title: Specific overexpression of rheumatoid arthritis-associated HLA-DR alleles and presentation of low-affinity peptides.
abstract: OBJECTIVE
  To compare levels of HLA-DR expression in rheumatoid arthritis (RA) patients and healthy controls for whom an ordered expression according to the DR alleles is demonstrated and to test the functional consequences of this expression on peptide presentation.
  
  
  METHODS
  Using monoclonal antibodies that recognize different DRB1 alleles, DR molecules were quantitated at the surface of the peripheral blood B cells of 23 RA patients and 17 healthy subjects. The functional consequences of the level of DR surface expression was tested using a universal model of antigen presentation and mutated peptides with variable affinities for the T cell receptor.
  
  
  RESULTS
  In healthy subjects, surface HLA-DR molecules were expressed at different levels according to allele (DR53, DR4, and DR11 less than DR1 less than DR7 less than DR15). In RA patients, this hierarchy was not conserved and, furthermore, the density of RA-associated DR4 and DR1 molecules was enhanced in patients compared with the basal density in healthy individuals. We demonstrated that an increased expression of DR molecules at the surface of antigen-presenting cells allowed a noteworthy presentation of low-affinity peptides that under normal conditions are not efficient in generating a T cell response at physiologic surface density of the DR molecules.
  
  
  CONCLUSIONS
  Our results suggest that the specific overexpression of RA-associated HLA molecules could be responsible for the presentation of low-affinity autopeptides and therefore the activation of peripheral autoreactive T cells.
authors.affiliation: INSERM U475, Hĵpital Saint-Eloi, Centre Hospitalier Universitaire de Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Kerlan-Candon
authors.forename: P
authors.initials: P
authors.lastname: Louis-Plence
authors.forename: A
authors.initials: A
authors.lastname: Wiedemann
authors.forename: B
authors.initials: B
authors.lastname: Combe
authors.forename: J
authors.initials: J
authors.lastname: Clot
authors.forename: J F
authors.initials: JF
authors.lastname: Eliaou
authors.forename: V
authors.initials: V
authors.lastname: Pinet
mesh_terms: D000483:Alleles; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism*; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D006684:HLA-DR Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010446:Peptide Fragments; D013936:Thymidine