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• W2947698879 abstract "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. Unlike their counterparts in lymphoid tissues, cutaneous IgM-secreting cells were completely dependent on survival factors such as a proliferation-inducing ligand or B cell–activating factor, which were constitutively expressed and upregulated during inflammation in skin. Our data support a model in which skin plasma cells supply natural and adaptive IgM to the cutaneous environment, thereby supporting homeostatic skin barrier functions and providing defense against pathogen intrusion. Our results are also of potential relevance for manipulation of cutaneous plasma cells in inflammatory skin diseases or cutaneous plasma cell malignancies. 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. Unlike their counterparts in lymphoid tissues, cutaneous IgM-secreting cells were completely dependent on survival factors such as a proliferation-inducing ligand or B cell–activating factor, which were constitutively expressed and upregulated during inflammation in skin. Our data support a model in which skin plasma cells supply natural and adaptive IgM to the cutaneous environment, thereby supporting homeostatic skin barrier functions and providing defense against pathogen intrusion. Our results are also of potential relevance for manipulation of cutaneous plasma cells in inflammatory skin diseases or cutaneous plasma cell malignancies. The skin is a large barrier organ that faces constant microbial and environmental threats, requiring the skin immune system to orchestrate appropriate responses that combat infection while limiting immunopathology. Antibodies are key to cutaneous host defense, as illustrated by the susceptibility to skin infections of individuals with immunodeficiencies that affect immunoglobulin production (Lehman, 2014Lehman H. Skin manifestations of primary immune deficiency.Clin Rev Allergy Immunol. 2014; 46: 112-119Crossref PubMed Scopus (32) Google Scholar). Antibodies have potent effector functions that include neutralization of toxins and pathogens, complement fixation, activation of effector cells, and promotion of phagocytosis (Lu et al., 2018Lu L.L. Suscovich T.J. Fortune S.M. Alter G. Beyond binding: antibody effector functions in infectious diseases.Nat Rev Immunol. 2018; 18: 46-61Crossref PubMed Scopus (323) Google Scholar). Although most antibodies are protective, when they recognize cutaneous autoantigens or allergens, they can promote inflammatory disorders of the skin, such as pemphigus vulgaris or atopic dermatitis (Cipriani et al., 2014Cipriani F. Ricci G. Leoni M.C. Capra L. Baviera G. Longo G. et al.Autoimmunity in atopic dermatitis: biomarker or simply epiphenomenon?.J Dermatol. 2014; 41: 569-576Crossref PubMed Scopus (29) Google Scholar, Hammers and Stanley, 2016Hammers C.M. Stanley J.R. Mechanisms of disease: pemphigus and bullous pemphigoid.Annu Rev Pathol. 2016; 11: 175-197Crossref PubMed Scopus (170) Google Scholar). While most antibodies are systemic, being produced in lymphoid tissues and reaching extralymphoid tissues via blood, there is an additional role for localized antibody production in tissues. For example, intestinally produced IgA, along with increasing evidence of IgM, regulates local microbiomes and prevents entry of toxins and pathogens (Bunker et al., 2015Bunker J.J. Flynn T.M. Koval J.C. Shaw D.G. Meisel M. McDonald B.D. et al.Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A.Immunity. 2015; 43: 541-553Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, Fadlallah et al., 2018Fadlallah J. El Kafsi H. Sterlin D. Juste C. Parizot C. Dorgham K. et al.Microbial ecology perturbation in human IgA deficiency.Sci Transl Med. 2018; 10Crossref PubMed Scopus (156) Google Scholar, Mantis et al., 2011Mantis N.J. Rol N. Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut.Mucosal Immunol. 