Human collagen II peptide 256-271 preferentially binds to HLA-DR molecules associated with susceptibility to rheumatoid arthritis

Abstract

The binding ability of 23 overlapping peptides, all derived from the CB11 fragment of CII, was tested on several HLA-DR molecules associated or not with disease susceptibility. These experiments were performed on a variety of cells expressing different HLA-DR molecules, using both indirect and direct binding assays. The CII (256-271) fragment was shown to bind to a restricted population among which the HLA-DR molecules associated with susceptibility to rheumatoid arthritis. The results also clearly indicate that the binding specificity of CII (256-271), among the DR4 molecules, is controlled by the nature of the HLA-DR molecule beta-chain residues 71 and 74, residues previously shown by X-ray crystallography to be involved in the HLA-DR/peptide interaction. The human CII (256-271) peptide is thus likely to play a role in the disease process.

HLA-DRB1*0402 (DW10) Transgene Protects Collagen- Induced Arthritis-Susceptible H2Aq and DRB1*0401 (DW4) Transgenic Mice from Arthritis

“…31 and data not shown). Both DW4 and DW10 have been shown to be able to bind this peptide, albeit with different anchors in P1 pocket (43). Presentation of this peptide in double transgenic mice might lead to increase in proliferation as observed with CFSE staining after in vitro culture with PII thus reaching a threshold for autoreactivity and development of arthritis.…”

New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis

“…According to the hypothesis, DRB1 alleles sharing a motif at positions 67, 70, 71, and 74 are implicated in the pathogenesis of RA by their ability to present similar antigens, leading to the development of arthritis. DRB1*0402 was found to be associated with nonsusceptibility to RA; however, both DRB1*0401 and DRB1*0402 can present the DR4-restricted immunodominant peptide of type II collagen (CII) (2,3).…”

Mice Producing Less Reactive Oxygen Species Are Relatively Resistant to Collagen Glycopeptide Vaccination against Arthritis

“…The glycosylated CII peptide binds to the human DR4/DR1 MHC-II molecules in a manner similar to A q , extending its galactose side chains to the TCR (4,57,58). Moreover, T cell specificity directed to this posttranslationally modified epitope also has been shown in human patients with RA (14), which indicates that therapy with this peptide would lead to a promising result in humans.…”

“…The animals were sacrificed 5 d later; spleens were harvested and pooled in two groups according to the type of treatment. The organs were passed through a 40-mm cell strainer (BD Discovery, Labware, Sparks, MD), and erythrocytes were lysed using 0.84% NH 4 Cl. The cells were washed again with PBS without Ca 2+ and Mg…”

“…It has been shown that ACPAs together with certain MHC class II (MHC II) and PTPN22 alleles are strong predictive factors arguing for a role of adaptive immunity in the disease pathogenesis (3). The MHC II region, coding a shared amino acid motif in the peptidebinding pocket of the b-chain of HLA-DR4 and DR1 haplotypes (the shared epitope hypothesis) (4,5) is the strongest genetic factor. This epitope includes amino acid residues 67, 70, 71, 74, which are similar in all RA-associated HLA-DR alleles and have crucial importance in determining the pocket structure as well as the T cell repertoire and its ability to recognize self peptides (4).…”