Journal Of Immunology Research Articles

IgE-associated allergic disorders: recent advances in etiology, diagnosis, and treatment.

IgE-associated allergic diseases belong to the most common inflammatory conditions. Their clinical manifestation ranges from mild symptoms to life-threatening episodes. Often patients experience a reduction in physical and psychologic well-being and suffer from a decreased quality of life due to disease activity. The continuously rising number of people that are affected by an allergic condition indicates an urgent need for better diagnostics and more efficient treatment options. Recent progress in the understanding of pathophysiologic mechanisms underlying IgE-associated allergic disorders has led to the identification of novel therapeutic targets and the development of drug candidates that are currently under evaluation. In this review, we highlight studies and clinical trials, which have helped to gain further insight in the etiology of IgE-associated allergic conditions as well as advances in the development of diagnostic tools and therapeutic approaches recently published in Allergy (European Journal of Allergy and Clinical Immunology).

Disease etiology and diagnosis by TCR repertoire analysis goes viral.

The importance of T-cell receptor (TCR) repertoire diversity is highlighted in murine models of immunodeficiency and in many human pathologies. However, the true extent of TCR diversity and how this diversity varies in health and disease is poorly understood. In a previous issue of the European Journal of Immunology, Lossius etal. [Eur. J. Immunol. 2014. 44: 3439-3452] dissected the composition of the TCR repertoire in the context of multiple sclerosis (MS) using high-throughput sequencing of TCR-β chains in cerebrospinal fluid samples and blood. The authors demonstrated that the TCR repertoire of the CSF was largely distinct from the blood and enriched in EBV-reactive CD8+ T cells in MS patients. Studies of this kind have long been hindered by technical limitations and remain scarce in the literature. However, TCR sequencing methodologies are progressing apace and will undoubtedly shed light on the genetic basis of T-cell responses and the ontogeny of T-cell-mediated diseases, such as MS.

Atopic dermatitis: A tale of two distinct pathomechanisms that make you itch.

Atopic dermatitis (AD) or eczema is the most common chronic inflammatory skin disease. It is a multifactorial disease with local and systemic immune changes. Current therapies focus on restoring the local skin barrier or inhibiting immune responses. In this issue of the European Journal of Immunology, Sehra etal. [Eur. J. Immunol. 2016. 46:2609-2613] describe a mouse model with T-cell-specific expression of constitutively active Stat6 in Flaky tail mice, which have mutations in the Flg and Tmem79 genes. The authors describe that it is the combination of changes in the skin barrier proteins filaggrin and Tmem79, together with Th2 cytokine signaling in the constitutively active Stat6 transgene, that drives the immune-pathomechanism in AD. These results are consistent with human studies where it is demonstrated that diminished filaggrin expression in skin is a predisposing factor for AD, but is neither required nor sufficient for disease indicating that additional factors are required for disease development. The current mouse model by Sehra etal. could be instrumental in evaluation new therapeutic strategies for AD.

What goes up must come down: A tripartite Dok-3/Grb2/SHIP1 inhibitory module limits BCR signaling.

Properly regulated immunity requires precise integration of activating and inhibitory signals. As for other lymphocytes, B cells express an antigen-specific activating receptor, the B-cell antigen receptor (BCR), and inhibitory receptors (e.g. FcγRIIb) that exercise checkpoint control on B-cell activation. Moreover, following BCR engagement, CD19 recruits proteins that amplify BCR signaling, while CD22 initiates a negative feedback loop by recruiting proteins that inhibit BCR signaling. Initial BCR signaling is mediated by protein tyrosine kinases and lipid kinases; inhibitory receptors directly antagonize the actions of these enzymes by recruiting protein tyrosine phosphatases and lipid phosphatases and positioning them close to actively signaling BCRs. Previously it was thought that inhibitory receptors such as FcγRIIb and CD22 were essential for bringing these phosphatases near the BCR. In this issue of the European Journal of Immunology, Manno etal. show that a tripartite inhibitory module consisting of the adaptor proteins Dok-3 and Grb2 and the lipid phosphatase SHIP1 binds directly to activated BCRs and limits the Ca2+ mobilization that is required for B lymphocyte activation. This reveals that the BCR can be both an activating and inhibitory receptor, one that activates signaling enzymes while initiating a negative feedback loop that prevents excessive signaling.

