Autoimmune Arthritis: Animal Models


Animal models are used for the study of a number of human autoimmune diseases, including multiple sclerosis, diabetes, rheumatoid arthritis, systemic lupus erythematosis and spondyloarthropathies. Induced, spontaneous and genetically manipulated animal models can be described in terms of their parallels to human disease and as valuable tools for the development of potential therapies. Studies in animal models have led to a number of important discoveries, which have increased our understanding of the pathogenesis of autoimmune disease, including the roles played by regulatory T cells and TH17 cells. In addition, important therapeutic advances have emerged as a result of studies of immune intervention in animal models of autoimmunity. For example, tumour necrosis factor (TNF) blocking drugs, which are widely used for the treatment of rheumatic diseases, were developed following pre‐clinical testing in animal models.

Key Concepts

  • Animal models may be either spontaneously occurring or induced as a result of genetic manipulation, immunisation with a self‐antigen or triggered by pathogen‐associated molecular patterns (PAMPs) in genetically susceptible hosts.
  • No animal model completely mimics human disease.
  • Animal models can be used to delineate common mammalian immunological mechanisms, test novel therapeutic concepts and understand mechanisms of drug action, but therapeutic efficacy therein is not predictive of response in clinical trials.
  • The use of transgenic and knockout strains facilitates the identification of key genes that contribute to disease susceptibility and pathogenesis.

Keywords: animal models; rheumatoid arthritis; spondyloarthropathy; ankylosing spondylitis; collagen‐induced arthritis; SKG

Figure 1. Collagen‐induced arthritis. (a) Normal proximal interphalangeal joint. (b) Inflammation and joint erosion in DBA/1 mouse 10 days after onset of arthritis. Haematoxylin and eosin.
Figure 2. Joint damage in human TNFα‐transgenic mice. Note the focal erosion of subchondral bone. Haematoxylin and eosin.
Figure 3. Inflammatory infiltrate in the spine is observed in curdlan‐challenged SKG mice.


Australo‐Anglo‐American Spondyloarthritis C, Reveille JD, Sims AM, et al. (2010) Genome‐wide association study of ankylosing spondylitis identifies non‐MHC susceptibility loci. Nature Genetics 42 (2): 123–127.

Backlund J, Li C, Jansson E, et al. (2013) C57BL/6 mice need MHC class II Aq to develop collagen‐induced arthritis dependent on autoreactive T cells. Annals of the Rheumatic Diseases 72 (7): 1225–1232.

Benham H, Rehaume LM, Hasnain SZ, et al. (2014) Interleukin‐23 mediates the intestinal response to microbial beta‐1,3‐glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis & Rheumatology 66 (7): 1755–1767.

Brown MA, Kennedy LG, MacGregor AJ, et al. (1997) Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis and Rheumatism 40 (10): 1823–1828.

Chang YH, Pearson CM and Chedid L (1981) Adjuvant polyarthritis. V. Induction by N‐acetylmuramyl‐L‐alanyl‐D‐isoglutamine, the smallest peptide subunit of bacterial peptidoglycan. Journal of Experimental Medicine 153 (4): 1021–1026.

Doodes PD, Cao Y, Hamel KM, et al. (2010) IFN‐gamma regulates the requirement for IL‐17 in proteoglycan‐induced arthritis. Journal of Immunology 184 (3): 1552–1559.

Glant TT, Mikecz K, Arzoumanian A, et al. (1987) Proteoglycan‐induced arthritis in BALB/c mice. Clinical features and histopathology. Arthritis and Rheumatism 30 (2): 201–212.

Gregersen PK, Silver J and Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis & Rheumatism 30: 1205–1213.

Gringhuis SI, den Dunnen J, Litjens M, et al. (2009) Dectin‐1 directs T helper cell differentiation by controlling noncanonical NF‐kappaB activation through Raf‐1 and Syk. Nature Immunology 10 (2): 203–213.

Hammer RE, Maika SD, Richardson JA, et al. (1990) Spontaneous inflammatory disease in transgenic rats expressing HLA‐B27 and human beta 2m: an animal model of HLA‐B27‐associated human disorders. Cell 63 (5): 1099–1112.

Haynes KR, Pettit AR, Duan R, et al. (2012) Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Research & Therapy 14 (6): R253.

Hirota K, Hashimoto M, Yoshitomi H, et al. (2007) T cell self‐reactivity forms a cytokine milieu for spontaneous development of IL‐17+ Th cells that cause autoimmune arthritis. Journal of Experimental Medicine 204 (1): 41–47.

Holmberg J, Tuncel J, Yamada H, et al. (2006) Pristane, a non‐antigenic adjuvant, induces MHC class II‐restricted, arthritogenic T cells in the rat. Journal of Immunology 176 (2): 1172–1179.

Hou FF, Miyata T, Boyce J, et al. (2001) beta(2)‐Microglobulin modified with advanced glycation end products delays monocyte apoptosis. Kidney International 59 (3): 990–1002.

Inglis JJ, Criado G, Medghalchi M, et al. (2007) Collagen‐induced arthritis in C57BL/6 mice is associated with a robust and sustained T‐cell response to type II collagen. Arthritis Research & Therapy 9 (5): R113.

Keffer J, Probert L, Cazlaris H, et al. (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. Embo Journal 10: 4025–4031.

Kouskoff V, Korganow AS, Duchatelle V, et al. (1996) Organ‐specific disease provoked by systemic autoimmunity. Cell 87 (5): 811–822.

Langrish CL, Chen Y, Blumenschein WM, et al. (2005) IL‐23 drives a pathogenic T cell population that induces autoimmune inflammation. Journal of Experimental Medicine 201 (2): 233–240.

