Prevalence of Antibodies to Nucleic Acids in Insulin-dependent Diabetics and Their Relatives

Huang, Shih-Wen; Haedt, L Hallquist; Rich, Stephen S.; Barbosa, José

doi:10.2337/diab.30.10.873

Cited by 24 publications

(4 citation statements)

References 5 publications

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“…Hence, loss of B cell anergy could potentially be instigated through initial binding to a non-islet antigen, such as DNA. Consistent with this hypothesis, and as mentioned above, patients with T1DM have increased antibodies against double-stranded DNA 50,51 . Together, these findings demonstrate that central and peripheral B cell tolerance mechanisms are impaired in patients with T1DM and that loss of anergy might be an early initiating step in disease development (FIG.…”

Section: B Cells In the Development Of T1dmsupporting

confidence: 82%

B cells in type 1 diabetes mellitus and diabetic kidney disease

2017

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Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that affects an estimated 30 million people worldwide. It is characterized by the destruction of pancreatic β cells by the immune system, which leads to lifelong dependency on exogenous insulin and imposes an enormous burden on patients and health-care resources. T1DM is also associated with an increased risk of comorbidities, such as cardiovascular disease, retinopathy, and diabetic kidney disease (DKD), further contributing to the burden of this disease. Although T cells are largely considered to be responsible for β-cell destruction in T1DM, increasing evidence points towards a role for B cells in disease pathogenesis. B cell-depletion, for example, delays disease progression in patients with newly diagnosed T1DM. Loss of tolerance of islet antigen-reactive B cells occurs early in disease and numbers of pancreatic CD20 B cells correlate with β-cell loss. Although the importance of B cells in T1DM is increasingly apparent, exactly how these cells contribute to disease and its comorbidities, such as DKD, is not well understood. Here we discuss the role of B cells in the pathogenesis of T1DM and how these cells are activated during disease development. Finally, we speculate on how B cells might contribute to the development of DKD.

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Section: B Cells In the Development Of T1dmsupporting

confidence: 82%

B cells in type 1 diabetes mellitus and diabetic kidney disease

2017

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“…Consistent with this, new-onset insulin autoantibody–positive patients have elevated serum antibodies reactive with chromatin relative to healthy control subjects, which is consistent with activation of anergic, polyreactive B cells found in healthy individuals. Although previous studies have found increased anti-DNA antibodies in the serum of T1D patients, as well as some of their FDRs ( 29 , 30 ), this is the first study to correlate this finding with loss of the anergic polyreactive B-cell population. Moreover, given that T1D patients are prone to development of other autoimmunities ( 31 , 32 ), including autoimmune thyroiditis and Addison’s disease, we suspect these polyreactive B cells are also reactive with self-antigens, such as thyroglobulin, as has been observed in the NOD mouse ( 33 ).…”

Section: Discussionmentioning

confidence: 50%

Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients

et al. 2014

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Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen–reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD+, IgM− B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles.

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“…Although diabetogenic T cells are mainly responsible for b-cell destruction 173 , increasing evidence has shown that B cells exercise their function through presenting islet autoantigens to diabetogenic T cells 174 , as well as the production of immunoglobulin G, facilitating the formation of an immune complex, and triggering subsequent complement activation in the blood 175 and kidney 21,172,176,177 . The immune complexes were reported to promote macrophage accrual 178 and ensuing inflammation in the glomerulus 179 , which further caused the release of damage-associated molecular patterns 172,180,181 . These data might point toward a larger role of B cells by antibodies and immune complexes in the pathogenesis of DKD.…”

Section: B Cells In Dkdmentioning

confidence: 99%

Role of the adaptive immune system in diabetic kidney disease

Kong

Andrikopoulos

MacIsaac

et al. 2021

J of Diabetes Invest

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Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end‐stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro‐inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon‐γ and tumor necrosis factor‐α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

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Prevalence of Antibodies to Nucleic Acids in Insulin-dependent Diabetics and Their Relatives

Cited by 24 publications

References 5 publications

B cells in type 1 diabetes mellitus and diabetic kidney disease

B cells in type 1 diabetes mellitus and diabetic kidney disease

Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients

Role of the adaptive immune system in diabetic kidney disease

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