Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases-Implications for Therapeutic Approaches

Abstract

B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL).

Keywords: B cells; BAFF; BLyS; autoantibodies; autoimmunity; lupus erythematosus; pemphigoid; pemphigus; skin; tertiary lymphoid structures.

Figure 1

Schematic illustration of a potential tertiary lymphoid structure (TLS) in skin autoimmunity. TLS represent accumulations of lymphoid and stromal cells arising at ectopic sites as a reflection of chronic inflammation. As depicted, they may consist of B- and T-cell clusters and a network of stromal cells, follicular dendritic cells (DC) and macrophages as well as vascular structures such as high endothelial venules (HEV) and lymphatic vessels, possibly forming GC-like structures [12,116,117,119]. TLS may create a microenvironment that enables localized autoantigen-directed immune responses such as T cell activation, which might also be driven by B cells with antigen-presenting features. Proinflammatory cytokines are subsequently released from activated T cells and autoantibody production by PCs as well as immune complex formation are iniated [124]. TLS formation has been described in pemphigus and lupus erythematosus panniculitis, yet data concerning the appearance and specific role of TLS in autoimmune skin diseases are limited [111,112,133].