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A Niche for Plasma Cells: The Skin

      Antibodies are key components of the skin immune barrier, and antibodies directed toward skin structures can result in disease. Wilson et al. (2019) show that healthy skin is a niche for antibody secreting plasma cells and plasmablasts, and that inflammation and immunization increase their numbers. This work advances our understanding of skin associated B and plasma cells in health and disease.
      • The skin is a niche for antibody secreting cells (ASC; plasma cells and plasmablasts). These ASC produce natural IgM, which is important for maintaining the microbial barrier, clearing apoptotic debris, repairing tissue damage, and preventing autoimmunity.
      • Inflammation and immunization induce massive accumulation of skin ASC. Skin ASC may generate high local concentrations of skin-directed autoantibodies in diseases such as pemphigus, pemphigoid, and scleroderma.
      • Survival of skin ASC is dependent on BAFF and APRIL, tumor necrosis factor family members. Blockade of BAFF with belimumab or other modalities may reduce pathogenic autoantibodies in skin disease.
      Antibodies play key roles maintaining protective skin immunity and driving cutaneous autoimmune disease. However, our understanding of the biology and function of B cells in the skin is limited. In this issue of the Journal of Investigative Dermatology, Wilson et al. lead with the novel observation that terminally differentiated B cells, antibody secreting cells (ASC; plasma cells and plasmablasts), are present in healthy skin. Through a series of thoughtful experiments, they characterize the dominant ASC population, evaluate how it changes in inflammation and immunization, and identify soluble factors required for ASC survival in the skin. Taken together, these data add significantly to our understanding of how B cells function, and antibodies accumulate in the skin.

       B cells in the skin

      Until recently, healthy skin was thought to be devoid of B cells. Seminal work by Gudrun Debes’ group showed that B cells are present in, and recirculate through, healthy dermis (
      • Geherin S.A.
      • Fintushel S.R.
      • Lee M.H.
      • Wilson R.P.
      • Patel R.T.
      • Alt C.
      • et al.
      The skin, a novel niche for recirculating B cells.
      ) (Figure 1). B cells are broadly divided into B1 cells, which function in innate-like immunity, and B2 cells, which participate in acquired, adaptive immunity. Both are present in the skin. Current understanding of skin B cells is reviewed in
      • Debes G.F.
      • McGettigan S.E.
      Skin-associated B cells in health and inflammation.
      .
      Figure thumbnail gr1
      Figure 1B cells, antibodies, and ASC in the skin. (Left) Healthy, uninflamed skin. IgA and IgM are present in the stratum corneum and the epidermis, where they bind microbes to inhibit microbial invasion during barrier breach. Antibodies are produced by ASC adjacent to eccrine coils, transferred into the lumen, and secreted onto the skin surface. Natural IgM binds apoptotic debris, which enhances efferocytosis by macrophages and dampens inflammation. B cells, both B1 and B2 cells, traffic in and out of the skin via blood and lymphatic vessels. ASC, which arise from terminal differentiation of B cells, are found in the dermis. In healthy skin, most secrete IgM and some secrete IgA or IgG. (Middle) Inflamed skin. Inflammation triggers increased migration of B cells into the dermis. ASC secreting IgM accumulate, reaching frequencies similar to those in the bone marrow, the classic plasma cell niche. Soluble tumor necrosis factor family members, BAFF and APRIL, expressed in uninflamed skin, are upregulated in inflamed skin. When BAFF and APRIL are genetically absent or BAFF is blocked therapeutically, dermal ASC are reduced. IL-10+ B cells secrete IL-10 and dampen inflammation. (Right) Immunized skin. Immunization with T-independent or T-dependent antigens results in an accumulation of immunogen-specific ASC in the dermis. Many are generated in draining lymph nodes, but some appear to be generated in the skin itself. T-independent immunization results primarily in IgM ASCs. In T-dependent immunization, antigen-specific B and T cells may form tertiary lymphoid organs that generate IgM and isotype-switched ASC. Activated B cells secrete pro-inflammatory cytokines, including IL-6. ASC, antibody secreting cell.
      B1 cells are present in healthy dermis and accumulate in the skin in even larger numbers during inflammation. In the absence of immunization or infection, B1 cells secrete natural antibody that defends against microbial invasion (
      • Baumgarth N.
      The double life of a B-1 cell: self-reactivity selects for protective effector functions.
      ,
      • Griffin D.O.
      • Holodick N.E.
      • Rothstein T.L.
      Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70-.
      ). Many B1 antibodies are self-reactive and have homeostatic function, facilitating cleanup of apoptotic debris and protecting against autoimmunity. B1 cells efficiently present antigen to T cells and can stimulate CD4+ T cell differentiation into T helper type 17 cells. A subset of B1 cells secretes IL-10+ and dampens skin inflammation. Deficiency of IL-10 B cells appears to play a role in psoriasis pathogenesis.
      B2 cells are also present in healthy skin. These cells express IgM or class-switched isotypes. B cells are increased in lesional skin in several autoimmune skin disorders, including atopic dermatitis, psoriasis, discoid lupus erythematosus, and systemic sclerosis. It is likely that many of these are conventional B cells that were expanded after participating in adaptive autoimmune responses.

