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.     

Gm ALLOTYPES IN SWEDISH MYASTHENIA GRAVIS PATIENTS

Gm phenotype frequencies were examined in 112 Swedish myasthenia gravis patients. The G1m 1,2,3 phenotype frequency in the total patient material did not differ significantly from that found in the normal population. However, when patients were subdivided, three different patient groups were observed with regard to Gml frequency: (1) Thymoma patients having a low frequenc of Gm1, (2) Non-thymoma patients with a mild disease having a low frequency of Gm1 and (3) Non-thymoma patients with a severe disease having a high frequency of Gm1. When patients were subdivided according to presence or absence of HLA-B8 and Gm1 respectively, severe symptoms were less frequent in the HLA-B8+, Gm(-1) group as compared to the HLA-B8+, Gm(+1) group. Furthermore, there was an increased frequency of sera with anti-immunoglobulins not inhibitable by pooled control immunoglobulins.     

Gm allotypes in multiple sclerosis: influence susceptibility in HLA-DQwl-positive patients from the North-East of Scotland

From the Grampian region of Scotland, 198 patients with MS and 128 normal individuals were typed for allotypes of the Gm system which encode for the constant region of IgG heavy chains. No significant independent association between a given Gm allotype or phenotype and susceptibility to MS was observed for the group of patients from this region. This was also the case when patients were classified according to sex, clinical course, and disease progression. However, a significant association was found between the Gm phenotype, Gm (3;5, 10, 11, 13, 14), and HLA DQwl in patients with MS. The relative risk of developing MS for individuals who carried both Gm (3;5,10, 11,13,14) and HLA DQwl was nearly five times greater than for individuals with neither determinant. These findings suggest that in the presence of HLA DQwl, genes associated with the Gm (3;5,10,11,13,14) phenotype have an important contributory influence on susceptibility to MS. The additive effects of Gm and HLA on susceptibility to MS would be one possible reason for the lack of a complete association between MS and a single genetic locus.     

Gm allotypes in IgA deficiency

Gm phenotypes were examined in 90 Swedish IgA-deficient (less than 0.05 g/litre of serum IgA) donors and 40 normal first and second degree relatives of six of these donors. The G1m1,2, G3m5 and Km1 frequency in the group of IgA-deficient donors did not differ from that found in the normal population. Among the relatives, HLA and/or Gm identical normal sibs were observed. Anti-IgA antibodies were present in 29 of the IgA-deficient donors and anti-IgG in seven. No association between the two was found. A statistically significant association between the G1m-2 phenotype and the presence of anti-IgA antibodies was observed. When subdivided according to HLA type, a non-random distribution of Gm phenotypes was seen in HLA-B8/DR3 positive individuals with anti-IgA antibodies (HLA-B8/DR3 being the haplotype associated with IgA deficiency). These data suggest an association between IgA deficiency, anti-IgA and the studied Gm allotypes.     

Immunoglobulin genes, HLA-B8/DR3, and immune responsiveness to primary immunogen and mitogens in normal subjects

The genetic regulation of immune responsiveness by genes from two independent, highly polymorphic genetic systems, namely immunoglobulin allotypes and human leukocyte antigens (HLA), was studied in 35 healthy Caucasian volunteers. The in vivo IgG class antibody response to the primary test immunogen alpha-helix pomatia hemocyanin (HPH) was increased in subjects with the Gm1,17;..;21 haplotype compared to that of the non-Gm1,17;..;21 group. The IgM-class response tended to be higher in the former group. Levels of in vivo IgA-class-specific anti-HPH antibodies tended to be higher in the group of individuals positive for HLA-B8/DR3 than in the non-B8/DR3 group. This difference was statistically significant only in the absence of the Gm1,17;..;21 haplotype. The in vitro lymphocyte proliferative response on mitogenic stimulation with phytohemagglutinin (1 micrograms/ml) and pokeweed mitogen (10 micrograms/ml) also appeared to be associated with both systems. The presence of the Gm1,17;..;21 haplotype was associated with decreased lymphocyte reactivity, whereas the B8/DR3 phenotype was associated with high responsiveness to these mitogens. However, in the presence of the Gm1,17;..;21 haplotype subjects positive for HLA-B8/DR3 did not respond better to mitogenic stimulation than those lacking this HLA haplotype. Our results imply that the immunogenetic make-up of test persons should be taken into account in the assessment of the immune status of individuals or groups of patients.     

