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Metabolism and Immune Tolerance

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889457250 Year: Pages: 116 DOI: 10.3389/978-2-88945-725-0 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:43
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Historically the study of the immune system and metabolism have been two very separate fields. In recent years, a growing literature has emerged illustrating how the multiple processes of cellular metabolism are intricately linked to several aspects of immune function and development. This Research Topic covers recent progress in the field now known as “Immunometabolism” and the role of metabolism in immune tolerance. Immune tolerance is operationally defined as a state where a host’s immune system is balanced such that although self-reactive lymphocytes are present, they are kept in check by immune regulation. Perturbations to this homeostasis may result in self-reactive lymphocytes gaining the upper hand and mediating auto-immune disease. Maintenance of immune tolerance involves a large cast of different cell types including effector T cells, regulatory T cells, B cells, stromal cells, dendritic cells and macrophages.Intracellular pathways and individual enzymes of metabolism have been shown to be harnessed by cells of both the adaptive and innate immune system to allow particular immune functions to be achieved. Examples include metabolic enzymes serving ‘moonlighting’ functions in mRNA translation, gene splicing, and kinase activation. Other examples include the requirement for de novo fatty acid synthesis for differentiation into Th17 effectors and CD8 memory T cells or products of the TCA cycle promoting pro-inflammatory cytokine production. Likewise, the availability of extracellular metabolic substrates has a large impact on the maintenance of local immune tolerance. For example, there are different requirements for glucose, glutamine and fatty acids for effector versus regulatory T cell development. Also tolerogenic dendritic cells mediate lowering of extracellular essential amino acids by their enhanced catabolism, promoting the induction of regulatory T cells. The purpose of this Research Topic is to provide an update on the current understanding of the multiple roles for metabolism in regulating the immune system.

Making Science Fun - A Tribute to Our Colleague and Friend, Prof. Antonius G. Rolink (1953-2017)

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889457519 Year: Pages: 211 DOI: 10.3389/978-2-88945-751-9 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:43
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This Research Topic honors the memory of Prof. Antonius “Ton” G. Rolink (April 19, 1953–August 06, 2017), our colleague, mentor and friend in immunology. It is now over a year since Ton left us. This article collection, authored by many of Ton’s friends and colleagues, reflects the huge contribution to cellular and molecular immunology that work emanating directly from Ton’s own hands and laboratory have made to the understanding of lymphocyte development. Ton’s hard work, expertise, generosity, passion for science and infectious humor were legendary and for all of those lucky enough to have been his colleague, he ensured that science was fun. We take this opportunity of thanking all contributors for submitting their manuscripts; we are sure that Ton would have enjoyed reading and making his own insightful comments on them. In the form of original research and review articles, these papers cover many of Ton’s scientific interests in different aspects of lymphocyte development in mouse and man. In the first section, Development of hematopoietic cells and lymphocytes, Klein et al. describe the accumulation of multipotent hematopoietic progenitors in peripheral lymphoid organs of IL-7xFlt3L double transgenic mice and Pang et al. the role of the transcription factor PU.1 on the development of Common Lymphoid Progenitors. In Early B cell development, Winkler and Mårtensson review the role of the Pre-B cell receptor in B cell development and papers by Hobeika et al. and Brennecke et al. describe models of inducible B cell development. For B cell selection, survival and tolerance, Smulski and Eibel review the role of BAFF and Kowalczyk-Quintans et al. analyse the role of membrane-bound BAFF. The impact of BIM on B cell homeostasis is discussed by Liu et al. The role of the MEK-ERK pathway in B cell tolerance is discussed by Greaves et al. and the transcriptional regulation of germinal center development is reviewed by Song and Matthias. For Hematological diseases, Ghia reviews how studies of B cell development help the understanding of Leukemia development, Kim and Schaniel review how iPS technology helps the understanding of hematological diseases and Hellmann et al. describe development of new therapeutic antibody drug conjugates. Finally, in T cell development, homeostasis and graft vs. host disease, Heiler et al. describe the therapeutic effects of IL-2/anti-IL-2 immune complexes in GvHD, Calvo-Asensio et al. describe the DNA damage response of thymocyte progenitors and Mori and Pieters review the role of Coronin 1 in T cell survival.

