Review Of Immunology Research Articles

Video podcast: Adoptive Immunotherapy for Cancer

Go to www.immunologicalreviews.com to watch an interview with Guest Editor Carl June. In this interview, Carl June, the Richard M. Vague Professor of Immunotherapy in the Department of Pathology and Laboratory Medicine and the Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania, discusses adoptive immunotherapy for cancer. Dr. June informs us about the history of the field and describes the exciting new applications that are successfully treating cancer patients today. Dr. June also gives an overview of the topics covered by the reviews in Volume 257 of Immunological Reviews.

NOTCH1 Mutations Are Associated With The 14q Deletion In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Deletions of the long arm of chromosome 14 are rare (<5%) but recurrently observed in mature B-cell neoplasms, particularly in CLL. The size of the deletions is variable, and the molecular consequences are unknown. The aim of our study is to characterize this abnormality in a large cohort of patients.The Groupe Francophone de Cytogenetique Hematologique (GFCH) collected data from 89 patients with CLL or Small Lymphocytic Lymphoma (SLL), harboring a del14q. Morphological review was performed for 65 of them and immunological review for 48. All karyotypes were reviewed by members of the GFCH. Fluorescence in situ hybridization (FISH) analysis was performed with CEP12, 13q14, TP53, ATM, 6q21, and IGH probes, and BACs RP11-35D12 and RP11-226F19 covering the ZFP36L1 gene on 14q24.1. SNP-array analysis (illumina omni1, omin2.5) was performed for 37 patients. The IGHV status was analyzed locally, or in our laboratory. The mutation hotspots of NOTCH1 (exon 34), SF3B1 (exons 14-16), XPO1 (exons 14-15), MYD88 (exon 5) and TP53 (exons 4-10) were analyzed by direct sequencing.Patients were classified as 49 CLL Matutes score 4-5, 5 atypical CLL score 3 (all CD5+, CD23+), and 27 SLL. Eight patients were excluded with a Matutes score<3 or not evaluable. The sex ratio M/F was 1.02, the median age at diagnosis was 64.5 years [29-87]. Regarding all CLL, there were 35 (66%) stages A, 10 (19%) stages B and 8 (15%) stages C. The median time between diagnosis and the first treatment (TTT) was 17 months [0-144], the overall survival (OS) at 5 years was 93.7%. For the 27 SLL patients, the median TTT was 1 month [0-85], and the OS at 5 years was 88.1%.The karyotype showed chromosomal translocation in 26/79 (33%) (10 balanced, 16 unbalanced) and was complex (> 3 abnormalities) in 26/79 (33%) cases. Using karyotype and FISH, we observed 28/79 (35%) trisomy 12, 12/79 (15%) 13q14 deletions, 11/80 (14%) TP53 deletions, 5/79 (6%) ATM deletions, 3/76 (4%) 6q21 deletions. The whole CLL cohort showed 15/53 (28%) tri 12, 11/53 (21%) del13q, 8/54 (15%) delTP53, 4/53 (7%) delATM, 2/50 (4%) del6q.IGHV status was not mutated in 41/53 (77%) patients, and the gene IGHV1-69 was rearranged in 21/52 (40%) cases. NOTCH1 gene was mutated in 14/45 (31%) patients, SF3B1 in 2/45 (4%), XPO1 in 2/45 (4%), MYD88 in 0/43, TP53 in 6/43 (14%) cases. A significant association was observed between TP53 disrupted and NOTCH1 mutations (p=.04). NOTCH1 mutation was not correlated with tri12.Regarding all the cytogenetic and molecular data, there was no significant difference between CLL score 4-5 and CLL score 3, and between CLL and SLL.Compared with common CLL in the literature, CLL with del14q dysplayed more tri12 (p<.03) and NOTCH1 mutations (p<.003), less del13q (p<.0006), more unmutated IGHV (p<.00001) and V1-69 repertoire (p<.00001). Compared with common SLL in the literature, SLL with del14q also exhibited more tri12, unmutated IGHV (p<.01) and V1-69 (p<.04).The 14q deletions appeared distributed along chromosome 14 from bands q11 to q32. The centromeric and telomeric breakpoints of the 14q deletion were investigated by FISH or SNP-array when material was available, and allowed us to identify a main group (Group 1) among 4 groups: Group 1: 37/77 (48%) patients, with IGH and ZFP36L1 loci rearranged; Group 2: 17/77 (22%), with ZFP36L1 deleted and IGH not deleted; Group 3: 7/77 (9%), with ZFP36L1 and IGH not deleted; Group 4, 16/77 (21%), all the other combinations. Group 1 showed a deletion del14q24.1-14q32.3 of about 38 megabases, which broke in or near ZFP36L1, and in the IGH gene. It included 26 (70%) CLL score 4-5 and 11 (30%) SLL. When compared to the other groups, Group 1 showed significantly more tri12 (p=.004), and NOTCH1 mutations (p=.02). IGHV status was unmutated in 22/24 (92%) patients in Group 1, 12/24 (50%) harboring the gene V1-69.In conclusion, the size of the 14q deletion is variable, with in about half of the cases a recurrent interstitial deletion 14q24.1-14q32.3. Both CLL and SLL with del14q, particularly with the 14q24.1-14q32.3 deletion, are associated with poor prognosis parameters, like short time to treatment, trisomy 12, NOTCH1 mutated, and unmutated IGHV status, with an overrepresentation of the V1-69 gene. Disclosures:No relevant conflicts of interest to declare.