2011; 4: 603-611Crossref PubMed Scopus (727) Google Scholar). In contrast, few studies address production of antibodies in mammalian skin. Specifically, two studies analyzed the origins of cutaneous IgA (Metze et al., 1989Metze D. Jurecka W. Gebhart W. Schmidt J. Mainitz M. Niebauer G. Immunohistochemical demonstration of immunoglobulin A in human sebaceous and sweat glands.J Invest Dermatol. 1989; 92: 13-17Abstract Full Text PDF PubMed Scopus (31) Google Scholar, Okada et al., 1988Okada T. Konishi H. Ito M. Nagura H. Asai J. Identification of secretory immunoglobulin A in human sweat and sweat glands.J Invest Dermatol. 1988; 90: 648-651Abstract Full Text PDF PubMed Scopus (59) Google Scholar). The authors found that in healthy human skin, IgA antibody secreting cells (ASCs) localize at eccrine sweat glands and IgA is found in sweat and sebum, consistent with polymeric immunoglobulin receptor–mediated transport into excretions and subsequent reach of skin epithelia (Metze et al., 1989Metze D. Jurecka W. Gebhart W. Schmidt J. Mainitz M. Niebauer G. Immunohistochemical demonstration of immunoglobulin A in human sebaceous and sweat glands.J Invest Dermatol. 1989; 92: 13-17Abstract Full Text PDF PubMed Scopus (31) Google Scholar, Okada et al., 1988Okada T. Konishi H. Ito M. Nagura H. Asai J. Identification of secretory immunoglobulin A in human sweat and sweat glands.J Invest Dermatol. 1988; 90: 648-651Abstract Full Text PDF PubMed Scopus (59) Google Scholar). In addition, ASCs of unknown isotype have been documented in healthy ovine skin (Geherin et al., 2012Geherin 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.J Immunol. 2012; 188: 6027-6035Crossref PubMed Scopus (68) Google Scholar). During inflammation, the existence of ASCs in skin is much better established. Moreover, there is recent evidence that pathogenic autoantibody production within lesional skin is part of the pathogenesis of pemphigus (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: 2362-2370Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) and likely other inflammatory skin disorders, including IgG4-related disease (Hsiao and Wu, 2016Hsiao P.F. Wu Y.H. Characterization of cutaneous plasmacytosis at different disease stages.Dermatology. 2016; 232: 738-747Crossref PubMed Scopus (7) Google Scholar, Tokura et al., 2014Tokura Y. Yagi H. Yanaguchi H. Majima Y. Kasuya A. Ito T. et al.IgG4-related skin disease.Br J Dermatol. 2014; 171: 959-967Crossref PubMed Scopus (80) Google Scholar) and scleroderma (Bosello et al., 2018Bosello 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.Arthritis Res Ther. 2018; 20: 75Crossref PubMed Scopus (34) Google Scholar). Despite the importance of antibodies to skin health, there is a dearth of knowledge of how antibody titers are sustained in skin and if and how skin-localized antibody production can be regulated. ASCs differentiate from B cells and encompass proliferating plasmablasts and senescent plasma cells. Responses by conventional (follicular) B cells that involve T-cell help and germinal center reactions give rise to potent isotype-switched antibodies of high affinity that develop over several weeks after primary antigen encounter (MacLennan, 1994MacLennan I.C. Germinal centers.Annu Rev Immunol. 1994; 12: 117-139Crossref PubMed Scopus (1701) Google Scholar). Innate-like B cells, which comprise B-1 B cells and marginal zone B cells, are enriched in B cell receptor specificities for conserved pathogen structures and respond rapidly without the need for T-cell help, making them important early after infection (Baumgarth, 2011Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions.Nat Rev Immunol. 2011; 11: 34-46Crossref PubMed Scopus (660) Google Scholar, Kearney, 2005Kearney J.F. Innate-like B cells.Springer Semin Immunopathol. 2005; 26: 377-383Crossref PubMed Scopus (61) Google Scholar). Consistent with the exposure to infectious agents, barrier sites, such as the intestinal mucosa and the skin, are enriched in B-1 B cells (Geherin et al., 2012Geherin 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.J Immunol. 