SP0077 Innate versus adaptive immunity in the pathogenesis of arthritis
Authors: R Holmdahl
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Despite large efforts, the genetic and environmental factors that cause rheumatoid arthritis (RA) have not been found. The only significant genetic clue today is an association with the major histocompatibility complex (MHC) region coding for class II peptide receptors, which are known to be crucial for immune responses. However, the MHC region only partially reflects the genetic influence as this is a polygenically controlled disease. In addition environmental factors are likely to strongly influence the disease. One such important environmental factors are adjuvants, derived from pathogenic organism or from other exogenous and endogenous sources. These complex issues are better clarified in animal models. In fact there are mainly two ways to induce arthritis in rodents. Firstly, injection of various adjuvants trigger arthritis in certain rat strains.<sup>1,2,3</sup> The properties of these adjuvants are that they are difficult to degrade <i>in vivo</i> and are soluble in cellular membranes. In contrast to antigens they do not bind to MHC molecules and can therefore not elicit an antigen specific response. Nevertheless, adjuvants trigger an arthritic disease which in certain cases closely mimics RA(3). One of the best models is pristine induced arthritis (PIA) which is a MHC class II dependent, ab T cell dependent chronic relapsing disease.<sup>3,4,5</sup> It can be prophylactically and therapeutically vaccinated against with the help of joint specific antigens.<sup>6</sup> Secondly, immunisation with joint-specific proteins may induce arthritis. In this case fragments of the protein bind to MHC molecules and elicit an immune response cross-reactive with joint antigens.<sup>7,8,9</sup> Subsequently the joints are attacked and may develop into a chronic relapsing disease depending on the specificity of the immune response and the genetics of the strain. Examples of joint antigen specific models are type II collagen induced arthritis (CIA) and cartilage oligomeric matrix protein-induced arthritis (COMPIA).<sup>10,11,12</sup> Genetic analyses of adjuvant and joint specific models show that most, but not all, genetic regions are shared indicating that they share pathogenic mechanisms. These models will be further discussed mainly based on genetic dissection of MHC and non-MHC genetic regions. <h3>References</h3> Pearson CM. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med. 1956;91:95 Vingsbo C, <i>et al</i>. Avridine-induced arthritis in rats; a T cell-dependent chronic disease influenced both by MHC genes and by non-MHC genes. Clin Exp Immunol. 1995;99:359 Vingsbo C, <i>et al</i>. Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes. Am J Pathol. 1996;149:1675 Vingsbo-Lundberg C, <i>et al</i>. Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats. Nat Genet. 1998;20:401 Vingsbo-Lundberg C, <i>et al</i>. Increased serum levels of cartilage oligomeric matrix protein in chronic erosive arthritis in rats. Arthritis Rheum. 1998;41:544 Lu S, Holmdahl R. Different therapeutic and bystander effects by intranasal administration of homologous type II and type IX collagens on the collagen-induced arthritis and pristane-induced arthritis in rats. Clin Immunol 1999;90:119 Holmdahl R, <i>et al</i>. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev. 1990;118:193 Brunsberg U, <i>et al</i>. Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur J Immunol. 1994;24:1698 Kjellén P, <i>et al</i>. The structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256–270 glycopeptide to H-2Aq and H-2Ap molecules. Eur J Immunol. 1998;28:755 Trentham DE, <i>et al</i>. Autoimmunity to type II collagen: an experimental model of arthritis. J Exp Med. 1977;146:857 Holmdahl R, <i>et al</i>. Homologous collagen-induced arthritis in rats and mice are associated with structurally different major histocompatibility complex DQ-like molecules. Eur J Immunol. 1992;22:419 Carlsén S, <i>et al</i>. Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats. Clin Exp Immunol 1998;114:477