Epidemiology, Pathogenesis and Genetics with Special Reference to the Major Histocompatibility Complex and Complement De¢ciency

Systemic lupus erythematosus (SLE) is the prototype for systemic autoimmune diseases. Epidemiological and genetic data suggest that expression of this disease re£ects a complex interplaybetween numerous genetic and environmental factors. This thesis deals with the epidemiology and psychiatric manifestations, the role of complement de¢ciency, and the relative contribution of major histocompatibility alleles to the pathogenesis in SLE patients in Iceland. The epidemiological study is the only nationwide survey where strict criteria were applied for the classi¢cation of SLE. The value of the study lies in its unselected nature and the application of widely accepted criteria to de¢ne SLE. Over a 10 year period (1975^1984) seventy-six new cases were found with an incidence of 5.9 and 0.8/100000 for females and males. The mean age at diagnosis was higher than in many previous studies and a clinical pattern diierent from most previous studies was found, as illustrated by a low incidence of renal disease. These ¢ndings may re£ect the unselected nature of the study, racial diierences or milder SLE disease manifestations in recent years. Comparison with a former study on SLE in Iceland shows an actual increase in incidence. The study of the psychiatric manifestations has relatively little referral bias and is probably more representative than most previous studies. A high prevalence of phobias in the SLE patients as compared to a population control group was observed. The ¢rst documented report of the association of SLE and complete C1q de¢ciency is presented. This report was the impetus to further studies of the role of complement de¢ciency in the pathogenesis of SLE. The experience of plasma replacement therapy in a C2 de¢cient patient is reported. This novel therapy was strikingly successful. The ¢ndings further support a causal relationship between complement de¢ciency and immune complex disease and may lead to more targeted treatment interventions. The relative contribution of single MHC alleles to the pathogenesis of SLE was examined. MHC class II alleles and C4 allotypes were determined in 64 Icelandic patients and in an ethnically matched control group. The frequency of C4AQO was signi¢cantly higher in patients than in controls. HLA-DRB1, DQA1and DQB1alleles were not significantly diierent from those of controls. On the other hand, an increase in DRB1*O3 was observed in the group of patients with C4AQO. Following these results a large multicase SLE family was studied clinically and typed for MHC class II and C4 allotypes. C4AQO is highly associated with morbidity in this family. However, the C4AQO is carried on 5 diierent haplotypes of which 4 were found in the patients with SLE. Two of the C4AQO bearing haplotypes run through the family line; the other 3 originate from the spouses. Three of the 5 C4AQ0 bearing haplotypes shared the fragment B8, Cw7, C4AQO, C4B1. The results are consistent with the argument that C4A de¢ciency contributes independently to susceptibility of SLE. C4AQO in SLE patients in Iceland shows less marked linkage disequilibrium with other MHC alleles than reported in most other studies on Caucasian populations and emphasizes the role of ethnicity. In progress are studies of a number of Icelandic families with multiple SLE cases involving genotyping and allotyping of C4 and other candidate genes as well as a genomewide scanning for the determination of susceptibility loci.