2012; 188: 6027-6035Crossref PubMed Scopus (68) Google Scholar, Geherin et al., 2016Geherin S.A. Gómez D. Glabman R.A. Ruthel G. Hamann A. Debes G.F. IL-10+ innate-like B cells are part of the skin immune system and require α4β1 integrin to Migrate between the peritoneum and inflamed skin.J Immunol. 2016; 196: 2514-2525Crossref PubMed Scopus (35) Google Scholar, Suzuki et al., 2010Suzuki K. Maruya M. Kawamoto S. Fagarasan S. Roles of B-1 and B-2 cells in innate and acquired IgA-mediated immunity.Immunol Rev. 2010; 237: 180-190Crossref PubMed Scopus (57) Google Scholar). Even in the absence of microbial stimulation (i.e., in germ-free mice), B-1 B cells give rise to natural IgM, which is important in the defense against a number of pathogens and also enhances uptake of apoptotic cells and cell debris by macrophages, while limiting tissue inflammation (Grönwall and Silverman, 2014Grönwall C. Silverman G.J. Natural IgM: beneficial autoantibodies for the control of inflammatory and autoimmune disease.J Clin Immunol. 2014; 34: S12-S21Crossref PubMed Scopus (102) Google Scholar). It is likely that multiple B cell subsets contribute to the development of skin ASCs during homeostasis and inflammation, and there are several factors that could potentially promote skin ASC generation and/or local survival. Potential candidates include the following tumor necrosis factor superfamily members: B cell–activating factor (BAFF, also known as BLyS) and a proliferation-inducing ligand (APRIL). Interactions between BAFF/APRIL and their receptors on B-lineage cells regulate B cell survival, differentiation, and antibody production, and they are critical for plasma cell survival (Schneider, 2005Schneider P. The role of APRIL and BAFF in lymphocyte activation.Curr Opin Immunol. 2005; 17: 282-289Crossref PubMed Scopus (276) Google Scholar, Sindhava et al., 2013Sindhava V.J. Scholz J.L. Cancro M.P. Roles for BLyS family members in meeting the distinct homeostatic demands of innate and adaptive B cells.Front Immunol. 2013; 4: 37Crossref PubMed Scopus (10) Google Scholar). In this study, we revisited the question of antibody production in the skin. We found that IgM is the predominant isotype produced by plasma cells in healthy murine skin and secreted in unperturbed human skin. In mice, cutaneous IgM plasma cells were independent of T cells and microbiota, suggesting that these cells provide natural antibodies for the skin to support homeostatic functions. Importantly, chronic inflammation caused the massive accumulation of IgM ASCs that were dependent on APRIL or BAFF in the skin but not in other sites. Thus, we reveal the skin as a niche for ASCs with important implications in the regulation of cutaneous antibodies in host defense and inflammation. We isolated leukocytes from the abdominal and back skin regions and from lymphatic organs of naïve 8-week old wild-type mice, and enumerated ASCs directly ex vivo by isotype-specific ELISPOT assay without exogenous cell stimulation. The skin of naïve mice harbored IgM ASCs at the highest frequency and number compared with IgA and IgG ASCs (Figure 1a). Numbers and frequencies of IgM ASCs were about 10-fold higher than that of IgA ASCs (42 vs. 4.8 cells per million cells; P < 0.05 for frequency; not significant for numbers), while individual IgG ASCs were present only occasionally (Figure 1a), and IgE ASCs were undetectable (data not shown). IgM ASCs also predominated in skin-draining lymph nodes, spleen, and bone marrow of naïve mice (Figure 1a). ASCs were undetectable at 4 weeks of age, appeared at 8 weeks, and had markedly increased by 16 weeks of age (P < 0.05, comparing 4 weeks relative to 16 weeks for IgM, IgA, and IgG ASCs; Figure 1b). At both 8 and 16 weeks of age, IgM was the predominant isotype produced (Figure 1b), and there was no significant further increase in IgM ASCs in the skin of 24-week old mice (not shown). Given the underrepresentation of other isotypes, we focused our studies on IgM. We performed intracellular staining of skin-isolated leukocytes for cytoplasmic IgM, which when combined with IgM surface staining, identifies ASCs by flow cytometry (Reynolds et al., 2015Reynolds A.E. Kuraoka M. Kelsoe G. Natural IgM is produced by CD5- plasma cells that occupy a distinct survival niche in bone marrow.J Immunol. 2015; 194: 231-242Crossref PubMed Scopus (61) Google Scholar). A cytoplasmic IgM+ ASC population was clearly identified in healthy skin (Figure 1c), comprising 0.2 ± 0.04% (mean ± standard error of the mean) of live CD45+ cells isolated from naïve skin (Figure 1d), corroborating with our ELISPOT data showing IgM ASCs in the skin (Figure 1a and b). Expression of transcription factor Blimp-1 (encoded by prdm1) in the B cell lineage marks ASCs and is part of their differentiation programming (Kallies et al., 2004Kallies A. Hasbold J. Tarlinton D.M. Dietrich W. Corcoran L.M. Hodgkin P.D. et al.Plasma cell ontogeny defined by quantitative changes in blimp-1 expression.J Exp Med. 2004; 200: 967-977Crossref PubMed Scopus (399) Google Scholar, Savage et al., 2017Savage H.P. Yenson V.M. Sawhney S.S. Mousseau B.J. Lund F.E. Baumgarth N. Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells.J Exp Med. 2017; 214: 2777-2794Crossref PubMed Scopus (60) Google Scholar, Shapiro-Shelef et al., 2003Shapiro-Shelef M. Lin K.I. McHeyzer-Williams L.J. Liao J. McHeyzer-Williams M.G. Calame K. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells.Immunity. 2003; 19: 607-620Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). Therefore, we examined the expression of Blimp-1 in skin IgM ASCs using Blimp-1GFP reporter mice (Kallies et al., 2004Kallies A. Hasbold J. Tarlinton D.M. Dietrich W. Corcoran L.M. Hodgkin P.D. et al.Plasma cell ontogeny defined by quantitative changes in blimp-1 expression.J Exp Med. 2004; 200: 967-977Crossref PubMed Scopus (399) Google Scholar). As expected, skin IgM ASCs (cytoplasmatic IgM+) were largely GFP+ (Blimp-1+) compared with colocalizing surface IgM+ cytoplasmic IgM- cells or cytoplasmic IgM+ ASCs from the spleen of wild-type mice (Figure 1e). To distinguish between proliferating plasmablasts and senescent plasma cells, we included staining for Ki-67, which marks proliferating cells, including plasmablasts (Pracht et al., 2017Pracht K. Meinzinger J. Daum P. Schulz S.R. Reimer D. Hauke M. et al.A new staining protocol for detection of murine antibody-secreting plasma cell subsets by flow cytometry.Eur J Immunol. 2017; 47: 1389-1392Crossref PubMed Scopus (76) Google Scholar). The majority (78.6 ± 11.9, mean ± standard deviation) of skin IgM ASCs from wild-type mice were negative for Ki-67 (Figure 1f). We conclude that healthy skin is home to ASCs that are mainly senescent IgM plasma cells. IgM ASCs can be generated as a result of B cell responses to thymus-dependent or -independent (TI) antigens and even without exogenous antigenic stimulation in the case of ASCs that produce natural IgM (Ehrenstein and Notley, 2010Ehrenstein M.R. Notley C.A. The importance of natural IgM: scavenger, protector and regulator.Nat Rev Immunol. 2010; 10: 778-786Crossref PubMed Scopus (397) Google Scholar). To test whether IgM ASCs in healthy skin required T-cell help, we analyzed naïve mice that lack all T cells (Tcrβδ–/– mice, crosses between Tcrβ–/– and Tcrδ–/– mice) and matched controls for the presence of cutaneous IgM using ELISPOT assay. Surprisingly, Tcrβδ–/– mice had the same frequency of skin IgM ASCs as control mice (Figure 2a), indicating that cutaneous IgM ASCs do not require T cells for their generation. As skin commensals orchestrate skin-infiltrating T-cell subsets (Naik et al., 2012Naik S. Bouladoux N. Wilhelm C. Molloy M.J. Salcedo R. Kastenmuller W. et al.Compartmentalized control of skin immunity by resident commensals.Science. 