T-cell expansions with conserved T-cell receptor beta chain motifs in the peripheral blood of HLA-DRB1*0401 positive patients with necrotizing vasculitis.
T lymphocytes are implicated in the pathogenesis of systemic vasculitis such as Wegener's granulomatosis (WG) and polyarteritis nodosa (PAN). In the present study, we have characterized in detail the T-cell receptor (TCR) of peripheral blood T cells from eight vasculitis patients of known HLA class II genotypes. We used flow cytometry to outline the exact TCR V gene expression, complementarity determining region 3 (CDR3) fragment analysis to estimate the degree of clonality and cDNA sequencing to define the exact TCR or beta chain sequences. The TCR CDR3 region interacts with antigenic peptides presented by HLA molecules, and it is normally immensely diverse. It was therefore of particular interest to identify a common dominating TCR BV8-F/L-G-G-A/Q-G-J2S3 beta chain sequence in the CD4(+) T cells of four unrelated vasculitis patients. Furthermore, this BV8-associated CDR3 motif was linked to the HLA-DRB1*0401 allele, as well as to active disease and/or an established BV8(+) CD4(+) T-cell expansion. In contrast, age- and HLA-matched patients with rheumatoid arthritis did not harbor the described BV8 motif. These results strongly suggest that BV8(+) CD4(+) T cells with the described CDR3 motif recognize a specific antigen presented by DR4 molecules, indicating the existence of a common vasculitis-associated antigen.
Grunewald
J
J
Microbiology and Tumorbiology Center (MTC), Karolinska Institute, Stockholm, Sweden. Johan.Grunewald@mtc.ki.se
Halapi
E
E
Wahlström
J
J
Giscombe
R
R
Nityanand
S
S
Sanjeevi
C
C
Lefvert
A K
AK
D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D005838:Genotype; D014890:Granulomatosis with Polyangiitis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010488:Polyarteritis Nodosa / Q000097:blood / Q000235:genetics / Q000276:immunology*; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016415:Sequence Alignment
D001324:Autoantigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta