Differential HLA class I and class II associations in pemphigus foliaceus and pemphigus vulgaris patients from a prevalent Southeastern Brazilian region.

Genetic factors, particularly those concerning HLA class II, have been associated with the pathogenesis of pemphigus. Taking advantage of an area where pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are prevalent in the northeastern region of the state of São Paulo, Southeastern Brazil, we have studied the HLA class I (A, B and C) and class II (DRB1 and DQA1/DQB1) profiles in 86 and 83 patients with PF and PV, respectively, as compared with 1592 controls from the same region. Among all the HLA alleles described herein, the more prevalent susceptibility alleles for PF were HLA-A*11, 33, -B*14; -DRB1*01:01, *01:02; -DQA1*01:02; and -DQB1*05:01. In PV patients, the HLA-B*38; -C*12; -DRB1*04:02, *08:04, *14:01, *14:04; -DQA1*03:01; and -DQB1*03:02 and *05:03 alleles were associated with susceptibility. The HLA-DRB1*01:02 allele and the HLA-DRB1*01-DQA1*01-DQB1*05 haplotype in PF patients and the HLA-DRB1*04:02 and *14:01 alleles and the HLA-DRB1*14-DQA1*01-DQB1*05 haplotype in PV patients were related with the highest etiologic fraction values. Distinct genetic patterns and not yet described HLA susceptibility/protection alleles/haplotypes profiles have been observed in this series. Our findings corroborate the differential genetic markers in PF and PV in an area where pemphigus is prevalent but not yet reported.

Polymorphisms in human leukocyte antigens, human platelet antigens, and cytokine genes in hantavirus cardiopulmonary syndrome patients from Ribeirão Preto, Brazil.

Hantavirus cardiopulmonary syndrome is a severe human disease associated with hantavirus infection. The clinical course of illness varies greatly among individuals, possibly due to viral and immunological elements and the influence of host genetic factors on clinical outcome. As the magnitude of immune activation has been associated with disease severity, polymorphisms in genes involved in the immune response that may affect the development of this syndrome were investigated. Polymorphisms in the TGF-ß, IL-10, IL-6, and IFN-γ genes, human leukocyte antigens (HLA), and human platelet alloantigens (HPA) genes were investigated in 122 patients with Araraquara virus infection from Ribeirão Preto, Brazil. Patients were divided into two groups: hantavirus cardiopulmonary syndrome (HCPS group; n = 26) and hantavirus seropositive only (n = 96). The frequencies of HLA alleles, cytokines and platelet antigen genotypes were evaluated in both groups and compared to a control group. The data demonstrated no significant influence of the HLA alleles, HPA, IL-6, and IL-10 genotypes on susceptibility to hantavirus infection. However, the hantavirus seropositive group presented a significantly higher frequency of a polymorphism associated with a high IFN-γ production than the HCPS group. In addition, a genotype associated with high TGF-ß production was found more frequently in individuals infected with hantavirus than in the control group. This phenotype was associated with a less intense thrombocytopenia in the HCPS group and may be protective against the most severe form of hantavirus disease. More studies are required to quantify further the influence of the high TGF-ß producer phenotype on the outcome of hantavirus infection.

Association of -308G/A polymorphism in the tumor necrosis factor-alpha gene promoter with susceptibility to development of hantavirus cardiopulmonary syndrome in the Ribeirão Preto region, Brazil.

Activation of the immune response in hantavirus cardiopulmonary syndrome (HCPS) leads to a high TNF production, probably contributing to the disease. The polymorphic TNF2 allele (TNF -308G/A) has been associated with increased cytokine production. We investigated the association of the TNF2 allele with the outcome of hantavirus infection in Brazilian patients. A total of 122 hantavirus-exposed individuals (26 presenting HCPS and 96 only hantavirus seroconversion) were studied. The TNF2 allele was more frequently found in HCPS patients than in individuals with positive serology for hantavirus but without a history of HCPS illness, suggesting that the TNF2 allele could represent a risk factor for developing HCPS.

Variability at the 3' untranslated region of the HLA-G gene: a study on patients with AIDS and cytomegalovirus retinochoroiditis.