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 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%).     

Microcomputer-generated antigen panel worksheets

Early reports of anti-Rodgers (anti-Rg) noted that there was an increased number of the HLA-B8 phenotype among this group. This HLA type has recently been Linked to a C4A (Rg) gene deletion found with increased frequency among systemic lupus erythematosus (SLE) patients. Healthy controls (n= 176) and SLE patients (n=102) were studied for their HLA haplotype and C4 allotype as well as their Rg phenotype Six of 53 white and 3 of 49 black SLE patients were C4A-null and Rodgers-negative, a significant difference from controls p=.002). A retrospective study of patients who produced ant-Rg showed that one third had symptoms often associated with SLE but none had SLE as a primary diagnosis.     

Interaction between HLA antigens and immunoglobulin (Gm) allotypes in susceptibility to type I diabetes

HLA-A,B,C and DR typing was performed on 108 Caucasian type I diabetic patients, 68 being Gm typed. The expected association with B8, B18, Bw62, DR3 and DR4 was observed as well as an excess of DR3/4 heterozygotes. DR2 was decreased in frequency. In the total patient group, no Gm association was observed but when the patients were subgrouped according to HLA type, HLA/Gm interactive effects were seen. An increase in Gm(1,3;5) was observed in DR3 positive, DR4 negative patients. This association occurred predominantly in females (compared with DR4 and DR3/4 patients of the same Gm phenotype who were predominantly male). Further genetic heterogeneity was identified within DR3/4 patients. Within this group, Bw62 was increased (strongly suggestive of Bw62-DR4 haplotypes) within B8, Gm heterozygotes compared with B8, Gm homozygotes. This finding can be interpreted as indicating a three-way interaction between genes on two HLA haplotypes and Gm-linked genes. These results reflect the genetic heterogeneity and complexity of insulin-dependent diabetes mellitus and explain in part the previous failure of simple genetic models to adequately explain inheritance patterns observed.     

Antiacetylcholine receptor and antinuclear antibodies in myasthenia gravis. Correlation with HLA, sex and Gm

Sera from 27 subjects with myasthenia gravis (MG) were examined by immunoassay for antibodies to double-stranded DNA (ds-DNA), RNA-nucleoprotein complexes (ENA) and acetylcholine receptor (ACHR). The prevalence of the genetic markers of sex, HLA and Gm were analyzed in relation to various parameters of these autoantibodies. The highest levels of ds-DNA antibodies were associated with HLA B8 as compared to other HLA antigens (p less than 0.05), females as compared with males (p less than 0.05), and females with HLA B8 (p less than 0.05) when both sex and HLA were analyzed concurrently. An association between low titers and HLA B7 (p less than 0.05), with a significant difference between the B8 females and B7 males (p less than 0.05) was also noted. By contrast, no Gm association was noted for antinuclear antibody parameters, but was observed in females between high ACHR antibody titers and the homozygous phenotype (3; 5, 13) (p less than 0.05). This study of MG implicated HLA and sex factors in the production of a broad spectrum of antinuclear antibodies, while the contrasting Gm association noted with ACHR antibody titers was indicative of distinctive immunogenetic influences over autoantibody production in MG.     

Influence of genetic factors on the susceptibility to HBV infection, its clinical pictures, and responsiveness to HBV vaccination

The association of genetic factors with hepatitis B virus (HBV) infection susceptibility, its different manifestations, and the different responses to hepatitis B antigen vaccination have been described by several authors. With regard to HLA class I molecules, association with HLA-B was especially observed.HLA-B35 and -B8 correlated with chronic active hepatitis (CAH)and with hepatitis B carriers. Correlation between HBV infection and HLA class II (loci DR and DQ)was also indicated, but results are not clear regarding the clinical pictures of the disease nor vaccination response. HLA class III (fourth complement component--C4,third complement component--C3, and properdin factor--BF) are associated with various manifestations of this disease. The gammaglobulin phenotype Gm (1,2,3,10,21)was more frequent in CAH. However, in only three publications was the impact of HLA on the efficacy of interferon therapy taken into account.     