2012; 337: 1115-1119Crossref PubMed Scopus (731) Google Scholar), we aimed to determine whether microbial colonization was required to generate skin IgM ASCs. Unexpectedly, skin IgM ASCs were present in similar numbers in germ-free and specific pathogen-free mice (Figure 2b). Thus, cutaneous IgM ASCs do not depend upon microbial stimulation of skin or other body sites and represent natural IgM-secreting cells. Having established the constitutive presence of IgM ASCs in healthy skin, we asked whether these cells would be affected by skin inflammation. Wild-type mice were injected subcutaneously with Complete Freund's Adjuvant (CFA), a treatment that rapidly induces localized neutrophilic inflammation that advances into chronic granulomatous skin inflammation with mononuclear infiltrates (Brown et al., 2010Brown M.N. Fintushel S.R. Lee M.H. Jennrich S. Geherin S.A. Hay J.B. et al.Chemoattractant receptors and lymphocyte egress from extralymphoid tissue: changing requirements during the course of inflammation.J Immunol. 2010; 185: 4873-4882Crossref PubMed Scopus (65) Google Scholar) and B cell infiltration (Geherin et al., 2016Geherin S.A. Gómez D. Glabman R.A. Ruthel G. Hamann A. Debes G.F. IL-10+ innate-like B cells are part of the skin immune system and require α4β1 integrin to Migrate between the peritoneum and inflamed skin.J Immunol. 2016; 196: 2514-2525Crossref PubMed Scopus (35) Google Scholar). Skin IgM ASCs increased within 1 week after induction of inflammation, albeit not reaching statistical significance (P > 0.05, compared with uninflamed skin; Figure 3a). After 2 and 3 weeks of inflammation, time points at which skin granulomas have formed (Brown et al., 2010Brown M.N. Fintushel S.R. Lee M.H. Jennrich S. Geherin S.A. Hay J.B. et al.Chemoattractant receptors and lymphocyte egress from extralymphoid tissue: changing requirements during the course of inflammation.J Immunol. 2010; 185: 4873-4882Crossref PubMed Scopus (65) Google Scholar), IgM ASCs had increased significantly about 20-fold at the site of inflammation compared with nonlesional skin (P < 0.05 and P < 0.01, respectively; Figure 3a). Importantly, IgM ASC frequencies in chronically inflamed skin (3 weeks after induction of inflammation) reached levels similar to that of typical lymphoid plasma cell niches, namely the bone marrow and spleen (Figure 3b). However, total numbers of IgM ASCs in the skin remained lower relative to bone marrow and spleen (Figure 3b), reflecting the smaller relative size of the lymphoid compartment in inflamed skin. Although the frequencies of IgM ASCs increased more than 20-fold in the skin-draining lymph node during inflammation, they stayed ∼10-fold below the IgM frequencies in the skin and the spleen (P < 0.01; Figure 3b, left). As ASCs accumulate in infected skin, we next addressed whether IgM ASC accumulation in inflamed skin required the presence of microbial signals by comparing granulomatous inflammation induced by CFA to that elicited by Incomplete Freund’s Adjuvant. Whereas both contain granuloma-inducing mineral oil, only CFA has a microbial component (inactivated mycobacteria). Notably, in both CFA and Incomplete Freund’s Adjuvant-elicited inflammation, the frequency of skin IgM ASCs increased to the same extent (∼50-fold, compared with nonlesional skin; Figure 3c). Thus, IgM ASCs accumulated in chronically inflamed skin also in the absence of mycobacterial signals. In chronically inflamed skin, IgM ASCs were localized in irregularly distributed clusters within the dermis outside of CD31+ vessels, as assessed by immunofluorescence histology (Figure 3d), validating our ELISPOT data (Figure 3a–c). Using cytoplasmatic IgM staining as in Figure 1, a population of IgM ASCs was readily identified in chronically inflamed skin by flow cytometry (Figure 3e). Employing Blimp-1GFP reporter mice, IgM ASCs (cytoplasmatic IgM+) from skin or spleen were GFP+ (Blimp-1+) compared with colocalizing surface IgM+ cytoplasmic IgM- cells or cytoplasmic IgM+ ASCs from wild-type mice (Figure 3f). The percentage of proliferating Ki-67+ plasmablasts was significantly higher among ASCs in chronically inflamed relative to uninflamed skin (P = 0.003; Figure 3g). We conclude that chronic inflammation promotes accumulation of IgM+ plasma cells and plasmablasts in the skin. To determine whether skin IgM ASCs are also part of the skin immune system of humans, we analyzed leukocytes isolated from healthy human skin using ELISPOT assay. Importantly, IgM ASCs were present in all