       Antibodies in the skin

      The role of antibodies in maintaining skin health is well established. IgA, IgM, and IgG are found in the stratum corneum where they bind pathogenic and commensal microorganisms. They are produced by ASC adjacent to eccrine glands, transcytosed across the eccrine lumen into sweat and sebum, and then secreted onto the skin surface. These antibodies help prevent microbial invasion when the barrier is breached and may regulate microbial diversity, as it has been described in the intestinal lumen (
      • Fadlallah J.
      • El Kafsi H.
      • Sterlin D.
      • Juste C.
      • Parizot C.
      • Dorgham K.
      • et al.
      Microbial ecology perturbation in human IgA deficiency.
      ).
      Skin antibodies also initiate and promote cutaneous disease. Skin-reactive IgG, IgA, and IgE can disrupt adhesions, interfere with signaling, fix complement, and trigger inflammatory cascades causing devastating autoimmunity. Classic examples are immunobullous disorders, and recent data suggest that systemic sclerosis may be similar (
      • Bosello S.
      • Angelucci C.
      • Lama G.
      • Alivernini S.
      • Proietti G.
      • Tolusso B.
      • et al.
      Characterization of inflammatory cell infiltrate of scleroderma skin: B cells and skin score progression.
      ). It has been presumed that pathogenic autoantibodies are generated by ASC in the bone marrow, spleen, and lymph node and are subsequently transported to the skin via blood. However, an elegant study recently challenged this view. Investigators identified desmoglein-specific B cells in lesional pemphigus skin and further visualized B, CD4+ T, and plasma cells clustering into tertiary lymphoid organ–like structures (
      • Yuan H.
      • Zhou S.
      • Liu Z.
      • Cong W.
      • Fei X.
      • Zeng W.
      • et al.
      Pivotal role of lesional and perilesional T/B lymphocytes in pemphigus pathogenesis.
      ). Anti-desmoglein antibodies were produced by skin lymphocytes, suggesting that skin ASC may be an additional source of pathogenic antibodies in the skin.

       Clinical implications

      Natural antibodies in the skin maintain the microbial barrier, facilitate cleanup of apoptotic debris, support tissue repair, and prevent cutaneous autoimmunity. Pathogenic autoantibodies in the skin drive diseases like pemphigus, pemphigoid, and possibly systemic sclerosis. As skin ASC are a likely source of protective and pathogenic antibodies, a more complete understanding of ASC in the skin may have significant clinical consequences.

