Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciences0869-60472414-3545"Paediatrician" Publishers LLC129810.15690/vramn1298Research ArticleThe role of homeostatic proliferation and SNP mutations in MHC genes in the development of rheumatoid arthritisShevyrevD. V.<p>MD, PhD, Junior Research Associate</p>dr.daniil25@mail.ruhttps://orcid.org/0000-0002-7084-081XKozlovV. A.<p>МD, PhD, Academician of the RAS</p>vakoz40@yandex.ruhttps://orcid.org/0000-0002-1756-1782Research Institute for Fundamental and Clinical Immunology151220207566386460203202022122020Copyright © 2020, "Paediatrician" Publishers LLC2020<p><em>Great efforts have been made to study the etiology and pathogenesis of rheumatoid arthritis in the last few decades, but this issue remains widely unknown. In this review, we suggest a hypothesis according to which the development of rheumatoid arthritis is associated with a genetically determined enhancement of self-antigens presentation and decrease in TCR repertoire diversity due to homeostatic proliferation (HP). We suppose that qualitative changes in the TCR landscape of effector and regulatory T-cells populations lead to immune disequilibrium. I.e. HP results in the condition when self-reactive T-cell clones appear to which no specific T-regulatory cells exist. If such self-reactive clones have TCR specific to modified auto-antigens, which presentation increased due to SNP mutations in MHC genes, then the adaptive immunity is activated, and rheumatoid arthritis develops. Obviously, therapy based on the deletion of self-reactive T-cells clones involved in the RA process or on the replenishment of Treg clones by CAR-T-cells is the perspective approach of personalized medicine.</em></p>homeostatic proliferationsingle nucleotide polymorphismautoimmunityrheumatoid arthritisTCR diversityгомеостатическая пролиферацияSNP мутацииаутоиммунные заболеванияревматоидный артритрепертуары TCR[Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–2038. doi: https://doi.org/10.1016/S0140-6736(16)30173-8][Calabresi E, Petrelli F, Bonifacio AF, et al. One year in review 2018: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2018;36(2):175–184.][Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–361. doi: https://doi.org/10.1038/nature01661][Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30(11):1205–1213. doi: https://doi.org/10.1002/art.1780301102][Weyand CM, Hicok KC, Conn DL, Goronzy JJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med. 1992;117(10):801–806. doi: https://doi.org/10.7326/0003-4819-117-10-801][Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. Immunity. 2017;46(2):183–196. doi: https://doi.org/10.1016/j.immuni.2017.02.006][Ting YT, Petersen J, Ramarathinam SH, et al. The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis. J Biol Chem. 2018;293(9):3236–3251. doi: https://doi.org/10.1074/jbc.RA117.001013][Okada Y, Kim K, Han B, et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum Mol Genet. 2014;23(25):6916–6926. doi: https://doi.org/10.1093/hmg/ddu387][Raychaudhuri S, Sandor C, Stahl EA, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44(3):291–296.doi: https://doi.org/10.1038/ng.1076][van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 2006;54(4):1117–1121. doi: https://doi.org/10.1002/art.21739][Rawlings DJ, Dai X, Buckner JH. The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human. J Immunol. 2015;194(7):2977–2984. doi: https://doi.org/10.4049/jimmunol.1403034][Yamamoto K, Okada Y, Suzuki A, Kochi Y. Genetics of rheumatoid arthritis in Asia — present and future. Nat Rev Rheumatol. 2015;11(6):375–379. doi: https://doi.org/10.1038/nrrheum.2015.7][Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34(4):395–402. doi: https://doi.org/10.1038/ng1206][Kaminsky ZA, Tang T, Wang SC, et al. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet. 2009;41(2):240–245. doi: https://doi.org/10.1038/ng.286][Croia C, Bursi R, Sutera D, et al. One year in review 2019: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2019;37(3):347–357][Guo Q, Wang Y, Xu D, et al. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6:15. doi: https://doi.org/10.1038/s41413-018-0016-9][van der Woude D, Rantapää-Dahlqvist S, Ioan-Facsinay A, et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis. 2010;69(8):1554–1561. doi: https://doi.org/10.1136/ard.2009.124537][Burmester GR, Dimitriu-Bona A, Waters SJ, Winchester RJ. Identification of three major synovial lining cell populations by monoclonal antibodies directed to Ia antigens and antigens associated with monocytes/macrophages and fibroblasts. Scand J Immunol. 1983;17(1):69–82. doi: https://doi.org/10.1111/j.1365-3083.1983.tb00767.x][Lu MC, Lai NS, Yu HC, et al. Anti-citrullinated protein antibodies bind surface-expressed citrullinated Grp78 on monocyte/macrophages and stimulate tumor necrosis factor alpha production. Arthritis Rheum. 