Class II major histocompatibility antigens and the etiology of systemic lupus erythematosus

It is hypothesized that the underlying immunoregulatory dysfunction in systemic lupus erythematosus (SLE) is altered recognition by T cells of self class II major histocompatibility antigens (Ia). The resultant cellular autoreactivity would directly cause certain of the immunopathological manifestations of SLE. The perception by T cells of self non-MHC antigens in the context of altered Ia on antigen presenting cells would also stimulate specific help for autoantibody production. Autoimmunity induced by the graft-versus-host reaction is an experimental model that illustrates this potential mechanism (A. G. Rolink, S. T. Pals, and E. Gleichmann, J. Exp. Med. 157, 755, 1983; R. A. Eisenberg, S. Y. Craven, and P. L. Cohen, Arth. Rheum. 26, S19, 1983).     

DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus

We investigated the Taq I digested DNA restriction fragment length polymorphism (RFLP) of the Major Histocompatibility Complex (MHC) class II genes: HLA-DRB, -DQA, and the class III genes: C4 and 21-hydroxylase(CYP21) in 56 caucasoid patients with systemic lupus erythematosus (SLE) and 62 control subjects in order to define the molecular variation of these genes and their association with SLE. The results showed that the gene frequencies of both HLA-DR2 and -DR3 were significantly increased in the SLE population compared to normal subjects (DR2: 21.4% vs 10.7% chi 2 = 4.5. DR3: 29.6% vs 13.3%; chi 2 = 8.3). A high frequency of C4A and CYP21A gene deletions was also found in SLE patients (SLE 52%, normals 24%). All of 22 SLE patients, and 12 of 15 normal subjects who had C4A and CYP21A gene deletions had a 10.0kb Taq 1 DRB RFLP attributable to the presence of HLA-DR3. Family studies showed linkage of C4A/CYP21A deletions with HLA-B8 and -DR3, and confirmed the previously demonstrated association of the HLA-B8, DR3, C4A*Q0, C4*B1, Bf*S, C2*C haplotype with SLE. Deletions affecting the C4A and CYP21A genes were the commonest cause of C4A null alleles in SLE. No strong association between C4 null phenotype or C4 gene deletion, as determined by RFLP, was observed in patients who possessed DR2.     

HLA class II haplotypes in Mexican systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is an autoimmune disease in which polymorphisms within the human leukocyte antigen (HLA) region have been associated to its etiology. For this study, HLA-DQB1, DQA1, and DRB1 genes were typed by polymerase chain reaction–sequence-specific primer in 237 individuals, taken from 74 families, who had a member with SLE, and who had their residence in the western region of Mexico; as well as in 159 ethnically matched healthy volunteers taken from 32 families. Genotype and allele frequency analysis was performed in 74 SLE patients and 54 unrelated controls. Precise three-loci identification of independent haplotypes was performed in 48 patients and 54 controls by familial segregation. Genotype distribution at each loci was concordant with Hardy-Weinberg’s equilibrium in the control group. In general, no genotype effect was observed in SLE patients. Allele distribution comparison showed in the SLE group a significant increase of HLA-DQA1*0102, DQB1*0402, and DRB1*15; whereas alleles HLA-DQB1*0303 and *0501 were significantly decreased. SLE patients showed haplotype DQB1*0602-DQA1-*0102-DRB1*15 increased. As expected, patients with SLE have a reduced haplotype genetic diversity. The associations found in this study are related to an ancestral haplotype that has been observed in SLE populations of different origins.     

HLA and systemic lupus erythematosus in Chinese

Seventy-five unrelated Chinese SLE patients were HLA typed and subdivided into mild and severe disease The HLA-B13 was associated with mild disease Fourteen of 30 (46.7%) mild disease patients had B13 compared to 63/330 (19.1%) normal subjects (p < 0 0005, corrected p < 0 013, RR = 3 7) The HLA-B17 on the other hand was observed in 29% of 45 severe disease patients compared to 13 9% of 330 normal subjects (p < 0 01, RR = 2.5). The frequency of HLA-B17 in 11 patients who died was even higher (45 5%).     

