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Immunogenetic and serological investigations in nonpregnant and in pregnant women with a history of recurrent spontaneous abortions. German RSA/IVIG Study Group.

In the context of a controlled multicenter study on intravenous immunoglobulin (IVIG) treatment of patients with a history of unexplained recurrent spontaneous abortions (RSA), a number of controversial immunological parameters were evaluated prior to and during pregnancy with respect to their diagnostic and/or prognostic significance. A total of 390 serum samples from 52 patients were investigated. Sharing of 2 or more HLA (A, B, DR, DQ) antigens was significantly more frequent in RSA couples than in controls. The rate of cytotoxic or Fc-receptor (FcR)-blocking antibodies was not significantly lower in RSA patients than in individuals with normal pregnancies. Both tumor necrosis factor-alpha (TNF-alpha) levels and IgG anticardiolipin antibodies (IgG-ACA) were significantly increased in the patient group. While the occurrence of HLA sharing, cytotoxic/FcR-blocking antibodies and IgG-ACA did not correlate with the outcome of pregnancy, TNF-alpha levels were found to be significantly higher in patients with subsequent miscarriage than in those with successful pregnancy. IgG-ACA, if present, significantly decreased during the course of successful pregnancy but remained high in patients with subsequent abortion. It is concluded that the diagnostic and/or prognostic value of HLA sharing and cytotoxic/FcR-blocking antibodies has been overestimated while TNF-alpha and ACA levels are potential diagnostic markers and/or exhibit prognostic significance in subgroups of RSA patients.

Abortion, Habitual↗

Functional and immunogenetic characterization of FcR-blocking antibody.

The characteristics and functional importance of FcR-blocking antibodies and their production were investigated after immunization with whole blood, "buffy coat" and purified platelets. We studied the presence of FcR-blocking antibody in haemodialyzed, transfused patients waiting for kidney transplantation, and we found strong correlation between the blocking effect and better graft survival. We suggest that this blocking antibody does not attack FcR as primary target. Investigation of blocking activity of ten different immune sera on 50 healthy panel cells showed that target antigen has some polymorphic varieties. On basis of family studies it seems that the target antigen is not linked to HLA haplotype. The blocking effect of sera could be removed by absorption of CD8+ cells, B lymphocytes, platelets and granulocytes, but not with erythrocytes, monocytes, CD8- cells and NK cells.

Absorption↗

Immunogenetic and nutritional profile in insulin-using youth-onset diabetics in Korea.

There are few reports on the genetic, immunological and nutritional characteristics of insulin-using youth-onset diabetes mellitus, insulin-dependent diabetes mellitus (IDDM) and malnutrition-related diabetes mellitus (MRDM) in Korea. Among 1266 hospitalized Korean diabetics, 29 (2.3%) were IDDM and 84 (6.6%) were MRDM. A diabetes history of first-relatives (28.6%) was more frequently found in the MRDM group than in the IDDM (14.8) and non-insulin-dependent diabetes mellitus (NIDDM) (19.0%) groups. HLA-DR4 was more common among IDDM (54.2%) and MRDM (52.4%) patients than controls (26.3%), and HLA-DR3 was more common among only IDDM patients (29.2%) than controls (10.9%). Conventional islet-cell antibodies were detected in 8 of 15 IDDM patients tested (53.3%) and in 11 of 22 MRDM patients (50.0%). MRDM patients had higher serum basal (1.02 +/- 0.51 ng/ml) and peak (1.44 +/- 0.76 ng/ml) C-peptide concentrations than IDDM patients, but lower concentrations than NIDDM patients. Before the onset of diabetes, the calorie intake of 21 MRDM patients assessed was 63.1% of the daily requirement and the intake of carbohydrate, protein and fat was 71.7%, 55.9% and 39.8%, respectively. In summary, our data suggest that IDDM in Korea is associated with HLA-DR3 or HLA-DR4, indicating a risk for IDDM in Western societies; furthermore, MRDM has a history of undernutrition at the preonset period and is also associated with HLA-DR4. It might be also concluded that MRDM in Korea is another expression of IDDM caused by the shortage of some nutrients for the structural and/or functional maintenance of pancreatic beta-cells.