Lin P, Bach M, Asquith M, et al. (2014) HLA‐B27 and human beta2‐microglobulin affect the gut microbiota of transgenic rats. PLoS One 9 (8): e105684.

Lubberts E (2010) Th17 cytokines and arthritis. Seminars in Immunopathology 32 (1): 43–53.

Maksymowych WP (2010) Disease modification in ankylosing spondylitis. Nature Reviews. Rheumatology 6 (2): 75–81.

Manoury‐Schwartz B, Chiocchia G, Bessis N, et al. (1997) High susceptibility to collagen‐induced arthritis in mice lacking IFN‐gamma receptors. Journal of Immunology 158 (11): 5501–5506.

Matsumoto I, Maccioni M, Lee DM, et al. (2002) How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint‐specific autoimmune disease. Nature Immunology 3 (4): 360–365.

Miyata T, Hori O, Zhang J, et al. (1996) The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE‐beta2microglobulin with human mononuclear phagocytes via an oxidant‐sensitive pathway. Implications for the pathogenesis of dialysis‐related amyloidosis. Journal of Clinical Investigation 98 (5): 1088–1094.

Murphy CA, Langrish CL, Chen Y, et al. (2003) Divergent pro‐ and antiinflammatory roles for IL‐23 and IL‐12 in joint autoimmune inflammation. Journal of Experimental Medicine 198 (12): 1951–1957.

Nakae S, Nambu A, Sudo K, et al. (2003) Suppression of immune induction of collagen‐induced arthritis in IL‐17‐deficient mice. Journal of Immunology 171 (11): 6173–6177.

Pearson CM (1956) Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proceedings of the Society for Experimental Biology and Medicine 91: 95–101.

Ronneberger M and Schett G (2011) Pathophysiology of spondyloarthritis. Current Rheumatology Reports 13 (5): 416–420.

Rosenbaum JT and Davey MP (2011) Time for a gut check: evidence for the hypothesis that HLA‐B27 predisposes to ankylosing spondylitis by altering the microbiome. Arthritis and Rheumatism 63 (11): 3195–3198.

Rosloniec EF, Brand DD, Myers LK, et al. (1997) An HLA‐DR1 transgene confers susceptibility to collagen‐induced arthritis elicited with human type II collagen. Journal of Experimental Medicine 185 (6): 1113–1122.

Ruutu M, Thomas G, Steck R, et al. (2012) Beta‐glucan triggers spondylarthritis and Crohn's disease‐like ileitis in SKG mice. Arthritis and Rheumatism 64 (7): 2211–2222.

Sakaguchi N, Takahashi T, Hata H, et al. (2003) Altered thymic T‐cell selection due to a mutation of the ZAP‐70 gene causes autoimmune arthritis in mice. Nature 426 (6965): 454–460.

Schellekens GA, de Jong BA, van den Hoogen FH, et al. (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis‐specific autoantibodies. Journal of Clinical Investigation 101 (1): 273–281.

Schmidt AM, Yan SD, Yan SF, et al. (2001) The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. Journal of Clinical Investigation 108 (7): 949–955.

Tran TM, Dorris ML, Satumtira N, et al. (2006) Additional human beta2‐microglobulin curbs HLA‐B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA‐B27‐transgenic rats. Arthritis and Rheumatism 54 (4): 1317–1327.

Trentham DE (1982) Collagen arthritis as a relevant model for rheumatoid arthritis: evidence pro and con. Arthritis & Rheumatism 25: 911–916.

Vermeire K, Heremans H, Vandeputte M, et al. (1997) Accelerated collagen‐induced arthritis in IFN‐gamma receptor‐deficient mice. Journal of Immunology 158 (11): 5507–5513.

Wellcome Trust Case Control C, C Australo‐Anglo‐American Spondylitis, Burton PR, et al. (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genetics 39 (11): 1329–1337.

Wilder RL (2001) Streptococcal cell wall arthritis. Current Protocols in Immunology Chapter 15: Unit 15 10.

Wooley PH, Luthra HS, Stuart JM, et al. (1981) Type II collagen‐induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. Journal of Experimental Medicine 154: 688–700.

Further Reading

Boissier MC, Semerano L, Challal S, et al. (2012) Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. Journal of Autoimmunity 39 (3): 222–228.

Hreggvidsdottir HS, Noordenbos T and Baeten DL (2014) Inflammatory pathways in spondyloarthritis. Molecular Immunology 57 (1): 28–37.

Lubberts E (2015) The IL‐23‐IL‐17 axis in inflammatory arthritis. Nature Reviews. Rheumatology 11 (7): 415–429.

McInnes IB and Schett G (2011) The pathogenesis of rheumatoid arthritis. New England Journal of Medicine 365 (23): 2205–2219.

McNamee K, Williams R and Seed M (2015) Animal models of rheumatoid arthritis: how informative are they? European Journal of Pharmacology 759: 278–286.

Milia AF, Ibba‐Manneschi L, Manetti M, et al. (2009) HLA‐B27 transgenic rat: an animal model mimicking gut and joint involvement in human spondyloarthritides. Annals of the New York Academy of Sciences 1173: 570–574.

Nabozny GH and David CS (1994) The immunogenetic basis of collagen induced arthritis in mice: an experimental model for the rational design of immunomodulatory treatments of rheumatoid arthritis. Advances in Experimental Medicine & Biology 347: 55–63.

Sakaguchi S, Benham H, Cope AP, et al. (2012) T‐cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. Immunology & Cell Biology 90 (3): 277–287.

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McCann, Fiona E, and Wythe, Sarah E(Oct 2015) Autoimmune Arthritis: Animal Models. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001436.pub3]