CURRENT UNDERSTANDING OF THE IMMUNOLOGICAL BASIS OF RHEUMATOID ARTHRITIS: FROM POST-TRANSLATIONAL MODIFICATION OF PROTEINS TO THE USE OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

Authors

  • Fedir Hladkykh V. N. Karazin Kharkiv National University of the Ministry of Education and Science of Ukraine, Kharkiv, Ukraine, Department of Infectious Diseases and Clinical Immunology; State Organization ''Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine'', Kharkiv, Ukraine, Department of Radiation Pathology and Palliative Medicine; Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, Kharkiv, Ukraine, Department of Experimental Cryomedicine https://orcid.org/0000-0001-7924-4048

DOI:

https://doi.org/10.21272/eumj.2023;11(4):326-336

Keywords:

systemic autoimmune diseases, rheumatoid arthritis, citrullination, T cells, mesenchymal stem cells, biological therapy, disease-modifying drugs

Abstract

Background. Rheumatoid arthritis (RA) is a multietiological chronic systemic autoimmune disease associated with inflammatory joint damage and extra-articular processes in internal organs. RA is recognized as the most common autoimmune inflammatory arthritis with an incidence of 0.4% to 1.3% of the population.

Objective. Summarize current information on the immunopathogenesis of RA based on data from open sources of information.

Methods. The selection of publications that covered information about the immunopathogenesis of rheumatoid arthritis was performed using the following keywords: systemic autoimmune diseases, RA, citrullination, carbamylation.

Results. RA is considered an immune-mediated disease with a strong genetic influence. An important role in the initiation of the development of RA is played by genetic factors and damage to the mucous membranes in the lungs, oral cavity, and gastrointestinal tract. In response to the appearance of post-translationally modified (citrullinated/carbamylated) proteins, B-cells induce the production of antibodies to cyclic citrullinated peptide (anti-citrullinated peptide antibodies – ACPA). Rheumatoid factor is another well-studied autoantibody involved in the development of RA. Given the complex role that dendritic cells play in the pathogenesis of RA, targeted therapies are being developed to block their immunogenic or enhance their tolerogenic functions. Dysfunction of fibroblast-like synoviocytes leads to synovial hyperplasia. Disease-modifying antirheumatic drugs (DMARDs) are used to target inflammation and prevent disease progression.

Conclusions. Genetic predisposition and specific post-translational modifications of proteins play a significant role in the development of RA. The introduction of DMARDs and the prospects for the use of mesenchymal stem cells and their derivatives allows for the development of new effective treatment strategies to implement more effective control over this disease

Downloads

Download data is not yet available.

References

Conforti A, Di Cola I, Pavlych V, Ruscitti P, Berardicurti O, Ursini F, Giacomelli R, Cipriani P. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmun Rev. 2021;20(2):102735. https://doi.org/10.1016/j.autrev.2020.102735

Radu AF, Bungau SG. Management of Rheumatoid Arthritis: An Overview. Cells. 2021;10(11):2857. https://doi.org/10.3390/cells10112857

Joseph A, Brasington R, Kahl L, Ranganathan P, Cheng TP, Atkinson J. Immunologic rheumatic disorders. J Allergy Clin Immunol. 2010;125:S204-15. https://doi.org/10.1016/j.jaci.2009.10.067

Littlejohn EA, Monrad SU. Early Diagnosis and Treatment of Rheumatoid Arthritis. Prim Care. 2018;45(2):237-255. https://doi.org/10.1016/j.pop.2018.02.010

Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-2038. https://doi.org/10.1016/S0140-6736(16)30173-8

Oberemok VV, Andreeva O, Laikova K, Alieva E, Temirova Z. Rheumatoid Arthritis Has Won the Battle but Not the War: How Many Joints Will We Save Tomorrow? Medicina (Kaunas). 2023;59(10):1853. https://doi.org/10.3390/medicina59101853

Lin YJ, Anzaghe M, Schülke S. Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells. 2020;9(4):880. https://doi.org/10.3390/cells9040880

Anzaghe M, Schülke S. Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells. 2020;9(4):880. https://doi.org/10.3390/cells9040880

Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. Immunity. 2017;46(2):183-196. https://doi.org/10.1016/j.immuni.2017.02.006

Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6:15. https://doi.org/10.1038/s41413-018-0016-9

Ospelt C, Gay S, Klein K. Epigenetics in the pathogenesis of RA. Semin Immunopathol. 2017;39(4):409-419. https://doi.org/10.1007/s00281-017-0621-5

Mydel P, Wang Z, Brisslert M, Hellvard A, Dahlberg LE, Hazen SL, Bokarewa M. Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis. J Immunol. 2010;184(12):6882-90. https://doi.org/10.4049/jimmunol.1000075

Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017;39(4):437-446. https://doi.org/10.1007/s00281-017-0627-z

Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med. 2016;8(369):369ra176. https://doi.org/10.1126/scitranslmed.aaj1921

Aquino SG, Abdollahi-Roodsaz S, Koenders MI, van de Loo FA, Pruijn GJ, Marijnissen RJ, Walgreen B, Helsen MM, et al. Periodontal pathogens directly promote autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 response. J Immunol.2014;192(9):4103-11. https://doi.org/10.4049/jimmunol.1301970

Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202. https://doi.org/10.7554/eLife.01202

Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, Yamamoto K. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. https://doi.org/10.1038/nrdp.2018.1

Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67(10):1488-92. https://doi.org/10.1136/ard.2007.075192

Malmström V, Grönwall C. The parallel worlds of ACPA-positive and RF-positive B cells. Nat Rev Rheumatol. 2018;14(11):626-628. https://doi.org/10.1038/s41584-018-0094-5

Tiwari V, Jandu JS, Bergman MJ. Rheumatoid Factor. 2023. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. PMID: 30422493.

Mueller AL, Payandeh Z, Mohammadkhani N, Mubarak SMH, Zakeri A, Alagheband Bahrami A, Brockmueller A, Shakibaei M. Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies. Cells. 2021;10(11):3017. https://doi.org/10.3390/cells10113017

Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM. 2010;103(3):139-46. https://doi.org/10.1093/qjmed/hcp165

Maibom-Thomsen SL, Trier NH, Holm BE, Hansen KB, Rasmussen MI, Chailyan A, Marcatili P, Højrup P, Houen G. Immunoglobulin G structure and rheumatoid factor epitopes. PLoS One. 2019;14(6):e0217624. https://doi.org/10.1371/journal.pone.0217624

Deane KD, Norris JM, Holers VM. Preclinical rheumatoid arthritis: identification, evaluation, and future directions for investigation. Rheum Dis Clin North Am. 2010;36(2):213-41. https://doi.org/10.1016/j.rdc.2010.02.001

Wu CY, Yang HY, Luo SF, Lai JH. From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis. Int J Mol Sci. 2021;22(2):686. https://doi.org/10.3390/ijms22020686

Falkenburg WJJ, von Richthofen HJ, Rispens T. On the origin of rheumatoid factors: Insights from analyses of variable region sequences. Semin Arthritis Rheum. 2019;48(4):603-610. https://doi.org/10.1016/j.semarthrit.2018.06.006

Bluett J, Sergeant JC, MacGregor AJ, Chipping JR, Marshall T, Symmons DPM, Verstappen SMM. Risk factors for oral methotrexate failure in patients with inflammatory polyarthritis: results from a UK prospective cohort study. Arthritis Res Ther. 2018;20(1):50. https://doi.org/10.1186/s13075-018-1544-9

Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: clinical applications. Dis Markers. 2013;35(6):727-34. https://doi.org/10.1155/2013/726598

Edilova MI, Akram A, Abdul-Sater AA. Innate immunity drives pathogenesis of rheumatoid arthritis. Biomed J. 2021;44(2):172-182. https://doi.org/10.1016/j.bj.2020.06.010

Iberg CA, Jones A, Hawiger D. Dendritic Cells As Inducers of Peripheral Tolerance. Trends Immunol. 2017;38(11):793-804. https://doi.org/10.1016/j.it.2017.07.007

Yu MB, Langridge WHR. The function of myeloid dendritic cells in rheumatoid arthritis. Rheumatol Int. 2017;37(7):1043-1051. https://doi.org/10.1007/s00296-017-3671-z

Eisenbarth SC. Dendritic cell subsets in T cell programming: location dictates function. Nat Rev Immunol. 2019;19(2):89-103. https://doi.org/10.1038/s41577-018-0088-1

Reynolds G, Gibbon JR, Pratt AG, Wood MJ, Coady D, Raftery G, Lorenzi AR, Gray A, Filer A, Buckley CD, Haniffa MA, Isaacs JD, Hilkens CM. Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis. Ann Rheum Dis. 2016;75(5):899-907. https://doi.org/10.1136/annrheumdis-2014-206578

Saferding V, Blüml S. Innate immunity as the trigger of systemic autoimmune diseases. J Autoimmun. 2020;110:102382. https://doi.org/10.1016/j.jaut.2019.102382

Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M, Soumelis V, Amigorena S. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity. 2013;38(2):336-48. https://doi.org/10.1016/j.immuni.2012.10.018

Khan S, Greenberg JD, Bhardwaj N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat Rev Rheumatol. 2009;5(10):566-71. https://doi.org/10.1038/nrrheum.2009.185

Bell GM, Anderson AE, Diboll J, Reece R, Eltherington O, Harry RA, Fouweather T, MacDonald C, Chadwick T, McColl E, Dunn J, Dickinson AM, Hilkens CM, Isaacs JD. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis. 2017;76(1):227-234. https://doi.org/10.1136/annrheumdis-2015-208456

Spiering R, Jansen MAA, Wood MJ, Fath AA, Eltherington O, Anderson AE, Pratt AG, van Eden W, Isaacs JD, Broere F, Hilkens CMU. Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis. J Transl Med. 2019;17(1):375. https://doi.org/10.1186/s12967-019-2128-4

Filer A, Parsonage G, Smith E, Osborne C, Thomas AM, Curnow SJ, Rainger GE, Raza K, 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):2096-108. https://doi.org/10.1002/art.21930

Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiol Rev. 2017;97(4):1295-1349. https://doi.org/10.1152/physrev.00036.2016

Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet. 2017;389(10086):2338-2348. https://doi.org/10.1016/S0140-6736(17)31491-5

Vollenhoven RF. New therapeutic approaches in rheumatoid arthritis. Presse Med. 2016;45(6 Pt 2):e179-92. https://doi.org/10.1016/j.lpm.2016.05.004

Fassmer AM, Garbe E, Schmedt N. Frequency and trends of disease-modifying antirheumatic drug (DMARD) use in Germany. Pharmacol Res Perspect. 2016;4(5):e00254. https://doi.org/10.1002/prp2.254

Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924-939. https://doi.org/10.1002/acr.24596

Miranda JP, Camões SP, Gaspar MM, Rodrigues JS, Carvalheiro M, Bárcia RN, Cruz P, Cruz H, Simões S, Santos JM. The Secretome Derived From 3D-Cultured Umbilical Cord Tissue MSCs Counteracts Manifestations Typifying Rheumatoid Arthritis. Front Immunol. 2019;10:18. https://doi.org/10.3389/fimmu.2019.00018

Fontaine MJ, Shih H, Schäfer R, Pittenger MF. Unraveling the Mesenchymal Stromal Cells' Paracrine Immunomodulatory Effects. Transfus Med Rev. 2016;30(1):37-43. https://doi.org/10.1016/j.tmrv.2015.11.004

Published

2023-12-21

How to Cite

Hladkykh, F. (2023). CURRENT UNDERSTANDING OF THE IMMUNOLOGICAL BASIS OF RHEUMATOID ARTHRITIS: FROM POST-TRANSLATIONAL MODIFICATION OF PROTEINS TO THE USE OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS. Eastern Ukrainian Medical Journal, 11(4), 326–336. https://doi.org/10.21272/eumj.2023;11(4):326-336

Issue

Section

LITERATURE REVIEW. GENERAL AND INTERNAL MEDICINE