Skin-Associated B Cells in Health and Inflammation

Abstract

Traditionally, the skin was believed to be devoid of B cells, and studies of the skin immune system have largely focused on other types of leukocytes. Exciting recent data show that B cells localize to the healthy skin of humans and other mammalian species with likely homeostatic functions in host defense, regulation of microbial communities, and wound healing. Distinct skin-associated B cell subsets drive or suppress cutaneous inflammatory responses with important clinical implications. Localized functions of skin-associated B cell subsets during inflammation comprise Ab production, interactions with skin T cells, tertiary lymphoid tissue formation, and production of proinflammatory cytokines but also include immunosuppression by providing IL-10. In this review, we delve into the intriguing new roles of skin-associated B cells in homeostasis and inflammation.

Figure 1.. Skin-associated B cells maintain normal healthy skin.

B-1 and B-2 lineage cells as well as antibody-secreting cells localize to healthy skin. [A -C] Secretory IgM and IgA are produced in healthy skin [A] and bind skin commensals [B] as well as invading microbes after barrier breach [C]. [D] Secreted natural IgM binds to and enhances uptake of apoptotic cells (efferocytosis) by macrophages, a process that induces anti-inflammatory programming in macrophages. [E] Skin-associated B cells, primarily B-1-like B cells, produce IL-10 to limit inflammation. [F] Additional cytokines and growth factors are produced by B cells and support wound healing. Inset, Summary of mechanisms by which B cells influence skin homeostasis. ASC, antibody-secreting cell; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor.

Figure 2.. Skin-associated B cells are critical to driving and suppressing inflammation.

Skin-associated B cells play several important roles in skin inflammation. [A] B cell subsets with various functions accumulate in inflamed skin. [B] Antibody-secreting cells accumulate in inflamed skin and secrete antibodies with reactivity to cutaneous antigens, including autoantigens and skin-associated allergens. [C] Aggregates of collaborating B and T cells form, and B cells initiate further development of tertiary lymphoid organs that support activation and differentiation of pathogenic B and T cells. [D] High affinity autoreactive plasma cells and IgGs emerge from GC reaction in TLO, exacerbating inflammation. [E] B cells act as APCs inducing T cell activation and pro-inflammatory cytokine production. [F] B cells produce pro-inflammatory cytokines, like IL-6, and potentially GM-CSF, IFN-γ, or IL-4, all of which promote local inflammation and, in case of IL-6, fibrosis via stimulation of fibroblasts. [G] B cells secrete IL-10 that suppresses activation of other leukocytes, including T cells and macrophages, thereby counteracting inflammation. [H] Pathogenic autoantibody deposition can destroy cell-cell junctions creating acantholysis or gaps between cells as in pemphigus. [I] Autoantibodies can accumulate at the dermoepidermal junction as in cutaneous lupus erythematosus, leading to complement activation and other inflammatory downstream effector functions. Inset, Summary of disease settings in which skin-associated B cells modulate skin inflammation. ASC, antibody secreting cell; SLE, systemic lupus erythematosus. GC, germinal center; TLO, tertiary lymphoid organ.