Global Regulatory T-Cell Research from 2000 to 2015: A Bibliometric Analysis.

We aimed to analyze the global scientific output of regulatory T-cell (Treg) research and built a model to qualitatively and quantitatively evaluate publications from 2000 to 2015. Data were obtained from the Web of Science Core Collection (WoSCC) of Thomson Reuters on January 1, 2016. The bibliometric method and Citespace III were used to analyze authors, journals, publication outputs, institutions, countries, research areas, research hotspots, and trends. In total, we identified 35,741 publications on Treg research from 2000 to 2015, and observed that the annual publication rate increased with time. The Journal of Immunology published the highest number of articles, the leading country was the USA, and the leading institute was Harvard University. Sakaguchi, Hori, Fontenot, and Wang were the top authors in Treg research. Immunology accounted for the highest number of publications, followed by oncology, experimental medicine, cell biology, and hematology. Keyword analysis indicated that autoimmunity, inflammation, cytokine, gene expression, foxp3, and immunotherapy were the research hotspots, whereas autoimmune inflammation, gene therapy, granzyme B, RORγt, and th17 were the frontiers of Treg research. This bibliometric analysis revealed that Treg-related studies are still research hotspots, and that Treg-related clinical therapies are the research frontiers; however, further study and collaborations are needed worldwide. Overall, our findings provide valuable information for the editors of immunology journals to identify new perspectives and shape future research directions.

Back to the drawing board: Understanding the complexity of hepatic innate lymphoid cells.

Recent studies of immune populations in nonlymphoid organs have highlighted the great diversity of the innate lymphoid system. It has also become apparent that mouse and human innate lymphoid cells (ILCs) have distinct phenotypes and properties. In this issue of the European Journal of Immunology, Harmon etal. [Eur. J. Immunol. 2016. 46: 2111-2120] characterized human hepatic NK-cell subsets. The authors report that hepatic CD56(bright) NK cells resemble mouse liver ILC1s in that they express CXCR6 and have an immature phenotype. However, unlike mouse ILC1s, they express high levels of Eomes and low levels of T-bet, and upon stimulation with tumor cells, secrete low amounts of cytokines. These unexpected findings further support the differences between human and mouse immune populations and prompt the study of the role of hepatic ILC subsets in immune responses.

MAIT be different-persisting dysfunction after DAA-mediated clearance of chronic hepatitis C virus infection.

MAIT cells are an abundant innate-like T-cell subset that is defined by the invariant T-cell receptor (iTCR) V-alpha chain Vα7.2-Jα33. Little is currently known about their frequency and function in chronic hepatitis C virus (HCV) infection and their fate after therapy-mediated HCV elimination by direct acting antivirals (DAA). In this issue of the European Journal of Immunology, Hengst etal. [Eur. J. Immunol. 2016. 46: 2204-2210] give important novel insights into the biological role of MAIT cells in a relevant human chronic viral infection by showing that first, MAIT cells are only present at low frequencies in chronic HCV infection; second, circulating MAIT cells in HCV patients also display an altered phenotype; third, they are impaired in their MR-1-dependent effector functions and finally, and maybe most importantly, MAIT-cell frequency and function was not restored after HCV elimination by DAA therapy. These results suggest that MAIT cells are severely affected by a chronic human viral infection in their frequency and function and that this impairment is not reversed after HCV elimination. This is in contrast to rapid DAA-mediated restorations of NK-cell and CD8(+) T-cell functions, and indicates a differential impact of chronic infection and clearance on different immune cell subsets.

SHP1-ing thymic selection.