Interaction of HLA and Gm in autoimmune chronic active hepatitis.

An immunogenetic study of autoimmune chronic active hepatitis (CAH) showed the relative risk (RR) for this disease was 11.6 for patients who were HLA-B8, 11.7 for patients who were DR3 and 2.3 for patients who were Gma+x+. Moreover, the Gm haplotype Gma+x+ was present in 18 of 40 (45%) patients with HLA-B8, but in none of 10 patients negative for HLA-B8, whereas in 180 healthy controls Gma+x+ was evenly distributed among those positive (24%) and negative (18%) for HLA-B8. The RR was lowest in patients lacking HLA-B8 but positive for Gma+x+. Relative to this low-risk group, the risk was increased 39 times in subjects with both HLA-B8 and Gma+x+, 15 times in subjects with HLA-B8 who were not Gma+x+ and twice in subjects who were neither HLA-B8 nor Gma+x+. Statistical analysis indicated that the three-factor effect (disease risk affected by non-additive effects of HLA-B8 and Gma+x+) was significant (P less than 0.01), as were the main effects of HLA-B8 (P less than 0.001) and Gma+x+ (P less than 0.02). Thus in the presence of HLA-B8, genes linked to Gma+x+, an immunoglobulin CH allotype, may contribute to the development of autoimmune chronic active hepatitis; in the absence of HLA-B8 these same genes appear to be inactive. This may indicate interactions between MHC gene products and VH gene products in the presentation and recognition of autoantigen(s) in autoimmune hepatitis.     

HLA and Kaposi's sarcoma in solid organ transplantation

Of 188 cases of Kaposi's sarcoma arising de novo after transplantation, HLA-A, -B typing was available for 135 and HLA-DR typing available for 67. Compared to the reported HLA phenotype frequencies of renal transplant recipients in the Southeast Organ Procurement Foundation (SEOPF), there is a significantly decreased frequency of HLA-A1 and HLA-B7, and increased frequency of HLA-B5, -B8, -B18, and -DR5. The most striking characteristic of the Kaposi's sarcoma group was its ethnic background. Fifty-six percent of patients were Italian, Greek, Jewish, or Arabic. When this ethnic background is considered, the expected HLA phenotype frequencies are almost exactly the same as in the Kaposi's sarcoma population. The quality of donor-recipient HLA match was evaluable for 106 patients. Only 22% had four or more mismatches, and 59% had at least two antigens matched. This argues against poor donor-recipient matching as a risk factor for developing Kaposi's sarcoma after transplantation.     

Resistance/susceptibility to Echinococcus multilocularis infection and cytokine profile in humans. II. Influence of the HLA B8, DR3, DQ2 haplotype

Differences have been shown between HLA characteristics of patients with different courses of alveolar echinococcosis (AE). Notably the HLA B8, DR3, DQ2 haplotype was associated with more severe forms of this granulomatous parasitic disease. We compared IL-10, IL-5, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) secretion by peripheral blood mononuclear cells (PBMC) isolated from eight HLA-DR3+, DQ2+, B8+ AE patients and from 10 HLA-DR3-, DQ2-, B8- patients after non-specific mitogenic and specific Echinococcus multilocularis antigenic in vitro stimulation. PBMC from seven HLA-DR3+, DQ2+, B8+ healthy subjects and nine HLA-DR3-, DQ2-, B8- subjects were also studied as controls. PBMC from AE patients with HLA DR3+, DQ2+ haplotype secreted higher levels of IL-10 without any stimulation and after specific antigenic stimulation than did patients without this haplotype. Higher levels of IL-5 and IFN-gamma were also produced by these patients' PBMC after stimulation with non-purified parasitic antigenic preparations; however, the specific alkaline phosphatase antigen extracted from E. multilocularis induced only Th2-type cytokine secretion. A spontaneous secretion of TNF by HLA DR3+, DQ2+ B8+ AE patients was also found. These results suggest that HLA characteristics of the host can influence immune-mediated mechanisms, and thus the course of AE in humans; specific antigenic components of E. multilocularis could contribute to the preferential Th2-type cytokine production favoured by the genetic background of the host.     

