Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice

Tan, Qiyuan; Tai, Ningwen; Li, Yangyang; Pearson, James A.; Pennetti, Sean; Zhou, Zhiguang; Wong, F. Susan; Liu, Wen

doi:10.1172/jci.insight.95882

Cited by 12 publications

(11 citation statements)

References 41 publications

(36 reference statements)

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“…Compared to NOD.AID +/+ littermates, diabetes onset was accelerated and diabetes incidence was higher in NOD.AID −/− mice ( Figure 3 B). In addition to the increased diabetes incidence and similar to previous reports, 34 NOD.AID −/− mice exhibited an enlargement of the spleen and pancreatic lymph nodes ( Figures 3 C and 3D), where diabetogenic T cells are primed by self-antigens. 35 , 36 In contrast, skin-draining lymph nodes were not enlarged in NOD.AID −/− mice relative to littermate controls ( Figures 3 D and S2 C).…”

Section: Resultssupporting

confidence: 90%

Activation-induced cytidine deaminase expression by thymic B cells promotes T-cell tolerance and limits autoimmunity

et al. 2023

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Section: Resultssupporting

confidence: 90%

Activation-induced cytidine deaminase expression by thymic B cells promotes T-cell tolerance and limits autoimmunity

et al. 2023

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“…Expansion of CD73 + regulatory B cells after treatment with a small molecule inhibitor that disrupts the Aicda -encoded activation-induced cytidine deaminase protein (AID) results in the inhibition of diabetes development in the NOD mouse ( 75 ). Conversely, AID deficiency in the NOD mouse model can accelerate type 1 diabetes development ( 76 ) and therefore the role of AID in diabetes progression requires further investigation. An additional B cell-targeted therapeutic approach is to selectively deplete effector B cells preserving regulatory B cells; however this is complicated by the lack of a definitive Breg marker.…”

Section: Discussion and Outstanding Questionsmentioning

confidence: 99%

Regulatory B Cells: Role in Type 1 Diabetes

Boldison

Wong

2021

Front. Immunol.

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Regulatory B cells (Bregs) have an anti-inflammatory role and can suppress autoimmunity, by employing both cytokine secretion and cell-contact mediated mechanisms. Numerous Breg subsets have been described and have overlapping phenotypes in terms of their immune expression markers or cytokine production. A hallmark feature of Bregs is the secretion of IL-10, although IL-35 and TGFβ−producing B cells have also been identified. To date, few reports have identified an impaired frequency or function of Bregs in individuals with type 1 diabetes; thus our understanding of the role played by these Breg subsets in the pathogenesis of this condition is limited. In this review we will focus on how regulatory B cells are altered in the development of type 1 diabetes, highlighting both frequency and function and discuss both human and animal studies.

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“…That is, human genetic risk alleles shared across multiple autoimmune diseases perturb the normal function of lymphocyte self-tolerance networks. To begin both to evaluate this model more systematically and to more fully understand the differences between the murine and human autoimmune disease genetic risk networks, we reviewed the literature and collected lists of putative causal genes in murine models of SLE and type 1 diabetes, as well as genes whose disruption lead to B cell central or peripheral tolerance defects ( 247 – 450 ). Together, each of these sets of genes comprise a molecular network and many of the genes in each network overlap with those in the other networks ( Figure 3 ).…”

Section: Gene Network For Murine Autoimmune Type 1 Diabetes Lupus Cen...mentioning

confidence: 99%

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

2022

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Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor via a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in the study of the immune system(s). In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large autoimmune disease cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. Despite the fact these seminal concepts were developed in animal (especially murine) models of autoimmune disease, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases – systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) along with spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, focusing on pathways relevant to anergy and central tolerance. We highlight some differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression and may, in turn, explain some of this discrepancy. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.

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Activation-induced cytidine deaminase deficiency accelerates autoimmune diabetes in NOD mice

Cited by 12 publications

References 41 publications

Activation-induced cytidine deaminase expression by thymic B cells promotes T-cell tolerance and limits autoimmunity

Activation-induced cytidine deaminase expression by thymic B cells promotes T-cell tolerance and limits autoimmunity

Regulatory B Cells: Role in Type 1 Diabetes

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

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