Thymocyte development and maintenance of peripheral T-cell numbers and functions are critically dependent on T-cell receptor (TCR) signal strength. SHP1 (Src homology region 2 domain-containing phosphatase-1), a tyrosine phosphatase, acts as a negative regulator of TCR signal strength. Moreover, germline SHP1 knockout mice have shown impaired thymic development. However, this has been recently questioned by an analysis of SHP1 conditional knockout mice, which reported normal thymic development of SHP1 deficient thymocytes. Using this SHP1 conditional knockout mice, in this issue of the European Journal of Immunology, Martinez etal. [Eur. J. Immunol. 2016. 46: 2103-2110] show that SHP1 indeed does have a role in the negative regulation of TCR signal strength in positively selected thymocytes, and in the final maturation of single positive thymocytes. They report that thymocyte development in such mice shows loss of mature, post-selection cells. This is due to increased TCR signal transduction in thymocytes immediately post positive-selection, and increased cell death in response to weak TCR ligands. Thus, SHP1-deficiency shows strong similarities to deficiency in the T-cell specific SHP1-associated protein Themis.

Editorial introductions

Editorial introductions

Macrophage tolerance in the gut: It is in the epigenome!

Intestinal macrophages are functionally specialized to phagocytose bacteria, including harmful and invading pathogens, without releasing pro-inflammatory mediators. This unique functional combination guarantees an optimal defense against millions of gut bacteria while at the same time protecting the host from inflammation-related tissue damage. IL-10 seems to be a critical tissue factor involved in this balance and deficiencies in IL-10 in humans and mice have been shown to deteriorate this fine balance, leading to chronic inflammation and diseases such as Crohn's disease. However, the molecular mechanisms downstream of IL-10 are poorly understood. In this issue of European Journal of Immunology, Simon etal. [Eur. J. Immunol. 2016. 46: 1912-1925] demonstrate that the chromatin landscape in gut macrophages derived from mice lacking IL-10 is characteristic of inflammatory macrophages, even in the absence of bacteria. The observed changes of the chromatin landscape represent an important initiating event in chronic intestinal inflammation. These observations are not only an excellent example linking a classical loss-of-function experiment to a molecular mechanism responsible for the induction of chronic inflammation; they also open up new avenues for targeting chromatin and remodeling enzymes in Crohn's disease.

TCGF: How Much? Oh, and by the Way, How Many?

![][1] The Pillars of Immunology article ([1][2]) selected for comment by the editors in this issue is a bit unusual. It is second on the list of the 100 most cited publications in The Journal of Immunology ( The JI ) with 4201 citations, and it was published in 1978, 38 years ago. Only 12

Occupational Asthma

MOC as well as CME credit can now be obtained, free for a limited time, by reviewing this Difficult Cases presentation. Please note the following instructions. 1.Review the target audience, learning objectives, and author disclosures. 2.Complete the pre-test online at the JACI: In Practice homepage at www.jaci-inpractice.org (click on the Online CME heading). 3.Follow the online instructions to review the full online version of the presentation. 4.Complete the post-test. At this time, you will have earned 1.0 AMA PRA Category 1 CME Credit™. 5.Approximately 4 weeks later you will receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive 2 MOC Part II Self-Assessment credits from the American Board of Allergy and Immunology. CME Exam: Occupational AsthmaThe Journal of Allergy and Clinical Immunology: In PracticeVol. 4Issue 4Preview Full-Text PDF

CD28 days later: Resurrecting costimulation for CD8(+) memory T cells.

Rapid activation and proliferative expansion of specific CD8(+) memory T (CD8(+) TM ) cells upon antigen re-encounter is a critical component of the adaptive immune response that confers enhanced immune protection. In this context, however, the requirements for costimulation in general, and CD28 signaling in particular, remain incompletely defined. In the current issue of the European Journal of Immunology, Fröhlich etal. [Eur. J. Immunol. 2016. 46: 1644-1655] provide definitive evidence that optimal elaboration of CD8(+) TM -cell recall responses is indeed contingent on CD28 expressed by these cells. Here, we discuss the "CD28 costimulation paradigm" in its historical context and highlight some of the unresolved complexities pertaining to CD28-dependent interactions that shape CD8(+) T-cell phenotypes, functionalities, and recall reactivity.

TIL 2.0: More effective and predictive T-cell products by enrichment for defined antigen specificities.

