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Pemphigus is an autoimmune bullous disease characterized by IgG production against desmogleins. The major sites of autoantibody production are thought to be lymph nodes, spleen, and bone marrow. Previously, it has been suggested that autoreactive B cells might exist in the skin lesions in pemphigus and produce autoantibodies. In their report, Zhou et al. expanded their previous studies and reported that ectopic lymphoid-like structures were found in pemphigus skin lesions, wherein B-cell differentiation and lesional B-cell expansion might progress. This finding provides novel insights into B-cell biology in pemphigus.

Clinical Implications

  • Ectopic lymphoid-like structures are found in lesional skin in patients with pemphigus.

  • B cell differentiation and expansion are suggested in ectopic lymphoid-like structures in skin.

  • These findings may provide an explanation for persistent skin lesions in localized forms of pemphigus.

Pemphigus is an autoimmune bullous disease in which autoantibodies bind to desmoglein (Dsg), a cell adhesion molecule in the epidermis. Pemphigus thus results in the loss of cell-cell adhesion between keratinocytes, leading to blister formation in the skin and mucous membranes (Amagai et al., 1991xAmagai et al., 1991Amagai, M., Klaus-Kovtun, V., and Stanley, J.R. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991; 67: 869–877

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; Kasperkiewicz et al., 2017xKasperkiewicz et al., 2017Kasperkiewicz, M., Ellebrecht, C.T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A.S. et al. Pemphigus. Nat Rev Dis Primers. 2017; 3: 17026

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). Pemphigus vulgaris (PV), which affects predominantly mucous membranes, is caused by IgG autoantibodies against Dsg3, whereas PV affecting both the skin and mucosa is induced by IgG autoantibodies against Dsg1 and Dsg3. Pemphigus foliaceus (PF) only affects the skin and is caused by IgG autoantibodies against Dsg1 (Kasperkiewicz et al., 2017xKasperkiewicz et al., 2017Kasperkiewicz, M., Ellebrecht, C.T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A.S. et al. Pemphigus. Nat Rev Dis Primers. 2017; 3: 17026

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). These autoantibodies are generated by antibody-secreting cells derived from Dsg-specific B cells, and rituximab, a monoclonal antibody against CD20+ B cells, has been shown to be effective as a treatment for pemphigus (Joly et al., 2017xJoly et al., 2017Joly, P., Maho-Vaillant, M., Prost-Squarcioni, C., Hebert, V., Houivet, E., Calbo, S. et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017; 389: 2031–2040

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). Despite this clear evidence that autoreactive B cells play a pivotal role in the pathophysiology of pemphigus, the detailed mechanism by which Dsg3-specific B cells generate autoantibodies has not been fully elucidated. Although the primary sites of autoantibody production are thought to be lymph nodes, spleen, and bone marrow, whether or not ectopic autoantibody production exists in other sites, especially in skin and mucous membranes, is unclear.

Recently, Yuan et al. (2017)xYuan et al., 2017Yuan, 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. J Invest Dermatol. 2017; 137: 2362–2370

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) reported that Dsg3-reactive B cells were found in pemphigus skin lesions and produced Dsg3-specific antibodies in vitro, suggesting that these cells could also produce autoantibodies in vivo. This unique observation offered new insights into B-cell biology in pemphigus with an opportunity to further clarify detailed pathomechanisms underlying the accumulation of these B cells and autoantibody production in lesions. In their report, Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) reported that diffuse ectopic lymphoid-like structures (ELSs) that resembled tertiary lymphoid structures (TLSs) were found in skin lesions of patients with both PV and PF. They suggested that B-cell differentiation and lesional B-cell expansion might occur in TLSs.

The role of TLSs in autoimmune diseases has recently attracted substantial research attention. TLSs are generated at sites of autoimmunity-mediated inflammation, including the synovium in rheumatoid arthritis (RA) and the salivary gland in Sjögren syndrome (Corsiero et al., 2019xCorsiero et al., 2019Corsiero, E., Delvecchio, F.R., Bombardieri, M., and Pitzalis, C. B cells in the formation of tertiary lymphoid organs in autoimmunity, transplantation and tumorigenesis. Curr Opin Immunol. 2019; 57: 46–52

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). TLSs can provide a suitable environment for the active differentiation, proliferation, and germinal center (GC) reaction of autoreactive B cells, leading to the production of autoantibodies (Corsiero et al., 2019xCorsiero et al., 2019Corsiero, E., Delvecchio, F.R., Bombardieri, M., and Pitzalis, C. B cells in the formation of tertiary lymphoid organs in autoimmunity, transplantation and tumorigenesis. Curr Opin Immunol. 2019; 57: 46–52

