Interaction between immunoglobulin allotypes and NK receptor genes in diabetes post-hepatitis C virus infection

Genetic interactions between natural killer (NK) cells immunoglobulin-like receptor (KIR) genes and immunoglobulin allotypes have been previously reported in type 2 diabetes mellitus (DM) patients. Puerto Rican Americans with a history of intravenous drug use who developed DM following HCV infection (n = 32) were compared to individuals infected with HCV without diabetes (n = 121) and to DM non-infected individuals (n = 95). Subjects were genotyped for KIRs and immunoglobulin allotypes. We found interactions of immunoglobulin allotypes KM3/KM3 with NK inhibitory receptors 2DL3/2DL3, 2DL1 in the absence of 2DS4 associated with susceptibility to DM in HCV infected individuals. These data suggest the possibility that a subset of patients with HCV could have an immune-mediated component contributing to the development of DM.     

HLA class II alleles and chronic hepatitis C virus infection

The aim of this study was to investigate association of human leucocyte antigens (HLA)-DRB1 and DQB1 polymorphisms with hepatitis C virus (HCV) infection and with the occurrence of severe liver fibrosis/cirrhosis in chronically infected patients. Ninety-nine white patients, from southeast Brazil, with confirmed HCV chronic infection were included in the study. Severe fibrosis/cirrhosis (METAVIR scores F3-F4) was present in 49 patients. HLA-DRB1 specificities and DRB1*11 and DQB1* alleles were determined by PCR-SSP, and their frequencies were compared between patients and a control group of 103 healthy white Brazilian individuals. The results confirmed previous reports of the association of DRB1*11 and DQB1*03 with protection from chronic HCV infection, but did not confirm their association with protection from severe fibrosis/cirrhosis. Furthermore, the results suggested that the polymorphic sites on HLA molecules responsible for protection from chronic HCV infection are encoded not only by the DRB1*1101 and DQB1*0301, as suggested in the literature, but also by other DRB1*11 and DQB1*03 alleles. Thus, we hypothesized that the common polymorphic residues shared by different DRB1*11 and/or DQB1*03 alleles might be responsible for selection of viral epitopes for presentation to CD4(+) T cells, leading to an efficient immune response against the virus.     

HLA-C and KIR genes in hepatitis C virus infection

Natural killer (NK) cells are key components of the innate antiviral immune response. NK cell function is regulated by the interaction of major histocompatibility complex class I molecules with NK inhibitory receptors. The aim of this study was to investigate the role of the HLA-C/KIR pair in hepatitis C virus clearance in our population. A total of 196 hepatitis C virus-infected patients (65 resolved and 131 with persistent infection) were included in the study. Genotyping of HLA-C was carried out using polymerase chain reaction followed by a reverse sequence-specific oligonucleotide probe detection system. NK receptor-specific polymerase chain reaction typing of KIR2DL1, KIR2DL2, and KIR2DL3 was performed on the same patient group. Frequencies of the KIR2DL2 gene and the KIR2DL2/KIR2DL2 genotype were lower among patients with persistent infection (32.3% vs 45.4% among resolved, P = 0.01, OR = 0.57, 95% CI = 0.36-0.91; and 16.2% vs 32.3% among resolved, P = 0.02, OR = 0.41, 95% CI = 0.19-0.87). Nevertheless, the frequency of the KIR2DL3 gene was higher among patients with persistent infection (66.9% vs 54.6% among resolved P = 0.02, OR = 1.68, 95% CI = 1.07-2.65). Trends toward lower frequencies of the HLA-C2C2 genotype and NK-HLA interactions with strong and moderate affinity among the patients with persistent infection were also observed.     

NK receptor interactions with MHC class I molecules in pregnancy

Both HLA class I molecules and their receptors on Natural Killer cells, the KIR molecules, are highly polymorphic. It is generally believed that this variation is driven in response to the role of these receptors and counter-receptors in resistance to disease. Uterine NK cells are the major maternal leukocyte population present within the decidua, and they express KIR2D receptors for HLA-C, the only polymorphic class I molecule on trophoblast. Genetic and functional data suggest that the maternal KIR/fetal HLA-C interaction in pregnancy may affect the delivery of an optimal blood supply to mother and fetus. The drive for novelty in HLA-C and KIR2D allelic diversity may relate not only to survival from infections but also to reproductive success.     

