{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:11:39Z","timestamp":1760127099050,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biotest Pharma AG","award":["2497\/TP01","TP08"],"award-info":[{"award-number":["2497\/TP01","TP08"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["2497\/TP01","TP08"],"award-info":[{"award-number":["2497\/TP01","TP08"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pemphigus vulgaris (PV) is a potentially lethal autoimmune bullous skin disorder caused by IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1. During the last three decades, high-dose intravenous immunoglobulins (IVIgs) have been applied as an effective and relatively safe treatment regime in severe, therapy-refractory PV. This prompted us to study T- and B- cell polarization by IVIg in a human-Dsg3-dependent mouse model for PV. Using humanized mice transgenic for HLA-DRB1*04:02, which is a highly prevalent haplotype in PV, we employed IVIg in two different experimental approaches: in prevention and quasi-therapeutic settings. Our data show that intraperitoneally applied IVIg was systemically distributed for up to 42 days or longer. IVIg-treated Dsg3-immunized mice exhibited, in contrast to Dsg3-immunized mice without IVIg, significantly less Dsg3-specific IgG, and showed induction of T regulatory cells in lymphatic tissue. Ex vivo splenocyte analysis upon Dsg3-specific stimulation revealed an initial, temporarily reduced antigen-induced cell proliferation, as well as IFN-\u03b3 secretion that became less apparent over the course of time. Marginal-zone B cells were initially reduced in the preventive approach but re-expanded over time. In contrast, in the quasi-therapeutic approach, a robust down-regulation in both spleen and lymph nodes was observed. We found a significant down-regulation of the immature transitional 1 (T1) B cells in IVIg-treated mice in the quasi-therapeutic approach, while T2 and T3, representing a healthy stage of B-cell development, appeared to be up-regulated by IVIg. In summary, in two experimental settings employing an active PV mouse model, we demonstrate distinct alterations of T- and B-cell populations upon IVIg treatment, compatible with a tolerance-associated polarization in lymphatic tissue. Our data suggest that the clinical efficacy of IVIg is at least modulated by distinct alterations of T- and B-cell populations compatible with a tolerance-associated polarization in lymphatic tissue.<\/jats:p>","DOI":"10.3390\/cells12091340","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T02:29:22Z","timestamp":1683512962000},"page":"1340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["T Regulatory Cell-Associated Tolerance Induction by High-Dose Immunoglobulins in an HLA-Transgenic Mouse Model of Pemphigus"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-6882","authenticated-orcid":false,"given":"Christoph","family":"Hudemann","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergology, Philipps-University Marburg, 35037 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Heidelberg, 69117 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enno","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"},{"name":"L\u00fcbeck Institute of Experimental Dermatology (LIED), University of L\u00fcbeck, 23562 L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Hertl","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, Philipps-University Marburg, 35037 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00fcdiger","family":"Eming","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, Philipps-University Marburg, 35037 Marburg, Germany"},{"name":"Department of Dermatology, Venerology and Allergology, German Armed Forces Central Hospital Koblenz, 56072 Koblenz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/S0140-6736(19)31778-7","article-title":"Pemphigus","volume":"394","author":"Schmidt","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12016-017-8662-z","article-title":"Pemphigus: A Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches","volume":"54","author":"Pollmann","year":"2018","journal-title":"Clin. 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