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Desmoglein 3-Reactive B Cells “Hiding” in Pemphigus Lesions

  • Hayato Takahashi
    Correspondence
    Correspondence: Hayato Takahashi, Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
    Affiliations
    Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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      Pemphigus vulgaris is an autoimmune blistering disease caused by anti-desmoglein 3 IgG autoantibodies. It is accepted that interactions between autoreactive B and T cells are key to humoral autoimmunity targeting desmoglein 3. This orchestrated process usually occurs in secondary lymphoid organs, including the spleen and lymph nodes. Thus, it seems likely that autoreactive B cells reside and produce autoantibodies in these tissues. Yuan et al. analyzed lymphocytes in the lesional skin of patients with pemphigus vulgaris using several experimental techniques and concluded that desmoglein 3-reactive B cells were present. This finding expands our understanding of the pathogenesis of pemphigus and should be considered when following the clinical course of skin lesions and thinking about adjunctive therapy.
      • Desmoglein 3-reactive B cells accumulate in the lesional skin of patients with pemphigus vulgaris.
      • IL-17 and IL-21 are produced by lesional T cells.
      • T and B cells colocalized and CCL19 was upregulated in inflamed lesional skin.
      Pemphigus is an autoimmune blistering disease that is induced by autoantibodies against the cadherin-type desmosomal adhesion molecules, desmoglein (Dsg) 1 and 3. Pemphigus vulgaris and pemphigus foliaceus are classical subtypes of pemphigus. Patients with pemphigus foliaceus produce only anti-Dsg1 antibodies, which can induce acantholysis within the granular layer of the epidermis, whereas patients with pemphigus vulgaris produce anti-Dsg antibodies, which can induce acantholysis at suprabasilar locations in the oral mucosa (in patients with anti-Dsg3 only) and skin (in patients with anti-Dsg3 and anti-Dsg1). Typically, biopsies from recent bullous lesions show acantholysis with only a few inflammatory cells in the dermis. In contrast to pemphigoid, pemphigus blister formation is not regularly accompanied by inflammation. Eosinophilic spongiosis is the only inflammatory hallmark that is regularly described in the early phase of disease as a characteristic finding in pemphigus (
      • Emmerson R.W.
      • Wilson-Jones E.
      Eosinophilic spongiosis in pemphigus. A report of an unusual histological change in pemphigus.
      ).
      It was recently reported that a large numbers of T lymphocytes (2 × 1010 cell per person) reside in healthy human skin, although inflammation is not apparent in vertical histologic sections (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ). This number is almost twice the number of T cells that circulate in peripheral blood. A previous report indicated that detecting B cells in skin using immunohistochemistry is difficult (
      • Nihal M.
      • Mikkola D.
      • Wood G.S.
      Detection of clonally restricted immunoglobulin heavy chain gene rearrangements in normal and lesional skin: analysis of the B cell component of the skin-associated lymphoid tissue and implications for the molecular diagnosis of cutaneous B cell lymphomas.
      ), and there is no reliable information on how many B cells reside in normal skin. Thus, detection of small numbers of B cells in normal or lesional skin may be very significant.
      Inflammation in chronic lesions in patients with pemphigus has been thought to be nonspecific and perhaps secondary to epithelial barrier dysfunction. The paper by
      • 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.
      reports that B cells are included among the inflammatory cells in skin lesions of patients with pemphigus vulgaris. No acantholysis was observed in the histology shown in Figure 3 of the paper. Thus, skin lesions analyzed in this study might be nonbullous lesions or re-epithelized resolving lesions. However, the B-cell accumulation in pemphigus vulgaris lesions was not nonspecific because Dsg3-reactive B cells were enriched in lesional tissue as compared with the systemic circulation.
      This interesting observation raises some new questions. What mechanisms are responsible for the accumulation of Dsg3-reactive B cells in skin? Is a special antigen-presenting cell, such as a follicular dendritic cell that presents antigens directly to B cells, involved in the antigen-specific B-cell recruitment in skin? Is there a tertiary lymphoid organ (TLO) that functions as a scaffold for this process? Answers to these questions would further our understanding of skin immunology, especially as it relates to tissue B cells.
      Unlike primary lymphoid organs (thymus and bone marrow) and secondary lymphoid organs (spleen and lymph node), the anatomic locations of TLOs are not fixed and TLOs can be induced during chronic inflammation. Histologically, distributions of T and B cells are compartmentalized in lymphoid organs. TLOs feature lymphoid follicles and support immune responses. In fact, germinal center formation (
      • Takemura S.
      • Braun A.
      • Crowson C.
      • Kurtin P.J.
      • Cofield R.H.
      • O'Fallon W.M.
      • et al.
      Lymphoid neogenesis in rheumatoid synovitis.
      ), activation-induced cytidine deaminase expression (
      • Bombardieri M.
      • Barone F.
      • Humby F.
      • Kelly S.
      • McGurk M.
      • Morgan P.
      • et al.
      Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjogren's syndrome.
      ) that is essential for class-switch recombination and somatic hypermutation in germinal center, and even recombination-activating gene (Rag) expression (
      • Armengol M.P.
      • Juan M.
      • Lucas-Martin A.
      • Fernandez-Figueras M.T.
      • Jaraquemada D.
      • Gallart T.
      • et al.
      Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers.
      ) have been observed in TLOs.
      TLOs can be induced by Helicobacter pylori infection (
      • Mazzucchelli L.
      • Blaser A.
      • Kappeler A.
      • Scharli P.
      • Laissue J.A.
      • Baggiolini M.
      • et al.
      BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma.
      ) and hepatitis C virus infection (
      • Mosnier J.F.
      • Degott C.
      • Marcellin P.
      • Henin D.
      • Erlinger S.
      • Benhamou J.P.
      The intraportal lymphoid nodule and its environment in chronic active hepatitis C: an immunohistochemical study.
      ), and can sustain chronic inflammation that counters invading pathogens by producing antibodies to pathogen components. In autoimmune diseases, TLOs have been observed in synovia of patients with rheumatoid arthritis (
      • Takemura S.
      • Braun A.
      • Crowson C.
      • Kurtin P.J.
      • Cofield R.H.
      • O'Fallon W.M.
      • et al.
      Lymphoid neogenesis in rheumatoid synovitis.
      ) and thyroids of patients with autoimmune thyroid disease (
      • Armengol M.P.
      • Juan M.
      • Lucas-Martin A.
      • Fernandez-Figueras M.T.
      • Jaraquemada D.
      • Gallart T.
      • et al.
      Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers.
      ). Anti-cyclic citrullinated peptide antibody and rheumatoid factor-producing cells were also detected in TLOs in lung tissue in patients with rheumatoid arthritis with pulmonary complications (
      • Rangel-Moreno J.
      • Hartson L.
      • Navarro C.
      • Gaxiola M.
      • Selman M.
      • Randall T.D.
      Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis.
      ). Developmental aspects of TLOs have been clarified. Stromal cell-derived homeostatic chemokines (e.g., CXCL13, CXCL12, CCL21, and CCL19) are important in lymphocyte homing and compartmentalization during secondary lymphoid tissue development (
      • Aloisi F.
      • Pujol-Borrell R.
      Lymphoid neogenesis in chronic inflammatory diseases.
      ), and those chemokines are similarly upregulated in TLOs. Stromal cell production of CXCL12 and CXCL12/13, induced by IL-17 (
      • Fleige H.
      • Ravens S.
      • Moschovakis G.L.
      • Bolter J.
      • Willenzon S.
      • Sutter G.
      • et al.
      IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs.
      ) and IL-22 (
      • Barone F.
      • Nayar S.
      • Campos J.
      • Cloake T.
      • Withers D.R.
      • Toellner K.M.
      • et al.
      IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs.
      ) respectively, has been shown to be important for TLO formation.
      • 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.
      demonstrated IL-17 and IL-21 production by a small number of CD4+ T cells, CCL19 upregulation, and colocalization of T and B cells in lesional skin, suggesting the possibility of TLO formation in pemphigus skin lesions (Figure 1). T cells and B cells were diffusely distributed, and compartmentalization was not observed. Thus, whether TLOs occur in pemphigus lesions is uncertain. Importantly, however, lesional B cells produced anti-Dsg3 antibodies without stimulation in vitro, suggesting that these cells probably produce autoantibodies in vivo (Figure 1). How important is local production of autoantibodies in pemphigus? In the case of pemphigus foliaceus, skin lesions sometimes persist in very limited areas, such as seborrheic areas, despite systemic therapy and clearing of lesions elsewhere. Theoretically, circulating autoantibodies should affect all areas. These observations suggest that autoreactive B cells could accumulate in chronic lesions, where local inflammation might contribute to further autoantibody production and lesional recalcitrance.
      Figure 1
      Figure 1Accumulation of Dsg3-sepcific B cells in pemphigus lesions. In the resolving phase of pemphigus lesions, stromal cells likely produce CCL19 chemokine that recruits lymphocyets and promotes tertiary lymphoid organ formation. Dsg3-reactive B cells and CD4+ T cells are included in among the cells that are recruited. CD4+ T cells in lesional skin produce IL-21 and IL-17A that facilitate antibody production from B cells and induce epithelial cells and stromal cells to produce chemokines, respectively. Ultimately, lesional Dsg3-specific B cells produce anti-Dsg3 antibodies, probably, in vivo. CCL, CC chemokine ligand; Dsg, desmoglein.
      The paper by
      • 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.
      reports an unexpected discovery and provides additional insights into the pathogenesis of pemphigus. If the mechanisms that facilitate B-cell accumulation and antibody production in pemphigus lesions can be defined, local treatment for that targets autoreactive B cells might become attractive as a supporting therapy in the future.

      Conflict of Interest

      The author states no conflict of interest.

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      • Pivotal Role of Lesional and Perilesional T/B Lymphocytes in Pemphigus Pathogenesis
        Journal of Investigative DermatologyVol. 137Issue 11
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          Pemphigus is a skin and mucosal membrane-targeting autoimmune bullous disease. Previous studies have shown that circulating anti-desmoglein1/3 antibodies are pathogenic and mediate blister formation. However, the role of infiltrating immune cells in lesional skin has not been fully investigated. In this study we showed that there existed a large number of B and T lymphocytes and plasma cells in the skin lesions by immunohistochemistry and immunofluorescence staining. In addition, a significantly increased number of Dsg1- and Dsg3-specific B cells could be identified by flow cytometric analysis or enzyme-linked immunospot technique (i.e., ELISPOT) assay.
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