Periphery

HLA-DQ8 Mimic peptide TCR

Autoimmune disease

Low affinity Positive selection

Expansion mice also induced a specific selection of CD4+ T cells with a normal Vp TCR repertoire. Upon immunization with bovine type II collagen, HLA-DQ8 transgenic mice mount a strong immunoglobulin G (IgG) response specific for type II collagen as well as proliferate vigorously against bovine CII. Bovine CII-immunized DQ8 mice also develop a severe polyarthritis with massive inflammation and swelling in the affected joints. Histological analysis of joints in these mice indicated synovitis, mononuclear cell infiltration with eventual bone and cartilage erosions leading to joint deformation. These findings demonstrated for the first time that expression of the RA linked HLA-DQ8 molecule in class II-deficient mice confer susceptibility to the induction of CIA.

Immunogenicity of peptides encompassing the amino acid sequence 65-79 of the HV3 region of known HLA-DRB1 alleles was analyzed in HLA-DQ8 transgenic mice. Peptides derived from alleles not associated with RA, namely DRB1*0402 and DRB1 "1103, showed the strongest response whereas alleles associated with RA susceptibility, for example, DRB1*0101 and *0401, were not stimulatory. These results showed that a correlation exists between peptides derived from the HV3 regions of DRB1 chains and nonassociation of the corresponding alleles with RA predisposition. Polymorphisms in the DRB1 alleles were further analyzed in the DQ8 mice. RA-protective DRB1*1502 (DR2) gene was introduced in arthritis-susceptible DQ8 transgenic mice. The DR2.DQ8 double transgenic mice were then immunized with bovine CII and monitored for arthritis. Arthritis incidence was significantly lower

Figure 1 Presentation of HLA-DRB1 HV3 peptides by HLA-DQ molecules shape T cell repertoire. During thymic selection, potential autoreactive T cells are deleted following presentation of the DRB1 *0402 HV3 pep tide by HLA-DQ8 molecules. Conversely, positive selection of the same autoreactive T cells occurs due to the low affinity of DRB1 *0401 peptide for the HLA-DQ8 molecule. These T cells are then activated and expand in the periphery by presentation of a foreign peptide and subsequently (via molecular mimicry) cause autoimmune inflammatory disease.

in these mice as compared to DR2-negative litter-mates. A similar reduction of disease incidence was found in CIA-susceptible B10.RQB3 (H-2") mice transgenic for the DRB1 * 1502 gene. HLA-DQ transgenic mice were further investigated to study polymorphisms within the DQ molecules in CIA susceptibility. RA nonassociated HLA-DQ6 transgenic mice generate a weak response to CII and do not develop CIA upon immunization with bovine CII. In contrast, bovine CU-immunized double transgenic mice expressing HLA-DQ6|3 and HLA-DQ8u|3 genes (DQ6/8) develop mild arthritis with delayed onset and lowered incidence. These studies using Hl.A-transgenic mice demonstrate that polymorphism in the HLA-DRB1 alleles probably modulate predisposition to RA by shaping the T cell repertoire, whereas susceptibility to human RA may be determined by polymorphism in the DQ loci.

Human type II collagen (HuCII) is a candidate autoantigen involved in human RA. Since arthritis-associated human MHC haplotypes (e.g. DQ8, DR4) may recognize unique sets of determinants on HuCII, HuCII peptide determinants recognized by DQ8 transgenic mice were analyzed. Using a series of 27 overlapping peptides (20 mer) encompassing the residues 124-403 of HuCII (CB11 fragment), T cell responses were analyzed both in DBA/1 and DQ8 transgenic mice. Unique peptide determinants were identified in DQ8 transgenic mice, namely peptide residues 174-193, 194-213, 284-303 and 314-343 when compared to responses in DBA/1 mice. Oral administration of HuCII peptides as well as native CII have been reported to suppress CIA in mice and rats, and to be beneficial in human RA patients. DQ8

transgenic mice orally tolerized with bovine CII show a marked reduction in incidence, severity, and delay in onset of disease.

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