Cytoskeletal function in the immune system

Cytoskeletal function in the immune system

The Th17 Cell Population and the Immune Homeostasis of the Gastrointestinal Tract

Th17 cells are a recently discovered subset of CD4+ T lymphocytes filling a hole in the repertoire of effector T cells. Th17 cells produce multiple cytokines, with pivotal impact on immune homeostasis, inflammation, and influencing a wide range of intestinal cell targets. The current issue of the International Reviews of Immunology is entirely dedicated to the various roles of Th17 T cells in the immune homeostasis and inflammation occurring in the gut. In addition to describing diverse Th17-mediated molecular pathways, a specific focus is being given to Th17 cell plasticity. This enables the Th17 cells to shift towards a Th1 profile, or to express IL-22, a protective cytokine in experimental colitis. Participation of microbiota-specific Th17 cells to normal immune homeostasis, and their role in the pathogenesis of inflammatory bowel disease (IBD), or of gluten specific-Th17 cells in celiac disease, are also being discussed. Neutralizing antibodies against IL-17A and IL-17F have commenced clinical testing in IBD. In conclusion, Th17 cells emerge as a key immune cell population and further elucidation of their roles and functional plasticity are warranted to support the discovery of novel therapies against IBD and other intestinal disorders.

Immunity to viruses

The analysis of the innate and adaptive immune response to viruses has provided fundamental insight into the functioning of the immune system. Early studies on the host response to virus infection were instrumental in establishing the concept of immunological tolerance (1). Similarly, the realization that T lymphocytes are ‘restricted’ in their recognition of antigens by gene products encoded within the major histocompatibility complex (MHC) locus came from the analysis of T-lymphocyte recognition of virus-infected cells (2). Likewise, important initial insights into antigen processing and presentation came from the analysis of viruses and virus-infected cells (3, 4). Until recently, it was convenient to view immunity to infectious agents like viruses as a separate branch of immunology distinct from immunity to tumors, self-molecules (antigens), or allergens. As demonstrated in many of the articles in this volume of Immunological Reviews, the mechanisms underlying the induction and regulation of the innate and adaptive immune response to viruses represent the same processes controlling immunity to tumor antigens, allergens, and self-constituents. Thus, the results summarized in these review articles and the implications of these findings are applicable not only to those of us who study immunity to viruses but also to the immunology community at large. In selecting the topics for review in this volume of Immunological Reviews, we were first and foremost limited by space. Consequently, many important contributors to the field of viral immunology (indeed several topics) are not represented in this volume. Our selection of topics and authors was biased towards emerging areas, such as the application of systems biology approaches to viral pathogenesis and immunity, the contribution of inflammatory and stress responses to the induction of Innate and adaptive immune responses, and the impact of the microbiome on immunity to virus infection. We also considered it relevant to include reviews focused on well defined areas where recent findings have resulted in potential paradigm shifts in our understanding of topics such as B-lymphocyte or T-lymphocyte responses to virus infection. This volume of Immunological Reviews is also somewhat weighted towards analyses of the immune response to respiratory viruses. With the recent episodic infections with the severe acute respiratory syndrome (SARS)-like coronavirus and the outbreak of human infections with the avian influenza A H7N9 virus, respiratory viruses such as these organisms are recognized as major human pathogens with the potential for pandemic spread. Therefore, this class of viruses is a focus of immunological research. The reviews in this volume can be grouped according to the following scheme: (i) molecules and cells regulating the induction of the innate and adaptive response, (ii) expression of immune effector activity, (iii) regulation of the antiviral immune response, and (iv) systems analysis of the host response to infection and vaccination (Fig. 1). Fig. 1 Immunity to viruses

