T Regulatory Cells in Autoimmune Diabetes: Past Challenges, Future Prospects

Bluestone, Jeffrey A.; Tang, Qizhi; Sedwick, Caitlin

doi:10.1007/s10875-008-9242-z

Cited by 105 publications

(75 citation statements)

References 43 publications

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“…Mouse models of autoimmunity support the pathogenic importance of such an imbalance (25). It also appears likely that decreases in the number of functional Tregs, or resistance of effector T cells to regulation, play a role in the initiation of human autoimmune disease.…”

Section: R E V I E W S E R I E S : a U T O I M M U N I T Ymentioning

confidence: 98%

Mechanisms of human autoimmunity

Rosenblum¹,

Remedios²,

Abbas³

2015

J. Clin. Invest.

386

258

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R e v i e w S e R i e S : A u t o i m m u n i t y2 2 2 9 jci.org Volume 125 Number 6 June 2015theories have been proposed to explain this association, including epitope spreading, antigenic complementarity, and excessive innate/pattern recognition receptor activation. For example, evidence of EBV infection in postmortem brain tissue has been associated with MS but not other inflammatory disorders (17). Additionally, systemic infections have been reported to trigger relapses in patients with relapsing-remitting MS through enhancement of myelin-specific T cell responses (15). Another example of the association of infections with autoimmunity is that of periodontal infections and rheumatoid arthritis (18). In contrast, infections are also postulated to protect against some autoimmune diseases. For example, infection of germ-free mice with Bacteroides fragilis has been reported to protect against experimental autoimmune encephalomyelitis, the mouse model of MS, through induction of Treg cells (19). Additionally, a higher incidence of MS and type 1 diabetes is correlated with a decreased number of infections in developed countries (20). Recent interest has focused on the possible role of the microbiome in influencing local and systemic immune responses. Much of the emphasis has been on the gut microbiome. It is now believed that inflammatory bowel disease (IBD) is initiated by dysregulated and exaggerated immune responses to intestinal commensal microbes. In fact, the major manifestations of IBD may be caused by antimicrobial immune reactions and not by true autoimmunity (i.e., directed at tissue self-antigens). There are also several studies in mice that implicate commensal microbes in autoimmune disease, including type 1 diabetes (reviewed in ref. 21).A well-recognized nonmicrobial environmental trigger is UV irradiation for cutaneous lupus. A possible explanation for this connection is that UV radiation induces apoptotic death of many cell types and increases the burden of nuclear antigens, especially if the dead cells cannot be efficiently cleared (22). It has been suggested that low-level natural cell death in tissues is a mechanism for maintaining peripheral tolerance to tissue antigens through tolerance-promoting dendritic cell populations (23). It is plausible that lupus patients have a genetic predisposition for this system to become easily overwhelmed and are thus unable to maintain tolerance in the presence of continual UV exposure.Defective regulation as the cause of autoimmunity. If failure of self-tolerance is the fundamental abnormality in autoimmune diseases, the central question becomes -which mechanisms of tolerance fail in specific diseases, and why? In patients with SLE, defects in deletion of immature B cells in the bone marrow, in receptor editing, and in control of mature B cells in peripheral tissues have all been proposed (24). In humans with SLE, mature naive B cells can produce autoantibodies even before encounter with antigen, suggesting that defects in early B cell tolerance checkpoints m...

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Section: R E V I E W S E R I E S : a U T O I M M U N I T Ymentioning

confidence: 98%

Mechanisms of human autoimmunity

Rosenblum¹,

Remedios²,

Abbas³

2015

J. Clin. Invest.

386

258

View full text Add to dashboard Cite

show abstract

“…With the advantage of MHC genotyping such an approach of personalized medicine is now easily realizable [140]. On the other hand, a single antigen treatment has been shown to be sufficient for preserving beta cell function, indicating that the effect of one T cell clone could force other T cell clones into peripheral tolerance [124,141].…”

Section: Application Of Apl In Situ and In Vivomentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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SummaryBoth CD4 + and CD8 + T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4 + T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.

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“…4 CD4 1 CD25 1 Foxp3 1 Treg cells are a specialized CD4 1 T-cell lineage that plays a central role in maintaining self-tolerance, and the dysfunction of these cells is implicated in the development of various autoimmune diseases. [5][6][7] CD4 1 CD25 1 Foxp3 1 Treg cells comprise at least two distinct subsets in the periphery, natural Treg cells (nTreg cells) produced by the thymus after recognition of high-affinity self-antigen and then move to the periphery, and induced Treg cells (iTreg cells) that are converted from conventional non-Treg cells as a consequence of peripheral exposure to antigens in the presence of transforming growth factor-beta (TGF-b) signaling. 8 The comparison of the similarities and differences between nTreg and iTreg cells has been previously reviewed.…”

Section: Introductionmentioning

confidence: 99%

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

et al. 2015

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Regulatory T (Treg) cells are necessary for immune system homeostasis and the prevention of autoimmune diseases. Foxp3 is specifically expressed in Treg cells and plays a key role in their differentiation and function. Foxp3 1 Treg cells are consisted of naturally occurring, thymus-derived Treg (nTreg) and peripheral-induced Treg (iTreg) cells that may have different functional characteristics or synergistic roles. All-trans retinoic acid (atRA), a vitamin A metabolite, regulates a wide range of biological processes, including cell differentiation and proliferation. Recent studies demonstrated that atRA also regulates the differentiation of T helper (Th) cells and Treg cells. Moreover, atRA also sustains nTreg stability under inflammatory conditions. In this review, we summarize the significant progress of our understanding of the role(s) and mechanisms of atRA in Treg biology.

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T Regulatory Cells in Autoimmune Diabetes: Past Challenges, Future Prospects

Abstract: This review will focus on the origins and function of Treg in peripheral self-tolerance. We will summarize the role of Treg in preventing autoimmune diseases, with a particular focus on Type 1 Diabetes (T1D), and discuss the prospects for Treg-based therapies for autoimmune diseases.

Cited by 105 publications

References 43 publications

Mechanisms of human autoimmunity

Mechanisms of human autoimmunity

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells

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