B Cells Drive Early T Cell Autoimmunity In Vivo prior to Dendritic Cell-Mediated Autoantigen Presentation

Abstract

Both B cells and dendritic cells (DCs) have been implicated as autoantigen-presenting cells in the activation of self-reactive T cells. However, most self-proteins are ubiquitously and/or developmentally expressed, making it difficult to determine the source and the exposure of autoantigens to APCs in a controlled manner. In this study, we have used an Ig transgenic mouse model to examine the mechanisms by which B cells and other APCs acquire and present lupus autoantigens in vivo. Targeting a lupus autoantigen, the small nuclear ribonucleoprotein particle D protein, to the BCR activates autoreactive T cells in the periphery. Our in vivo studies demonstrate that autoantigen-specific B cells, when present in the repertoire, are the first subset of APCs to capture and present self-proteins for activating T cells. Thereafter, DCs acquire self-Ag and become effective APCs for stimulating the same subsets of autoreactive T cells. This mechanism provides one explanation of how early steps in autoimmunity can focus responses, via BCR, at a small group of self-proteins among the total milieu of intracellular self-proteins. Subsequently, DCs and other professional APCs may then amplify and perpetuate the autoimmune T cell response.

Short-Term Effects of Rituximab in Children with Steroid- and Calcineurin-Dependent Nephrotic Syndrome

“…Accumulating evidence suggests that B cells play a role in regulating the immune response in both physiologic and pathologic conditions (30). B cell depletion therapy with RTX may be effective not only in autoantibody-associated but also in T cell-mediated autoimmune diseases (31). Data on the positive effects of RTX in INS support this role of B cells including effects on podocytes.…”

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

“…However, B cells can influence T cell function through a variety of means (21,(34)(35)(36)(37)(38). It has been suggested that they are involved in regulating the activation status and number of effector T lymphocytes based on observations of abnormal CD4 ϩ T cell responses in B cell-deficient mice (36, 37).…”

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4+ T helper type 1 subset differentiation

“…58 In many models of autoimmunity it is evident that B cell APC function is required for the optimal induction of autoreactive CD4 + T cell responses. [10][11][12][13][14][15][16][17] Of particular interest to this study, is the demonstration that antigenspecific transgenic B cells (incapable of antibody secretion) are required for optimal anti-aggrecan CD4 + T cell activation. 14 Additionally, mice with a B cell-restricted deficiency in the CD80/86 co-stimulatory molecules 16 show reduced susceptibility to PGIA.…”

“…[7][8][9] In the context of autoimmunity, autoantigen-specific B cells have been shown to activate autoreactive CD4 + T cells. [10][11][12][13][14][15][16][17] These findings have led to the development of…”