Vestnik dermatologii i venerologiiVestnik dermatologii i venerologiiВестник дерматологии и венерологии0042-46092313-6294Rossijskoe Obschestvo Dermatovenerologov i Kosmetologov1689910.25208/vdv16899gxlbysREVIEWSОБЗОР ЛИТЕРАТУРЫReview ArticleRole of desmoglein-3 protein domains in the pathogenesis of pemphigusРоль доменов белка десмоглеина-3 в патогенезе пузырчаткиhttps://orcid.org/0000-0003-3805-84893604-6491KaramovaArfenya E.КарамоваАрфеня Эдуардовна
Russian Federation

MD, Cand. Sci. (Med.), Assistant Professor

к.м.н., доцент

karamova@cnikvi.ruhttps://orcid.org/0000-0002-2553-04849552-7850ZnamenskayaLyudmila F.ЗнаменскаяЛюдмила Федоровна
Russian Federation

MD, Dr. Sci. (Med.), Leading Researcher

д.м.н., ведущий научный сотрудник

znaml@cnikvi.ruhttps://orcid.org/0000-0001-7723-87019506-0978GirkoEkaterina V.ГирькоЕкатерина Витальевна
Russian Federation

Junior Research Associate

младший научный сотрудник

katrin_45_34@mail.ruhttps://orcid.org/0000-0002-9688-27273385-4723ChikinVadim V.ЧикинВадим Викторович
Russian Federation

MD, Dr. Sci. (Med.), Senior Research Associate

д.м.н., старший научный сотрудник

chikin@cnikvi.ruhttps://orcid.org/0009-0007-8923-2228KuklinaEkaterina S.КуклинаЕкатерина Сергеевна
Russian Federation

Clinical Resident

клинический ординатор

ekaterina.kuklina.00@mail.ruState Research Center of Dermatovenereology and CosmetologyГосударственный научный центр дерматовенерологии и косметологии2008202530092025101410160505202506082025Copyright ©; 2025, Karamova A.E., Znamenskaya L.F., Girko E.V., Chikin V.V., Kuklina E.S.Copyright ©; 2025, Карамова А.Э., Знаменская Л.Ф., Гирько Е.В., Чикин В.В., Куклина Е.С.2025Karamova A.E., Znamenskaya L.F., Girko E.V., Chikin V.V., Kuklina E.S.Карамова А.Э., Знаменская Л.Ф., Гирько Е.В., Чикин В.В., Куклина Е.С.https://creativecommons.org/licenses/by-nc/4.0https://vestnikdv.ru/jour/article/view/16899

Pemphigus is a group of autoimmune bullous dermatoses that affect the skin and/or mucous membranes, potentially fatal outcome. The most common clinical form is pemphigus vulgaris (PV) which is characterized by IgG circulating in the blood and fixed in the epidermis directed against desmoglein-3 (Dsg3) in mucosal lesions and against desmoglein-1 (Dsg1) in skin lesions. The extracellular part of Dsg3 consists of five domains (EC1–EC5) which ensure strong adhesion between adjacent molecules of neighboring cells. The important role of Dsg3 and its individual extracellular domains, primarily EC1 and EC2, in initiating the autoimmune process and generating the clinical phenotype of the disease is described. Variability of antibody pathogenicity depending on its domain specificity may be used as a marker for assessing the prognosis of the disease, and it also opens up new opportunities for developing targeted therapeutic strategies.

Пузырчатка — это группа аутоиммунных буллезных дерматозов, поражающих кожу и/или слизистые оболочки, с потенциальным летальным исходом. Наиболее частой клинической формой является вульгарная пузырчатка, которая характеризуется циркулирующими в крови и фиксированными в эпидермисе IgG, направленными против десмоглеина-3 (Dsg3) при поражении слизистых оболочек и десмоглеина-1 (Dsg1) при поражении кожи. Внеклеточная часть Dsg3 состоит из пяти доменов (EC1–EC5), которые обеспечивают крепкую адгезию прилегающих друг к другу молекул соседних клеток. Описана важная роль Dsg3 и его отдельных внеклеточных доменов, прежде всего EC1 и EC2, в инициации аутоиммунного процесса и формировании клинического фенотипа заболевания. Вариабельность патогенности антител в зависимости от их доменной специфичности может быть использована в качестве маркера оценки прогноза заболевания, а также открывает новые возможности для разработки таргетных терапевтических стратегий.

