Phenotype and Functional Characteristics of Islet-Infiltrating B-Cells Suggest the Existence of Immune Regulatory Mechanisms in Islet Milieu

Puertas, María C.; Carrillo, Jorge; Pastor, Xavier; Ampudia, Rosa-Maria; Alba, Anna; Planas, Raquel; Pujol-Borrell, Ricardo; Vives-Pi, Marta; Verdaguer, Joan

doi:10.2337/db06-0428

Cited by 17 publications

(10 citation statements)

References 42 publications

(31 reference statements)

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“…Moreover, FO B cells are preferentially recruited into inflamed thyroids, where they express costimulatory molecules and produce proinflammatory cytokines (Supplementry Fig.1). Similarly, others have shown that 90% of B cells infiltrating the pancreatic islets of NOD mice are FO B cells that are IgD hi and IgM low (48). These results are consistent with the fact that most circulating B cells are FO B cells, although circulating peripheral memory B cells in humans were shown to have a MZ phenotype (49), and MZ B cells were shown to migrate to the pancreatic lymph nodes of NOD mice during diabetes development (8).…”

Section: Resultsmentioning

confidence: 85%

Follicular B Cells in Thyroids of Mice with Spontaneous Autoimmune Thyroiditis Contribute to Disease Pathogenesis and Are Targets of Anti-CD20 Antibody Therapy

Hong

Braley‐Mullen

2014

The Journal of Immunology

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B cells are required for development of spontaneous autoimmune thyroiditis (SAT) in NOD.H-2h4 mice where they function as important antigen presenting cells (APCs) for activation of CD4+ T cells. Depletion of B cells using anti-CD20 effectively inhibits SAT development. The goals of this study were to characterize the B cells that migrate to thyroids in SAT, and determine if anti-CD20 effectively targets those B cells in mice with established SAT. The results showed that most thyroid infiltrating B cells in mice with SAT are follicular (FO) B cells. Expression of CD80, CD86 and CD40 was significantly increased on follicular (FO), but not marginal zone (MZ) splenic B cells after SAT development. Thyroid-infiltrating and peripheral blood B cells had lower expresion of CD20 and CD24 compared to splenic and LN FO B cells. Despite reduced CD20 expression, anti-CD20 depleted most B cells in thyroids of mice with established SAT within 3 days. B cell depletion in thyroids of mice given anti-CD20 was more complete and longer lasting than in spleen and LN and was comparable to that in blood. Circulation of B cells was required for effective and rapid removal of B cells in thyroids since preventing lymphocyte egress by administration of FTY20 abrogated the effects of anti-CD20 on thyroid B cells. Therefore the FO subset of B cells preferentially contributes to SAT development and persistence, and anti-CD20 targeting of FO B cells effectively eliminates B cells in the target organ even though thyroid B cells have decreased CD20 expression.

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Section: Resultsmentioning

confidence: 85%

Follicular B Cells in Thyroids of Mice with Spontaneous Autoimmune Thyroiditis Contribute to Disease Pathogenesis and Are Targets of Anti-CD20 Antibody Therapy

Hong

Braley‐Mullen

2014

The Journal of Immunology

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“…This suggested that while the B cells do not directly cause T1D, they are involved in the development. Studies showed that the islet-infiltrating B cells were antigen-experienced and able to act as APCs to the islet-infiltrating T cells [143]. A specific subset of B cells known as B1a cells (CD5 + CD19 + CD1d med ) play an important role in the pathogenesis of T1D through activation of DCs as depleting the peritoneal B1a cells delayed diabetes onset [15, 144].…”

Section: The Role Of B Cells In the Pathogenesis Of Autoimmune Diamentioning

confidence: 99%

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

Pearson

Wong

2016

Journal of Autoimmunity

238

197

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Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mice and the development of humanized NOD mice, providing novel insights into human T1D.

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“…The importance of B cells for the development of type 1 diabetes in NOD mice has become increasingly evident over the last 10 years [1][2][3][4][5][6]. Several reports have demonstrated that eliminating B cells protects against type 1 diabetes in mice [1,3,6].…”

Section: Introductionmentioning

confidence: 99%

“…B1 cells moreover produce natural antibodies and recognise common bacterial antigens as well as self-antigens [7]. The specific role of NOD marginal zone B cells has been evaluated in a type 1 diabetes context [4,5]. These B cells expand with the onset of diabetes and are able to present insulin peptides to diabetogenic T cells [5].…”

Section: Introductionmentioning

confidence: 99%

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

et al. 2009

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Aims/hypothesis NOD.Igµ null mice lacking mature B cells are highly resistant to diabetes and display poor CD4 T cell responses to autoantigens. Nevertheless, the degree to which different B cell subsets contribute to diabetes in NOD mice remains unresolved. Due to their role in the recognition of microbial and autoantigens, peritoneal B cell characteristics were examined in NOD mice to see if they differ developmentally, phenotypically or functionally in aspects relevant to diabetogenesis. Methods The population dynamics, activation state, migratory behaviour and antigen presentation function were investigated in NOD peritoneal B cells. Results NOD peritoneal B cells were found to express abnormally high levels of co-stimulatory molecules (CD40, CD86 and CD69). In contrast, the expression of L-selectin and integrin α4β1 was markedly reduced in NOD mice compared with BALB/c and C57BL/6 mice. The number of B cells in the peritoneum was lower in NOD than in control mice throughout development; migration of B cells from the peritoneum to the pancreatic lymph nodes in NOD mice was enhanced tenfold. NOD B cells showed no chemotactic response to sphingosine-1-phosphate, which normally acts to retain B cells in the peritoneum. Peritoneal B cells of NOD mice also presented insulin autoantigen to CD4 T cells, inducing T cell proliferation. Conclusions/interpretation NOD peritoneal B cells are hyperactivated, migrate to the pancreatic lymph nodes and are capable of driving insulin-specific CD4 T cell activation. These characteristics could make them important for inducing or amplifying T cell responses against islet-antigens.

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Phenotype and Functional Characteristics of Islet-Infiltrating B-Cells Suggest the Existence of Immune Regulatory Mechanisms in Islet Milieu

Cited by 17 publications

References 42 publications

Follicular B Cells in Thyroids of Mice with Spontaneous Autoimmune Thyroiditis Contribute to Disease Pathogenesis and Are Targets of Anti-CD20 Antibody Therapy

Follicular B Cells in Thyroids of Mice with Spontaneous Autoimmune Thyroiditis Contribute to Disease Pathogenesis and Are Targets of Anti-CD20 Antibody Therapy

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

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