HLA and immunoglobulin polymorphisms in idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is an idiopathic heart muscle disorder. The presence of circulating cardiac antibodies and the association with HLA-DR4 are consistent with autoimmune pathogenesis in a subset of patients. Sixty-eight DCM patients and 277 controls were typed for IgG heavy-chain constant region (Gm) and kappa light-chain (Km) allotypes. All patients and 210 of the 277 controls were HLA-DR typed. The Gm (1, 3, 17; 23; 5*, 21, 28) phenotype was overrepresented in DCM compared with controls (25% vs 13%, p = 0.0139, pc = NS, RR = 2.23). The frequency of this phenotype was higher in patients with younger age at onset, shorter symptom duration, and among those who were positive for cardiac as well as for non-organ-specific autoantibodies than in controls. A higher frequency of the Gm (1, +/- 2, 3, 17; +/- 23; 5*, 21, 28) heterozygous phenotypes was also found in DCM compared to controls (40.91% vs 26.89%; p = 0.02, pc = 0.04, RR = 1.88). The finding of Gm heterozygosity in DCM was associated with serum positivity for cardiac antibodies. A higher proportion of DCM patients were positive for both the Gm (1, 3, 17; 23; 5*, 21, 28) phenotype and HLA-DR4 compared to normals (3/68 vs 0/210; p = 0.04, RR = 22.50).(ABSTRACT TRUNCATED AT 250 WORDS)     

HETEROGENEITY OF SYSTEMIC LUPUS ERYTHEMATOSUS ELUCIDATED BY CLUSTER ANALYSIS

For 75 patients with systemic lupus erythematosus (SLE), 39 laboratory and clinical characteristics, including HLA-A, B, C and DR typing, were analysed using a cluster analysis technique. Three groups were identified. Group I (46 patients) was characterized by infrequently severe disease, good response to therapy and infrequent multisystem involvement. Group I1 (24 patients) was characterized by a severe course of disease (although the tendency to remit after therapy was not unusual), and, frequently, renal involvement and pericarditis. Group 111 (5 patients) was characterized by more severe renal disease. Of the 75 patients studied, 38.7% possessed HLA-DR3, compared to 17.4% of controls. Group I patients did not differ from controls but 80% of Group II patients and 4/5 Group III patients had DR3. Cluster analysis identifies subsets of SLE patients who show marked differences in disease course and severity, correlated with possession of the HLA B8, DR3 phenotype.     

Heterogeneity of systemic lupus erythematosus elucidated by cluster analysis. The influence of HLA

For 75 patients with systemic lupus erythematosus (SLE), 39 laboratory and clinical characteristics, including HLA-A, B, C and DR typing, were analysed using a cluster analysis technique. Three groups were identified. Group I (46 patients) was characterized by infrequently severe disease, good response to therapy and infrequent multisystem involvement. Group II (24 patients) was characterized by a severe course of disease (although the tendency to remit after therapy was not unusual), and frequently, renal involvement and pericarditis. Group III (5 patients) was characterized by more severe renal disease. Of the 75 patients studied, 38.7% possessed HLA-DR3, compared to 17.4% of controls. Group I patients did not differ from controls but 80% of Group II patients and 4/5 Group III patients had DR3. Cluster analysis identifies subsets of SLE patients who show marked differences in disease course and severity, correlated with possession of the HLA B8, DR3 phenotype.     