pemphigus vulgarisdesmoglein-3domainIgGвульгарная пузырчаткадесмоглеин-3доменIgGStanley JR. Pemphigus. In: Eisen AZ, Wolff K, Freedberg IM, Austen KF. (eds) Fitzpatrick’s dermatology in general medicine. 8th ed. Vol. 2. N.Y.: MacGraw-Hill; 2012. P. 606–614.Hertl M. Autoimmune diseases of the skin: pathogenesis, diagnosis, management. 3rd ed. N.Y.: Springer Wien; 2011. P. 593.Махнева Н.В., Теплюк Н.П., Белецкая Л.В. Аутоиммунная пузырчатка. От истоков развития до наших дней. М.: Издательские решения; 2016. С. 308. [Mahneva NV, Tepluk NP, Beletskaya LV. Autoimmune pemphigus. From the origins of development to the present day. Moscow: Publishing solutions; 2016. P. 308. (In Russ.)]Porro AM, Seque CA, Ferreira MCC, Enokihara MMSES. Pemphigus vulgaris. An Bras Dermatol. 2019;94(3):264–278. doi: 10.1590/abd1806-4841.20199011Rosi-Schumacher M, Baker J, Waris J, Seiffert-Sinha K, Sinha AA. Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid. Front Immunol. 2023;14:1159351. doi: 10.3389/fimmu.2023.1159351Amber KT, Valdebran M, Grando SA. Non-Desmoglein Antibodies in Patients with Pemphigus Vulgaris. Front Immunol. 2018;9:1190 doi: 10.3389/fimmu.2018.01190Amber KT, Staropoli P, Shiman MI, Elgart GW, Hertl M. Autoreactive T cells in the immune pathogenesis of pemphigus vulgaris. Exp Dermatol. 2013;22(11):699–704. doi: 10.1111/exd.12229Burns T, Breathnachet S, Cox N, Griffiths CEM. Rook’s textbook of dermatology. N.J.: John Wiley & Sons; 2008. P. 4192.Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Vol. 1. Philadelphia: Elsevier; 2012. P. 469–471.Карамова А.Э., Знаменская Л.Ф., Городничев П.В., Краснова К.И., Плотникова Е.Ю., Нефедова М.А., и др. Эффективность применения ритуксимаба в лечении пациентов с вульгарной пузырчаткой. Вестник дерматологии и венерологии. 2024;100(5):68–78. [Karamova AE, Znamenskaya LF, Gorodnichev PV, Krasnova KI, Plotnikova EU, Nefedova MA, et al. Effectiveness of rituximab in the treatment of patients with pemphigus vulgarus. Vestnik Dermatologii i Venerologii. 2024;100(5):68–78. (In Russ.)] doi: 10.25208/vdv16803Абрамова Т.В., Шпилевая М.В., Кубанов А.А. Новый твердофазный иммуносорбент для селективного связывания аутоантител к десмоглеину 3 типа у больных вульгарной пузырчаткой. Acta Naturae. 2020;12(2):63–69. [Abramova TV, Spilevaya MV, Kubanov AA. A New Solid-Phase Immunosorbent for Selective Binding of Desmoglein 3 Autoantibodies in Patients with Pemphigus Vulgaris. Acta Naturae. 2020;12(2):63–69. (In Russ.)] doi: 10.32607/actanaturae.10893Harman KE, Seed PT, Gratian MJ, Bhogal BS, Challacombe SJ, Black MM. The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels. Br J Dermatol. 2001;144(4):775–780. doi: 10.1046/j.1365-2133.2001.04132.xКубанов А.А., Знаменская Л.Ф., Абрамова Т.В., Свищенко С.И. К вопросам диагностики истинной (акантолитической) пузырчатки. Вестник дерматологии и венерологии; 2014;90(6):121–130. [Kubanov AA, Znamenskaya LF, Abramova TV, Svishchenko SI. Revisited diagnostics of true (acantholytic) pemphigus. Vestnik Dermatologii i Venerologii. 2014;90(6):121–130. (In Russ.)] doi: 10.25208/0042-4609-2014-90-6-121-130Bhol K, Natarajan K, Nagarwalla N, Mohimen A, Aoki V, Ahmed AR. Correlation of peptide specificity and IgG subclass with pathogenic and nonpathogenic autoantibodies in pemphigus vulgaris: a model for autoimmunity. Proc Natl Acad Sci U S A. 1995;92(11):5239–5243. doi: 10.1073/pnas.92.11.5239Jones CC, Hamilton RG, Jordon RE. Subclass distribution of human IgG autoantibodies in pemphigus. J Clin Immunol. 1988;8(1):43–49. doi: 10.1007/BF00915155Oloumi A, Le ST, Liu Y, Herbert S, Ji-Xu A, Merleev AA, et al. Pemphigus-Associated Desmoglein-Specific IgG1 and IgG4 Have a Dominant Agalactosylated Glycan Modification. J Invest Dermatol. 