Autoimmune Disease
A number sign (#) is used with this entry because it relates to a category of disorders.
In many of the disorders in which autoimmunity has been incriminated, or at least accused, as a leading etiologic factor, familial aggregation is observed. For example, see thyroid autoantibodies (140300), alopecia areata (104000), pernicious anemia (170900), hypoadrenocorticism with hypoparathyroidism and superficial moniliasis (240300), Schmidt syndrome (269200), systemic lupus erythematosus (152700), Sjogren syndrome (270150), and anemia, autoimmune hemolytic (205700). The genetic significance of this is unclear. It is possible that if maternal antithyroid antibodies are responsible for athyreotic cretinism, then multiple sibs might be affected by this congenital anomaly without any genetic basis. Reports on the aggregation of possible autoimmune disorders include the following: Greenberg (1964) described 2 sisters with myasthenia gravis and thyrotoxicosis and a third sister with Hashimoto struma. Pirofsky (1968) found that 20% of 44 patients with idiopathic autoimmune hemolytic anemia had close relatives with clinically detectable autoimmune disease. Karpatkin et al. (1981) described a family in which the mother and 3 of her 4 children (a son and 2 daughters) had autoimmune thrombocytopenia purpura with bound platelet antibody. The 4 affected persons shared an HLA haplotype: A1, C-, B8, DR3 and Dw3. Lippman et al. (1982) found a high frequency of autoimmune manifestations, both clinical and laboratory, in relatives of a proband with autoimmune hemolytic anemia, 1 with immune thrombocytopenic purpura and 8 with systemic lupus erythematosus (SLE; 152700). Segregation analysis was most compatible with an autosomal dominant pattern. The odds against linkage to HLA were 100:1.
Bias et al. (1983) suggested that autoimmunity is an autosomal dominant trait. They studied 2 large kindreds in which serologic abnormalities as well as overt autoimmune disease were used in the definition of the autoimmune phenotype. Linkage studies in a second series of 23 families excluded linkage with HLA, Gm, and Km. The only positive score was with MNS (0.78 at theta = 0.30). Cales et al. (1983) studied the family of 2 brothers with primary biliary cirrhosis. Granulomatous hepatitis associated with autoimmune thyroiditis was found in a sister. Immunologic abnormalities were found in 6 members of the family: antinuclear antimitochondrial and antithyroid autoantibodies and rheumatoid factor. In a study of 6 families of probands with primary Sjogren syndrome (270150), Reveille et al. (1984) found various other autoimmune diseases and autoantibodies. Maclaren and Riley (1986) found that autoimmune Addison disease was strongly associated with HLA-DR3 and DR4; relative risks were 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/DR4, respectively. This is similar to the findings for insulin-dependent diabetes. Patients with type I autoimmune polyglandular syndrome did not show the association. Bias et al. (1986) suggested that although autoimmune diseases show a distribution in families consistent with multifactorial etiology, the autoimmune trait is defined by the presence of autoimmune disease and/or high titer autoantibody as a familial occurrence consistent with autosomal dominant inheritance. They analyzed 18 autoimmune kindreds, concluding that the population frequency of the postulated autoimmune gene is approximately 0.10 with penetrance estimates of 92% in females and 49% in males. They proposed the existence of a primary autoimmune disease gene that is epistatic to other secondary genes that influence the autoimmune phenotype, including those of the major histocompatibility complex (MHC). The secondary genes, according to their hypothesis, confer specificity to the phenotype. (See comments of Grundbacher (1988) and of Bias (1988).)
Adams and Knight (1980) suggested that autoimmunity results from somatic mutations permitting the emergence of 'forbidden clones' of immunocytes. Reveille et al. (1989) described a father and son with polyarteritis nodosa (PAN) following hepatitis B infection. Further study of the family showed that the spouse of the father had long-standing SLE, a 38-year-old maternal uncle had had seropositive nodular rheumatoid arthritis since age 10, a 30-year-old maternal aunt had had seropositive rheumatoid arthritis since age 13, and a 68-year-old maternal aunt had rheumatoid factor-negative rheumatoid-like polyarthritis associated with xerophthalmia. The 75-year-old paternal grandmother had had idiopathic thrombocytopenic purpura, and a 69-year-old paternal great aunt had a 10-year history of seropositive nodular rheumatoid arthritis. Transmission of hepatitis in this family was thought to be due to the sharing of a razor. No correlation with a specific HLA haplotype could be demonstrated.
Epplen (1992) discussed autoimmunity from the perspective of evolution. The immune system furnished the organism with the utmost effective defense mechanisms against 'foreign' or 'nonself' as well as against changes in 'self' without doing self-harm. Optimized efficacy in the defense against the immense variety of foreign antigens generates a higher risk for inadvertent self challenge--what in the military would be referred to as the consequences of 'friendly fire.'
Mason et al. (1994) described polyarteritis nodosa in an Asian boy who presented at 13 years of age with livedo reticularis, Raynaud phenomenon, arthralgia, and hypertension. At the age of 17, he was shown by arteriography to have multiple small aneurysms of the renal, hepatic, and celiac axis vessels, consistent with a diagnosis of polyarteritis nodosa. He was treated successfully with prednisolone and immunosuppressive agents but pursued a relapsing, intermittent course, the relapses being associated with recurrence of a positive perinuclear antinucleophil cytoplasmic antibody test. His sister was admitted to the hospital at age 17 with fever and epigastric pain and showed palpable nodules over both temporal arteries, marked livedo reticularis, and hypertension. The parents were first cousins. A sib had died at the age of 9 within 24 hours of collapsing suddenly. Autopsy demonstrated a ruptured superficial vessel in the posterior part of the left frontal lobe. The father, having recently been diagnosed as hypertensive, collapsed and died suddenly at the age of 44 years while traveling abroad. Despite their consanguinity, the parents shared no HLA haplotypes. The 2 sibs with proven PAN shared 1 HLA haplotype derived from the mother.
Becker et al. (1998) compared linkage results from 23 published genomewide scans in autoimmune or immune-mediated diseases. Human diseases included multiple sclerosis, Crohn disease, familial psoriasis, asthma, and type I diabetes (IDDM). Experimental animal disease studies included mouse experimental autoimmune encephalomyelitis, rat inflammatory arthritis, rat and mouse IDDM, histamine sensitization, immunity to exogenous antigens, and mouse lupus. A majority (approximately 65%) of the human positive linkages mapped nonrandomly into 18 distinct clusters. Overlapping of susceptibility loci occurred between different human immune diseases and by comparing conserved regions with experimental autoimmune/immune disease models. This nonrandom clustering supported a hypothesis that, in some cases, clinically distinct autoimmune diseases may be controlled by a common set of susceptibility genes. The clusters occurred on 18 of the 22 autosomes and on the X chromosome.
Pando et al. (1999) studied class II major histocompatibility complex types in children and adults with type I autoimmune hepatitis in Argentina. They found that different HLA-DRB1 (142857) allotypes confer susceptibility to autoimmune hepatitis in children and adults, raising the possibility that the pediatric and adult forms of the disorder may be triggered by different factors.
For information on an autoimmune disease susceptibility locus on chromosome 1p31, see AIS1 (607836).