluble factors and cells together forming inflammatory
circuits that otherwise exist as constitutive or inducible pathways in normal skin and become pathologically amplificated in
psoriasis. Targeting IL-22 may be promising as a potential therapeutic for plaque psoriasis.
Keywords Immune system · IL-22 · Psoriasis · T-cell culture
Human Microbiome: Composition and Role in Inflammatory Skin
Diseases
Anna Balato1 · Sara Cacciapuoti2 · Roberta Di Caprio2 · Claudio Marasca2 · Anna Masarà2 · Annunziata Raimondo2 ·
Gabriella Fabbrocini2
Received: 1 February 2018 / Accepted: 3 September 2018 / Published online: 9 October 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
This review focuses on recent evidences about human microbiome composition and functions, exploring the potential impli-
cation of its impairment in some diffuse and invalidating inflammatory skin diseases, such as atopic dermatitis, psoriasis,
hidradenitis suppurativa and acne. We analysed current scientific literature, focusing on the current evidences about gut and
skin microbiome composition and the complex dialogue between microbes and the host. Finally, we examined the conse-
quences of this dialogue for health and skin diseases. This review highlights how human microbes interact with different
anatomic niches modifying the state of immune activation, skin barrier status, microbe–host and microbe–microbe interac-
tions. It also shows as most of the factors affecting gut and skin microorganisms’ activity have demonstrated to be effective
also in modulating chronic inflammatory skin diseases. More and more evidences demonstrate that human microbiome plays
a key role in human health and diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic
and preventive measures in the context of personalized/precision medicine.
Keywords Skin · Microbiome · Bacteria · Inflammatory skin diseases
Building the Prestige of Archivum Immunologiae et Therapiae
Experimentalis: From a Little Known to an Internationally Recognized
Journal
Hubert Krotkiewski1 · Andrzej Górski1 · Michał Zimecki1
Received: 29 September 2018 / Accepted: 1 October 2018 / Published online: 16 October 2018
© The Author(s) 2018
Abstract
Archivum Immunologiae et Therapiae Experimentalis (AITE) was founded in 1953 by Ludwik Hirszfeld, a world famous
Polish physician and scientist in the field of microbiology and immunology. Initially, AITE was published in Polish, but
within a few years, it changed to English to increase the range and number of international readers. In its over 65 year his-
tory, AITE has had several Editors and a number of Publishers. In the period 1977–1991, AITE was listed in the system of
scientific information Current Contents/Life Sciences, but for several years, its impact on the international readership of the
Journal was negligible. The political and economic crisis in Poland in late 1980s led to serious delays in printing of successive
AITE issues, so the Journal was removed from the Current Contents. Year 1991 was a turning point for the Journal, guided
since then by prof. Dubowska-Inglot, who changed its image and format, and allowed acceptance of review articles. In 1999,
prof. Górski became the Editor-in-Chief, giving a new impulse for further development of the Journal. In a consequence,
AITE was accepted to Science Citation Index Expanded (in 2001) and to Institute for Scientific Information Master Journal
List (in 2002). Eventually, AITE has evolved to become a truly international, multidisciplinary journal, publishing original
articles, and reviews relating to basic and clinical immunology, experimental therapy, immunogenetics, transplantology,
microbiology, immunochemistry, as well as bioethics. Currently, AITE is cited in a number of major scientific information
databases. Since 2011, the Journal is published by Springer Publishing House, it has achieved international recognition with
its latest impact factor (for 2017) of 3.018. AITE, whose Editors are professors of Hirszfeld Institute of Immunology and
Experimental Therapy, strengthens the status and position of the Institute as one of the leading scientific institutions in Poland.
