HLA associations with inclusion body myositis

Abstract

SUMMARYInclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8"^ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class ITT region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class T, DR and complement loci along with the C4 and CYP21 RFLP. TenoftheDR3 * subjects had a 6 4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class 11 and HI regions, of the extended haplotype marked by B8/C4A*Q0/C4Bl/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11 % of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B]8/C4A3/C4BQ*0/BfFl/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: An analysis of disease-associated alleles and diplotypes

“…This association has been confirmed in a number of studies in different populations (Love et al, 1991;Garlepp et al, 1994;Koffman et al, 1998;Lampe et al, 2003;Badrising et al, 2004;Price et al, 2004;O'Hanlon et al, 2005;Needham et al, 2008). In addition, in a previous study of HLA serotypes we found that individuals with the HLA-DR3/DR1 combination have a higher disease risk as well as an earlier age-of-onset and more severe weakness (Mastaglia et al, 2009).…”

Frequency of autoantibodies and correlation with HLA-DRB1 genotype in sporadic inclusion body myositis (s-IBM): A population control study

“…Whether the frequency of organ-specific and non-organ-specific MAA and MSA is increased in a West Australian s-IBM patient cohort when compared with an ethnically matched population control group; 2. If there is any correlation between AAb and carriage of HLA-DRB1*0301 which encodes HLA-DR3 and is an important risk factor and genetic biomarker for s-IBM (Garlepp et al, 1994;Koffman et al, 1998;Lampe et al, 2003;Badrising et al, 2004;Mastaglia, 2009). As a number of previous studies have compared the relative frequencies of AAb in s-IBM and other inflammatory myopathies this was not addressed in the present study.…”

A three-way interplay of DR4, autoantibodies and synovitis in biopsy-proven idiopathic inflammatory myositis

“…In addition, the 8.1 ancestral haplotype (HLA A1, B8, DRB3*0101, DRB1*0301, DQB1*0201) predisposes to many autoimmune diseases and has been strongly linked with IBM [10][11][12], PM and DM [13].…”