A rare HLA DQB allele sequenced from patients with systemic lupus erythematosus

Most autoimmune disorders are associated with particular alleles of the major histocompatibility complex (MHC) class II genes. However, only a minority of individuals with these alleles develop autoimmunity. The identification of alleles more closely associated with an autoimmune disorder such as lupus would facilitate screening and diagnosis and perhaps the understanding of mechanisms of disease. Analysis of sequence variation in the polymorphic first domain of the MHC genes HLA DQ beta and DQ alpha has revealed a novel DQ beta allele in two Caucasian lupus patients and no Caucasian controls. The novel DQ beta allele shares polymorphic amino acids at positions 26 to 30 and 57 with other lupus-associated DQ beta alleles. These hypervariable regions may play a role in lupus susceptibility and may provide insights into the molecular mechanism for this susceptibility.     

HLA and Gm genes in systemic lupus erythematosus

HLA and Gm phenotypes were compared in 53 patients with unequivocal systemic lupus erythematosus (SLE) and in 180 healthy subjects. SLE was associated with HLA-B8 (relative risk (RR) = 3.5, P less than 0.001) and with HLA-DR3 (RR = 2.8, P less than 0.01). There was an increased risk of SLE with HLA-B8/B27 (RR = 27.6) and with HLA-B15/B35 (RR greater than 13) and, in contrast, the risk was decreased in subjects with HLA-B40 (RR = 0.3). The risk of SLE in subjects who were heterozygous for the Gm phenotypes a,f,x; b,g was increased (RR = 2.0, P = 0.03) relative to the risk in subjects who were homozygous for these Gm phenotypes. These findings suggest that susceptibility to SLE is influenced by one or more genes in linkage disequilibrium with the HLA-B8-DR3 haplotype, by "augmentor" or "protector" genes associated with other HLA antigens and by separate genes, possibly VH genes, in linkage disequilibrium with the Gm (CH allotype) locus.     

Major histocompatibility complex class II and C4 alleles in Mexican Americans with systemic lupus erythematosus

Abstract: Few data exist on associations of class II and class III alleles of the major histocompatibility complex (MHC) and susceptibility to systemic lupus erythematosus (SLE) in Mexican Americans, a group of predominantly mixed Spanish and Native American ancestry. Therefore, MHC class II alleles (HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 alleles) and C4 allotypes were determined in 52 Mexican American SLE patients and 105 ethnic-matched controls. HLA-DRB1*0301 and C4A*Q0 were each increased in the SLE patients, especially HLA-DRB1*0301 in those with anti-Ro/SSA autoantibodies. C4A*Q0 was associated with HLA-DRB1*0301 only in a minority of patients and controls. Anti-U1-RNP antibodies were significantly associated with the presence of HLA-DQB1*0302, and the risk for the production of anti-Ro antibodies was heightened by the presence of at least three (out of four possible) DQA1 chains possessing a glutamine at position 34 and/or DQB1 chains a leucine at position 26 of their outermost domains. Thus the HLA class II and C4 null allele associations that have been noted in other ethnic groups are also found in Mexican Americans, suggesting shared susceptibility factors across ethnic lines in predisposition to SLE.     

Immunogenetics of systemic lupus erythematosus in Spanish patients: differential HLA markers

HLA-DR3 antigen included in the compound phenotype B18BfF1 (but not the one linked to the B8BfS compound phenotype) was found to be significantly increased in our SLE patients. It is remarkable that in our Southern-Mediterranean population, B18BfF1DR3 individuals (but not B8BfSDR3) are prone to SLE with renal disease, in contrast with other Northern European and Caucasoid populations. Also, patients with autoantibodies to Ro/La have a significant increase of the B8DR3 compound phenotype. Production of autoantibodies against Ro alone was associated to DR2 and production of anti-Sm/nRNP to DR3 (either B18BfF1 or B8BfS associated) only in the subgroup without renal disease. The distinctive HLA and autoimmune associations to SLE with and without renal disease suggests that both clinical forms may not share a common identical pathogenesis.     