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). Although little is known about the functions of TLSs in skin, several features are coming to light through studies of dermatological diseases. For example, aggregates of B cells and plasma cells or lymphoid follicles containing GCs have recently been identified in lesions of lupus profundus (Kogame et al., 2018xKogame et al., 2018Kogame, T., Yamashita, R., Hirata, M., Kataoka, T.R., Kamido, H., Ueshima, C. et al. Analysis of possible structures of inducible skin-associated lymphoid tissue in lupus erythematosus profundus. J Dermatol. 2018; 45: 1117–1121

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). Assemblages of B cells and T cells have also been detected in skin manifestations of Sjögren syndrome (Roguedas et al., 2010xRoguedas et al., 2010Roguedas, A.M., Pers, J.O., Lemasson, G., Devauchelle, V., Tobón, G.J., Saraux, A. et al. Memory B-cell aggregates in skin biopsy are diagnostic for primary Sjogren's syndrome. J Autoimmun. 2010; 35: 241–247

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). By forming such localized TLSs, autoreactive B cells may exacerbate skin diseases.

The new contribution by Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) suggests the possibility that B-cell differentiation and expansion may occur in pemphigus ELSs in skin. They identified centroblasts, plasmablasts, and plasma cells in pemphigus lesions, thereby suggesting B-cell differentiation in ELSs. They also demonstrated that mRNA expression levels corresponding to the B-cell differentiation–associated transcription factors BCL-6, BLIMP-1, and IRF4 were elevated in pemphigus lesions. BCL-6 is an essential factor for induction of GC responses, and IRF-4 plays a crucial role in the early phase of GC formation and plasma cell development. BLIMP-1 is an indispensable protein required to promote the differentiation of B cells into plasma cells. Thus, the elevated expression levels of these transcription factors in pemphigus lesions further suggested that the GC reaction and plasma cell differentiation may occur in the ELSs of pemphigus lesions.

Through B-cell receptor repertoire analysis, Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) detected clonal expansions in lesional B cells, which might recirculate among lesions, lymph nodes, and peripheral blood. A previous study indicated that a dominant antigen-specific local immune response shapes synovium-specific B cell clones in the TLSs of RA, and specific B cell clones expand within salivary glands in primary Sjögren syndrome (Pipi et al., 2018xPipi et al., 2018Pipi, E., Nayar, S., Gardner, D.H., Colafrancesco, S., Smith, C., and Barone, F. Tertiary lymphoid structures: autoimmunity goes local. Front Immunol. 2018; 9: 1952

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). The new observations by Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) suggest that specific clones also can be generated in pemphigus ELSs located in skin. It is interesting that lesional B cell clones overlap with peripheral B cell clones, and that a much higher fraction of clonal B cells was detected in the skin lesions than in peripheral blood.

Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) also indicate that multiple chemokines and chemokine receptors can be involved in the migration of lesional B cells. Lesional B cells expressed CXCR5 and CCR6 less often than peripheral B cells. This observation is in line with a previous report on synovial B cells in RA (Armas-González et al., 2018xArmas-González et al., 2018Armas-González, E., Domínguez-Luis, M.J., Díaz-Martín, A., Arce-Franco, M., Castro-Hernández, J., Danelon, G. et al. Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis. Arthritis Res Ther. 2018; 20: 114

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). Moreover, mRNA levels of CXCL13 (Yuan et al., 2017xYuan et al., 2017Yuan, 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. J Invest Dermatol. 2017; 137: 2362–2370

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) and CCL20, encoding the respective ligands of CXCR5 and CCR6, were significantly elevated in pemphigus lesions. Because the surface expression of chemokine receptors is usually reduced via ligand binding, this suggests that CXCL13 and CCL20 negatively regulate the expression of CXCR5 and CCR6 in B cells upon binding. CXCR5 and CCR6 were also suggested to play a role in the migration of naive and memory B cells to the inflammatory synovium in RA (Armas-González et al., 2018xArmas-González et al., 2018Armas-González, E., Domínguez-Luis, M.J., Díaz-Martín, A., Arce-Franco, M., Castro-Hernández, J., Danelon, G. et al. Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis. Arthritis Res Ther. 2018; 20: 114

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). Thus, these chemokines may also be utilized to recruit naïve and memory B cells into ELSs to coordinate GC reactions and drive the differentiation of lesional B cells into plasma cells and the migration of peripheral B cells into ELSs.

