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

Abstract

Most autoimmune diseases are associated with certain HLA types. Therefore, spondyloarthropathies (SpA) strongly associated with HLA-B27, are also often classified as autoimmune diseases. This study questions whether SpA indeed fulfils the criteria of an autoimmune disease. The Medline database was searched for all reports between 1966 and April 1998 on the presence of autoimmune reactivity in SpA patients. This search yielded 45 articles on this subject. Only eight articles study T cell reactivity. Twelve reports were found on the assessment of antibodies crossreacting between bacteria and HLA-B27. In the 45 studies demonstrating autoimmune reactions in SpA patients proper controls matched for HLA-B27, sex and age were nearly always lacking. Therefore, it is concluded that the frequency of increased autoreactivity in sera from patients and controls is not significantly diVerent, and that this lack of autoreactivity does not justify classification of SpA as an autoimmune disease. As crossreactive antibodies against bacteria and HLA-B27 were equally present in sera from patients and controls, the pathogenetic significance of molecular mimicry between various bacteria and HLA-B27 is questionable. Furthermore, the regions of the B27 molecule that are supposed to be crossreactive with bacteria, diVer in one or more amino acids among the distinct B27 subtypes. Although these diVerences strongly influence the binding of antibodies to the B27 molecule, there was no relation between the degree of crossreactivity of certain subtypes and the association of these subtypes with SpA. In conclusion, there is no evident proof that SpA is an autoimmune disease attributable to crossreactivity between bacteria and HLA-B27. (Ann Rheum Dis 1999;58:598-610)

Comparison of amino acid compositions of peptides eluted from HLA-B27 molecules of healthy individuals and patients with ankylosing spondylitis

“…This theory is supported by B27 association with post-infectious arthritis due to gram-negative bacteria. Cross-reaction of anti-bacterial T-cell or antibodies with autologous antigens were suggested, but not proved conclusively [1,[12][13][14][15]. The arthritogenic peptides have so far not been identified; (b) alternatively, or in combination, some structural features of the HLA molecule itself, such as misfolding, homodimers, dual conformation mode of peptide binding, acceptance of longer peptides, strong binding with ␤2-microglobulin [6,[16][17][18][19][20][21], have been proposed to be responsible for the disease association.…”

“…The vast majority of B27 binding peptides are nonamers with two anchors: arginine (Arg) at position 2 (P2) for all subtypes and leucine (Leu), phenylalanine (Phe), tyrosine (Tyr), and lysine (Lys) (less stringent and dependent on subtype) at P9 [4,22]. Differences in HLA-B27 binding peptide profiles exist also between mouse and human cells [23] and between bacterial transfected and not transfected cell lines [12,15], however with a large degree of overlap. In the sequences listed on the B27 peptide register [22] about 95% of the peptides contain arginine at P2, but pool sequencing data show that this residue represents only 50-80% [8,9,24,25].…”

“…Previous studies involving B27 transgenic rodents [6,7], B27 subtypes [8,9] and HLA-class I molecules with B27-like peptide binding motif in gorillas with Spa [10] suggested that the HLA-B27 molecule itself determines the susceptibility to joint pathology. Two major hypotheses have been proposed: (a) the arthritogenic peptide theory [11] suggests that peptides bound by HLA-B27 mimic bacterial components and induce an autoimmune reaction [1,[11][12][13]. This theory is supported by B27 association with post-infectious arthritis due to gram-negative bacteria.…”

“…All healthy blood donors (HLT) and AS patients had susceptible B27 subtype, which eliminates any subtype dependent differences. PBL being relevant [1,12,14] though not an ideal cellular source of B27-peptides were used, because cells from joint lesions would not be accessible and/or would be of insufficient quantity. Blood samples (400 ml) were found insufficient for MS (mass spectrometry) sequencing of individual peptides, thus, SPED pool sequencing was employed.…”

Portrait of the artist as a sick man. Rheumatological pathography of James Joyce (1882-1941)

“…Gioverà inoltre ricordare che la sindrome di Reiter è stata proposta anche per altri illustri personaggi del passato, quali Cristoforo Colombo e Benvenuto Cellini, sebbene in entrambi i casi la diagnosi sia risultata controversa e l'artista rinascimentale abbia sofferto certamente di una malattia venerea trattata come sifilide (38)(39)(40)(41). Il meccanismo patogenetico che caratterizza sia l'artrite reattiva che la spondilite anchilosante risulta ancora controverso, sebbene la suscettibilità genetica sembri giocare un ruolo determinante (42,43). La presenza dell'antigene di istocompatibilità HLA-B27, riscontrabile nell'80% dei pazienti con artrite reattiva produrrebbe una risposta immunitaria esagerata a specifici agenti infettivi (33,37).…”