Untitled

Abstract

Most patients with rheumatoid arthritis (RA) express HLA-DR4, HLA-DR1 or HLA-DR10. These alleles share a common amino acid motif in their third hypervariable regions: the shared epitope. In normals and patients with RA, HLA-DR genes exert a major influence on the CD4 αβ T-cell repertoire, as shown by studies of AV and BV gene usage and BV BJ gene usage by peripheral blood CD4 αβ T cells. However, the rheumatoid T-cell repertoire is not entirely under HLA-DR influence, as demonstrated by discrepancies in VB JB gene usage between identical twins discordant for RA and by contraction of the CD4 αβ T-cell repertoire in RA patients. Shared epitope positive HLA-DR alleles may shape the T-cell repertoire by presenting self peptides to CD4 T cells in the thymus. Peptides processed from HLA-DR molecules and encompassing the shared epitope may also be presented by HLA-DQ and select CD4 αβ T cells in the thymus. Thus, shared epitope-positive alleles impose a frame on the T-cell repertoire. This predisposing frame is further modified (by unknown factors) to obtain the contracted rheumatoid repertoire.

Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations

“…The MHC region harbors the highest density of genes in the genome, yet most, if not all, of the genetic associations point to the class II classic genes in humans (Feder et al, 1996; Lie et al, 1999a and b; Undlien et al, 1999; Fugger and Svejgaard, 2000; Roudier, 2000; Weyand and Goronzy, 2000; Ota et al, 2001; Undlien et al, 2001; Turner and Colbert, 2002; Raymond et al, 2005; Thorsby and Lie, 2005; Vandiedonck et al, 2005; Ettinger et al, 2006; Gorodezky et al, 2006; Falorni et al, 2008; Eike et al, 2009) and dogs (Ollier et al, 2001; Kennedy et al, 2006a, b and c, 2007c, 2008; Catchpole et al, 2008; Wilbe et al, 2009, 2010). In humans, an obstacle to localizing disease-predisposing genetic variants within the HLA is the strong LD typical of this region (Malfroy et al, 1997), presumably due to selection (Raymond et al, 2005).…”

Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis

“…The mechanism underlying SE-positive RA remains unclear [ 45 , 46 , 47 , 48 , 49 ]. It has been hypothesized that SE-positive DRB1 alleles confer disease susceptibility through a mechanism that involves alteration of the peripheral T-cell repertoire or through the selective presentation of arthritogenic self or foreign peptides [ 45 , 46 , 47 , 48 , 49 ]. In addition, it has been described that the DRB1*04:01 protein interacts with citrullinated peptides with higher affinity than with non-citrullinated peptides, which may indicate that the SE alleles exert pathogenic effects through the presentation of citrullinated peptides, which are recognized as non-self by T-cells [ 50 ].…”

Genetic variation in MHC proteins is associated with T cell receptor expression biases

“…The TCR repertoire is reshaped in response to infection 8 , 12 and varies between individuals 13 . However, little is known about the extent to which the usage of different V-genes in the TCR repertoire is shaped by host genetics, apart from limited observations of increased repertoire similarity among close relatives 14 , 15 , and a report that usage of Vα genes in response to an EBV epitope depends on HLA-B genotype 16 .…”