2024;144(11):2584–2587.e6. doi: 10.1016/j.jid.2024.03.044Sitaru C, Mihai S, Zillikens D. The relevance of the IgG subclass of autoantibodies for blister induction in autoimmune bullous skin diseases. Arch Dermatol Res. 2007;299(1):1–8. doi: 10.1007/s00403-007-0734-0Torzecka JD, Woźniak K, Kowalewski C, Waszczykowska E, Sysa-Jedrzejowska A, Pas HH, et al. Circulating pemphigus autoantibodies in healthy relatives of pemphigus patients: coincidental phenomenon with a risk of disease development? Arch Dermatol Res. 2007;299(5–6):239–243. doi: 10.1007/s00403-007-0760-yGolinski ML, Lemieux A, Maho-Vaillant M, Barray M, Drouot L, Schapman D, et al. The Diversity of Serum Anti-DSG3 IgG Subclasses Has a Major Impact on Pemphigus Activity and Is Predictive of Relapses after Treatment with Rituximab. Front Immunol. 2022;13:849790. doi: 10.3389/fimmu.2022.849790Kitajima Y. New insights into desmosome regulation and pemphigus blistering as a desmosome-remodeling disease. Kaohsiung J Med Sci. 2013;29(1):1–13. doi: 10.1016/j.kjms.2012.08.001Кубанова А.А., Карамова А.Э., Кубанов А.А. Поиск мишеней для таргетной терапии аутоимунных заболеваний в дерматологии. Вестник РАМН. 2015;70(2):159–164. [Kubanova AA, Karamova AE, Kubanov AA. Furute therapeutic targets in management of autoimmune skin diseases Annals of the Russian Academy of Medical Sciences. 2015;70(2):159–164. (In Russ.)] doi: 10.15690/vramn.v70i2.1308Fuchs M, Foresti M, Radeva MY, Kugelmann D, Keil R, Hatzfeld M, et al. Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering. Cell Mol Life Sci. 2019;76(17):3465–3476. doi: 10.1007/s00018-019-03083-8Tselepis C, Chidgey M, North A, Garrod D. Desmosomal adhesion inhibits invasive behavior. Proc Natl Acad Sci U S A. 1998;95(14):8064–8069. doi: 10.1073/pnas.95.14.8064Müller R, Svoboda V, Wenzel E, Gebert S, Hunzelmann N, Müller HH, et al. IgG reactivity against non-conformational NH-terminal epitopes of the desmoglein 3 ectodomain relates to clinical activity and phenotype of pemphigus vulgaris. Exp Dermatol. 2006;15(8):606–614. doi: 10.1111/j.1600-0625.2006.00451.xBrasch J, Harrison OJ, Honig B, Shapiro L. Thinking outside the cell: how cadherins drive adhesion. Trends Cell Biol. 2012;22(6):299–310. doi: 10.1016/j.tcb.2012.03.004Heupel WM, Zillikens D, Drenckhahn D, Waschke J. Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction. J Immunol. 2008;181(3):1825–1834. doi: 10.4049/jimmunol.181.3.1825Payne AS, Ishii K, Kacir S, Lin C, Li H, Hanakawa Y, Tsunoda K, et al. Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J Clin Invest. 2005;115(4):888–899. doi: 10.1172/JCI24185Tsunoda K, Ota T, Aoki M, Yamada T, Nagai T, Nakagawa T, et al. Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3. J Immunol. 2003;170(4):2170–2178. doi: 10.4049/jimmunol.170.4.2170Yokouchi M, Saleh MA, Kuroda K, Hachiya T, Stanley JR, Amagai M, et al. Pathogenic epitopes of autoantibodies in pemphigus reside in the amino-terminal adhesive region of desmogleins which are unmasked by proteolytic processing of prosequence. J Invest Dermatol. 2009;129(9):2156–2166. doi: 10.1038/jid.2009.61Schmitt T, Hudemann C, Moztarzadeh S, Hertl M, Tikkanen R, Waschke J. Dsg3 epitope-specific signalling in pemphigus. Front Immunol. 2023;14:1163066. doi: 10.3389/fimmu.2023.1163066Hudemann C, Maglie R, Llamazares-Prada M, Beckert B, Didona D, Tikkanen R, et al. Human Desmocollin 3 — Specific IgG Antibodies Are Pathogenic in a Humanized HLA Class II Transgenic Mouse Model of Pemphigus. J Invest Dermatol. 2022;142(3 Pt B):915–923.e3. doi: 10.1016/j.jid.2021.06.017Cirillo N, Lanza M, De Rosa A, Femiano F, Gombos F, Lanza A. At least three phosphorylation events induced by pemphigus vulgaris sera are pathogenically involved in keratinocyte acantholysis. Int J Immunopathol Pharmacol. 