Adolescent↗

Immunogenetic heterogeneity in type 1 (insulin-dependent) diabetes among Japanese--class II antigen and autoimmune thyroid disease.

HLA-DQA1 and DPB1 alleles were examined in relation to autoimmune thyroid disease (AITD) in the Japanese type 1 diabetic patients. The subjects consisted of 14 type 1 diabetic patients with Graves' disease, 12 patients with Hashimoto's thyroiditis and 32 type 1 diabetic patients without AITD. Comparisons were made with 35 normal controls. Among the type 1 diabetic patients with Graves' disease, the age at onset of diabetes was 31.8 +/- 14.6 years old, which was later than that of those without AITD (P < 0.01). DR9 was increased (57.1% vs. 25.9%, P < 0.05, RR: 3.85, chi 2:4.36) in the patients with Graves' disease. DQA1*0301 was increased and DQA1*0103 was decreased in the patients with Graves' disease and those without AITD. HLA-DPB1*0501 was increased (92.9% vs. 54.3%, P < 0.05, RR: 11.0, chi 2:6.57) in the patients with Graves' disease. These findings suggest the existence of a Graves' complicated subgroup characterized by the increasing association of DPB1*0501 and late onset of diabetes in Japanese type 1 diabetic patients. There exists a heterogeneity in Japanese type 1 diabetes.

Adult↗

Helminth immunogenetics: Why bother?

The importance of host genotype as a determinant of protective responses against helminth infection is well established. In contrast, there have been relatively few investigations of the role of helminth genotype, despite the importance accorded to the genetics of other disease-causing organisms. Here, Andrew Read and Mark Viney discuss the reasons for this oversight. They argue that it is not for any compelling empirical reason: there is at least as much evidence that worm genetics affects host protective responsiveness as there is that it does not.

Journal Article↗

Immunogenetic findings in cutaneous lupus erythematosus.

The serologic features and histocompatibility antigen associations of 93 patients with cutaneous lupus erythematosus are reported. Of them, 37 had chronic cutaneous lupus erythematosus and 56 had subacute cutaneous lupus erythematosus. Subacute cutaneous lupus erythematosus with an annular pattern occurred in 32 patients; 24 had a papulosquamous morphology. Sixty percent of patients with annular subacute cutaneous lupus erythematosus had anti-Ro antibodies. The incidence of this antibody in the other two groups was lower. In addition, patients with annular skin lesions had significant antigen association with HLA-B8 (37.5%; relative risk, 4.6) and HLA-DR3 (59.4%; relative risk, 4.3). There were no significant differences among chronic cutaneous lupus erythematosus and subacute cutaneous lupus erythematosus of the papulosquamous type and the control population for any HLA loci. Thus only patients with annular skin lesions represent a homogeneous subgroup in which there is a striking concordance of anti-Ro antibodies and the HLA-B8 and HLA-DR3 phenotypes.

Acute Disease↗

Expansion of human lymphocyte populations expressing specific immune reactivities. III. Specific colonies, either cytotoxic or proliferative, obtained from a population of responder cells primed in vitro. Preliminary immunogenetic analysis.

Human alloreactive cell lines were maintained in culture over prolonged periods of time using conditioned medium. Primed lymphocyte typing reactivity was observed in these T cell lines for only 1 mo, but these T cell lines have remained for more than 7 mo highly and specifically cytotoxic. Using as growth promoter an irradiated autologous feeder consisting of irradiated peripheral blood lymphocytes and the lectin leucoagglutinin, we have derived by limiting dilution cloning of in vitro primed allogeneic combinations, primary colonies (or primary clones) with monofunctional immune reactivities: either cytotoxic (the rarest observed) or PLT reactive (the majority of the colonies). Furthermore, each monofunctional primary colony when tested for PLT or CML reactivity on a panel of unrelated PBL, always showed a restricted specificity when compared to the original primed population. The PLT reactivity of each of the primary clones was short lasting in contrast to their growth potential. The CML reactivity of the primary clones, as for the T cell lines, was long lasting as was their growth potential.