2010;62(5):1213–1223. doi: https://doi.org/10.1002/art.27386][Fukui S, Iwamoto N, Takatani A, et al. M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis. Front Immunol. 2018;8:1958. Published 2018 Jan 8. doi: https://doi.org/10.3389/fimmu.2017.01958][Hueber AJ, Asquith DL, Miller AM, et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol. 2010;184(7):3336–3340. doi: https://doi.org/10.4049/jimmunol.0903566][Suurmond J, Rivellese F, Dorjée AL, et al. Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated protein antibodies. Ann Rheum Dis. 2015;74(10):1915–1923. doi: https://doi.org/10.1136/annrheumdis-2014-205562][Filer A, Parsonage G, Smith E, et al. Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. Arthritis Rheum. 2006;54(7):2096–2108. doi: https://doi.org/10.1002/art.21930][Aupperle KR, Boyle DL, Hendrix M, et al. Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene. Am J Pathol. 1998;152(4):1091–1098][Schett G, Redlich K, Xu Q, et al. Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. J Clin Invest. 1998;102(2):302–311. doi: https://doi.org/10.1172/JCI2465][Okamoto K, Nakashima T, Shinohara M, et al. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiol Rev. 2017;97(4):1295–1349. doi: https://doi.org/10.1152/physrev.00036.2016][Pettit AR, Walsh NC, Manning C, Goldring SR, Gravallese EM. RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(9):1068–1076. doi: https://doi.org/10.1093/rheumatology/kel045][Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122(5):1791–1802. doi: https://doi.org/10.1172/JCI60975][Turesson C, O’Fallon WM, Crowson CS, et al. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29(1):62–67][Cimmino MA, Salvarani C, Macchioni P, et al. Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis. Rheumatol Int. 2000;19(6):213–217. doi: https://doi.org/10.1007/pl00006853][del Rincón ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44(12):2737–2745. doi: https://doi.org/10.1002/1529-0131(200112)44:12<2737::AID-ART460>3.0.CO;2-%23][Young S. Ocular involvement in connective tissue disorders. Curr Allergy Asthma Rep. 2005;5(4):323–326. doi: 10.1007/s11882-005-0076-y][Genta MS, Genta RM, Gabay C. Systemic rheumatoid vasculitis: a review. Semin Arthritis Rheum. 2006;36(2):88–98. doi: https://doi.org/10.1016/j.semarthrit.2006.04.006][Duarte AC, Porter JC, Leandro MJ. The lung in a cohort of rheumatoid arthritis patients-an overview of different types of involvement and treatment. Rheumatology (Oxford). 2019;58(11):2031–2038. doi: https://doi.org/10.1093/rheumatology/kez177][Bowman SJ. Hematological manifestations of rheumatoid arthritis. Scand J Rheumatol. 2002;31(5):251–259. doi: https://doi.org/10.1080/030097402760375124][Agrawal S, Misra R, Aggarwal A. Anemia in rheumatoid arthritis: high prevalence of iron-deficiency anemia in Indian patients. Rheumatol Int. 2006;26(12):1091–1095. doi: https://doi.org/10.1007/s00296-006-0133-4][Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med. 2004;116(Suppl7A):50S–57S. doi: https://doi.org/10.1016/j.amjmed.2003.12.012][Moreland LW, Curtis JR. Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. Semin Arthritis Rheum. 2009;39(2):132–143. doi: https://doi.org/10.1016/j.semarthrit.2008.08.003][Papadaki HA, Kritikos HD, Valatas V, et al. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood. 2002;100(2):474–482. doi: https://doi.org/10.1182/blood-2002-01-0136][Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–1276. doi: https://doi.org/10.1172/JCI20945][Bluestone JA. Mechanisms of tolerance. Immunol Rev. 2011;241(1):5–19. doi: https://doi.org/10.1111/j.1600-065X.2011.01019.x][Krupica T Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. 2006;120(2):121–128. doi: https://doi.org/10.1016/j.clim.2006.04.569][L’Huillier A, Ren G, Shi Y, Zhang J. A two-hit model of autoimmunity: lymphopenia and unresponsiveness to TGF-β signaling. Cell Mol Immunol. 2012;9(5):369–370. doi: https://doi.org/10.1038/cmi.2012.25][Stutman O. Postthymic T-cell development. Immunol Rev. 1986;91:159–194. doi: https://doi.org/10.1111/j.1600-065x.1986.tb01488.x][Gleeson PA, Toh BH, van Driel IR. Organ-specific autoimmunity induced by lymphopenia. Immunol Rev. 1996;149:97–125. doi: https://doi.org/10.1111/j.1600-065x.1996.tb00901.x][King C, Ilic A, Koelsch K, Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004;117(2):265–277. doi: https://doi.org/10.1016/s0092-8674(04)00335-6][Zhang N, Bevan MJ. TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat Immunol. 