Cytomegalovirus retinochoroiditis (CMV-R) is the primary cause of blindness among AIDS patients. Since HLA-G is associated with the modulation of the immune response, we hypothesized that variability at the 3' untraslated region (3'UTR) of the gene could be implicated on the predisposition to CMV-R. We evaluated whether HLA-G 3'UTR influences CMV-R development in Brazilian AIDS patients. Peripheral blood DNA was obtained from two groups of patients: (1) AIDS exhibiting CMV-R (n = 40) and (2) AIDS without CMV-R (n = 147). HLA-G 3'UTR typing was performed using sequencing analysis. Allele, genotype and haplotype frequencies were evaluated using Fisher's exact test accompanied by the calculation of the odds ratio and its 95% confidence interval (95% CI). The etiologic (EF) and preventive fractions were also estimated. Compared to AIDS patients without CMV-R, AIDS patients with CMV-R showed increased frequencies of the: (1) + 3001T allele, (2) the + 3001C/T genotype and (3) the UTR-17 (InsTTCCGTGACG) haplotype (EFs = 0.02-0.04). The UTR-3 (DelTCCGCGACG) haplotype was associated with protection against CMV-R development. Although the risk for developing CMR-V at the population level was relatively low (EF), the identification of HLA-G 3'UTR variation sites may help to further evaluate the role of post-transcriptional factors that may contribute to the existent immunosuppresion caused by HIV per se.

Family study of monozygotic twins affected by pemphigus vulgaris.

Rare are the family studies that include siblings affected by pemphigus vulgaris (PV) and in whom HLA class II alleles are related. HLA-DR and -DQ genotyping and profiling of antibodies against desmogleins (Dsg) 1 and Dsg3 were performed in ten members of a family including monozygotic twins affected by PV. The twin sisters were heterozygotes; they presented the haplotypes most commonly associated with increased susceptibility to PV (DRB1∗04:02-DQA1∗03:01-DQB1∗03:02 and DRB1∗14:04-DQA1∗01:01-DQB1∗05:03). Their parents and five siblings had only one or none of these two haplotypes in combination with the alleles or haplotypes associated with resistance to PV (DRB1∗07:01-DQA1∗02:01-DQB1∗02:02 and DRB1∗13:01-DQA1∗01:03-DQB1∗06:03). Only the monozygotic twins presented IgG antibodies against both Dsg1 and Dsg3. According to our knowledge based on a review of published literature on the topic, this is the first report of PV affecting monozygotic twins.

Association of HLA-G 3' untranslated region variants with type 1 diabetes mellitus.

Besides the well recognized association of HLA-DRB1 and DQB1 alleles with type 1 diabetes mellitus (T1D), linkage studies have identified a gene region close to the non-classical class I HLA-G gene as an independent susceptibility marker. HLA-G is constitutively expressed in the endocrine compartment of the human pancreas and may play a role in controlling autoimmune responses. We evaluated the genetic diversity of the 3' untranslated region (3'UTR) of HLA-G, which have been associated with HLA-G mRNA post-transcriptional regulation, in 120 Brazilian T1D patients and in 120 healthy controls. We found the +3001 T allele was observed only in T1D patients. Notably, the +3001 T allele was in linkage disequilibrium with polymorphic sites associated with low production of HLA-G mRNA or soluble HLA-G levels. Moreover, T1D patients showed a low frequency of the HLA-G 3'UTR-17 (14bpINS/+3001T/+3003T/+3010C/+3027C/+3035T/+3142G/+3187A/+3196C). The +3010 CC genotype and the UTR-3 haplotype (14bpDEL/+3001C/+3003T/+3010C/+3027C/+3035C/+3142G/+3187A/+3196C), associated with low and moderate soluble HLA-G expression, respectively, were underrepresented in patients. The decreased expression of HLA-G at the pancreas level should be detrimental in individuals genetically prone to produce less HLA-G.

Frequency of HLA class 1 and 2 alleles in Brazilian patients with AIDS and cytomegalovirus retinitis.

PURPOSE: To evaluate the human leucocyte antigen (HLA) class 1 (HLA-A and HLA-B) and HLA class 2 (HLA-DRB1 and HLA-DQB1) allele profiles in the susceptibility to cytomegalovirus retinitis (CMV-R) in patients with AIDS. METHODS: Cytomegalovirus retinitis was clinically diagnosed by indirect binocular ophthalmoscopy. Human leucocyte antigens class 1 were typed using a complement-dependent microlymphocytotoxicity assay, and HLA class 2 alleles were identified using amplified DNA hybridized to sequence-specific oligonucleotide primers. RESULTS: The frequencies of HLA class 1 antigens and HLA class 2 alleles observed in patients and controls were similar; however, HLA-A31 antigen was over-represented in patients with AIDS, independent of the presence of CMV-R. CONCLUSION: There was no association between HLA molecules/alleles and CMV-R in Brazilian patients with AIDS. However, the results support the role of the HLA system in the susceptibility to developing AIDS.