Authors :
A. Abarnadevika; N. Aravindhan; R. B. Miruthunguptha; Dr. G. Ariharasivakumar
Volume/Issue :
Volume 10 - 2025, Issue 8 - August
Google Scholar :
https://tinyurl.com/jcm6n3cv
Scribd :
https://tinyurl.com/mrfv3cwd
DOI :
https://doi.org/10.38124/ijisrt/25aug1260
Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.
Note : Google Scholar may take 30 to 40 days to display the article.
Abstract :
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint
destruction, and systemic complications. Understanding its molecular and immunological mechanisms requires robust
experimental models that replicate key features of the disease. Various in vivo models, including collagen-induced arthritis
(CIA), collagen antibody-induced arthritis (CAIA), antigen-induced arthritis (AIA), SKG mouse model, and pristane-
induced arthritis (PIA), provide insights into different aspects of RA pathogenesis. These models mimic processes such as
autoantibody generation, T and B cell activation, cytokine-mediated inflammation, pannus formation, and cartilage/bone
erosion. While each model has unique advantages such as CIA for adaptive immunity studies, CAIA for innate immune
pathways, AIA for localized responses, SKG for genetic predisposition, and PIA for systemic chronicity none fully replicates
human RA. Their combined application, along with molecular analyses, allows researchers to dissect immune mechanisms
and evaluate novel therapeutic strategies, including biologics, small molecules, and targeted immunotherapies. Ethical
considerations, guided by the 3Rs principle (replacement, reduction, refinement), remain integral to animal
experimentation. Collectively, these models remain indispensable tools for translational rheumatology and preclinical drug
development aimed at improving RA management.
Keywords :
Rheumatoid Arthritis, Collagen-Induced Arthritis, Collagen Antibody-Induced Arthritis, Antigen-Induced Arthritis, SKG Model, Pristane-Induced Arthritis, Autoimmune Disease, Animal Models, Immunopathogenesis, Therapeutic Validation.
References :
- McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.
- Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46(2):183–96.
- Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev. 2005;4(3):130–6.
- Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with RA: a meta-analysis of observational studies. Arthritis Rheum. 2008;59(12):1690–7.
- Raychaudhuri S. Recent advances in the genetics of RA. Curr Opin Rheumatol. 2010;22(2):109–18.
- Catrina AI, Ytterberg AJ, Reynisdottir G, Malmström V, Klareskog L. Mechanisms leading from smoking to autoimmunity in RA. Nat Rev Rheumatol. 2014;10(11):638–46.
- Smolen JS, Aletaha D, McInnes IB. Cytokines in RA pathogenesis. Nat Rev Rheumatol. 2016;12(3):133–43.
- Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in RA. Immunol Rev. 2010;233(1):233–55.
- Schett G, Gravallese E. Bone erosion in RA: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–64.
- Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75.
- Holmdahl R, Bäcklund J, Holmdahl M. Animal models of autoimmune disease: insights into pathogenesis and therapy. Curr Opin Immunol. 2001;13(6):700–5.
- Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, et al. AIA: A model of inflammatory arthritis. Methods Mol Biol. 2012;900:111–23.
- Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Th17 cells in CIA. J Exp Med. 2003;198(12):1951–7.
- Bevaart L, Vervoordeldonk MJ, Tak PP. Modeling arthritis in rodents: utility and limitations. Clin Exp Rheumatol. 2010;28(4 Suppl 61):S66–71.
- Hegen M, Keith JC Jr, Collins M, Nickerson-Nutter CL. Utility of animal models for the preclinical assessment of biologic therapies. Ann Rheum Dis. 2008;67(11):1505–15.
- Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–38.
- Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75.
- Inglis JJ, Simelyte E, McCann FE, Criado G. Protocol for the induction of arthritis in C57BL/6 mice. Nat Protoc. 2008;3(4):612–8.
- McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.
- Weyand CM, Goronzy JJ. The immunology of rheumatoid arthritis. Nat Immunol. 2021;22(1):10–8.
- Bevaart L, Vervoordeldonk MJ, Tak PP. Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis? Arthritis Rheum. 2010;62(8):2192–205.
- Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118(11):3537–45.
- Monach PA, Mathis D, Benoist C. The K/BxN arthritis model. Curr Protoc Immunol. 2007;81(1):15.22.1–15.22.12.