Cells, Cultured↗

Immunogenetic profile of multiple sclerosis in Mexicans.

This is the first study on genetic markers in Mexican Mestizos with multiple sclerosis (MS). Patients were born in Mexico, had no family history of MS are middle-class, and have a high-level education. HLA class I, class II determinants, C2, C4, BF, GLO-1, ABO, and Rb red cell systems were analyzed and compared with results of 295 controls. Measles antibodies, glucose, IgG, total proteins, and cell count were measured in cerebrospinal fluid; anti-neuron, T-cell, and B-cell antibodies were determined in serum. MS in Mexican Mestizos was clinically similar to MS reported in high prevalence countries. DRw6, as previously found in Japanese patients, and its subtype, DRw13, were increased in patients in our study (pc = 0.0007, pc = 0.01, respectively), and the combination A3, B7, DR2, was also elevated (pc = 0.003). The polygenicity of the disease is emphasized by the excess of AB group carriers (pc = 0.01). IgG levels were high in patients with DR2 or DRw6 and 67% of the latter had anti-T cell antibodies. Severity of the disease was also related to the DR markers. It is suggested that at least two HLA-DR linked genes and the industrialized environment are important for the expression of MS in Mestizos.

ABO Blood-Group System↗

Viral antibody titers, immunogenetic markers, and their interrelations in multiple sclerosis patients and controls.

Our purpose was to investigate possible interrelations between antibody titers against seven viruses (measles, rubella, herpes simplex, mumps, varicella-zoster, coronavirus, cytomegalovirus), HLA-class II antigens, and immunoglobulin Gm allotypes in multiple sclerosis (MS). We studied 57 MS patients and 59 controls with similar age and sex distributions. In MS patients, we found the classical increased frequency of HLA-DR2, HLA-DQw1 and also an excess of Gm (3; +/- 23; 5*). Mumps antibody levels were higher in MS patients than in controls; elevation was not significant for measles antibodies. Analysis suggests that an association between HLA-DQw1 and antibody titers against various viruses exists in controls but is absent in MS patients. In particular, we found that mumps antibody titers were higher in DQw1-positive than in DQw1-negative controls, while there was no significant difference among MS cases. Accordingly, we found that the overall difference between patients and controls was due to the fact that DQw1-positive patients had higher titers than controls, while DQw1-negative cases had similar titers as controls. These findings suggest that biological and molecular characteristics of DQw1 might differ in MS patients.

Adult↗

Immunogenetics of human American cutaneous leishmaniasis. Study of HLA haplotypes in 24 families from Venezuela.

Twenty-four families with one or multiple cases of localized cutaneous leishmaniasis (LCL) from an endemic region with the highest incidence of LCL in Venezuela were typed from HLA-ABC, DR, DQ antigens and complement factors. The parental HLA haplotypes segregated at random among healthy and affected siblings but in backcross families significantly higher frequencies of HLA-A28 (p = 0.0018), -Bw22 (p = 0.0122), or -DQw8 (p = 0.0364) were present in affected compared to healthy siblings. HLA-B15 showed a higher frequency (p = 0.0062) among the latter group. Haplotypes Bw22CF31 (p = 0.0076) and Bw22DRw11DQw7 (p = 0.0163) were also significantly more frequent in affected compared to healthy siblings and A2Cw- (p = 0.0445) among the latter. No HLA genetic linkage with a putative LCL susceptibility gene(s) could be demonstrated in this study. A case/control comparison of 26 unrelated LCL patients (one proband from each family) and healthy individuals of the same ethnic origin confirmed the association of HLA-Bw22 (pc = 0.048) and -DQw3 (pc = 0.036) with LCL. The relative risk reached 12.5 for Bw22 and 4.25 for DQw3 with ethiologic factors of 0.17 and 0.64, respectively. HLA-DQw3 apparently makes the major contribution as a genetic risk factor for LCL at the population level.

Female↗

Progress report on the ASHI/CAP Proficiency Survey Program in Histocompatibility Testing. I. HLA-A,B,C typing, antibody screening, and lymphocytotoxicity crossmatching. American Society for Histocompatibility and Immunogenetics. College of American Pathologists.