PI3K signalling

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194193 Year: Pages: 139 DOI: 10.3389/978-2-88919-419-3 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-10 11:59:06
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The PI3Ks control many key functions in immune cells. PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3. Initially, PI3K inhibitors such as Wortmannin, LY294002 and Rapamycin were used to establish a central role for Pi3K pathway in immune cells. Considerable progress in understanding the role of this pathway in cells of the immune system has been made in recent years, starting with analysis of various PI3K and Pten knockout mice and subsequently mTOR and Foxo knockout mice. Together, these experiments have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell development and function, B cell and T cell trafficking, immunoglobulin class switching and much, much more. The PI3Kd inhibitor idelalisib has recently been approved for the treatment of B cell lymphoma. Clinical trials of other PI3K inhibitors in autoimmune and inflammatory diseases are also in progress. This is an opportune time to consider a Research Topic considering when what we have learned about the PI3K signalling module in lymphocyte biology and how this is making an impact on clinical immunology and haematology.

The Origin of the Plasma Cell Heterogeneity

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197347 Year: Pages: 80 DOI: 10.3389/978-2-88919-734-7 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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Plasma cells (PCs) are terminally differentiated B-cells producing large amounts of immunoglobulins (Ig). In humans, most of circulating Ig are produced by bone marrow plasma cells. PCs differentiate from activated naïve or memory B-cells usually activated by specific antigens. It is still controversial whether the regulation of PCs numbers and the “active” in vivo Ig diversity depend or not on non-specific reactivation of B-cells during infections. Depending on the stimulus (T-independent/T-dependent antigen, cytokines, partner cells) and B-cell types (naïve or memory, circulating or germinal center, lymph nodes or spleen, B1 or B2...), both the phenotype and isotype of PCs differ suggesting that PC diversity is either linked to B-cell diversity or to the type of stimulus or to both. Knowledge of the mechanisms supporting PC diversity has important consequences for the management of i) plasma cell neoplasia such as Multiple Myeloma and Waldenström's Macroglobulinemia, ii) vaccine protection against pathogens and iii) auto-immune diseases.

Keywords

Plasma cell --- B-cell --- differentiation --- Cell Cycle --- IL21 --- Autophagy --- B1 --- Autoimmunity --- Myeloma

The Role of Aire, microRNAs and Cell-Cell Interactions on Thymic Architecture and Induction of Tolerance

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197705 Year: Pages: 107 DOI: 10.3389/978-2-88919-770-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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The focus of this eBook is to bring new insights into central immune tolerance. To fulfill that, much has been discussed about the master in the regulation of tolerance, the autoimmune regulator (Aire) gene the main thymus cell type that expresses this gene, the medullary thymic epithelial cells (mTECs). It includes one Editorial and 12 other excellent contributions in the format of mini reviews or original research papers covering one or more of these aspects: promiscuous gene expression (PGE), epigenetics, miRNAs, association of the Aire gene and miRNAs, thymocyte–TEC interaction, coxsackievirus and type 1 diabetes, exosomes in the thymus, thymic crosstalk, thymic B cells, T cell development, chemokines and migration of T cells, miRNAs and the thymic atrophy, cell–cell interactions, and thymus ontogeny. Authors raised hypothesis, discuss concepts, and show open questions. The remaining important issues to resolve questions within the central tolerance research are briefly discussed below.