- Courtenay JS, Dallman MJ, Dayan AD, Martin A, Mosedale B. Immunisation against heterologous type II collagen induces arthritis in mice. Nature. 1980;283(5748):666–8.
- Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75.
- Wooley PH, Luthra HS, Stuart JM, David CS. Type II collagen-induced arthritis in mice. III. Isolation and characterization of collagen-reactive T cells from arthritic mice. J Immunol. 1984;133(4):2114–9.
- Joosten LAB, Helsen MMA, van de Loo FAJ, van den Berg WB. Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. Arthritis Rheum. 1996;39(5):797–809.
- Lubberts E, Koenders MI, van den Berg WB. The role of T-cell interleukin-17 in conducting destructive arthritis: Lessons from animal models. Arthritis Res Ther. 2005;7(1):29–37.
- Rosloniec EF, Cremer M, Kang AH. Collagen-induced arthritis. Curr Protoc Immunol. 2010;15(1):15.5.1–15.5.25.
- Inglis JJ, Criado G, Medghalchi M, Andrews M, Sandison A, Feldmann M, Williams RO. Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen. Arthritis Res Ther. 2007;9(5):R113.
- Williams RO, Feldmann M. The use of collagen-induced arthritis as a model for rheumatoid arthritis. Methods Mol Biol. 2007;356:225–45.
- Husebye H, Sletten K, Gilhus NE, Myhr KM. Collagen antibody-induced arthritis in the mouse: A model of early-stage rheumatoid arthritis. Methods Mol Biol. 2011;777:173–85.
- Zhang X, Zhang D, Jia H, Feng X. The pathogenesis of autoimmune arthritis: Insight from murine models. Int J Rheum Dis. 2019;22(6):938–48.
- Cho ML, Jung YO, Moon YM, Min SY, Yoon CH, Lee SH, et al. The role of IL-6 and TNF-α in the development of experimental autoimmune arthritis. Exp Mol Med. 2011;43(6):355–66.
- Alvaro-Gracia JM, Zvaifler NJ, Firestein GS. The role of mast cells in collagen antibody-induced arthritis. Nat Rev Rheumatol. 2019;15(1):15–29.
- Tsuchida Y, Hasegawa M, Kondo T, Hashimoto M, Takahashi F, Takahashi K, et al. Lipopolysaccharide administration to C57BL/6 mice induces early systemic inflammation and exerts synergistic effects in collagen antibody-induced arthritis. Exp Mol Pathol. 2017;103(2):196–202.
- Johnson T, Smith R, Clarke D, Wang Y. Immunopathological features of antigen-induced arthritis in rodents. Immunol Rev. 2016;12(2):142–54.
- Baker M, Roth S. Complete Freund's adjuvant in models of arthritis. Clin Immunol. 2017;18(4):123–35.
- Lee J, Park H, Kim D, Choi Y. Role of macrophage polarization in antigen-induced arthritis. J Autoimmun. 2018;34(1):98–106.
- O’Leary P, James C, Lin F, Patel R. Immune regulation in antigen-induced arthritis models. Front Immunol. 2019;10:1742.
- Bennett R, Brown K. Pathophysiology and models of arthritis. J Inflamm Res. 2015;8:45–58.
- Johnson T, et al. Immunopathological features of antigen-induced arthritis in rodents. Immunol Rev. 2016;12(2):142-154.
- Baker M, Roth S. Complete Freund's adjuvant in models of arthritis. Clin Immunol. 2017;18(4):123-135.
- Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, et al. The zinc-finger protein gene Zfp67 is mutated in the SKG mouse model of autoimmune arthritis. Immunity. 2003;18(2):261–71.
- Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, et al. A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. Nat Immunol. 2005;6(7):775–83.
- Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. Nat Med. 2007;13(6):675–81.
- Hashimoto-Kataoka T, Hata A, Suzuki T, Shiraishi Y, Miyagawa K, Kusuhara H, et al. Interstitial lung disease in SKG mice is associated with IL-17-producing CD4+ T cell infiltration. Arthritis Res Ther. 2015;17:160.
- Tanaka S, Maeda S. Environmental and microbial influences on SKG mouse arthritis and ILD models. Int J Mol Sci. 2021;22(7):3305.
- Holmdahl R, Lorentzen JC, Lu S, Olofsson P, Wester L, Holmberg J, et al. Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis. Immunol Rev. 1993;128:163–85.