Genetic and functional relationships between MHC and NK receptor genes

HLA class I and NK receptors are encoded within dense clusters of immune loci. The MHC, at 6p21.3, and the complex containing the KIR loci, at 19q13.4, both feature variation in the number of genes, as well as sequence polymorphism. In addition to T cell receptors, several variable class I-related molecules interact with polymorphic NK receptors. Some of the lectin-related NK receptor genes, at 12p13.1, also have ligands belonging to the extended class I family. The expanding clusters of class I-related sequences and their receptors, some of which evolved recently, reveal further complexity in immune recognition of disease.     

MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P<0.0001), DQA1*0101 (P=0.001), and DQB1*0503 (P<0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB 1 * 1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p<0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB 1*0302 (p=0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67–74 of the P domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB 1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB 1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.     

MHC class I and class II genes in Mexican patients with Chagas disease

Chagas' disease contributes significantly to cardiovascular morbidity and mortality in several Latin-American countries. Previous studies have reported the effect of the human leukocyte antigen (HLA) molecules in the immune response regulation of Trypanosoma cruzi infection, and the association of HLA antigens with heart damage. We studied the major histocompatibility complex (MHC) class I (HLA-A and HLA-B), and class II (HLA-DR) genes in a sample of 66 serologically positive individuals with and without cardiomyopathy, and in 127 healthy controls. The total group of seropositive individuals revealed increased frequencies of HLA-B39 (pc=4.3x10(-5), odds ratio [OR]=3.35) and DR4 (pc=1.8x10(-5), OR=2.91) when compared to healthy controls. Increased frequencies of HLA-A68 and HLA-B39 were found in asymptomatic individuals when compared to patients with cardiomyopathy (pc=0.014, OR=4.99 and pc=0.001, OR=4.46, respectively). Also, patients with cardiomyopathy exhibited increased frequency of HLA-B35 when compared to healthy controls (pc=0.048, OR=2.56). The HLA-DR16 frequency was increased in patients with cardiomyopathy compared with asymptomatic individuals (pc=0.05, OR=No determined) and healthy controls (pc=0.02, OR=5.0). The results suggest that MHC alleles might be associated with the development of chronic infection and with heart damage in Chagas' disease. HLA-DR4 and HLA-B39 could be associated directly with the infection by T. cruzi, whereas, HLA-DR16 could be marker of susceptibility to heart damage and HLA-A68 might confer protection to develop cardiomyopathy.     

MHC class II alleles associated with clinical and immunological manifestations of HIV-1 infection among children in Catalonia, Spain

Children with perinatally-acquired HIV-1 infection were studied to determine if major histocompatibility complex (MHC) genes are involved in progression to pediatric AIDS. Molecular genetic techniques were used to genotype loci in the class II region (DRB1, DQA1, DQB1, DPA1, DPB1, LMP2 and LMP7). HIV-infected children were classified by clinical manifestations and degree of immunosuppression using age-specific CD4 T-lymphocyte counts at enrollment. Alleles at the DPB1 and DQB1 loci showed independent and opposite associations; DPB1*0301 showed a trend toward protection while DQB1*0201 appeared to be a risk factor for developing severe immunosuppression and severe clinical outcomes. Presence of DQB1*0201 conferred a greater than 10-fold increased odds of having severe clinical manifestations and a 2.8-fold increased odds of severe immunosuppression. Presence of DPB1*0301 was associated with a greater than 8-fold decreased odds of severe immunosuppression and severe clinical manifestations. These results support host genetic influences on HIV-1 outcomes in children.     

MHC class II genes in Mexican patients with idiopathic dilated cardiomyopathy

The purpose of the present study was to evaluate the relationship between class II major histocompatibility complex (MHC) genes (HLA-DR and HLA-DQB) and the genetic susceptibility to idiopathic dilated cardiomyopathy (IDC) in Mexican patients. The HLA-DR and DQB alleles were analyzed in 53 patients with IDC and 99 ethnically matched healthy controls using the polymerase chain reaction-sequence specific oligonucleotides (PCR-SSO) technique. IDC patients showed increased frequencies of HLA-DR4 (pC=0.02, OR=1.87), HLA-DQB1*0301 (pC=0.02, OR=1.92) and HLA-DQB1*0302 (pC=0.02, OR=1.87) when compared to healthy controls. On the other hand, IDC patients also showed decreased frequencies of HLA-DR11 allele (pC=0.03, OR=0.26) and HLA-DQB1*0201 (pC=0.04, OR=0.41). These data suggest that variation in class II HLA alleles could be a genetic factor involved in the susceptibility to IDC of the Mexican Mestizo population.     