Atypical B Cell Receptor Signaling: Straddling Immune Diseases and Cancer

The B-cell receptor (BCR) signaling pathway plays an essential role in the survival, proliferation, differentiation and trafficking of lymphocytic. Recent findings associate aberrant BCR signaling with specific disease pathologies, including B-cell malignancies and autoimmune disorders. Inhibition of the BCR signaling pathway may therefore provide promising new strategies for the treatment of B-cell diseases. This special issue of International Reviews of Immunology focuses on atypical B-cell receptor signaling, its role in immune diseases and cancer, and its implications for potential therapeutic intervention.

Less Travelled Roads in Clinical Immunology and Allergy: Drug Reactions and the Environmental Influence

Allergy and clinical immunology are examples of areas of knowledge in which working hypotheses are dominant over mechanistic understanding. As such, sometimes scientific efforts follow major streams and overlook some epidemiologically prevalent conditions that thus become underestimated by the research community. For this reason, we welcome the present issue of Clinical Reviews in Allergy and Immunology that is dedicated to uncommon themes in clinical immunology and allergy. First, comprehensive discussions are provided for allergy phenomena of large potential impact in clinical practice such as reactions to cephalosporins or aspirin-induced asthma and in everyday life such as allergies to food additives or legumes. Further, the issue addresses other uncommon themes such as urticaria and angioedema, cercarial dermatitis, or late-onset inflammation to soft tissue fillers. Last, there will be discussion on transversal issues such as olfactory defects in autoimmunity, interleukin 1 beta pathway, and the search for new serological markers in chronic inflammation. As a result, we are convinced that this issue will be of help to clinicians involved in internal medicine as well as to allergists and clinical immunologists. More importantly, we are convinced that these discussions will be of interest also to basic scientists for the numerous translational implications.

Vaccine adjuvants: in search of new paradigms

Interview with Jenaid Rees, Commissioning EditorNikolai Petrovsky is the Chairman and Research Director of Vaxine Pty Ltd, an Australian biotech company that specializes in novel vaccine adjuvants. He also holds the position of Director of Endocrinology at Flinders Medical Centre (Adelaide, Australia), Professor of Medicine at Flinders University, Vice President and Secretary General of the International Immunomics Society and serves on the Editorial Board of our sister journal, Expert Review of Clinical Immunology. He completed his PhD at the University of Melbourne (Victoria, Australia) then moved to Canberra (Australia) where he held conjoint positions at the Canberra Hospital, University of Sydney, Canberra University, Australian National University and the National Health Sciences Centre. In 2004, he moved to his current position at Flinders Medical Centre. His research interests include vaccine adjuvants, autoimmunity and immuno informatics. In 2009, his company Vaxine won the AMP Innovation Award at the Telstra business awards and Australia’s coolest company award from Australian Anthill magazine. He has been an investigator for major international diabetes studies including ADVANCE, FIELD and DREAM and is a principal investigator on several large grants from the NIH. He has authored over 140 scientific papers, and his team has developed novel vaccines against influenza, hepatitis B, sting allergy, malaria, Japanese encephalitis, rabies and HIV, in addition to developing the world’s first effective H1N1/2009pdm (swine flu) pandemic influenza vaccine.

THU0109 The PTPN22 C1858T Polymorphism and Rheumatoid Arthritis: A Meta-Analysis

BackgroundThe protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encodes a lymphoid-specific phosphatase (Lyp). Lyp is an intracellular PTP, and physically binds through its proline-rich motif to the SH3 domain of...