Epigenetics of B Cells and Antibody Responses

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197903 Year: Pages: 121 DOI: 10.3389/978-2-88919-790-3 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2017-02-03 17:04:57
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Epigenetics is the study of changes in gene activity that are heritable but not caused by changes in the DNA sequence. By modulating gene activities, epigenetic changes regulate cell functions. They include DNA methylation, histone posttranslational modifications and gene silencing by the action of non-coding RNAs, particularly microRNAs. It is now clear that epigenetic changes regulate B cell development. By acting in concert with networks of transcription factors, they modulate the activation of B cell lineage specific gene programs and repress inappropriate gene transcription in particular B cell differentiation states. A hallmark of B cell development in the bone marrow is the assembly of the B cell receptor (BCR) for antigen through rearrangement of immunoglobulin heavy (IgH) and light (IgL) chain V(D)J genes, as mediated by RAG1/RAG2 recombinases. Ig V(D)J rearrangement critically times the progression from pro-B cell to pre-B cell and, finally, mature B cell. Such progression is modulated by epigenetic marks, such as DNA methylation and histone posttranslational modifications, that increase chromatin accessibility and target RAG/RAG2 to V, D and J DNA. It is also dependent on the expression of multiple microRNAs. Mice deficient in Ago2, which is essential for microRNA biogenesis and function, have B cell development blocked at the pro-B cell stage. In agreement with this, B cell specific ablation of microRNA by B cell-specific knockout of Dicer virtually blocks B cell differentiation at the pro-B to pre-B cell transition. After mature B cells encounter antigen, changes of the epigenetic landscape are induced by the same stimuli that drive the antibody response; such epigenetic changes underpin the maturation of the antibody response itself. They instruct those B cell differentiation processes, somatic hypermutation (SHM), class switch DNA recombination (CSR) and plasma cell differentiation, that are central to the maturation of the antibody response as well as differentiation of memory B cells. Inducible histone modifications, together with DNA methylation and microRNAs modulate the transcriptome, particularly the expression of activation-induced cytidine deaminase (AID), central to SHM and CSR, and B lymphocyte-induced maturation protein-1 (Blimp-1), which is central to plasma cell differentiation. Combinatorial histone modifications also function as histone codes in the targeting of the CSR and, possibly, the SHM machinery to the Ig locus by recruiting specific adaptors (histone code readers) that can in turn target and/or stabilize CSR/SHM factors. Epigenetic alterations in memory B cells contribute to their functionally distinction from their naive counterparts. Memory B cells inherit epigenetic information from their precursors and acquire new epigenetic marks, which make these resting B cells poised to promptly respond to antigen. The cross/feedback regulation of different epigenetic modifications/elements further increases the complexity of the B cell epigenome, which interacts with the genetic information for precise modulation of gene expression. It is increasingly evident that epigenetic dysregulation in B cells, including aberrant expression of microRNAs, can result in aberrant antibody responses to microbial pathogens, emergence of pathogenic autoantibodies or B cell neoplastic transformation. Epigenetic marks are potential targets for new therapeutics in autoimmunity and B cell malignancy.

Epitope Discovery and Synthetic Vaccine Design

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889455225 Year: Pages: 284 DOI: 10.3389/978-2-88945-522-5 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:42
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Since variolation, conventional approaches to vaccine development are based on live-attenuated, inactivated or purified pathogen-derived components. However, effective vaccines against global health threats such as HIV, parasite infections and tumors are difficult to achieve. On the other hand, synthetic vaccines based on immunogenic epitopes offer advantages over traditional vaccines since they are chemically defined antigens free from deleterious effects. Additionally, in contrast to live-attenuated vaccines, they do not revert to virulence in immunocompromised subjects, and different from genetic vaccines, they do not involve ethical questions. Traditional vaccines contain PAMPs and induce strong immune responses, while recombinant vaccines are less potent. In spite of the immunogenic weakness previously attributed to epitope-based vaccines a synthetic vaccine containing a 17 amino acid-epitope of the Pseudomonas aeruginosa Type IV pilus exceeded the protective potential of its cognate protein composed of 115 amino acids. Therefore, the efficacy yield of a synthetic vaccine can be potentiated by using the proper combination of target epitopes. Recent advances in adjuvant development, immunogen platforms for DNA vaccines and viral vectors also contributed to optimize immunogenicity. Another constraint to the use of epitope vaccines was their restriction to some MHC or HLA phenotypes. However, epitopes containing 20 or less amino acids of Plasmodium falciparum and Leishmania donovani bind to multiple HLA-DR and MHC receptors. Thus synthetic epitope vaccines may better meet the requirements of the regulatory agencies since they have lower costs and are easier to produce. The classical experimental approach for the development of an epitope-based vaccine involves the use of recombinant domains or overlapping 15-mer peptides spanning the full length of the target antigen, and the analysis of the induced antibody and/or T cell immune responses in vitro or in vivo. On the other hand, in silico tools can select peptides that are more likely to contain epitopes, reducing the number of sequence candidates. T cell epitope prediction dates back to 1980s, when the first algorithm was developed based on the identification of amphipathic helical regions on protein antigens. Since then, new methods based on MHC peptide-binding motifs or MHC-binding properties have been developed. The recent reverse vaccinology concept uses high-throughput genome sequencing and bioinformatics tools to identify potential targets of immune responses. The feasibility of this approach was shown for the first time in the design of a vaccine against Neisseria meningitides that is now in phase III clinical trials. In addition, different computational tools allow the determination of crucial gene(s) through comparative analyses between different pathogenic strains Alternatively, carbohydrates have been considered as key targets in developing safe and effective vaccines to combat cancer, bacterial and viral infections. Tumor associated carbohydrate antigens can be coupled covalently to protein carriers to target MHC receptors and improve immunogenicity and have reached already pre-clinical and clinical studies. In light of the recent availability of genomic tools, we believe that in the near future an increasing number of vaccine candidates, composed of defined epitopes, will be available for synthetic vaccines showing improved protection.

