Expression of a transgenic class II Ab gene confers susceptibility to collagen‐induced arthritis

Abstract

The major histocompatibility complex (MHC) class II region is assumed to influence autoimmune diseases such as rheumatoid arthritis. In the mouse, the H-2q haplotype is associated with susceptibility to collagen-induced arthritis, while the H-2p haplotype is not. The class II A molecules of these haplotypes differ by only four amino acids in the first domain of the beta chain. To test if this difference accounts for the MHC influence on susceptibility to collagen-induced arthritis, H-2p mice were made transgenic with an Abp gene altered to resemble the Abq gene. The transgenic A beta chain hybridized with the A alpha p chain and was shown to be physiologically expressed by testing antigen-presentation capacity to Aq-restricted T cell hybridomas and with FACS analyses. These transgenic mice developed an autoimmune response to type II collagen and also collagen-induced arthritis. The data unequivocally suggest the Ab gene as a major genetic susceptibility locus for autoimmune collagen-induced arthritis.

The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans

“…CIA in mice is induced by immunization with CII in adjuvant. Like RA -which is genetically linked to HLA-DR class II molecules [DR1 (DRB1*0101, DRB1*1001) and DR4 (DRB1*0401, DRB1*0404, DRB1*0405)] [4,5] -susceptibility to CIA in mice is associated with the expression of specific MHC haplotypes [6] and one of the underlying genes has been identified as the class II gene coding for A q [7].…”

“…Interestingly, the human class II molecules associated with RA -DR4 and DR1 -present the same peptide, and transgenic mice expressing A q , DR4 or DR1 are susceptible to CIA [7][8][9]. The T cell response is directed towards the same immunodominant core, CII residues 260-270 [9,10].…”

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

“…Susceptibility to CIA is associated with class II MHC (25). In this model, mice are immunized with rat CII, which is taken up and presented by antigenpresenting cells and recognized by lymphocytes to generate CII-specific CD4ϩ T cells and B cells.…”

“…Plasminogen-deficient mice (24) of C57BL/6 background were backcrossed twice with DBA/1 (H-2q) mice and further intercrossed in order to obtain wild-type, plasminogen-heterozygous, and plasminogen-deficient mice. In mice, the plasminogen locus is linked to the major histocompatibility complex (MHC) region on chromosome 17; therefore, mice expressing the MHC region from DBA/1 were selected to determine that the mice expressed the class II MHC gene Ab (25). The plasminogen genotypes of the mice were determined by polymerase chain reaction and by measuring plasma levels of plasminogen, as previously described (26).…”

Genetics of Autoimmune Diseases: A Multistep Process

“…Within the previous QTL on chromosome 3 (Eae3), we were able to identify three separate loci (Cia5, Cia21, and Cia22) and within the previous QTL on chromosome 15 (Eae2) we found four loci (Cia26, Cia30, Cia31, and Cia32). Most of these loci interacted with each other ( with which it has been possible to insert both specific murine class II genes [39,40] and their human counterparts [41][42][43][44], and thereby prove the role of these genes for the development of autoimmune disease such as RA and MS. These studies also show the risk in transgenic technology as overexpression of class II genes may also lead to an artifactual toxicity in B cells [45,46], which is the most likely explanation for a suppressive effect by transgenic class II genes, as has been reported in diabetes in the NOD mouse.…”