samples of healthy adult human skin (n = 8) but frequencies varied widely among individual donors (range 3–5,800 IgM ASCs per million cells; geometric mean = 165; Figure 4a), without an obvious association with skin site (not shown). We were unable to assess an influence by sex or age because of limited information available for the de-identified human skin samples. Next, we aimed to test where IgM ASCs localize at chronically inflamed human skin. We assessed paraffin sections of acne keloidalis, a chronic inflammatory skin disorder featuring accumulation of plasma cells (Dinehart et al., 1989Dinehart S.M. Herzberg A.J. Kerns B.J. Pollack S.V. Acne keloidalis: a review.J Dermatol Surg Oncol. 1989; 15: 642-647Crossref PubMed Scopus (64) Google Scholar), for the presence of IgM+ plasma cells using immunohistochemistry. As in mouse skin granulomas, acne keloidalis harbored irregularly distributed clusters of IgM ASCs within the inflamed dermis (Figure 4b). We conclude that healthy and chronically inflamed human skin represent niches for IgM ASCs. Skin-resident IgM ASCs were independent of T cells in unperturbed skin (Figure 2). To address whether IgM ASC accumulation in inflamed skin requires T cells, we induced skin inflammation with CFA in T cell–deficient Tcrβδ–/– and wild-type mice and analyzed chronically inflamed skin for accumulation of skin IgM ASCs 3 weeks later. As in healthy skin (Figure 2), Tcrβδ–/– mice contained IgM ASCs in inflamed skin at the same frequency as wild-type mice (Figure 5a). Because the skin is an important entry point for various pathogens and IgM is potent in host defense, we wondered whether antigen-specific IgM ASCs induced by cutaneous immune responses would localize in the skin. We immunized wild-type mice subcutaneously with standard experimental antigens 4-hydroxy-3-nitrophenylacetyl (NP)-Ficoll or NP-ovalbumin, which are TI type II and T cell–dependent antigens, respectively. Consistent with the notion that skin IgM ASCs do not require T cells (Figure 5a), NP-specific IgM ASCs were found in immunized skin 3 weeks after immunization with NP-Ficoll in CFA (Figure 5b). The data show that adaptive T cell– independent IgM ASCs localize in the inflamed skin. Importantly, after immunization with NP-ovalbumin in CFA, NP-specific IgM ASCs were also detected in the inflamed skin; this shows that ASCs generated in T cell–dependent immune responses localize in the immunized skin (Figure 5c). Thus, inflamed skin supports the accumulation of both T cell–dependent and –independent IgM ASCs, and antigen-specific ASCs can be directed to the skin through vaccination. Having established that IgM ASCs reside in unperturbed and inflamed skin, we assessed whether the cytokines BAFF and APRIL played a role in creating an ASC survival niche in the skin. Using quantitative reverse transcriptase–PCR, we examined chronically inflamed and control skin for expression of mRNA for BAFF and APRIL, encoded by Tnfs13b and Tnfs13, respectively. Both APRIL and BAFF mRNAs were detected in healthy skin (Figure 6a). Importantly, mirroring the local accumulation of IgM ASCs (Figures 3a–c), in chronically inflamed skin both BAFF and APRIL transcripts mRNAs were upregulated by 13.2- and 4.5-fold (P = 0.0006 and P = 0.0001), respectively, compared with skin from naïve mice (Figure 6a). To test the roles of BAFF and APRIL in IgM ASCs localization in the skin, we induced chronic skin inflammation with CFA in Tnfs13b–/– and Tnfs13–/– as well as double-deficient Tnfs13b–/– and Tnfs13–/– mice. With exception of the inflamed skin-draining lymph node, IgM ASCs were reduced only modestly and not significantly in any of the organs of mice singly-deficient in either APRIL or BAFF (P > 0.05; Figure 6b). Strikingly, whereas all analyzed lymphoid organs (skin-draining lymph node, spleen, and bone marrow) showed a similar mild reduction in IgM ASCs in Tnfs13b–/– and Tnfs13–/– mice, the inflamed and uninflamed skin were completely devoid of these cells (P < 0.001 and P < 0.01, respectively; Figure 6b). To test if anti-BAFF would