Major histocompatibility complex class II genes in glomerular diseases

The identification of genes within the human major histocompatibility complex (MHC) class II region, which confer susceptibility of immune mediated nephritis can help to understand the immunopathogenesis and inheritance of these diseases. Classically, this is performed using serological typing. The use of DNA technology in genotyping is more specific and would reveal greater polymorphism within this region. The MHC class II studies of IgA nephropathy (IgAN) and Goodpasture's disease are illustrative. We have shown that by the polymerase chain reaction (PCR) using sequence specific oligonucleotide (SSO) probing techniques, there was an increase of human leucocyte antigen (HLA) DQ7 in Caucasian IgAN patients (71%) when compared with controls (27.8%). In a Chinese family of IgAN, all three siblings with IgAN were homozygous for DR12, DQ7, DQ alpha 1b. When we examined 79 Chinese IgAN patients, there was an increase in homozygous DQ7 in patients (16.4%) compared with controls (5.7%). There was also a significant increase in frequency of DQA2 U allele in patients with chronic renal failure (66.9%) compared with patients with normal renal function (26.9%). Goodpasture's disease (GPD) was initially reported to be associated with HLA-DR2. With molecular techniques, it was found that 75.5% of GPD had DR15 (a specificity of DR 2) when compared with controls (31%). The frequency of DR4 was also increased. Nucleotide sequences of these two alleles were identical to those previously published. Compared with derived amino acid sequences of expressed DR beta chains showed that the DR beta chains of DR15 and DR4 shared a six aminoacid motif from positions 26-31. An SSO detected this amino acid motif in 91.8% of GPD patients tested. Thus, this particular motif, which lies on the floor of the antigen binding groove, has a stronger association with GPD than an individual allele, and may be of pathogenetic significance. It is therefore concluded that the study of MHC class II genes is important in the elucidation of the pathogenetic mechanisms and possibly in the prediction of disease severity in glomerulonephritis.