2012;13(7):667–673. Published 2012 May 27. doi: https://doi.org/10.1038/ni.2319][Li MO, Wan YY, Sanjabi S, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146. doi: https://doi.org/10.1146/annurev.immunol.24.021605.090737][Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity. 2006;25(3):441–454. doi: https://doi.org/10.1016/j.immuni.2006.07.012][Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68–73. doi: https://doi.org/10.1038/83784][Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol. 2003;15(4):430–435. doi: https://doi.org/10.1097/00002281-200307000-00010][Schulze-Koops H. Lymphopenia and autoimmune diseases. Arthritis Res Ther. 2004;6(4):178–180. doi: https://doi.org/10.1186/ar1208][Symmons DP, Farr M, Salmon M, Bacon PA. Lymphopenia in rheumatoid arthritis. J R Soc Med. 1989;82(8):462–463][Koetz K, Bryl E, Spickschen K, et al. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA. 2000;97(16):9203–9208. doi: https://doi.org/10.1073/pnas.97.16.9203][Jones JL, Thompson SA, Loh P, et al. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci USA. 2013;110(50):20200–20205. doi: https://doi.org/10.1073/pnas.1313654110][Шевырев Д.В., Терещенко В.П., Козлов В.А. Гомеостатическая пролиферация: от нормы к патологии // Российский иммунологический журнал. — 2018. — № 15. — С. 91–105 [Shevyrev DV, Tereshchenko VP, Kozlov VA. Homeostatic proliferation: from health to pathology. Russian Journal of Immunology. 2018;21(4):91–105 (In Russ.)]. doi: https://doi.org/10.7868/S1028722118020016][Shevyrev D, Tereshchenko V, Manova O, Kozlov V. Homeostatic proliferation as a physiological process and a risk factor for autoimmune pathology. AIMS Allergy and Immunology. 2021;5(1):18–32. doi: https://doi.org/10.3934/Allergy.2021002][Шевырев Д.В., Блинова Е.А., Козлов В.А. Влияние гуморальных факторов гомеостатической пролиферации на T-регуляторные клетки in vitro // Бюллетень сибирской медицины. – 2019. – Т. 18. – № 1. – С. 286–293 [Shevyrev DV, Blinova EA, Kozlov VA. The influence of humoral factors of homeostatistic proliferation on T-regulatory cells in vitro. Bulletin of Siberian Medicine. 2019;18(1):286–293. doi: https://doi.org/10.20538/1682-0363-2019-1-286-293][Ge Q, Rao VP, Cho BK, et al. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/ MHC epitopes and strength of their interaction with T cell receptors. Proc Natl Acad Sci USA. 2001;98(4):1728–1733. doi: https://doi.org/10.1073/pnas.98.4.1728][Theofilopoulos AN, Dummer W, Kono DH. T cell homeostasis and systemic autoimmunity. J Clin Invest. 2001;108(3):335–340. doi: https://doi.org/10.1172/JCI12173][Kassiotis G, Zamoyska R, Stockinger B. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J Exp Med. 2003;197(8):1007–1016. doi: https://doi.org/10.1084/jem.20021812][Kieper WC, Burghardt JT, Surh CD. A role for TCR affinity in regulating naive T cell homeostasis. J Immunol. 2004;172(1):40–44. doi: https://doi.org/10.4049/jimmunol.172.1.40][Heninger AK, Theil A, Wilhelm C, et al. IL-7 abrogates suppressive activity of human CD4+CD25+FOXP3+ regulatory T cells and allows expansion of alloreactive and autoreactive T cells. J Immunol. 2012;189(12):5649–5658. doi: https://doi.org/10.4049/jimmunol.1201286][Ge Q, Rao VP, Cho BK, et al. Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/ MHC epitopes and strength of their interaction with T cell receptors. Proc Natl Acad Sci USA. 2001;98(4):1728–1733. doi: https://doi.org/10.1073/pnas.98.4.1728][Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 is essential for TGF-beta to convert naive CD4+CD25-cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol. 2007;178(4):2018–2027. doi: https://doi.org/10.4049/jimmunol.178.4.2018][Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity. 2006;25(2):249–259. doi: https://doi.org/10.1016/j.immuni.2006.05.016][Rossetti M, Spreafico R, Consolaro A, et al. TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis. Ann Rheum Dis. 2017;76(2):435–441. doi: https://doi.org/10.1136/annrheumdis-2015-208992][Britanova OV, Putintseva EV, Shugay M, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192(6):2689–2698. doi: https://doi.org/10.4049/jimmunol.1302064][Murray JM, Kaufmann GR, Hodgkin PD, et al. Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty. Immunol Cell Biol. 2003;81(6):487–495. doi: https://doi.org/10.1046/j.1440-1711.2003.01191.x][Shugay M, Bagaev DV, Zvyagin IV, et al. VDJdb: a curated database of T-cell receptor sequences with known antigen specificity. Nucleic Acids Res. 2018;46(D1):D419–D427. doi: https://doi.org/10.1093/nar/gkx760][Oh J, Warshaviak DT, Mkrtichyan M, et al. Single variable domains from the T cell receptor β chain function as mono- and bifunctional CARs and TCRs. Sci Rep. 2019;9(1):17291. doi: https://doi.org/10.1038/s41598-019-53756-4][Migalska M, Sebastian A, Radwan J. Profiling of the TCRβ repertoire in non-model species using high-throughput sequencing. Sci Rep. 2018;8(1):11613. doi: https://doi.org/10.1038/s41598-018-30037-0][Israelson MA, Stepanov AV, Staroverov DB, et al. Testing of monoclonal antibodies against T-cell receptor associated with ankylosing spondylitis. Bulletin of Russian State Medical University. 2018;(5):71–79. doi: https://doi.org/10.24075/brsmu.2018.064]