Breaking the cycle: Attacking the malaria parasite in the liver

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196951 Year: Pages: 173 DOI: 10.3389/978-2-88919-695-1 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General) --- Microbiology --- Science (General)
Added to DOAB on : 2016-04-07 11:22:02
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Despite significant progress in the global fight against malaria, this parasitic infection is still responsible for nearly 300 million clinical cases and more than half a million deaths each year, predominantly in African children less than 5 years of age. The infection starts when mosquitoes transmit small numbers of parasites into the skin. From here, the parasites travel with the bloodstream to the liver where they undergo an initial round of replication and maturation to the next developmental stage that infects red blood cells. A vaccine capable of blocking the clinically silent liver phase of the Plasmodium life cycle would prevent the subsequent symptomatic phase of this tropical disease, including its frequently fatal manifestations such as severe anemia, acute lung injury, and cerebral malaria. Parasitologists, immunologists, and vaccinologists have come to appreciate the complexity of the adaptive immune response against the liver stages of this deadly parasite. Lymphocytes play a central role in the elimination of Plasmodium infected hepatocytes, both in humans and animal models, but our understanding of the exact cellular interactions and molecular effector mechanisms that lead to parasite killing within the complex hepatic microenvironment of an immune host is still rudimentary. Nevertheless, recent collaborative efforts have led to promising vaccine approaches based on liver stages that have conferred sterile immunity in humans – the University of Oxford's Ad prime / MVA boost vaccine, the Naval Medical Research Center’s DNA prime / Ad boost vaccine, Sanaria Inc.'s radiation-attenuated whole sporozoite vaccine, and Radboud University Medical Centre’s and Sanaria's derived chemoprophylaxis with sporozoites vaccines. The aim of this Research Topic is to bring together researchers with expertise in malariology, immunology, hepatology, antigen discovery and vaccine development to provide a better understanding of the basic biology of Plasmodium in the liver and the host’s innate and adaptive immune responses. Understanding the conditions required to generate complete protection in a vaccinated individual will bring us closer to our ultimate goal, namely to develop a safe, scalable, and affordable malaria vaccine capable of inducing sustained high-level protective immunity in the large proportion of the world’s population constantly at risk of malaria.

Antibody Repertoire and Graft Outcome Following Solid Organ Transplantation

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889452415 Year: Pages: 176 DOI: 10.3389/978-2-88945-241-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2017-10-13 14:57:01
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The first real major breakthrough that laid the basis of HLA antibody detection in the field of solid organ transplantation, came with the introduction of the complement dependent cytotoxicity (CDC) test in 1964 by Terasaki and McClelland. Since then, methods for antibody detection have evolved remarkably from conventional cell-based assays to the current advanced solid phase systems on the Luminex platform, with increasing degree of sensitivity and specificity. The latter have been indispensable for more accurate identification of donor specific HLA antibodies in broadly reactive allo antisera, and to guide donor selection and kidney paired exchange programs through virtual crossmatching, in addition to serving as excellent tools for initiating pre-transplant desensitization and post- transplant antibody monitoring. Consensus is evolving on the optimal routine employment of these methods in donor selection strategies along with an understanding of the clinical relevance of antibodies detected by each of them. The immunoassays based on the Luminex platform and flow cytometric beads are however unable to discriminate complement fixing from non-complement fixing HLA antibodies. This is important because the former are considered clinically more pertinent in the peri-transplant period. The C1q assay which is a modification of the solid phase assay based on Luminex single antigen beads, which can be used effectively to monitor high dose IVIG desensitization is essentially a surrogate complement fixing assay, retaining the exquisite sensitivity and specificity of the Luminex platform. Currently, information obtained from these assays is preliminary and much needs to be done to standardize technologies and set a consensus ‘MFI cut off’ for antibody positivity. Besides the overriding influence of anti-HLA antibodies on overall solid organ graft survival, immune response to non-HLA antigens has become a topic of substantial interest in recent years. An ever expanding list of non-HLA antigens has been implicated in graft rejection for various organs, of which the most noted are the Major Histocompatibility Complex class I chain-related molecule A (MICA), Vimentin, Myosin, Angiotensin II type 1 receptor (AT1R), Tubulin and Collagen. MICA is one of the most polymorphic and extensively studied non-HLA antigenic targets especially in renal transplantation. Although there are clear indications of MICA antibodies being associated with adverse graft outcome, to date a definitive consensus on this relationship has not been agreed. Because MICA molecules are not expressed constitutively on immunocompetent cells such as T and B lymphocytes, it is of utmost importance to address the impact of MICA donor specific antibodies (DSA) as compared to those that are non- donor specific (NDSA) on graft outcome. The soluble isoform of MICA molecule (sMICA) that is derived from the proteolytic shedding of membrane bound molecules has the potential to engage the NK-cell activating receptor NKG2D and down-regulate its expression. Consequent to the interaction of NKG2D by sMICA, the receptor ligand complex is endocytosed and degraded and thus suppresses NKG2D mediated lysis of the target by NK cells. Thus interaction between NKG2D and sMICA leads to expansion of immunosuppressive/anergic T cells thereby resulting in suppression of NKG2D mediated host innate immunity. These concept support the possible involvement of an immunosuppressive role for sMICA during allotransplantation as shown recently for heart transplantation. This research topic focuses on the clinical utility of investigating the complete antibody repertoire in solid organ transplantation.

