Multiple Germline κ Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice

Woodward, Emily; Thomas, James W.

doi:10.4049/jimmunol.175.2.1073

Cited by 21 publications

(31 citation statements)

References 52 publications

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“…Multiple nucleotide differences from the nonautoimmune strain that are shared by all NOD V isolates likely represent polymorphisms (Fig. 6, shaded areas), as we have previously reported in other NOD L chain genes (42). These shared differences were present in all V 3-4 sequences, including clones from multiple different mice (n ϭ 9, data not shown), consistent with a germline gene origin.…”

Section: B Lymphocytes In the Pancreas Of Prediabetic V H 125tg/nod Msupporting

confidence: 49%

“…In the presence of a restricted H chain, a more substantial difference in V expression is found when B lymphocytes populating the pancreas are compared with those in the draining lymph nodes. The V 1 and 9 gene families predominated in the pancreatic lymph nodes of V H 125Tg/NOD mice, the same pattern of predominance that was previously reported in V H 125Tg/NOD spleens (42). In contrast, a marked shift away from V 1 and 9 to V 4 gene families was revealed in the pancreas of V H 125Tg/NOD mice ( p ϭ 0.006 by Fisher's exact test).…”

Section: H 125tg/nod B Cells From the Pancreas Skew V Gene Expressimentioning

confidence: 46%

“…Therefore, these studies were extended to V H 125Tg/NOD mice, in which the BCR is generated by a fixed anti-insulin Ig H chain transgene (V H 125), combined with endogenous light chains. Unbiased recombination with multiple V s results in a diverse repertoire in these mice, with only 1-3% of splenic B cells binding insulin (42). B lymphocytes in V H 125Tg/NOD mice support the development of T1D, and induce disease at an accelerated rate compared with wild-type NOD mice (36).…”

Section: H 125tg/nod B Cells From the Pancreas Skew V Gene Expressimentioning

confidence: 99%

“…To delineate the relationship between lymphocytes in this inflamed setting and those populating the draining pancreatic lymph nodes, we analyzed the Ig L chain repertoire expressed by B cells at these two sites in NOD mice. To simplify the analysis while maintaining a diverse repertoire, we also used a disease-promoting transgenic model in which B cells express a fixed H chain, V H 125Tg/NOD (36), that is capable of recombining with a wide range of V (L chain) genes (42). This strategy detects a difference in the repertoire in the pancreas as compared with lymph nodes in both wild-type and HC transgenic NOD mice.…”

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confidence: 99%

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Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

Kendall¹,

Yu²,

Woodward

et al. 2007

The Journal of Immunology

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Autoimmune diabetes occurs when invading lymphocytes destroy insulin-producing β cells in pancreatic islets. The role of lymphocytic aggregates at this inflammatory site is not understood. We find that B and T lymphocytes attacking islets in NOD mice organize into lymphoid structures with germinal centers. Analysis of BCR L chain genes was used to investigate selection of B lymphocytes in these tertiary lymphoid structures and in draining pancreatic lymph nodes. The pancreatic repertoire as a whole was found to be highly diverse, with the profile of L chain genes isolated from whole pancreas differing from that observed in regional lymph nodes. A Vκ14 L chain predominated within the complex pancreatic repertoire of NOD mice. Skewing toward Vκ4 genes was observed in the pancreas when the repertoire of NOD mice was restricted using a fixed Ig H chain transgene. Nucleotide sequencing of expressed Vκs identified shared mutations in some sequences consistent with Ag-driven selection and clonal expansion at the site of inflammation. Isolated islets contained oligoclonal B lymphocytes enriched for the germinal center marker GL7 and for sequences containing multiple mutations within CDRs, suggesting local T-B interactions. Together, these findings identify a process that selects B lymphocyte specificities within the pancreas, with further evolution of the selected repertoire at the inflamed site. This interpretation is reinforced by Ag-binding studies showing a large population of insulin-binding B lymphocytes in the pancreas compared with draining lymph nodes.

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Section: B Lymphocytes In the Pancreas Of Prediabetic V H 125tg/nod Msupporting

confidence: 49%

Section: H 125tg/nod B Cells From the Pancreas Skew V Gene Expressimentioning

confidence: 46%

Section: H 125tg/nod B Cells From the Pancreas Skew V Gene Expressimentioning

confidence: 99%

mentioning

confidence: 99%

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Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

Kendall¹,

Yu²,

Woodward

et al. 2007

The Journal of Immunology

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“…In contrast, when these mice were backcrossed onto the NOD background, selection of appropriate light chains to allow insulin binding occurred and the NOD 125Tg mice expressed B cells producing autoantibodies that were able to bind insulin [66]. Interestingly, a number of different κ light chains were selected that were clonally independent and not due to oligoclonal expansion [77]. The most frequently expressed Vκ1 and Vκ9 genes selected to pair with the 125Tg were shared with the autoimmune model, lupus-prone New Zealand Black/BINJ mice.…”

Section: The B Cell Repertoire Contributes To the Development Of Automentioning

confidence: 99%

B Cells in Autoimmune Diabetes

Wong

Liu²

2005

Rev Diab Stud

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■ AbstractAutoantibodies have been used as good markers for the prediction of future development of type 1 diabetes mellitus (T1DM), but are not thought to be pathogenic in this disease. The role of B cells that produce autoantibodies in the pathogenesis of human T1DM is largely unknown. In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, it has been shown that B cells may contribute multifariously to the pathogenesis of the disease. Some aspects of deficiencies of B cell tolerance may lead to the circulation of autoreactive B cells. In addition, the antigenpresenting function of autoantigen specific B cells is likely to be particularly important, and autoantibodies are also considered to play a critical role. This review discusses the possible aspects of B cells involved in the development of autoimmune diabetes.

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Insulinoma‐released exosomes activate autoreactive marginal zone‐like B cells that expand endogenously in prediabetic NOD mice

et al. 2013

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Summary Exosomes (EXOs) are nano-sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO-induced immune responses in non-obese diabetic (NOD) mice, an autoimmune-prone strain with tissue-specific targeting at insulin-secreting beta cells. EXOs released by insulinoma cells can activate various antigen-presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone (MZ) B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic-resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88-mediated innate TLR signals were essential for the B-cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO-induced B-cell response, suggesting that both innate and antigen-specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes (T1D) in NOD mice, partially via activating autoreactive MZ-like B cells.

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Multiple Germline κ Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice

Cited by 21 publications

References 52 publications

Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

B Cells in Autoimmune Diabetes

Insulinoma‐released exosomes activate autoreactive marginal zone‐like B cells that expand endogenously in prediabetic NOD mice

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