extraspinal disease in HLA-B27 positive individuals with ankylosing spondylitis

Objective-To investigate the potential influence of the HLA-linked LMP2 gene on disease susceptibility in HLA-B27 individuals with ankylosing spondylitis (AS). Methods-A polymorphic CfoI restriction enzyme site in the coding region of the LMP2 gene was evaluated in genomic DNA samples from 193 white and 49 Chinese B27 individuals with well documented AS, 97 of whom had had acute anterior uveitis (AAU) and 97 peripheral arthritis; 42 samples from normal, white, B27 positive blood donors in whom AS was excluded were also evaluated. Results-Analysis of B27 white AS individuals with AAU, peripheral arthritis, or both, revealed significant differences in genotypic distribution of this bi-allelic locus compared with B27 AS patients without extraspinal manifestations (p< 0-005) or B27 controls (p < 0-01). Furthermore, homozygosity for one LMP2 gene allele was significantly more prevalent in AS patients with AAU (71.3%) (p < 0-01) or peripheral arthritis (68-3%) (p < 0.02) than in B27 controls (45-2%). A similar genotypic distribution was noted in B27 Chinese AS individuals with extraspinal manifestations compared with those with axial disease alone. Conclusions-These findings support the involvement ofthe HLA linked LMP2 gene in the expression of disease in B27 individuals and represent a novel finding in rheumatic disease. (Ann Rheum Dis 1995; 54: 321-324) Department of Medicine, University ofAlberta, Edmonton, Canada W P Maksymowych M Suarez-Almazor A S Russell China Medical College Hospital, Taichung, Taiwan C-T Chou Correspondence to: Dr Walter P Maksymowych, 562 Heritage Building, University of Alberta, Edmonton, AB, Canada, T6G 2S2. Accepted for publication 17 November 1994 The strong association between ankylosing spondylitis (AS) and HLA-B27 is now generally accepted, although it is also clear that only a minority of all B27 positive individuals (2%) develop the disease. The prevalence may be as high as 20% in B27 positive first degree relatives of probands with AS,' suggesting a significant role for additional genetic or other factors in the development of AS in B27 positive individuals. A number of genes mapping to the class II region of the human major histocompatibility complex (MHC) appear to be involved in antigen processsing for presentation via the HLA class I pathway.2 Two such genes, LMP2 and LMP7, encode proteins demonstrating homology to subunits of a large multicatalytic cytosolic proteinase complex, the proteasome.3 4 The proteasome is thought to be involved in the cellular degradation of proteins and generation of oligopeptides5 before transport into the lumen of the endoplasmic reticulum where binding of peptides to HLA class I molecules normally occurs. Indirect evidence suggests that the LMP2 and LMP7 genes modify the proteolytic action of the proteasome complex by influencing both the efficiency and spectrum of peptides generated which are suitable for binding to HLA class I