Two HLA DRB 1 alleles confer independent genetic susceptibility to Graves disease: relevance of cross-population studies.

Recent studies of Graves disease (GD) employing genome scanning techniques excluded the major histocompatibility complex as a contributor to disease liability. These findings contradict earlier population association studies. Our own earlier studies have also emphasized that genetic variation in human populations may give novel clues to disease liability and manifestations. To this end, we studied HLA class II alleles in 47 Latvian GD patients and 111 matched healthy controls. As expected, we found that DRB1*03 and DQA1*0501 (OR = 3.6, P = 0.029 and OR 2.35, P = 0.0373, respectively) were associated with GD. Unforeseen, DRB1*04 was found to be significantly increased in the patients compared to controls (OR 3.267, corrected P = 0.0319). The two DRB1 alleles conferred two non-overlapping and independent susceptibilities to GD, in that only three patients were positive for both alleles, and the removal of each allele in turn resulted in only the other DRB1 allele showing significant association with the disease. There was no heterogeneity between the two patient groups (DRB1*03 positive and DRB1*04 positive) in clinical characteristics or disease manifestations. The phenotype DRB1*03 and/or DRB1*04 was found in 34/47 patients compared to 27/111 controls yielding an OR of 7.395 (P corrected = 0.000019). We examined the structural basis of DRB1 susceptibility to GD in light of this and previous studies, showing that DRB1*03, 04, and 08 were positively associated with the disease, whereas DRB1*07 was negatively associated. Differences in protein sequences were noted at residues 54, 57, 59, and 66; positions 54, 57, and 66 are on the same face of the alpha helix. The canonical arginine 54 is replaced by glutamine in DRB1*07. At position 66, asparagine in DRB1*03 and tyrosine in DRB1*04 are replaced by phenylalanine in DRB1*07. Residue 59, likely involved in pocket formation in the antigen binding groove, is modified by replacement of tyrosine in DRB1*03, 08, and 04 and by leucine in DRB1*07. The predicted differences in the shape and charges of the proximal reaches of the antigen binding groove between DRB1*07, and 03, 04, and 08, could determine whether or not a peptide from an auto-antigen would be bound or not. Genetic variation among human populations may yield important clues to specific disease liability.

Distribution of insulin-dependent diabetes mellitus (IDDM)-related HLA alleles correlates with the difference in IDDM incidence in four populations of the Eastern Baltic region.

The high incidence of insulin-dependent diabetes mellitus (IDDM) in Finland contrasts strikingly with the low rates in the neighbouring populations of countries in the Eastern Baltic region: Estonia, Latvia and Russia. To evaluate the possible contribution of genetic factors to these differences, the frequencies of HLA-DQB1 alleles and relevant DQB1-DQA1 or DQB1-DRB1 haplotypes associated with IDDM risk or protection were analysed among IDDM patients and control subjects from these four populations. An increased frequency of HLA-DQB1*0302, DQB1*02-DQA1*05 and DQB1*0302-DRB1*0401 was observed in subjects with IDDM in all studied populations, whereas the prevalence of DQB1*0301 and DQB1*0602 and/or *0603 was decreased among patients. The degree of IDDM risk associated with HLA alleles analysed here did not differ significantly between the populations. Comparisons of the distribution of IDDM-related HLA alleles and haplotypes in the background populations revealed its consonance with IDDM incidence. The combined frequency of high risk genotypes was significantly higher among Finns than in other populations studied. Our data support the hypothesis that variance in the dispersion of HLA alleles is the genetic basis of variation of IDDM incidence observed in the Eastern Baltic region.

HLA class II genes in Latvian patients with juvenile rheumatoid arthritis.

PCR-based HLA genotyping was used to analyze the association of HLA-DR and -DQ genes in 127 juvenile rheumatoid arthritis patients and 111 population-based controls from Latvia. The results show DQA1*03 to be positively associated in overall patients and DRB1*01-DQA1*0101-DQB1*0501 to be negatively associated with JRA in overall patients and in polyarthritis patients compared to controls. These data indicate the immunogenetic heterogeneity in the JRA patients, in the disease subgroups and in different ethnic groups. Rheumatoid factor (RF) was assayed in patients (n = 119) and controls (n = 98). RF was present in patients (7/119, 6%) compared to controls (5/98, 5%). None of the DQA1, DQB1 alleles, DQ and DR-DQ haplotypes was associated in seropositive patients compared to seropositive controls. DR1-DQ5 (DQA1*0101-B*0501) was decreased in seronegative patients (11/111, 10%) compared to seronegative controls (24/105, 23%), but the difference was not significant after correction of the p value.

Chronic hepatitis C: T-helper1/T-helper2 imbalance could cause virus persistence in peripheral blood.