MHC class II genes in HCV viral clearance of hepatitis C infected Hispanic patients

The frequency of class II human leukocyte antigen (HLA) alleles in 112 infected patients of Hispanic ancestry with serology positive for hepatitis C virus (HCV) was investigated. Our studies failed to demonstrate significant association between class II HLA alleles and the outcome of HCV infection: chronic viremia versus spontaneous viral clearance. Our results suggest that the genes responsible for the outcome are unknown, so far, and those HLA associations reported in several ethnic groups may represent genetic markers in nonrandom association with the responsible genes involved in determining viral clearance or chronic viremia following HCV infection.     

Association between HLA class II alleles and hepatitis B virus infection in Transylvania,Romania

ABSTRACT

Infection with hepatitis B virus (HBV) is a major problem worldwide. The major histocompatibility complex plays an essential role in host immunity and can help eliminate the HBV of infected hepatocytes. Our study aimed to determine the role of certain human leukocyte antigen (HLA) class II molecules (i.e. HLA-DRB1 and HLA-DQB1) in the persistence or removal of HBV. Sixty patients confirmed to be HBV-positive via real-time polymerase chain reaction (PCR), i.e. people with chronic active hepatitis, were included in the study along with a control group of 100 healthy individuals without evidence of HBV infection. The DNA was subsequently used to determine HLA-DRB1 and HLA-DQB1 low-resolution typing genetic profile via PCR amplification. The univariate analysis performed revealed significant association of the HLA-DRB1*03 and HLA-DQB1*05 alleles to the infected persons (study group), while HLA-DRB1*01 was shown to be protective against HBV infection. To our knowledge, this is the first Romanian study associating HLA with HBV, and it can provide valuable insight concerning the relationship between genetic factors and immune response in the sampled population.     

MHC class II antigen presentation and immunological abnormalities due to deficiency of MHC class II and its associated genes

Antigen presentation by Major Histocompatibility Complex (MHC) class II molecules plays an important role in controlling immunity and autoimmunity. Multiple co-factors including the invariant chain (Ii), HLA-DM and HLA-DO are involved in this process. While the role for Ii and DM has been well defined, the biological function of DO remains obscure. Our data indicate that DO inhibits presentation of endogenous self-antigens and that developmentally-regulated DO expression enables antigen presenting cells to preferentially present different sources of peptide antigens at different stages of development. Disruption of this regulatory mechanism can result in not only immunodeficiency but also autoimmunity. Despite the fact that deletion of each of the three genes in experimental animals is associated with profound immunological abnormalities, no corresponding human diseases have been reported. This discrepancy suggests the possibility that primary immunodeficiencies due to a genetic defect of Ii, DM and DO in humans are under diagnosed or diagnosed as “common variable immunodeficiency”, a category of immunodeficiency of heterogeneous or undefined etiology. Clinical tests for any of these potential genetic defects are not yet available. We propose the use of multi-color flow cytometry in conjunction with intracellular staining to detect expression of Ii, DM, DO in peripheral blood B cells as a convenient reliable screening test to identify individuals with defects in antigen presentation.     

Molecular biology of murine MHC class II genes.

The murine class II genes are contained in the I region of the major histocompatibility complex (MHC). In the mouse, there are seven class II genes: A beta 3, A beta 2, A beta, E beta, E beta 2, A alpha, and E alpha. The A beta and A alpha genes code for the two polypeptide chains that form the I-A immune response molecule. The E beta and E alpha genes code for the two polypeptide chains that form the I-E immune response molecule. This review covers the genetic organization of the I region and the exon-intron structure of the class II genes. This review also discusses site-directed mutagenesis and exon shuffling studies and the effect of these changes on the function of Ia genes. Regulation of the cellular expression of Ia genes is discussed with emphasis on recent studies involving class II transgenic mice. Also, studies mapping recombination hotspots within the E alpha and E beta genes are reviewed.