Adoptive transfer of in vitro-expanded Tcells derived from tumor-infiltrating lymphocytes (TILs) in melanoma patients started the era of tumor immunotherapy three decades ago. The approach has demonstrated remarkable clinical responses in several studies since. Reinfusion of TIL-derived Tcells represents a highly personalized form of immunotherapy, taking into account the enormous interindividual tumor heterogeneity. However, despite its successes, TIL therapy does not lead to objective clinical responses in all cases. It is thus crucial to find out which tumor antigens are particularly valuable targets and to develop strategies to enhance the reactivity of T-cell products toward them. In this issue of the European Journal of Immunology, Kelderman etal. [Eur. J. Immunol. 2016. 46: 1351-1360] present a platform for the generation of antigen-specific TIL therapy. Combining recently developed technologies for clinical identification and enrichment of antigen-specific CD8(+) Tcells, such as MHC Streptamers and UV-mediated peptide exchange, the authors could enrich T-cell populations with defined antigen specificities from melanoma-derived TILs. This T-cell product showed higher reactivity against autologous tumor cell lines than bulk TIL-derived Tcells. The novel platform might enable the generation of more effective and predictable TIL-derived T-cell products for future clinical applications.

CatacLysMic specificity when targeting myeloid cells?

The antibacterial enzyme lysozyme M (LysM) encoded by the Lyz2 gene is broadly expressed in myeloblasts, macrophages, and neutrophils, and thus has been used for a long time as a cell-specific marker for myeloid cells in mice. In order to delete loxP-site flanked genes in myeloid cells, a Cre-recombinase (Cre) expressing mouse line was created by inserting Cre-coding sequence into the translational start site of the LysM gene. In this issue of the European Journal of Immunology [2016. 46: 1529-1532], Orthgiess etal. verify, with the help of tdTomato and YFP reporter mouse lines, LysM-driven recombination. Unexpectedly, the authors also describe major expression of the tdTomato reporter protein in brain neurons of the central nervous system (CNS), with only a very small percentage of gene recombination in myeloid cells of the brain, called microglia. These findings cause justified concerns regarding the efficient and specific targeting of microglia and peripheral myeloid cells using LysM-Cre mice and should stimulate thoughts on conclusions drawn from past experiments on the diseased CNS employing this Cre/loxP-deleter line.

Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot.

T follicular regulatory (Tfr) cells are a subpopulation of Treg cells that have adopted the T follicular helper cell program to localize to the B-cell follicle. Because of the difficulties in generating mouse models in which Tfr cells are selectively affected, determining where and how Tfr cells regulate the germinal center response remains to be resolved. In this issue of the European Journal of Immunology, Dent and colleagues [Eur. J. Immunol. 2016. 46: 1152-1161] describe a simple, elegant mouse model to conditionally delete Tfr cells without impacting on the Treg- and Tfh-cell populations. Their initial studies suggest that Tfr cells have a more complex role than previously thought, particularly with respect to the regulation of immunoglobulin isotype switching to IgA.

Anaphyl Actic Reaction After the Intravenous Administration of Omeprazole: A Case Report