The findings reported by Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) bring new insights into the clinical complexities of pemphigus. In some cases, localized recalcitrant lesions persist without detectable circulating Dsg-specific antibodies, which could be explained by local antibody production from ELSs in pemphigus skin lesions (Vinay et al., 2015xVinay et al., 2015Vinay, K., Kanwar, A.J., Mittal, A., Dogra, S., Minz, R.W., and Hashimoto, T. Intralesional rituximab in the treatment of refractory oral pemphigus vulgaris. JAMA Dermatol. 2015; 151: 878–882

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). In some cases, topical steroid monotherapy has been reported to be effective in localized pemphigus (Scully et al., 1999xScully et al., 1999Scully, C., Paes De Almeida, O., Porter, S.R., and Gilkes, J.J. Pemphigus vulgaris: the manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol. 1999; 140: 84–89

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), and the effectiveness of intralesional rituximab (Vinay et al., 2015xVinay et al., 2015Vinay, K., Kanwar, A.J., Mittal, A., Dogra, S., Minz, R.W., and Hashimoto, T. Intralesional rituximab in the treatment of refractory oral pemphigus vulgaris. JAMA Dermatol. 2015; 151: 878–882

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) has also been reported. These observations suggest ongoing local autoimmune reactions in lesional ELSs.

Important innovative studies always provoke further questions that remain to be answered. First, how sizeable is the contribution by local production of IgG autoantibodies in skin lesions to systemic circulating autoantibody levels? Second, if blister formation is caused by the Dsg-specific IgG autoantibodies produced in situ, does B-cell infiltration into skin precede blister formation? Or does anti-Dsg B-cell infiltration occur after blister formation induced by anti-Dsg IgG autoantibodies? Third, are lesional B cells that expand in skin and share repertoires with peripheral B cells specific for desmogleins? Do single-chain variable fragments or monoclonal IgG antibodies derived from the variable region sequences represented in lesional B cells bind specifically to desmogleins?

The findings of Zhou et al. (2019)xZhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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) open a door to potentially novel insights into autoimmune pathophysiological mechanisms that are operative in pemphigus.

ORCIDs

Conflict of Interest

The authors state no conflict of interest.

References

  1. Amagai et al., 1991Amagai, M., Klaus-Kovtun, V., and Stanley, J.R. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991; 67: 869–877
  2. Armas-González et al., 2018Armas-González, E., Domínguez-Luis, M.J., Díaz-Martín, A., Arce-Franco, M., Castro-Hernández, J., Danelon, G. et al. Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis. Arthritis Res Ther. 2018; 20: 114
  3. Corsiero et al., 2019Corsiero, E., Delvecchio, F.R., Bombardieri, M., and Pitzalis, C. B cells in the formation of tertiary lymphoid organs in autoimmunity, transplantation and tumorigenesis. Curr Opin Immunol. 2019; 57: 46–52
  4. Joly et al., 2017Joly, P., Maho-Vaillant, M., Prost-Squarcioni, C., Hebert, V., Houivet, E., Calbo, S. et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017; 389: 2031–2040
  5. Kasperkiewicz et al., 2017Kasperkiewicz, M., Ellebrecht, C.T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A.S. et al. Pemphigus. Nat Rev Dis Primers. 2017; 3: 17026
  6. Kogame et al., 2018Kogame, T., Yamashita, R., Hirata, M., Kataoka, T.R., Kamido, H., Ueshima, C. et al. Analysis of possible structures of inducible skin-associated lymphoid tissue in lupus erythematosus profundus. J Dermatol. 2018; 45: 1117–1121
  7. Pipi et al., 2018Pipi, E., Nayar, S., Gardner, D.H., Colafrancesco, S., Smith, C., and Barone, F. Tertiary lymphoid structures: autoimmunity goes local. Front Immunol. 2018; 9: 1952
  8. Roguedas et al., 2010Roguedas, A.M., Pers, J.O., Lemasson, G., Devauchelle, V., Tobón, G.J., Saraux, A. et al. Memory B-cell aggregates in skin biopsy are diagnostic for primary Sjogren's syndrome. J Autoimmun. 2010; 35: 241–247
  9. Scully et al., 1999Scully, C., Paes De Almeida, O., Porter, S.R., and Gilkes, J.J. Pemphigus vulgaris: the manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol. 1999; 140: 84–89
  10. Vinay et al., 2015Vinay, K., Kanwar, A.J., Mittal, A., Dogra, S., Minz, R.W., and Hashimoto, T. Intralesional rituximab in the treatment of refractory oral pemphigus vulgaris. JAMA Dermatol. 2015; 151: 878–882
  11. Yuan et al., 2017Yuan, 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. J Invest Dermatol. 2017; 137: 2362–2370
  12. Zhou et al., 2019Zhou, S., Liu, Z., Yuan, H., Zhao, X., Zou, Y., Zheng, J. et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020; 140: 309–318.e8

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