Activating systemic autoimmunity: B's, T's, and tolls

Abstract

A recent advance in the treatment and understanding of autoimmune disease has been the efficacy of B-cell-targeted therapy. Such therapies are effective for several such diseases, with systemic autoimmunity being a prototypical example. The mechanism of action is not fully defined, but blocking B cell Ag presentation to T cells is likely to be important. T-B interactions probably engender a positive feedback loop that amplifies and sustains autoimmunity. But how is self-tolerance first broken to initiate this loop? I propose, based on recent data, a model in which autoreactive B cells are activated first, independent of T cells, but dependent upon BCR and TLR signals. These activated B cells then break T cell tolerance, resulting in full-blown autoimmunity.

Figure 1. Proposed model for B cell-mediated, TLR-dependent initiation of the autoimmunity feedback cycle

In step 1, B cell tolerance (or ignorance) is broken in autoAg-specific B cells that recognize self-Ags that carry an endogenous TLR ligand, such as DNA. In step 2, these B cells present autoAg to any self-reactive T cell that can recognize an epitope that is contained on the self-Ag recognized by the B cell. In this case, it is the “blue circle”. The T cell becomes activated, expressing CD40L and IL-21 (shown in step 3) along with other costimulatory molecules and cytokines (not shown). In step 3, these activated T cells provide help to the cognate B cells, leading to enhanced Ab production, isotype switching, clonal expansion and somatic hypermutation. In step 4, the activated B cells can present various different epitopes to T cells with different specificity allowing these in turn to promote the activation of additional autoreactive B cells. Some of these may not need a TLR ligand for activation as they have help now from previously activated T cells. Examples of this include cells specific for the “semi-circular light blue disk” on the right of the panel.