SESSION TITLE: Critical Care SESSION TYPE: Case Report Poster PRESENTED ON: Sunday, April 17, 2016 at 11:45 AM - 12:45 PM INTRODUCTION: Omeprazole, one of proton pump inhibitors, is widely used and a rare cause of anaphylactic reactions such as dyspnea and shock, which could be extremely life threatening. This is an observational descriptive case report. CASE PRESENTATION: A 64-year-old non-atopic man with lung cancer was admitted in our unit for chemotherapy. He had two similar allergic episodes with good outcomes after active treatment in the past month. For the first time, allergic reaction, including urticaria, dyspnea, appeared within a few minutes after the intravenous administration of 800mg pemetrexed disodium for injection followed by 40mg omeprazole. In the second preparation we adjusted the medication order. Omeprazole (40mg) was infused firstly, unfortunately, severe allergic event occurred within 10 minutes. The patient experienced urticaria, wheeze, decline of oxygen saturation (less than 90%), low systolic blood pressure (less than 90 mmHg), and tachycardia (more than 130 beats per min). Serum IgE measurement was significantly higher than that in normal subjects within 24 h after the second event and intradermal skin test with omepazole was positive (the patients had signed written informed consent before treatment and check). He received immediate treatment with oxygen inhalation followed by intravenous dexamethasone and promethazine, and the symptoms disappeared in less than 2 hours. Under strict medical supervision, no adverse reaction was found induced by lansoprazole for replacement therapy after skin test came back negative. DISCUSSION: It was reported that omeprazole would lead to allergic reactions. In this case, intradermal skin test with omepazole was positive. Several of these reports described anaphylactic symptoms occurring within few minutes of ingestion of omeprazole, which was suggestive of an IgE-mediated event. In our patient, the level of serum IgE was significantly higher than that in normal subjects after exposure to omeprazole. Although more studies would be needed to confirm this result, it is highly suggestive that omeprazole is capable of triggering a specific IgE mediated response. Some reports showed lansoprazole caused anaphylactic reaction during oral or intravenous infusion. It had been proved that skin test had high sensitivity and specificity. In this case, skin test with lansoprazole was negative, therefore we used lansoprazole instead of omeprazole to combate the potential GI side effects of chemotherapy. The patient showed good tolerance. CONCLUSIONS: It is highly suggestive that omeprazole is capable of triggering anaphylactic reaction mediated by IgE. Reference #1: Ottervanger JP, Phaff RA, Vermeulen EG, Stricker BH: Anaphylaxis to omeprazole. The Journal of allergy and clinical immunology 1996, 97(6):1413-1414. [PMID: 8648040] DISCLOSURE: The following authors have nothing to disclose: Kun Xiao, Yi Hu, Lixin Xie No Product/Research Disclosure Information

Thymus medulla under construction: Time and space oddities.

The development of effective T-cell-based immunotherapies to treat infection, cancer, and autoimmunity should incorporate the ground rules that control differentiation of T cells in the thymus. Within the thymus, thymic epithelial cells (TECs) provide microenvironments supportive of the generation and selection of T cells that are responsive to pathogen-derived antigens, and yet tolerant to self-determinants. Defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental and clinical importance to comprehend how immunity and tolerance are balanced. Critical to tolerance induction are medullary thymic epithelial cells (mTECs), which purge autoreactive T cells, or redirect them to a regulatory T-cell lineage. In this issue of the European Journal of Immunology, studies by Baik et al. and Mayer et al. [Eur. J. Immunol. 2016. 46: XXXX-XXXX and 46: XXXX-XXXX]) document novel spatial-temporal singularities in the lineage specification and maintenance of mTECs. While Baik et al. define a developmental checkpoint during mTEC specification in the embryo, Mayer et al. reveal that the generation and maintenance of the adult mTEC compartment is temporally controlled in vivo. The two reports described new developmentally related, but temporally distinct principles that underlie the homeostasis of the thymic medulla across life.

Albert Coons: harnessing the power of the antibody

Albert Coons: harnessing the power of the antibody

The NIK of time for B cells.

NF-κB-inducing kinase (NIK) is a key mediator of the noncanonical NF-κB signaling pathway, which is critical for B-cell development and function. Although complete deletion of NIK in mice has been shown to result in defective B cells and impaired secondary lymphoid organogenesis, the consequences of deleting NIK exclusively in B cells have not been determined. In this issue of the European Journal of Immunology, Hahn et al. [Eur. J. Immunol. 2016. 46: 732-741] describe mice in which the NF-κB2 pathway mediator, NIK, is deleted at different points in B-cell lineage differentiation and activation. The results show that the survival of mature peripheral B cells, as well as appropriate kinetics of germinal center reactions, rely on noncanonical NF-κB signaling. These findings confirm and extend prior observations implicating a nonredundant role for NF-κB2 downstream of BAFF signaling via BAFF-R, and prompt assessment of the growing literature regarding the relative roles of BCR and BAFF signals in B-cell homeostasis, as well as the downstream pathways responsible.