2008;21(1):189–195. doi: 10.1177/039463200802100121Tavakolpour S, Noormohammadi Z, Daneshpazhooh M, Gholami A, Mahmoudi H. IgG reactivity to different desmoglein-3 ectodomains in pemphigus vulgaris: novel panels for assessing disease severity. Front Immunol. 2024;15:1469937. doi: 10.3389/fimmu.2024.1469937Tsunoda K, Ota T, Aoki M, Yamada T, Nagai T, Nakagawa T, et al. Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3. J Immunol. 2003;170(4):2170–2178. doi: 10.4049/jimmunol.170.4.2170Ларина Е.Н., Карасев В.С., Шпилевая М.В., Алиев Т.К., Бочкова О.П., Карамова А.Е., и др. Рекомбинантный фрагмент внеклеточного домена десмоглеина 3 человека, слитый с Fc-фрагментом человеческого IgG1, селективно адсорбирует аутореактивные антитела из сыворотки пациентов с пузырчаткой. Доклады Академии наук. 2022;507(6):708–712. [Larina EN, Karasev VS, Shpilevaya MV, Aliev TK, Bochkova OP, Karamova AE, et al. Recombinant fragment of the extracellular domain of human desmoglein 3 fused with the Fc-fragment of human IgG1 selectively adsorbs autoreactive antibodies from the sera of pemphigus patients. Doklady Akademii Nauk. 2022;507(6):708–712. (In Russ.)] doi: 10.31857/S0869565222060103Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991;67(5):869–877. doi: 10.1016/0092-8674(91)90360-bSaito M, Stahley SN, Caughman CY, Mao X, Tucker DK, Payne AS, et al. Signaling dependent and independent mechanisms in pemphigus vulgaris blister formation. PloS One. 2012;7(12):e50696. doi: 10.1371/journal.pone.0050696Seishima M, Esaki C, Osada K, Mori S, Hashimoto T, Kitajima Y. Pemphigus IgG, but not bullous pemphigoid IgG, causes a transient increase in intracellular calcium and inositol 1,4,5-triphosphate in DJM-1 cells, a squamous cell carcinoma line. J Invest Dermatol. 1995;104(1):33– 37. doi: 10.1111/1523-1747.ep12613469Esaki C, Seishima M, Yamada T, Osada K, Kitajima Y. Pharmacologic evidence for involvement of phospholipase C in pemphigus IgG-induced inositol 1,4,5-trisphosphate generation, intracellular calcium increase, and plasminogen activator secretion in DJM-1 cells, a squamous cell carcinoma line. J Invest Dermatol. 1995;105(3):329–333. doi: 10.1111/1523-1747.ep12319948Schmitt T, Waschke J. Autoantibody-specific signalling in pemphigus. Front Med (Lausanne). 2021;8:701809. doi: 10.3389/fmed.2021.701809Egami S, Yamagami J, Amagai M. Autoimmune bullous skin diseases, pemphigus and pemphigoid. J Allergy Clin Immunol. 2020;145(4):1031–1047. doi: 10.1016/j.jaci.2020.02.013Strandmoe AL, Bremer J, Diercks GFH, Gostyński A, Ammatuna E, Pas HH, et al. Beyond the skin: B cells in pemphigus vulgaris, tolerance and treatment. Br J Dermatol. 2024;191(2):164–176. doi: 10.1093/bjd/ljae107Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179–184. doi: 10.1126/science.aaf6756Schmidt E, Dähnrich C, Rosemann A, Probst C, Komorowski L, Saschenbrecker S, et al. Novel ELISA systems for antibodies to desmoglein 1 and 3: correlation of disease activity with serum autoantibody levels in individual pemphigus patients. Exp Dermatol. 2010;19(5):458–463. doi: 10.1111/j.1600-0625.2010.01069.xVan ATT, Nguyen TV, Huu SN, Thi LP, Minh PPT, Huu N, et al. Improving treatment outcome of pemphigus vulgaris on Vietnamese patients by using desmoglein elisa test. Open Access Maced J Med Sci. 2019;7(2):195–197. doi: 10.3889/oamjms.2019.003Mohebi F, Tavakolpour S, Teimourpour A, Toosi R, Mahmoudi H, Balighi K, et al. Estimated cut-off values for pemphigus severity classification according to pemphigus disease area index (PDAI), autoimmune bullous skin disorder intensity score (ABSIS), and anti-desmoglein 1 autoantibodies. BMC Dermatol. 2020;20(1):13. doi: 10.1186/s12895-020-00105-yDelavarian Z, Layegh P, Pakfetrat A, Zarghi N, Khorashadizadeh M, Ghazi A. Evaluation of desmoglein 1 and 3 autoantibodies in pemphigus vulgaris: correlation with disease severity. J Clin Exp Dent. 2020;12(5):e440–e445. doi: 10.4317/jced.56289