reduce ASC accumulation in inflamed skin, we induced skin inflammation with CFA in wild-type mice and 2 weeks later treated with blocking anti-BAFF or isotype antibody. Two weeks after initiation of antibody treatment (4 weeks after induction of inflammation), anti-BAFF treatment significantly reduced accumulation of IgM ASCs in inflamed skin, relative to skin from both isotype-treated mice and the pre-treatment 2-week time point of inflammation, on average by 94% (P < 0.001) and 84% (P < 0.05), respectively (Figure 6c). In contrast, anti-BAFF had no effect on IgM ASCs in spleen (Figure 6c). In conclusion, our data show that whereas the presence of IgM ASCs at lymphoid sites is largely independent of BAFF or APRIL, IgM ASC development and/or survival in skin is absolutely dependent on the presence of at least one of these survival cytokines. In this study, we established the existence of IgM ASCs in the skin of mice and humans. In mice, skin plasma cells developed independently of T cells and microbial-derived signals. Natural IgM is an evolutionarily conserved and polyreactive antibody produced constitutively from birth even in the absence of microbial stimulation. Natural antibody secretion primarily occurs in the spleen and the bone marrow, with the majority of natural IgM coming from B-1 B lineage ASCs (Savage and Baumgarth, 2015Savage H.P. Baumgarth N. Characteristics of natural antibody-secreting cells.Ann N Y Acad Sci. 2015; 1362: 132-142Crossref PubMed Scopus (57) Google Scholar, Savage et al., 2017Savage H.P. Yenson V.M. Sawhney S.S. Mousseau B.J. Lund F.E. Baumgarth N. Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells.J Exp Med. 2017; 214: 2777-2794Crossref PubMed Scopus (60) Google Scholar). Therefore, our data are in line with our previous observation that healthy skin harbors B-1-like B cells (Geherin et al., 2016Geherin S.A. Gómez D. Glabman R.A. Ruthel G. Hamann A. Debes G.F. IL-10+ innate-like B cells are part of the skin immune system and require α4β1 integrin to Migrate between the peritoneum and inflamed skin.J Immunol. 2016; 196: 2514-2525Crossref PubMed Scopus (35) Google Scholar) and introduces the skin as a site for natural antibody production. After immunization with thymus-dependent or TI antigens, antigen-specific IgM-secreting cells accumulated in skin, demonstrating that adaptive IgM, in addition to natural IgM, is produced in the skin and that this pathway can be targeted by vaccination. A main function of IgM is host defense (Ehrenstein and Notley, 2010Ehrenstein M.R. Notley C.A. The importance of natural IgM: scavenger, protector and regulator.Nat Rev Immunol. 2010; 10: 778-786Crossref PubMed Scopus (397) Google Scholar); therefore, selective IgM deficiency, a rare immunodeficiency, is associated with recurring bacterial and viral skin infections, including infection with the skin-untypical pathogen Streptococcus pneumoniae (Belgemen et al., 2009Belgemen T. Suskan E. Dogu F. Ikinciogullari A. Selective immunoglobulin M deficiency presenting with recurrent impetigo: a case report and review of the literature.Int Arch Allergy Immunol. 2009; 149: 283-288Crossref PubMed Scopus (16) Google Scholar, Louis and Gupta, 2014Louis A.G. Gupta S. Primary selective IgM deficiency: an ignored immunodeficiency.Clin Rev Allergy Immunol. 2014; 46: 104-111Crossref PubMed Scopus (61) Google Scholar). Human sweat contains IgM with reactivity for the skin pathogen Staphylococcus aureus, and many skin microbes are covered in IgM, IgG, and IgA (Metze et al., 1991Metze D. Kersten A. Jurecka W. Gebhart W. Immunoglobulins coat microorganisms of skin surface: a comparative immunohistochemical and ultrastructural study of cutaneous and oral m" @default.
• W2947698879 created "2019-06-07" @default.
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• W2947698879 date "2019-12-01" @default.
• W2947698879 modified "2023-10-01" @default.
• W2947698879 title "IgM Plasma Cells Reside in Healthy Skin and Accumulate with Chronic Inflammation" @default.
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