HLA—DR,DQ基因多态性与系统性红斑狼疮相关性的研究

应用聚合酶链反应结合顺序特异的寡核苷酸探针杂交（ＰＣＲ／ＳＳＯＰＨ）方法对江苏籍汉族ＳＬＥ患者和健康对照组ＨＬＡ－ＤＲＢ１、ＤＱＡ１：ＤＱＢ１基因作寡核苷酸分型。结果发现患者组中ＤＲＢ１＊１５０１、ＤＱＡ１＊０１０２等位基因频率及ＨＬＡ－ＤＲＢ１＊１５０１、－ＤＱＡ１＊０１０２、－ＤＱＢ１＊０６０２单倍型频率均明显高于正常对照组；相反，ＤＲＢ１＊０４（ＤＲ４）、ＤＱＡ１＊０６０１频率则明显低于正常对照组。所有ＤＱＢ１等位基因频率在两组间无显著差异，而ＤＱＡ１＊０１０２仅存在于ＤＲ２阳性的个体之中，推测汉族ＳＬＥ的易感基因可能靠近ＤＲ位点，且与单倍型ＨＬＡ－ＤＲＢ１＊１５０１、－ＤＱＡ１＊０１０２、－ＤＱＢ１＊０６０２紧密连锁，该单倍型可作为汉族ＳＬＥ易感的遗传标记。相反ＤＲ４，ＤＱＡ１＊０６０１则对ＳＬＥ发病可能有一定的保护性。     

Tuberculosis in patients with systemic lupus erythematosus

In a retrospective analysis of 146 systemic lupus erythematosus (SLE) patients seen over a 5 year period, 17 patients of tuberculosis (TB) were identified yielding a prevalence rate of 11.6%. The median duration of SLE was 12 months (range 2-96 months) and 12/17 patients had disease activity score of more than five. The median duration of steroid treatment was 12 months (range 0-96 months) and the median cummulative dose of steroid was 7.75 gms (range 0-22.1 gms). Pulmonary TB (miliary-5, nonmiliary infiltrates-7 and pleural effusion-2) was the commonest type and there was an average diagnostic delay of approximately 1 month. While, majority of the patients responded adequately to treatment, 1 patient had a relapse and 1 expired due to a combination of active lupus and disseminated TB. Only 1 patient had received prophylactic isoniazid.     

Expression of the major rheumatoid factor cross-reactive idiotype in pediatric patients with systemic lupus erythematosus

Rheumatoid factor cross-reactive idiotype (RF-CRI) is expressed in high concentrations in the sera of some patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). To determine if RF-CRI is specifically expressed in rheumatic disease or if it is secondary to polyclonal B-cell activation, we examined sera of 23 children with SLE, 16 adolescents with infectious mononucleosis (IM), and age-matched pediatric controls for RF-CRI expression. Concentrations of RF-CRI in serum, determined by an inhibition ELISA, were 24 +/- 17 micrograms/ml (mean +/- SD) in 25 normal children, 31 +/- 17 in 16 young adults with IM, and were significantly increased, 70 +/- 80 micrograms/ml, in the 23 children with SLE (p less than 0.036). Eleven of 23 SLE patients had serum RF-CRI greater than the mean +/- 2 SD for normal children. Ten of 23 SLE sera contained IgM rheumatoid factor (RF) activity. One patient with IM had a borderline elevated RF-CRI level, and 5 IM patients had RF in their sera. The serum IgM concentrations in sera were: SLE (192 +/- 93 mg/dl) and IM (234 +/- 77 mg/dl) sera. These levels were significantly elevated compared to controls (132 +/- 44 mg/dl), p less than 0.031 for SLE and p less than 0.001 for IM, suggesting that polyclonal activation of B cells was present in SLE and IM patient groups. Increased expression of RF-CRI in the SLE patients correlated directly with high titer anti-DNA antibody values (r = 0.3965, p less than 0.05) and RF activity when human IgG (r = 0.5026, p less than 0.05) was used as the RF binding substrate and inversely with serum C3 levels (r = 0.3925, p less than 0.05). RF-CRI expression did not correlate with RF that bound rabbit (r = 0.3123, p greater than 0.05). Increased serum RF-CRI expression is not a result of polyclonal B-cell activation. RF-CRI may be selectively up-regulated in patients with SLE.     

