Multiple immuno-regulatory defects in type-1 diabetes

Kukreja, Anjli; Cost, Giulia; Marker, John; Zhang, Chenhui; Sun, Zhong Sheng; Lin‐Su, Karen; Ten, Svetlana; Sanz, Maureen M.; Exley, Mark A.; Wilson, Brian; Porcelli, Steven A.; Maclaren, Noel K.

doi:10.1172/jci0213605

Cited by 597 publications

(472 citation statements)

References 67 publications

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“…A similar subpopulation of CD4 + CD25 high T cells is present in human peripheral blood and lymphoid organs [6][7][8][9][10][11][12][13]. From a few recent studies, it appears that T reg numbers are reduced or their function is impaired in patients with various autoimmune disorders [17][18][19][20][21][22][23][24]. The impact of CD4 + CD25 high T cells in immunoregulation is critically supported by observations of Bennett et al [37] who demonstrated that mutations of Foxp3, a transcription factor which is essential for CD4 + CD25 high T cell function, cause the immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX).…”

Section: Discussionmentioning

confidence: 93%

“…Implication of T reg in human autoimmune disease is currently under intense investigation. Either reduced numbers or suppressive capacities of T reg were recently reported in patients affected by type-1 diabetes [17,18], juvenile idiopathic arthritis [19], systemic lupus erythematosus [20], hepatitis C-associated mixed cryoclobulinemia vasculitis [21], autoimmune polyglandular syndrome type II [22], and psoriasis [23].…”

Section: Introductionmentioning

confidence: 99%

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Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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Immunoregulatory T cells of CD4 + CD25 + phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of CD4 + CD25 high regulatory T cells (T reg ) to confer suppression of myelin-specific immune responses. Whereas T reg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived CD4 + CD25 high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of T reg , suggesting that a defective immunoregulation of peripheral T cells mediated by CD4 + CD25 high T lymphocytes promotes CNS autoimmunity in MS.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

et al. 2005

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“…19,20,[22][23][24][25] Whether there is a distinct pattern of Treg cell deviation in T1D patients is still not clear. [35][36][37] In the studies referenced above, the numbers of Treg cells were assessed in the peripheral blood of T1D patients. The discrepancy regarding alterations in the Treg cell numbers in the peripheral circulation of the T1D patients reported in these publications might reflect fluctuations among individuals.…”

Section: Treg Cells In Plns In T1dmentioning

confidence: 99%

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

et al. 2012

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Previously, we established a model in which physiologically adequate function of the autologous b cells was recovered in non-obese diabetic (NOD) mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory (Treg) cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes (PLNs). The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and b cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the b cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes (T1D).

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“…A large number of studies have shown that Treg cells are major players in autoimmune responses in humans (8)(9)(10) and that they may be affected by immunomodulatory therapy (11,12). We have previously demonstrated that patients with MC vasculitis have a quantitative defect in peripheral blood Treg cells (13) as compared with patients chronically infected with HCV but without autoimmune manifestations.…”

Section: Conclusion the Strong Positive Correlation Between Clinicalmentioning

confidence: 99%

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

Landau¹,

Rosenzwajg²,

Saadoun³

et al. 2008

Arthritis & Rheumatism

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Objective. Mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells. The aim of this study was to prospectively evaluate the evolution of this defect during the course of antiviral treatment.Methods. Treg cell frequencies and numbers were analyzed in 131 patients with chronic HCV infection (including 66 with MC vasculitis) and 20 healthy volunteer donors. Measurements were taken before, during, and after treatment with PEGylated interferon alfa-2b plus ribavirin.Results. At baseline, patients with MC vasculitis had a significantly lower frequency and number of Treg cells than did patients without MC vasculitis. Complete remission of MC vasculitis following antiviral treatment was associated with a significant increase in Treg cell levels compared with baseline. In contrast, Treg cell levels in nonresponders or partial responders, which did not differ from those in complete responders at baseline, remained unchanged over the course of the study. Conclusion. The strong positive correlation between clinical responses and Treg cell levels provides further support for the central role of Treg cells in the pathogenesis of HCV-induced MC vasculitis and emphasizes the dual role of Treg cells in chronic HCV infection: while Treg cells may hinder viral elimination, they also limit autoimmune injury.Chronic infection with hepatitis C virus (HCV) is the main cause of mixed cryoglobulinemia (MC) vasculitis, a potentially life-threatening systemic vasculitis (1). MC is a B cell proliferative disorder characterized by polyclonal or monoclonal activation and autoantibody production. MC may lead to clinical manifestations ranging from an MC syndrome (purpura, arthralgia, asthenia) to a more serious vasculitis with nervous system and renal involvement (1). The observation of T cells in the vascular infiltrates and the presence of autoantibodies, together with the observation that some HLA groups confer susceptibility to MC vasculitis in HCV-infected patients, suggest that autoimmune processes are implied in this virus-induced disease (2,3). It has been demonstrated that antiviral treatment can lead to the disappearance of symptoms and can induce an immunologic response, i.e., a significant decrease in plasma cryoglobulin levels (4). Furthermore, the clinical response is closely related to effective viral elimination (4,5), supporting the causal link between chronic HCV infection and the autoimmune process.During the past several years, CD4ϩCD25 high immunoregulatory T cells have been identified in

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Multiple immuno-regulatory defects in type-1 diabetes

Cited by 597 publications

References 67 publications

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

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