The Histocompatibility Survey Program was organized in 1982 as a joint project by the ASHI and CAP to evaluate laboratory performance in HLA typing, lymphocytotoxicity crossmatching, and antibody analysis. This report summarizes the experience with the HS surveys on HLA class I serology. During a 12-year period, the number of participating laboratories increased from 150 to 285 and HLA typing was done with 90 survey specimens representing 20 HLA-A and 35 HLA-B antigens. Most unsplit antigens were correctly identified in more than 90% of the laboratories. For many antigens, a high percentage of participants reported a split and there was generally a high consensus of a correct assignment. Nevertheless, several antigens were difficult to define, as shown by low consensus rates. During recent years, the assignments of Bw4/6 and HLA-C antigens have significantly improved. Lymphocytotoxicity crossmatching was analyzed for 138 cell-serum combinations tested by an average of 143 laboratories. Comparisons between four techniques (basic NIH, Amos modified, LI, and AHG) showed consistent results (greater than 90% crossmatch compatibility or incompatibility) for 71% of the cell-serum combinations. The crossmatch results with the remaining combinations were more variable for one or more of the crossmatch techniques. Serum antibody identification showed a continued improvement during recent years, and the average consensus for assigning acceptable antibody specificity reached 88%. A performance grading system based on a 90% consensus rate among participants is used to satisfy requirements for laboratory accreditation.

Cytotoxicity Tests, Immunologic↗

Progress report on the ASHI/CAP Proficiency Survey Program in Histocompatibility Testing. II. HLA-DR, DQ serologic typing, antibody identification, and B-cell crossmatching. American Society for Histocompatibility of Immunogenetics. College of American Pathologists.

This report summarizes the 8-year experience of the DR survey program designed to evaluate the performance of histocompatibility laboratories in the serologic typing of cell specimens for HLA-DR and HLA-DQ polymorphisms and the HLA class II antibody identification and B-cell crossmatching of serum specimens. The number of participants increased from 45 in 1985 to 214 in 1992. Although the performance criteria are based on laboratory consensus, the availability of DNA typing since 1990 has enabled a critical assessment of the reliability of serologic HLA-DR, DQ typing. The survey results shows that unsplit HLA class II antigens DR1-DR8, DR52/53, and DQ1-3 are generally correctly identified in over 90% of the participating laboratories. DR9 and DR10 have not yet been tested and testing for DQ4 has not yet achieved this level on consensus. In contrast, the assignments of serologic subtypes of HLA-DR and HLA-DQ are less consistent and frequently unreliable. Although the B-cell crossmatches show generally high laboratory consensus rates, the serum screening results show frequently inconsistent results regarding HLA class-II-specific antibody identification.

Antibody Specificity↗

Immunogenetic analysis of Trichinella spiralis infections in swine.

The immune responses of outbred swine, inoculated with several different low doses of Trichinella spiralis muscle larvae (ML), was followed over 5-6 weeks of primary infection, in order to determine an inoculation dose which could be used to identify genetic controls on the response to this helminth parasite. Reproducible infections were established when swine were inoculated with 100-300 ML. Humoral antibody responses to different larval stages were evident at 4 weeks using enzyme-linked immunosorbent assay (ELISA) of antibody-binding to excretory-secretory (ES) products of ML, and flow cytometric (FCM) analysis of antibody-binding to newborn larvae. T-cell blastogenesis to T. spiralis ML antigens was predominantly in the CD4+, class II restricted, T-cell subset. Having established an appropriate inoculation dose, swine leukocyte antigen (SLA) inbred miniature swine were then inoculated with this low dose of T. spiralis ML, to determine whether major histocompatibility complex (MHC) genes regulate swine immune responses to T. spiralis, as has been found in rodent models. Preliminary evidence indicated that swine of the SLA c/c haplotype may exhibit a lower burden of T. spiralis larvae in the tongue and diaphragm. This lower muscle burden correlated with the earlier development of a humoral antibody response in these genetically-defined swine.

Animals↗