       Antibody secreting cells in the skin

      • Wilson R.P.
      • McGettigan S.E.
      • Dang V.D.
      • Kumar A.
      • Cancro M.P.
      • Nikbakht N.
      • et al.
      IgM plasma cells reside in healthy skin and accumulate with chronic inflammation.
      show that ASC are present in healthy dermis of humans and mice. In mice, the majority of ASC produce IgM, and a minority secrete IgA or IgG. The focus of this work is on the dominant population of IgM ASC in murine skin. In healthy mice, IgM ASC are primarily non-dividing plasma cells and comprise about 0.2% of the total immune cells in the skin. Developmental studies show that they accumulate in an ordered sequence, even in the absence of microbial stimulation or T cells. These properties indicate that skin IgM ASC arise from B1 lineage B cells and, therefore are likely to produce natural IgM.
      During inflammation, IgM ASC massively expand in number (Figure 1). Neither microbial nor T cell stimulation is required, indicating that these ASC are arising from B1 B cells. In chronic inflammation, ASC frequency about equals that in bone marrow, the central plasma cell niche. Although in healthy skin most ASC are resting plasma cells, in inflamed skin most ASC are proliferating plasmablasts.
      Dermal ASC also accumulate after stimuli modeling cutaneous infection. Mice were immunized subcutaneously with T-independent or T-dependent antigens, given along with an inflammatory stimulus (complete Freund’s adjuvant). Thus, the skin is a niche that promotes accumulation of ASC arising from both innate and adaptive immune responses.
      ASC reside in specialized niches that provide survival signals (
      • Chu V.T.
      • Berek C.
      The establishment of the plasma cell survival niche in the bone marrow.
      ). BAFF and APRIL are tumor necrosis fator (TNF) family members that play critical roles in B-cell development, differentiation, activation, and survival. APRIL is a key survival factor for plasma cells, whereas BAFF is important for newly formed plasmablasts. Here,
      • Wilson R.P.
      • McGettigan S.E.
      • Dang V.D.
      • Kumar A.
      • Cancro M.P.
      • Nikbakht N.
      • et al.
      IgM plasma cells reside in healthy skin and accumulate with chronic inflammation.
      show that BAFF and APRIL are expressed in healthy skin and upregulated in inflamed skin. In the absence of both BAFF and APRIL (double knockout mice), skin IgM ASC are virtually absent from the skin but not from other lymphoid tissues. BAFF blockade reduces ASC accumulation during inflammation. Taken together, these data begin to elucidate the factors that define the ASC niche in the skin.
      IgM ASC were present in all healthy human samples studied, a total of eight donors. ASC frequency varied dramatically (from 3 to ∼6,000 per million total skin leukocytes), suggesting that frequency may be influenced by skin site and host factors. IgM ASC were also observed in inflamed human skin (acne keloidalis nuchae). Whether or not skin ASC produce natural IgM or arise from B1 cells was not explored. Given the distinct functions of natural antibodies in skin homeostasis, these fundamental questions should be addressed in the future.

       Significance

      This study adds to a growing literature showing the significance of innate-like B cells, ASC, and antibodies in skin health and homeostasis. ASC produce natural IgM in healthy dermis and IgM ASC are massively expanded in inflammation. Natural antibodies play critical roles in defense against microbial invasion, in tissue cleanup after damage, and in prevention of initiation of autoimmunity in the setting of damage (
      • Kaveri S.V.
      • Silverman G.J.
      • Bayry J.
      Natural IgM in immune equilibrium and harnessing their therapeutic potential.
      ). Taken together, the findings presented here show that natural skin immunity is dynamic in a previously unappreciated manner.
      The paper by
      • Wilson R.P.
      • McGettigan S.E.
      • Dang V.D.
      • Kumar A.
      • Cancro M.P.
      • Nikbakht N.
      • et al.
      IgM plasma cells reside in healthy skin and accumulate with chronic inflammation.
      newly defines healthy dermis as a niche for plasma cells and plasmablasts. Plasmablasts are dividing and short-lived (days), but plasma cells are quiescent and can live for years within specialized niches that provide survival factors. TNF family members BAFF and APRIL appear to be critical for ASC in the skin. Thus, treatment with anti-BAFF monoclonal antibody, belimumab, may offer an approach to intentionally decrease pathogenic skin ASC in autoimmune disease. However, beneficial skin ASC may be inadvertently depleted when BAFF or APRIL blockade is used for other indications.

       Questions and future directions

      • Wilson R.P.
      • McGettigan S.E.
      • Dang V.D.
      • Kumar A.
      • Cancro M.P.
      • Nikbakht N.
      • et al.
      IgM plasma cells reside in healthy skin and accumulate with chronic inflammation.
      raise our awareness about the presence of ASC in healthy skin and characterize the dominant population of IgM ASC producing natural antibody. Other populations of skin ASC, including those secreting IgG or IgE and those arising from acquired immunity, are left to be explored. Given the importance of acquired B-cell responses in driving autoimmunity and allergic disease, studies detailing the biology of skin ASC arising from T-dependent immune responses will be welcome.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      MMT is supported by the National Institutes of Health ( R01AI122448 ). The authors thank Katherine Henderson for assistance with figure production.

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      Linked Article

      • IgM Plasma Cells Reside in Healthy Skin and Accumulate with Chronic Inflammation
        Journal of Investigative DermatologyVol. 139Issue 12
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          Antibodies are key to cutaneous host defense and inflammation. Despite their importance, the mechanisms by which skin antibodies are sustained are poorly described. Here, we identified that, in addition to antibody production in lymphoid tissues, plasma cells reside in healthy mouse and human skin. In naïve mice, IgM was the predominant isotype produced in skin. Skin plasma cells developed independently of T cells and microbiota. Importantly, chronic skin inflammation promoted the massive accumulation of IgM-secreting cells, and cutaneous immunization directed both T cell–dependent and –independent antigen-specific IgM-secreting cells into skin.
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