Clinical significance of circulating immune complex assay in patients with systemic lupus erythematosus

Circulating immune complexes (IC) were assayed in 65 patients with systemic lupus erythematosus (SLE), 34 patients with rheumatoid arthritis (RA), 40 patients with progressive systemic sclerosis (PSS), 35 patients with chronic glomerulonephritis (GN) and 30 healthy controls. Immunoglobulin components of PEG-precipitated IC from 10 patients with SLE were also determined. Cryoglobulins isolated from 11 patients with SLE were assayed for their IC-like activity. The effect of corticosteroid treatment on IC levels were also studied in SLE patients with nephritis. IC levels significantly increased in all groups but those of SLE patients were the highest values. The SLE patients with nephritis had higher levels than those without renal involvement. IgG- d IgM- but no IgA-components were found in 100% and, 90%, respectively, of IC preparations. IC-like activity of cryoglobulins were found to correlate with disease severity and appeared to be characteristic of clinical manifestations. Corticosteroid therapy significantly decreased IC levels, however, related to the entire patient group, the mean of IC level was still higher than that of healthy controls. The degree of IC level decrease (as percentage), but not absolute values, appeared to be significant in assessing disease activity. The clinical significance of IC determination and IC activity of cryoglobulins are discussed.     

Lymphocytotoxic antibodies in patients with systemic lupus erythematosus

Lymphocytotoxic activity could be demonstrated in the sera of patients with systemic lupus erythematosus. The number of positive reactions varied with temperature of incubation. Lymphocytotoxicity was present in 88%, 49% and 11% of sera tested at 15°C, 22°C and 37°C respectively. At an incubation temperature of 22°C, the presence of the lymphocytotoxic antibody in the sera could be correlated with significantly higher titres of anti-nuclear factor, anti-single-stranded DNA and the histological appearance of active diffuse glomerulonephritis in renal biopsies.     

Lymphocyte subpopulations in patients with systemic lupus erythematosus

A discrepancy between E-rosette-forming cells and total T cells identified by monoclonal antibodies (Leu-1+) was observed in patients with systemic lupus erythematosus (SLE). E-Rosette-forming cell percentages of peripheral blood mononuclear cells (MNC) were significantly lower than those observed in normal individuals, in contrast to the percentage of Leu-1+ cells in SLE patients which were not different from those of normal values. The cells which did not form E rosettes, but stained positively with the monoclonal anti-Leu-1 antibody (E-, Leu-1+) had certain functional capability evidenced by their ability to amount a proliferative response to T-cell mitogens, phytohemagglutinin and concanavalin A, but failed to provide T-helper-cell activity to support the differentiation of normal B lymphocytes into immunoglobulin-secreting cells following stimulation with pokeweed mitogen. Inhibition of E-rosette formation, but not of the staining for Leu-1, was demonstrated by incubating sera from SLE patients with normal MNC. These studies suggest that the T-cell markers, E+ and Leu-1+, do not necessarily characterize identical subpopulations of T cells. When referring to E- cells in studies with MNC from SLE patients, it should be realized that this population includes, in addition to B cells and macrophages, cells staining positively for Leu-1 antigen and reactive to T-cell mitogens.     

Radioimmunoassay of the attack complex of complement in serum from patients with systemic lupus erythematosus

We developed a radioimmunoassay to measure the attack complex of complement (SC5b-9) in serum from patients with systemic lupus erythematosus. The radioimmunoassay used a monoclonal antibody to an antigen of C9, which is absent from native C9 but present on SC5b-9. SC5b-9 was detectable in 13 of 63 normal subjects, with a mean value of 0.5 unit (range, 0 to 4.8), and elevated in 13 of 14 patients with active lupus. Analysis of 108 samples from the patients with lupus revealed a mean value of 10.1 units (range, 0 to 35) when the disease was active and 1.0 unit (range, 0 to 433) when it was clinically stable. SC5b-9 was a more sensitive measure of disease activity than C3, C4, or CH50; its specificity was equivalent to that of C3 and C4. SC5b-9 was elevated in serum from 6 of 49 patients with other forms of glomerulonephritis. Our study documents the presence of SC5b-9 in abnormal serum and correlates its elevation with clinical disease activity in patients with active systemic lupus erythematosus.