Four cytotoxic human-human hybridoma antibodies that react with HLA-B27

PBMC were isolated from a multiparous woman with HLA-B27 specific Abs in her serum. The HLA type of the donor was A2,9:B7. The PBMC were EBV transformed, and four cell lines making cytotoxic Abs to HLA-B27+ cells prepared. Hybridomas were constructed by fusing the EBV lines with the human fusion partner KR4. All four mAbs were of IgM isotype. One mAb (TrBH12) reacted specifically with B27+, B37+ and Bw47+ lymphoblastoid cell lines and with all B27+ PBMC except for a rare variant so far found only in one Norwegian family. Another mAb (Tr3B6) was cytotoxic for all B27+ cells tested, including the TrBH12- variant; in addition, it showed weaker cross-reactions to Bw42, B49 and a cell line with the probable phenotype B7,38. Supernatant from the Tr3B6 hybridoma was tested in lymphocytotoxicity against a panel of 658 individuals, 141 of whom were B27+. With this panel, Tr3B6 showed perfect correlation with HLA-B27. The two last mAbs (TrCG10 and TrBF1) reacted with all B27+ cells tested, but in addition showed quite extensive cross-reactions.     

DNA polymorphism of the HLA-B35 gene associated to different HLA-C locus alleles

Peripheral blood leukocyte DNA from 31 donors, previously typed as HLA-B35, was digested with EcoRV and analyzed by Southern transfer and hybridization to an HLA class I probe. Out of 31 HLA-B35 positive (+) individuals, 24 showed a 4.6-kb band, previously associated with the B35 allele by Cohen et al. (Proc Natl Acad Sci USA 80: 6289–6292). The HLA-B35 allele has a strong linkage disequilibrium (70%) with the Cw4 allele. All samples having the 4.6-kb band corresponded to HLA-B35+,Cw4 + cells, whereas those lacking the band came from HLA-B35+,Cw4-negative (−) cells. Five HLA-B35−,Cw4+ samples were also studied and none showed the band. An HLA-B locus-specific probe gave a strong hybridization signal to this fragment, whereas an HLA-C locus-specific probe revealed different bands. The results suggest that the 4.6-kb fragment contains the B35 gene. Digestion with other restriction enzymes, located the polymorphic site to the 3′ end of the gene. Analysis of 18 additional individuals with other specificities of the “4c” antigenic cluster (HLA-B18, B51, B52 and B53) showed that the EcoRV 14.6 kb-band was also present in 5/5 B52 cells and 4/4 B53 samples.     

HLA-associated hemorrhagic fever with renal syndrome disease progression in slovenian patients

Major histocompatibility complex (MHC) class I and class II genes regulate the balance between appropriate aggressive responses and invading pathogens while minimizing the destruction of host tissue. Several studies have shown that in hemorrhagic fever with renal syndrome (HFRS) patients, the disease outcome is determined by a complex interaction between the virus and immunopathologic and human genetic factors. In Slovenia, the severity of the disease caused by Puumala virus (PUUV) is significantly lower than that of HFRS due to Dobrava virus (DOBV). We have determined 23 different HLA-B and 12 different HLA-DRB1 types in Slovenian HFRS patients. Comparison of HLA frequencies between healthy individuals and HFRS patients showed no strong association with the susceptibility for hantaviral infection. Significant associations were recognized when the patient group was separated according to the virus responsible for the infection. DOBV-infected patients have a significantly higher frequency of HLA-B*35 than PUUV-infected patients. For HLA class II genes, the biggest difference between the PUUV- and DOBV-infected groups of patients was in HLA-DRB1*13, where this phenotype was more frequent in PUUV-infected patients, especially in the severe form of the disease. HLA-B*07 could play a protective role in PUUV-caused HFRS in the Slovenian population. Our study shows diverse associations of HLA molecules with DOBV- and PUUV-induced HFRS, and therefore, we presume that different hantaviruses are presented differently through the same HLA molecules and that this might lead to either a more severe or a milder form of the disease. In line with this idea, we have noticed that HLA-B*35 might be a genetic risk factor for DOBV infection in the Slovenian population.