Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

Abstract

In this Review we focus on the initiation of autoantibody production and autoantibody pathogenicity, with a special emphasis on the targeted antigens. Release of intracellular antigens due to excessive cell death or to ineffective clearance of apoptotic debris, modification of self-antigens during inflammatory responses, and molecular mimicry contribute to the initiation of autoantibody production. We hypothesize that those autoreactive B cells that survive and produce pathogenic autoantibodies have specificity for self-antigens that are TLR ligands. Such B cells experience both B cell receptor (BCR) activation and TLR engagement, leading to an escape from tolerance. Moreover, the autoantibodies they produce form immune complexes that can activate myeloid cells and thereby establish the proinflammatory milieu that further negates tolerance mechanisms of both B and T cells.

Figure 2. Proposed role of PRR activation and cross-reactivity in expansion of autoreactive B cells and their effector functions.

(A) Self-antigens that bind PRRs can activate B cells. We hypothesize that the combined recognition of self-antigens by BCRs and PRRs is required for tolerance escape in autoreactive B cells. (B) B cells require recognition of antigen through their BCR for clonal expansion. As most autoantibodies recognize intracellular self-antigens, cross-reactivity to cell surface or extracellular molecules enhances clonal expansion and differentiation into memory and plasma cells.

Figure 3. The role of PRR activation by self-antigens in autoantibody pathogenesis.

During autoimmune responses, inflammation can lead to cell death and release of endogenous PRR or TLR ligands. When recognized by autoantibodies, these ligands can activate myeloid immune cells through both Fc receptors and PRRs, leading to an enhanced inflammatory response. This response, in turn, can lead to tissue destruction and release of ligands for PRRs and autoantibodies, which further amplifies the chronic inflammatory response.

Figure 1. Mechanisms for autoantibody production: apoptosis, antigen modification, and cross-reactivity.

Three models can explain the recognition of intracellular antigens by autoantibodies. (A) Cell death through apoptosis or necrosis leads to extracellular exposure of intracellular self-antigens through release of intracellular contents into the extracellular environment, formation of apoptosis blebs, or NETosis. If clearance mechanisms are insufficient, there may be recognition of these antigens by B cells and autoantibody production. (B) Modification of self-antigen generates neoantigens, to which B cells have not been tolerized. (C) Autoantibody production arises from responses to foreign antigens, which cross-react with self-antigens.