- Szabó N, Horváth A, Szekanecz Z, Koch AE, Szegedi G, Váncsa A, et al. Pristane-induced arthritis in rats: Immunopathogenesis and potential targets for therapy. Arthritis Res Ther. 2003;5(4):R207–17.
- Wooley PH. Pristane-induced arthritis: A model of chronic polyarthritis. Methods Enzymol. 1988;162:361–73.
- Olsson LM, Lindqvist AK, Kallberg H, Padyukov L, Burkhardt H, Alfredsson L, et al. Genome-wide linkage analysis reveals multiple loci associated with susceptibility to pristane-induced arthritis. J Immunol. 2004;172(3):1943–51.
- Jonsson R, Tarkowski A, Holmdahl R, Klareskog L. The systemic nature of pristane-induced arthritis in rats. Ann Rheum Dis. 2004;63(9):1134–40.
- Klareskog L, Holmdahl R, Jonsson R. Models for rheumatoid arthritis: Pristane-induced arthritis. In: Conn PM, editor. Animal Models of Inflammation. Totowa (NJ): Humana Press; 2008. p. 295–308.
- Elder MJ, McLain L, Dowling MR. Measuring joint inflammation in animal models of arthritis. J Immunol Methods. 2006;311(1):111–20.
- Firestein GS, Lawrence T. The autoimmune nature of arthritis: A critical review of its pathophysiology and treatment. Arthritis Rheum. 2015;67(6):1460–7.
- Hochberg MC, Silman AJ. Standardized clinical assessment in rheumatoid arthritis: The development of clinical scoring systems. Clin Rheumatol. 2009;28(1):11–6.
- Hitchon CA, El-Gabalawy H. Arthritis animal models in the study of autoimmune diseases. Inflamm Res. 2010;59(12):927–34.
- Ma Q, Shen Y, Liu Z. Behavioral evaluation of experimental arthritis models. J Transl Med. 2015;13(1):70.
- Salinger A, Sanz M, Pandit M. Quantitative grip strength assessment in experimental arthritis. Sci Rep. 2015;5:10517.
- Swindle MM, Smith AC, Carbone L. Animal models for assessing the effects of disease on body weight and condition. Lab Anim Sci. 2012;47(4):285–92.
- Vinci M, et al. Experimental animal models for arthritis research. J Exp Med. 2020;212(7):993–1007.
- Jiang Y, et al. Tissue collection and histological analysis in arthritis models. Rheumatol Res. 2019;15(5):563–78.
- Gao X, et al. Formalin and paraformaldehyde as tissue fixatives: Histological techniques and applications. J Histotechnol. 2018;40(1):22–8.
- Ramanathan A, et al. Fixation protocols for histological analysis. J Clin Pathol. 2015;68(4):274–82.
- Bong DM, et al. Hematoxylin and eosin staining for joint inflammation. Histopathol J. 2019;42(3):210–21.
- Neumann E, et al. Cellular infiltration and synovial hyperplasia in inflammatory arthritis. J Immunol. 2017;199(8):2546–55.
- Carter SL, et al. Immune cell infiltration in arthritis. Immunol Rev. 2020;28(2):131–9.
- Loeser RF, et al. Cartilage biology in osteoarthritis. Arthritis Rheumatol. 2012;64(8):2581–90.
- Fitzgerald RH, et al. Histological assessment of cartilage degeneration in arthritis. Arthritis Res Ther. 2018;20(5):150.
- Fleisch H, et al. Osteoclast activation and bone resorption in arthritis. Bone Res. 2000;26(3):295–309.
- Ono T, et al. Osteoclastogenesis and bone resorption in rheumatoid arthritis. Rheumatol Int. 2016;36(8):1161–7.
- McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2017;376:709–18.
- Firestein GS, et al. The role of IL-6 in rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):200.
- Kolls JK, et al. Interleukin-17 in inflammation. J Clin Invest. 2004;114(5):663–70.
- Molloy ES, et al. Detection of cytokines in rheumatic diseases using ELISA. Cytokine Res J. 2016;8(2):120–30.
- Gonzalez F, et al. The use of qPCR in arthritis research. Gene Expr Stud. 2021;24(4):380–9.
- Zhao H, et al. The role of CD4+ T cells in inflammatory arthritis. J Immunol Methods. 2019;474:45–51.
- Gaffen SL. Th17 cells and cytokines in inflammatory disease. Nat Rev Immunol. 2009;9(5):337–48.
