Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree.

OBJECTIVE: To evaluate an unusual pedigree with 8 members diagnosed with systemic lupus erythematosus (SLE) METHODS: Pedigree members were evaluated through questionnaires, interviews, and medical records. Sixty members contributed serum samples for autoantibody analysis. RESULTS: The 8 affected females shared several disease features, including arthritis (8/8), antinuclear antibodies (ANA) (8/8), pleuritis (6/8), malar rash (6/8), photosensitivity (5/8), and nephritis (4/8). A total of 15 of 51 (29%) blood relatives had autoantibodies; 9 had autoimmune disease, including 7 with SLE, one with psoriasis, and one with Sjögren's syndrome. Five of 11 (45%) nonconsanguineous spouses also had autoantibodies; one spouse had SLE, and 2 others had thyroid disease. Among 68 spouses of patients with SLE in other pedigrees, only 9 (13%) had autoantibodies, and none were symptomatic (p = 0.02). CONCLUSION: The high rate of autoimmunity among both blood relatives and nonconsanguineous mates in this unusual pedigree suggests a complex interaction of genetic and environmental factors contributing to disease.

Heredity and systemic lupus erythematosus: dissecting a complex genetic disease.

The etiology of SLE appears to be exceedingly complex and possibly heterogeneous, with genetics and environment both making substantial contributions. A schematic representation of potential mechanisms is depicted in Figure 2. We may not fully understand the pathogenesis of this disease until we unravel the relative contributions of each component to the development of SLE. While genetic mechanisms involved in SLE remain obscure, we now have available elegant laboratory techniques for analysis of genetic loci as well as computer technology which permits simulation and analysis of the transmission of complex genetic traits among multiple families and demographic groups. What remains is the painstaking task of collecting families multiplex for SLE and analyzing multiple sets of clinical, serologic, and genetic data within and between these pedigrees. Such studies are currently underway and will hopefully increase understanding of this enigmatic and complex autoimmune disorder.

Systemic lupus erythematosus: considerations for a genetic approach.

There is a powerful evidence suggesting that etiology and pathogenesis of systemic lupus erythematosus has both genetic and environmental components. Unfortunately, understanding the genetics of lupus has been impeded by knowing the pattern of inheritance. Indeed, a complex mode of inheritance for the lupus disease phenotype is suggested by the known characteristics of this disorder. Twenty-five multiplex pedigrees for lupus have been enrolled and have been used to evaluate power to reveal linkage. The power to find linkage in these pedigrees is greater for autosomal recessive than for autosomal dominant modes of inheritance. Once 100 similar pedigrees are available for analysis our results predict that linkage is likely to be present for genetic models with relatively relaxed requirements. At loci operating by autosomal recessive inheritance linkage should be detectable despite genetic homogeneity as low as 40% and penetrance as low as 50%. For loci operating by autosomal dominant inheritance genetic homogeneity must be 60% or more when penetrance is as low as 50% to be able to establish linkage. Available preliminary data are also consistent with a possible genetic linkage of Fc gamma RIIIPMN with lupus in American Black pedigrees multiplex for lupus.

Autosomal recessive polycystic kidney disease in a murine model. A gross and microscopic description.

The C57BL/6J-cpk genetic murine model of autosomal recessive polycystic kidney disease was examined to gain insight into the pathogenesis of renal cystic disease. Fetal through 3-week-old offspring of heterozygote matings were used to study growth parameters and morphology of this genetic form of cystic disease. The kidneys were examined by light and electron microscopy and nephron segments were microdissected. Two phases of cystic disease development were morphologically identified. The first phase in fetal and newborn affected pups was characterized by proximal tubule enlargement and a general increase in the tubular mitotic index. The proximal tubules showed cytologic abnormalities along with an increased necrotic cell index. The later phase, in one through 3-week-old cystic pups, was characterized by progressive enlargement of the kidneys due mainly to cystic change of the collecting ducts and by development of azotemia. Secondary to the azotemia was a stunted body growth. Significant tubular epithelial hyperplasia was not found by mitotic index during the second phase, but an increase in collecting duct cellularity was present. Histone H4 gene expression, which is tightly coupled to DNA synthesis and thus an index of cell proliferation, showed only a minimal increase in cystic kidneys at 1, 2, and 3 weeks of age. Therefore, the degree of cell proliferation necessary to allow the observed tubular enlargement appears to be minimal.