RNA regulation of the immune system

This volume of Immunological Reviews focuses on RNA regulation of the immune system, with a heavy dose of microRNAs (miRNAs) and a sampling of other key processes, including alternative splicing, RNA-binding proteins that control messenger RNA (mRNA) stability and translation, and attempts to harness the miRNA machinery for therapeutic ends through RNA interference (RNAi). Conspicuously and intentionally underrepresented due to space constraints are two topics that deserve issues of their own: Mechanisms of transcriptional regulation and immune recognition of RNA and its role in genome defense, host defense, and autoimmunity. The authors have all made important contributions to our understanding of RNA regulation of the immune system, and in some cases have pioneered and defined whole sectors of the field. Major topics of their reviews are indicated using the initials of each corresponding author in Fig. 1. The figure also provides a simplified schematic overview of RNA regulation of gene expression within a cell and its effects on cell biology and emergent properties of the immune system. Fig. 1 Schematic overview of RNA biogenesis and regulation in the immune system, and pictorial table of contents for this issue of Immunological Reviews

Is IutA from Escherichia coli a type 1 Thymus-independent antigen?

Is IutA from Escherichia coli a type 1 Thymus-independent antigen?

Preview of Immunological Reviews for 2013

Preview of <i>Immunological Reviews</i> for 2013

Cell:cell interactions in the immune system

Video podcast available Go to www.immunologicalreviews.com to watch an interview with Guest Editor Facundo Batista. The cells of the immune system are continually on the move! Naive T cells in a human collectively crawl over 10 000 miles a day in search of antigens (1). Each dendritic cell (DC) touches 5000 T cells an hour to scan repertoires over a million deep (2, 3). The adaptive immune system functions through a vast network of provisional cell–cell interactions that are continuously changing. When this frenetic scanning finds a fit between T-cell antigen receptor (TCR) and DC antigen, the interaction can be prolonged with a pronounced deceleration of the T cell and finally a long-lived interaction that has been described as an immunological synapse (2, 4). In vitro studies on the immunological synapse suggest a profound supramolecular organization that serves focused trans-synaptic and juxtracrine information transfer between cells (5–8). Immunological synapses are not restricted to T cells but are also formed by natural killer (NK) cells, B cells, granulocytes, and phagocytes using related immunotyrosine-based activation motif-containing receptors (9, 10). These interactions are profoundly influenced by the three-dimensional (3D) tissue environment (11). This volume of Immunological Reviews takes a broader look at the cell–cell interactions in the immune system from the molecular organization of antigen receptors during surveillance to the organization of stromal cell networks in lymph nodes, bone marrow, and the lung (Fig. 1). The organization of the plasma membrane is a fundamental issue in biology that sets the stage for cell–cell interaction and communication. The classical fluid mosaic model suggested membrane proteins diffusing in a lipid sea with potential for interactions with cytoplasmic and extra-cytoplasmic binding partners that account for regulation and processes like adhesion and receptor capping. Observations on lipid phases in model systems with disordered, liquidordered, and gel phases in order of increasing viscosity suggested that such phases could also exist in biological membranes on some scale (12). Biophysical observations of liquid-ordered domains enriched in various lipid-modified proteins have led to models in which lipids have a role in providing a higher level of organization (13). Most recently, evidence for protein-driven domains, referred to as Immunological Reviews 2013 Vol. 251: 7–12 Printed in Singapore. All rights reserved

In this Issue: Nef, A Lingering Problem; Are There Better Immunoglobulins for Human Use; and Takayasu Arteritis, Still a Mystery

The current issue of the International Reviews of Immunology brings the latest in three different areas of basic and clinical immunology. First, there is the lingering question of residual HIV-related pathology in patients on chronic antiretroviral therapy. The specific role of Nef in the macrophage-mediated disease manifested through lymphoma, metabolic disease and neurological disorder, is extensively discussed. A second topic is a clinical immunology one, a critical perspective on the efficacy and safety profile of various preparations of immunoglobulin products currently prescribed for a range of immunodeficiencies. Surprisingly, the authors showed that while the available preparations are equivalent from efficacy standpoint, they differ from the standpoint of toxicity. The third subject is again, in the arena of clinical immunology and deals with a relatively rare yet extremely puzzling disease –Takayasu arteritis –with a pathogenesis that needs elucidation and a dire need for better treatments. The authors provide a state of the art in terms of genetic association, other factors possibly involved in the onset and progression of this unusual inflammatory disease of large arteries, and provide a perspective on current standard of care and potential usefulness of TNF-α blockade as therapy for Takayasu arteritis.

