Antibody activity in ankylosing spondylitis sera to two sites on HLA B27.1 at the MHC groove region (within sequence 65-85), and to a Klebsiella pneumoniae nitrogenase reductase peptide (within sequence 181-199).

Abstract

74 overlapping peptides of varying lengths from Klebsiella pneumoniae nitrogenase reductase (residues 181-199) and from the HLA B27.1 molecule (residues 65-85) were synthesized and tested by ELISA against sera from HLA B27+ ankylosing spondylitis (AS) patients, and sera from HLA B27+ and HLA B27- healthy first-degree relatives. Antibody activity in AS sera to Klebsiella peptides of four to eight amino acids was maximal with the peptide NSRQTDR. Activity to HLA B27 peptides was maximal with the peptide KAKAQTDR (named epitope I). These peptides overlap with, but are proximal to the NH2 terminus from QTDRED, which is homologous in HLA B27.1 and K. pneumoniae nitrogenase reductase. A second weaker reactive site was noted in the HLA B27.1 peptides, proximal to the COOH terminus from the homologous sequence, namely peptide REDLRTLL (named epitope II). Little activity was seen against peptides that included the entire homologous sequence. Sera from 50 AS patients showed higher total Ig activity against peptides KAKAQTDR (p less than 0.001) and NSRQTDR (p less than 0.02) than did sera from 22 B27+ and 22 B27- healthy controls. These data indicate that AS patient sera contain antibodies that bind to K. pneumoniae nitrogenase peptides and HLA B27.1 peptides, and that there are at least two epitopes on HLA B27.1 in the alpha 1 domain, at the MHC groove region, that are autoantigenic in AS patients. Epitope I may be a site for crossreactivity between HLA B27 and Klebsiella.

HLA-B27 and Ankylosing Spondylitis

“…Further support of this hypothesis is the finding that HLA class II antigen associated with rheumatoid arthritis shared the same amino acid sequences with some viral antigens ( Albani & Carson, 1996 ). Data from serologic studies also indicated that patients with AS had high incidence of antibodies against microbial pathogens (Ewing et al, 1990). This study indicate that AS patient sera contain antibodies which were reactive to K. pneumoniae nitrogenase peptides and HLA B27.1 peptides, and that there are at least two epitopes in the alpha 1 domain at the groove region, that are autoantigenic.…”

How does HLA-B27 confer susceptibility to inflammatory arthritis?

“…The question is whether any of these undoubted examples of molecular mimicry actually give rise to anti-B27 immune responses and whether these are in any way pathological. Low titres of antibody to cross-reacting epitopes have been described in patients with ankylosing spondylitis and reactive arthritis (Schwimmbeck et al, 1987;Ewing et at., 1990) but their significance is unclear (Tsuchiya, Husby & Williams, 1989) and it is difficult to envisage these diseases as being antibody mediated. Since the examples of molecular mimicry have been identified using antibodies, they do not provide much information about the possibility of molecular mimicry occurring at the T cell level; T cells specific for a microbial antigen would have to crossrecognize B27 occupied by a self-peptide.…”

HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27?

“…Ewing et al 77 used a variety of synthetic peptides derived from HLA-B27 as substrates in ELISA systems. Analysing the specificity of a number of patient sera recognising peptides from B*2705, they found two different reactive sites in the B27 peptides.…”

“…A very elegant study was carried out by Ewing et al 77. Using overlapping peptides of eight residues from the B*2705 molecule, they showed that in fact the antibody response against the part of B*2705 containing the Klebsiella homologous sequence was not directed to the complete homologous 72-QTDRED-77 sequence, but rather to flanking regions that included only a few of the homologous residues—that is, 68-KAKAQTDR-75 and 76-REDLRTLL-83 of HLA-B27.…”