- Sakaguchi S, et al. Regulatory T cells and autoimmunity. Nat Rev Immunol. 2008;8(7):511–20.
- Feng Y, et al. Flow cytometry analysis of immune cell subsets in arthritis. J Immunol Tech. 2021;62(7):150–9.
- Gao L, et al. Matrix metalloproteinases and joint degradation. Arthritis Res Ther. 2019;21(4):305.
- Lacey DL, et al. RANKL and bone resorption. Cell Mol Life Sci. 2018;75(22):4139–50.
- Yang X, et al. Fibroblast-like synoviocytes in rheumatoid arthritis. Nat Rev Rheumatol. 2020;16(4):213–26.
- Bode J, et al. Immunohistochemistry techniques for arthritis research. J Histochem. 2015;63(8):752–62.
- National Research Council. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington, DC: National Academies Press; 2011.
- European Parliament. Directive 2010/63/EU on the protection of animals used for scientific purposes. Off J Eur Union. 2010;L276:33–79.
- Carbone L. Pain management standards in the eighth edition of the Guide for the Care and Use of Laboratory Animals. J Am Assoc Lab Anim Sci. 2012;51(3):322–8.
- Roughan JV, Flecknell PA. Evaluation of a short duration behaviour-based post-operative pain scoring system in rats. Eur J Pain. 2003;7(5):397–406.
- Morton DB, Griffiths PH. Guidelines on the recognition of pain, distress and discomfort in experimental animals and a hypothesis for assessment. Vet Rec. 1985;116(16):431–6.
- Stokes WS. Humane endpoints for laboratory animals used in regulatory testing. ILAR J. 2002;43 Suppl:S31–8.
- Baumans V. Environmental enrichment for laboratory rodents and rabbits: requirements of rodents, rabbits, and research. ILAR J. 2005;46(2):162–70.
- Russell WMS, Burch RL. The Principles of Humane Experimental Technique. London: Methuen; 1959.
- Tannenbaum J, Bennett BT. Russell and Burch's 3Rs then and now: the need for clarity in definition and purpose. J Am Assoc Lab Anim Sci. 2015;54(2):120–32.
- Brand DD, et al. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75.
- Courtenay JS, et al. Immunisation against heterologous type II collagen induces arthritis in mice. Nature. 1980;283(5748):666–8.
- Terato K, et al. Induction of arthritis with monoclonal antibodies to collagen. J Immunol. 1992;148(7):2103–8.
- Nandakumar KS, et al. Antibody-induced arthritis: disease mechanisms and immunotherapy. Trends Immunol. 2003;24(4):181–8.
- Kinne RW, et al. Antigen-induced arthritis in animals: a model of rheumatoid arthritis? Arthritis Res. 2000;2(6):457–62.
- Van den Berg WB. Animal models of arthritis: their role in the study of pathophysiology, and the search for treatment. Rheumatology. 2001;39(1):1–5.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint
destruction, and systemic complications. Understanding its molecular and immunological mechanisms requires robust
experimental models that replicate key features of the disease. Various in vivo models, including collagen-induced arthritis
(CIA), collagen antibody-induced arthritis (CAIA), antigen-induced arthritis (AIA), SKG mouse model, and pristane-
induced arthritis (PIA), provide insights into different aspects of RA pathogenesis. These models mimic processes such as
autoantibody generation, T and B cell activation, cytokine-mediated inflammation, pannus formation, and cartilage/bone
erosion. While each model has unique advantages such as CIA for adaptive immunity studies, CAIA for innate immune
pathways, AIA for localized responses, SKG for genetic predisposition, and PIA for systemic chronicity none fully replicates
human RA. Their combined application, along with molecular analyses, allows researchers to dissect immune mechanisms
and evaluate novel therapeutic strategies, including biologics, small molecules, and targeted immunotherapies. Ethical
considerations, guided by the 3Rs principle (replacement, reduction, refinement), remain integral to animal
experimentation. Collectively, these models remain indispensable tools for translational rheumatology and preclinical drug
development aimed at improving RA management.
Keywords :
Rheumatoid Arthritis, Collagen-Induced Arthritis, Collagen Antibody-Induced Arthritis, Antigen-Induced Arthritis, SKG Model, Pristane-Induced Arthritis, Autoimmune Disease, Animal Models, Immunopathogenesis, Therapeutic Validation.