Topics in This Issue: Cancer Testes Antigens, Immune Checkpoints, Inflammation Associated with Ischemia-Reperfusion and Integrin Targeting

This issue of the International Reviews of Immunology is dedicated to several topics: cancer immunotherapy, and basic and translational aspects of immunity. Two reviews, one focused on breast and the other on lung cancer, highlight the need to redefine the cancer testes antigens (CTAs) as novel information regarding their expression profile and biological role emerges. Two other reviews showcase pivotal molecules that keep in check immunity at two different levels: the transcription factor autoimmune regulator (AIRE) important to negative selection of the T-cell repertoire, and CD22 that limits the antigen-initiated B-cell response. Two other articles focus on the debated role of Toll-like receptors (TLRs) and inflammation in general, in ischemia-reperfusion lesions that follow cardiovascular disorders and stroke. Last but not the least, this issue hosts a review that discusses the role and translational potential of the α4 integrin for the treatment of inflammatory bowel disease (IBD).

Erratum

The authors would like to make the following corrections for the article, “Bruton Tyrosine Kinase (BTK) and its Role in B Cell Malignancy” by J. Buggy and L. Elias in International Reviews of Immunology 31 (02): 119–132.

The Autoimmune Side of Heart and Lung Diseases

The elevated cardiovascular morbidity in rheumatoid arthritis, systemic lupus erythematosus, and the antiphospholipid syndrome is well known, as well as the pulmonary involvement observed in these conditions and to a major extent in systemic sclerosis. These manifestations constitute a major challenge for clinicians involved in patient management. Moreover, several issues regarding the link between autoimmune rheumatic diseases and cardio pulmonary morbidity remain largely enigmatic. The mechanistic role of certain autoantibodies frequently observed in association with heart and lung diseases or the pathogenetic link between chronic inflammation and the pathways leading to atherosclerosis or pulmonary vascular changes are yet to be elucidated. As such, these questions as well as treatment strategies are of common interest to rheumatologists, immunologist, pulmonologists, and cardiologists and thus call for an interdisciplinary approach. This paradigm has been well established for rare conditions such as the Churg-Strauss syndrome. Nowadays, it seems that this approach should be expanded to encompass more common conditions such as coronary heart disease, pulmonary arterial hypertension or dilated cardiomyopathy. The present issue of Clinical Reviews in Allergy and Immunology addresses the new knowledge and concepts of autoimmune-related cardiopulmonary diseases. The issue derives from the 2010 International Autoimmunity Meeting held in Ljubljana, Slovenia and is thus timely and dedicated to the latest developments in this new multidisciplinary field.

Insights into immune structure, recognition, and signaling

In this volume of Immunological Reviews, the articles focus on the structural biology of immunoreceptors and what structure is telling us about function. The issue is unabashedly ‘receptor-centric’ and the proteins covered range from antigen receptors, innate receptors, and cytokine receptors, thereby providing an unusually comprehensive snapshot of the current state of the art in molecular immunology. Of all the major fields in biomedical research, including neurobiology, developmental biology, immunology, microbiology, and genetics, just to name a subset, perhaps structure in the broadest sense has had more of an impact on immunology and played more of a major role in guiding the evolution and maturation of the field than any other. Here, I use the term ‘structure’ to encompass not only direct structural approaches, such as x-ray crystallography and nuclear magnetic resonance spectroscopy (NMR), but also imaging, biophysical, molecular, and mechanistic approaches to interrogate aspects of molecular recognition, oligomerization, and signaling. Perhaps the fact that immunobiology is centered on questions of recognition and discrimination and is largely controlled by receptor-ligand systems has led to an unusually high level of sophistication about structure among immunologists. Personally speaking, having delved into structural questions in neurobiology and developmental biology, I can state without equivocation that the structural and molecular savvy of immunologists has led to greater mechanistic clarity underlying central tenets of the field compared to other disciplines. Dating back to the days of elucidating the first antibody structures and the relation between hypervariable regions and antigen recognition, to the transformative clarity of the first major histocompatibility complex (MHC) structures in explaining MHC restriction, to more recent biophysical and structural investigations of T-cell receptor (TCR) recognition of both classical and non-classical MHC, innate immune receptors such as natural killer (NK) and Toll-like receptors, and cytokine receptors, molecular science has illuminated the path for the experimentalists and assumed a large and highly visible role in immunobiology as a whole.

In this issue of the International Reviews of Immunology

This issue hosts diverse topics, from myeloid derived suppressor cells (MDSC) with their mechanism and role in cancer, the interplay between diet and emerging allergies studied in a genetically closed population, the pleiotropic anti-inflammatory effects of resveratrol, to the quest to achieve more reliable immune correlates of protection against the hepatitis C virus (HCV).

Germinal centers

Germinal centers