Keywords AITE · Ludwik Hirszfeld · Impact factor · Editorial policy · Immunology · Experimental therapy
Characterization of Regulatory T Cells in Preterm and Term Infants
Asmaa M. Zahran1 · Khaled Saad2 · Yasser F. Abdel‑Raheem2 · Khalid I. Elsayh2 · Amira A. El‑Houfey3,4 ·
Mohamed Diab Aboul‑Khair5 · Mohamd A. Alblihed6
Received: 26 July 2018 / Accepted: 17 September 2018 / Published online: 29 October 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Our study aimed to study regulatory T cells (Tregs) and their expression of CD45RA, HLA-DR, and CD39 in preterm and
full-term infants. In an observational study, we used a three-color flow cytometry for determination of Tregs and their expres-
sion of CD45RA, HLA-DR, and CD39 in preterm and full-term infants. The percentages of CD4+CD25+highFoxp3+, CD39+
Tregs, HLA-DR+ Tregs and the expression of Foxp3+ in CD4+CD25+highFoxp3 Tregs cells were significantly lower in neo-
nates when compared to healthy adult controls. The levels of naïve resting Tregs (CD45RA+Tregs) were significantly higher
in neonates than controls. The percentages of CD4+CD25+highFoxp3+Tregs, total CD4+CD25+ and CD4+CD25+high were
significantly higher in preterm infants when compared to the full-term group. Moreover, CD45RA+Tregs were significantly
higher in preterm than in term infants. We found significant inverse correlations between the gestational age and the levels
of both Tregs (r = − 0.395, p = 0.017) and CD45RA+Tregs (r = − 0.422, p = 0.010). Relative to full-term, the frequencies,
and phenotypes of Tregs were affected by prematurity. A larger longitudinal study with a sufficient number of newborns is
needed to investigate the Treg pool of term and preterm infants thoroughly and to explore the association between the Treg
pool and clinical variables.
Keywords Regulatory T cells · Preterm · Full-term newborn
Roles of Myeloid-Derived Suppressor Cells in Cancer Metastasis:
Immunosuppression and Beyond
Amin Pastaki Khoshbin1,2 · Mahsa Eskian1,3,4 · Mahsa Keshavarz‑Fathi1,2,3,5 · Nima Rezaei3,4,6,7
Received: 16 April 2018 / Accepted: 8 October 2018 / Published online: 2 November 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Abstract
Metastasis is the direst face of cancer, and it is not a feature solely dependent on cancer cells; however, a complex interac-
tion between cancer cells and host causes this process. Investigating the mechanisms of metastasis can lead to its control.
Myeloid-derived suppressor cells (MDSCs) are key components of tumor microenvironment that favor cancer progression.
These cells result from altered myelopoiesis in response to the presence of tumor. The most recognized function of MDSCs
is suppressing anti-tumor immune responses. Strikingly, these cells are among important players in cancer dissemination
and metastasis. They can exert their effect on metastatic process by affecting anti-cancer immunity, epithelial–mesenchymal
transition, cancer stem cell formation, angiogenesis, establishing premetastatic niche, and supporting cancer cell survival
and growth in metastatic sites. In this article, we review and discuss the mechanisms by which MDSCs contribute to cancer
metastasis.
Keywords Myeloid-derived suppressor cells · Metastasis · Immunosuppression · Premetastatic niche · Angiogenesis ·
Apoptosis
Modulation of the Immune System in Chronic Hepatitis C and During
Antiviral Interferon-Free Therapy
Arkadiusz Urbanowicz1 · Radosław Zagożdżon1,2,3 · Michał Ciszek1
Received: 31 January 2018 / Accepted: 8 November 2018 / Published online: 15 November 2018
© The Author(s) 2018
Abstract
The treatment of patients with chronic hepatitis C virus (HCV) infection has changed tremendously over the past 2 years,
with an increasing variety of all-oral direct-acting antiviral (DAA) treatment regimens available for different HCV genotypes
and distinct clinical settings. These treatments have significantly improved safety in patients with advanced liver disease
compared with interferon (IFN)-based regimens. HCV modifies the human immune system to escape immunosurveillance
via several mechanisms. One of the basic mechanisms of HCV is the ability to “switch” the immune response by reducing the
activity of cells responsible for the elimination of virus-infected cells. IFN-free DAA treatment regimens provide a unique
opportunity to assess the effect of HCV elimination on the immune system. Abrupt changes in the immune system can in
some cases be responsible for two alarming processes: viral reactivation in patients with chronic hepatitis B and recurrence
of hepatocellular carcinoma in patients with previous successful cancer treatment.
Keywords HCV · Immune system · Direct-acting antivirals · Hepatocellular carcinoma
Correction to: Building the Prestige of Archivum Immunologiae et
Therapiae Experimentalis: From a Little Known to an Internationally
Recognized Journal
Hubert Krotkiewski1 · Andrzej Górski1 · Michał Zimecki1
Published online: 7 December 2018
© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018
Correction to:
Archivum Immunologiae et Therapiae Experimentalis
(2018) 66:407–413
https ://doi.org/10.1007/s0000 5-018-0529-3
“According to JCR data, updated in October 2018 by Clari-
vate Analytics, the corrected IF value of Archivum Immu-
nologiae et Therapiae Experimentalis for the year 2017 is
2.991”.