Lymphocytes in MS and EAE: More than just a CD4+ World

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453023 Year: Pages: 160 DOI: 10.3389/978-2-88945-302-3 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-02-27 16:16:45
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Multiple sclerosis is degenerative disease of the central nervous system (CNS) in which myelin destruction and axon loss leads to the accumulation of physical, cognitive, and mental deficits. MS affects more than a million people worldwide and managing this chronic disease presents a significant health challenge. Multiple lines of evidence indicate that MS is an autoimmune disorder in which immune cells launch an inflammatory attack targeting myelin antigens. Indeed, myelin-reactive T cells and antibodies have been identified in MS patients and in animal models (namely experimental autoimmune encephalomyelitis, or EAE) that recapitulate many features of human disease. Animal model studies have demonstrated that T cells are both necessary and sufficient to initiate and sustain CNS autoimmunity. However, most MS animal models rely on the role played by CD4+ T cells and partially replicate the multiple aspects of MS pathogenesis. Thus, research in the past has focused heavily on the contribution of CD4+ T cells to the disease process; searching PubMed for “MS AND CD4” yields twice the results as corresponding searches for “CD8” or “B cell” and four times that for “NK cells”. While CD4+ T cells may represent the minimum requirement to mediate CNS autoimmunity, it is clear that the immune response underlying human MS is far more complex and involves numerous other immune cells and subsets. This is well illustrated by the observation that MS patients treated with an anti-CD4 depleting antibody did not gain any clinical benefits whereas removal of several lymphocyte subsets using an anti-CD52 depleting antibody has been shown to impede disease progression. In particular, the pathogenic role(s) of non-CD4+ T cell lymphocytes is relatively poorly understood and under-researched, despite evidence that these subsets contribute to disease pathology or regulation. For example, the observed oligoclonal expansion of CD8+ T cells within the CNS compartment supports a local activation. CD8+ T cells with polarized cytolytic granules are seen in close proximity to oligodendrocytes and demyelinated axons in MS tissues. The presence of B cells in inflammatory lesions and antibodies in the CSF have long been recognized as features of MS and Rituximab, a B cell depleting therapy, has been shown to be highly effective to treat MS. Intriguingly, the putative MS therapeutic reagent Daclizumab may function in part through the expansion of a subset of immunoregulatory NK cells. NKT and ?d T cells may also play a role in CNS autoimmunity, given that they respond to lipid antigens and that myelin is lipid-rich. While different animal models recapitulate some of these aspects of human disease, identifying appropriate models and measures to investigate the role of these less well-understood lymphocytes in MS remains a challenge for the field. This Frontiers research topic aims to create a platform for both animal- and human-focused researchers to share their original data, hypotheses, future perspectives and commentaries regarding the role of these less-well understood lymphocyte subsets (CD8+ T cells, B cells, NK cells, NK T cells, ?d T cells) in the pathogenesis of CNS autoimmunity.

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