From neglect to spotlight: the underappreciated role of B cells in cutaneous inflammatory diseases

Abstract

The skin, covering our entire body as its largest organ, manifests enormous complexities and a profound interplay of systemic and local responses. In this heterogeneous domain, B cells were considered strangers. Yet, recent studies have highlighted their existence in the skin and their distinct role in modulating cutaneous immunity across various immune contexts. Accumulating evidence is progressively shedding light on the significance of B cells in maintaining skin health and in skin disorders. Herein, we integrate current insights on the systemic and local contributions of B cells in three prevalent inflammatory skin conditions: Pemphigus Vulgaris (PV), Systemic Lupus Erythematosus (SLE), and Atopic Dermatitis (AD), underscoring the previously underappreciated importance of B cells within skin immunity. Moreover, we address the potential adverse effects of current treatments used for skin diseases, emphasizing their unintentional consequences on B cells. These comprehensive approaches may pave the way for innovative therapeutic strategies that effectively address the intricate nature of skin disorders.

Keywords: B cells; atopic dermatitis; inflammatory disease; pemphigus vulgaris; skin; skin-infiltrating B cells; systemic lupus erythematosus.

Figure 1

Integrative B-cell profiling in the pathophysiology of inflammatory skin diseases. (A) In pemphigus vulgaris (PV), disease severity correlates with both the level of circulating anti-DSG1/3 autoantibodies and the portion of DSG1/3-specific B cells in peripheral blood. Also, skin-localized B cells play crucial roles in disease progression by forming cutaneous tertiary lymphoid organs (TLOs) with IL-21⁺CD4⁺ T helper cells and locally producing anti-DSG1/3 antibodies. (B) In systemic lupus erythematosus (SLE), recently identified B cell subpopulations, namely atypical memory B cells (atMBCs) and CD27^-IgD^- double-negative B cells (DN2 B cells), appear poised to differentiate into antibody-secreting cells (ASCs), which may amplify the disease severity (dashed arrows indicate potential differentiation pathways). Similar to PV, local contribution of skin-localized B cells in the pathogenesis of SLE has been elucidated through enhanced B cell infiltration, TLO formation in lesional skin, and presence of distinct germinal centers with peripheral node addressin(+) high endothelial venules (PNA⁺ HEVs). (C) Unlike the two previous disorders, the establishment of TLOs has not been demonstrated yet in atopic dermatitis (AD). However, recent AD research suggests the concept of “autoallergy”, where autoimmunity and atopic conditions overlap, marked by autoreactive IgE antibodies. Also, systemic B-cell abnormalities have been observed in the patients with AD.

Figure 2

Current therapeutics for inflammatory skin diseases and their potential side effects on B cells. (A) B-cell-directed therapies include 1) direct B-cell depletion using monoclonal antibodies that target B cell surface markers, 2) inhibition of survival and signaling factors such as B cell activating factor (BAFF) and Bruton tyrosine kinase (BTK), and 3) chimeric antigen receptor (CAR) T cell therapy. These strategies are not capable of distinguishing between pathogenic and non-pathogenic B cells, resulting in an overall B-cell depletion. This widespread B-cell deficiency may compromise humoral immune responses, leading to increased vulnerability to infections and diminished vaccine efficacy. (B) While IL-4R blockade was not initially intended to specifically target B cells, it has emerged as a potential regulator of B cell responses. Naïve B cells rely on IL-4 signaling pathways for their survival and development. Additionally, recent studies have demonstrated the pivotal roles of IL-4 in modulating the germinal center microenvironment. Consequently, IL-4R blockade could potentially suppress overall humoral immunity.