Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Abstract

Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)-encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQwl, and especially the rare allele DQPl.AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQP1.1, the DQPl.AZH, or the DQP1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that involves the skin, joints, serosal surface, kidneys, central nervous system, and blood elements. It is characterized by abnormalities in B cell activation, with resultant autoantibody production, and by dysregulation of T cells, the complement cascade, and the clearing of immune complexes. Genetic factors in SLE have been implicated by results of studies of family aggregation of the disease ( l ) , increased concordance of SLE among monozygotic versus dizygotic twins (2), Gm markers (3), decreased red cell CRl receptors (4), abnormal T cell suppressor function in healthy relatives of SLE patients (3, and associations with several major histocompatibility complex (MHC) loci (summarized in refs. 6 and 7).Population studies have shown an increased association between SLE and class I1 MHC DR2 and/or DR3 antigen alleles, as well as an association with class 111 MHC C2 and C4A deficiencies (8,9). The strengths of these associations vary from study to study, and they can vary in ethnically different populations (7-10). The relative risk (RR) of SLE in a person positive for any 1 of these markers has been reported to be 3 or less. However, the RR is significantly increased if multiple alleles are present, such as homozygosity of C4A null (RR = 16) or C4A null and DR2 (RR = 25) (9), which supports the notion that susceptibility to this disease may be polygenic. The class 11 loci of the human major histocompatibility complex encode the HLA-D cell-surface

Response to steroids in de novo autoimmune hepatitis after liver transplantation

“…These antigens are tightly linked constituting a class II haplotype that has been associated with 2 recognized AD, namely systemic lupus erythematosus and multiple sclerosis. 48,49 The importance of this genetic background may partly explain the recurrent disease in one of our patients, who was DR3/DR15-, DR51/DR52-, and DQ2/DQ6-positive. Finally, the term of de novo AIH may also be controversial as it is possible that the immune response is initiated against nonnative proteins of the grafted liver.…”

“…We studied HLA class I and II polymorphism by standard complement-dependent microcytotoxicity assays and/or by PCR with sequence-specific primers for the following antigens/alleles: A (1,2,3,11,23,24,25,26,29,30,31,32,33,34,66,68,69,80), B (7,8,13,18,27,35,37,38,39,41,42,44,45,47,48,49,50,51,52,53,55,56,57,58,60,61,62,63,64,65,67,70,73), Cw (1,2,3,4,…”

Clinical correlations with HLA type in Japanese patients with connective tissue disease and anti–U1 small nuclear RNP antibodies

“…Recent analyses by a British group have also shown that the development of rheumatoid arthritis in MCTD patients is associated with DR4 or DRI excluding DRBl"C1103 (11). An association between DQBlh0502 and lupus nephritis was reported in Caucasian patients with SLE (12). In North American patients with SLE, methionine at position 14 and leucine at position 26 in the DQBl pl domain, which are common among DQBl'"O602, DQBI'''0201, and DQB1":0302, were speculated to be important for anti-&DNA antibody production (3).…”

Clinical, serologic, and immunogenetic studies in childhood‐onset systemic lupus erythematosus

“…The study population consisted of 80 children with SLE who had onset of disease at age <18, who were being followed up by the rheumatology services at Texas Children's Hospital (Houston) and The Hospital for Sick Children (Toronto), or by the Division of Clinical Immunology and Rheumatology or the Division of Pediatric Nephrology at the University of Alabama at Birmingham. There were 38 Caucasian children (7 boys, 31 girls), 29 black children (4 boys, 25 girls), and 13 Asian children (1 boy, 12 girls). The 80 children with childhood-onset SLE were divided into 2 groups according to age at disease onset.…”