Interferon gamma (IFN gamma) and interleukin 4, 10 and 12 (IL-4, -10, -12) production was measured in whole peripheral blood (WPB) and peripheral blood mononuclear cells (PBMC) of 10 chronic hepatitis C (CHC) patients. The level of IFN gamma in supernatants in mitogen-activated WPB was lower than in healthy donors. IL-10 served as a possible downregulative factor for IFN gamma, since its spontaneous IL-10 production was enhanced in CHC. Neutralization of IL-10 partly restored IFN gamma response in CHC patients. Recombinant IL-12 (rIL-12) also enhanced IFN gamma of CHC patients, but IL-12 production was decreased in CHC. Thus, IFN gamma production deficiency in CHC patients is secondary to blockage by high levels of IL-10-impaired IL-12 production.

Interferon gamma production in whole peripheral blood culture in acute hepatitis B.

Interferon gamma (IFNg) production in whole peripheral blood (WPB) and mononuclear (MN) cell culture in acute hepatitis B (AHB) was compared. IFNg production was induced by phytogem agglutinin and measured in the cell supernatants of 14 AHB patients in the course of the disease. There were some up-regulating factors of IFNg production that probably operated in WPB culture: the presence of autoerythrocytes as well as the low content of monocytes. Autoserum regulated IFNg production in a stage-dependent way: it decreased IFNg activity at the bilirubin peak in hepatitis B infection, but not in convalescence. In contrast, we did not find a serum blocking effect in the corresponding stage of acute hepatitis A. The nature of this serum blocking factor in AHB is unclear.

[HLA antigens in juvenile rheumatoid arthritis]. / Antigeny sistemy HLA pri iuvenil'nom revmatoidnom artrite.

Antigens of I class HLA system (locus A and B) were investigated in 67 patients of Latvian nationality suffering from juvenile rheumatoid arthritis (JRA). Associations of HLA antigens with juvenile rheumatoid arthritis partially coincided with the ones revealed earlier. Typing established an increased incidence of antigen B27 (p less than 0.01) and gaplotype A2, B40 (p less than 0.01). Antigen B15 possessed a protective action with respect to JRA. Interlocus combinations demonstrated a closer association with the disease than a single antigen. The authors also revealed markers of various clinico-anatomical variants of JRA.

[The immune status of children with differing intensities of caries]. / Immunnyi status u detei s razlichnoi intensivnost'iu kariesa.

The present paper reports on the results of the studies of the quantity, functional activity of immunocytes and interrelation between their parameters in healthy children (12-14) with healthy periodontium which were ascribed either to caries-resistant or caries-prone group. In all the subjects venous blood and mixed saliva were investigated. Immune state was described through its parameters interrelations. This yields better detection of differences in immune states of both groups.

[The lymphocytotoxic test as a method of identifying subpopulations of T lymphocytes using monoclonal antibodies]. / Limfotsitotoksicheskii test kak metod identifikatsii subpopuliatsii T-limfotsitov monoklonal'nymi antitelami.

The authors analyse the findings of the lymphocytotoxicity test with monoclonal antibodies and the indirect immunofluorescence method used for the assays of T lymphocyte subpopulations. The mean values of the total count of T lymphocytes, T helpers, T suppressors, as well as the immunoregulation index obtained by both methods have proved practically the same. The lymphocytotoxicity data have been in good correlation with the findings of indirect immunofluorescence in tests with all the monoclonal OCT antisera.

[Chronic T-cell lymphoid leukemia with helper cell phenotype]. / T-kletochnyi khronicheskii limfoleikoz s khelpernym fenotipom kletok.

Tumour cells of a patient with T-cell chronic lymphocytic leukemia had surface (E+, OKT3+, OKT4+, OKT8-, SIg-, Ia-) and cytochemical (properties positive reaction to acid phosphatase, acid nonspecific esterase and negative reaction to terminal deoxynucleotidyl transferase) specific for T-helper lymphocytes. They had no activity of NK and K-cells, reacted weakly to mitogens (PHA, Con A, PWM) and allogenic cells. Con A and PWM stimulated synthesis of specific receptors (OKT3 and OKT4) on the surface of malignant cells, whereas PHA decreased the amount of above receptors.

[Isolation of purified populations of T- and B-lymphocytes under clinical conditions]. / Vydelenie ochishchennykh populiatsii T- i B-limfotsitov v klinicheskikh usloviiakh.

The authors present comparative characteristics of the methods of isolation of T- and B-lymphocytes in patients with chronic renal insufficiency. T-lymphocytes were obtained on columns with neilon cotton wool. B-cells were fractionated by repeated centrifugation in the gradient of phycol-urotrast density after staging E-rosette formation with the total lymphocyte pool. Methodical peculiarities of single-stage and two-stage B-lymphocyte fractionation were revealed.