Role for HLA in susceptibility to infectious mononucleosis

Factors involved in determining whether infectious mononucleosis occurs after primary EBV infection may include age, dose of virus received, and various genetic markers. A study by McAulay and colleagues reported in this issue of the JCI shows that the presence of certain HLA class I alleles correlates with the incidence and severity of infectious mononucleosis. These same HLA alleles are also risk factors for EBV-associated Hodgkin lymphoma (HL), supporting recent epidemiology that indicates that a history of infectious mononucleosis predisposes to HL. Recent studies suggest that an EBV vaccine might help to prevent infectious mononucleosis, and further development of this should now be considered.     

Genetic susceptibility to Hodgkin's lymphoma associated with the human leukocyte antigen region

Based on the presence of an abundant inflammatory infiltrate, expression of a broad spectrum of cytokines and the professional antigen presenting phenotype of Hodgkin Reed-Sternberg cells it can be anticipated that immunological mechanisms play a major role in the pathogenesis of Hodgkin's lymphoma (HL). Genetic susceptibility to HL probably relates to functionality of the immune system and the large number of associations with the human leukocyte antigen (HLA) region in family and population-based studies supports this relation. In Epstein-Barr virus (EBV) positive HL cases, which usually demonstrate HLA class I expression, HRS cells should be able to present EBV derived antigenic peptides and trigger the immune system. This process depends on the affinity of the HLA binding groove for binding immunogenic peptides and thus on the HLA alleles. It can be anticipated that certain combinations of alleles predispose to or protect from the development of EBV positive HL. In EBV negative HL cases other antigenic peptides, related to malignant transformation, in combination with other HLA alleles may be involved. In addition, differential attraction and activation of inflammatory cells may influence HL subtype. In this article, possible roles of HLA in HL pathogenesis are explored and genetic associations of HLA with HL are reviewed and commented on.     

Distribution of the HLA class I allele in chronic hepatitis C and its association with serum ALT level in chronic hepatitis C

An essential process for resolution of viral infections is the efficient recognition and elimination of intracellular virus. Recognition of viral antigens in the form of short peptides associated with HLA class I molecule is a major task of CD8+ cytotoxic T lymphocytes. In this study, we have evaluated the frequency of the HLA class I alleles in patients with chronic hepatitis C. HLA-B51, -B52, -B55, -B56, -B61, B70, -Cw1, -Cw3, and -Cw4 are less frequent in patients with chronic hepatitis C than in Japanese individuals. The frequency of HLA-A2 is slightly lower in the patients but tends to be higher in patients with normal alanine aminotransferase (ALT) level than in those with elevated ALT level (p = 0.07). Other HLA alleles are not significantly different between two groups. Comparison of HLA homozygosity at HLA-A and -B or -C or at two or three loci did not show a significant association with levels of serum ALT or with the clinical outcome of interferon therapy in patients with hepatitis C. These results suggest a possibility that the alterations of host response, which depends on genetic background, influence disease activities of HCV infection.     

The clinical value of immunological markers of EBV infection in children with infectious mononucleosis

A hundred and sixteen patients aged 1 to 14 years who had infectious mononucleosis (IM) caused by the Epstein-Barr virus (EBV) were followed up in its acute phase and 3, 6, and 12 months after the disease experienced by them. The clinical significance of the markers of EBV infection was assessed in children with IM. The high diagnostic capacity of detection of EBV DNA in the lymphocytes was established in patients with IM. It was shown that it is necessary to use the serological markers of EBV infection to monitor the course of this disease in children.     

Epstein-Barr virus: the spectrum of its manifestations in human beings

Epstein-Barr virus (EBV) infects virtually everyone by adulthood, and a lifelong latency is maintained. It infects children silently, whereas the majority of adolescents have infectious mononucleosis (IM). Children who have IM before 5 years of age are often heterophil negative; EBV-specific antibodies are required for diagnosis. On rare occasions the symptoms of IM may persist in a chronic or recurrent form, and fatal infectious mononucleosis occurs rarely. Depending on the type and degree of immune deficiency and the time the EBV infection occurs in the life cycle, various atypical outcomes can occur. Children with primary immune deficiency can have fatal or chronic IM, malignant B cell lymphoma, virus-associated hemophagocytic syndrome, aplastic anemia, or acquired hypogammaglobulinemia. The various outcomes of the EBV infections are likely governed by the immune response of the individual. The increased frequency of B cell neoplasms in immunodeficient patients is likely due, in part, to EBV. Individuals with acquired immune deficiency disorders such as AIDS or allograft recipients may develop malignant B cell lymphomas which tend to be polyclonal, but which may progress through stages of oligoclonality to monoclonality. This conversion likely results from specific reciprocal chromosomal translocations such as t(8;14), which is seen in Burkitt's lymphoma. Detection of EBV in immunodeficient patients is achieved by EBV-specific antibody studies or isolation of virus by obtaining spontaneous lymphoblastoid cell lines from peripheral blood, isolating virus from throat washings, or identifying EBV genome by molecular hybridization techniques. Prevention of primary immune deficiency by early detection and genetic counseling and monitoring of patients for occurrence of EBV infection may lead to early treatment. Acyclovir and immunoglobulin therapy can be of value in some patients with active EBV infection.     

Epstein Barr virus-specific immune defects in patients with persistent symptoms following infectious mononucleosis

In a number of patients recovery from infectious mononucleosis (IM) following primary Epstein Barr virus (EBV) infection, is complicated by the persistence of symptoms for months or years. Normally recovery from infectious mononucleosis is associated with the development of EBV-specific antibodies and memory cytotoxic T-cells, which are present in the peripheral blood of all normal seropositive individuals. We studied four patients who had persistent symptoms for more than two years after infectious mononucleosis to determine if this abnormality was associated with a defect in EBV-specific or non-specific immune responses. All four patients had normal immunoglobulin concentrations, T- and B-cell numbers, T-cell proliferative responses and natural killer cell activity. However three of the four had reduced or absent antibodies to the EBV nuclear antigen (EBNA) although other EBV-specific antibody titres were normal. All four also had reduced EBV-specific cytotoxic T-cell activity as measured by the EBV regression assay. This defect was probably EBV-specific as alloreactive cytotoxic T-cell responses were normal. In addition, three of three patients tested had reduced in vitro antibody synthesis following pokeweed mitogen stimulation. These studies indicate that the syndrome of persistent symptoms following EBV mononucleosis may be associated with a defect in EBV-specific immunity, and thus suggest a possible immunological basis for the syndrome.     

Synthetic peptide derived from the epstein-barr virus encoded early diffuse antigen (ea-d) reactive with human antibodies

Primary infection with Epstein-Barr virus (EBV) and reactivation of latent virus are associated with increased antibody titers against the diffuse early antigen (EA-D). In order to better define the antigenic epitopes recognized by antibodies from patients with infectious mononucleosis (IM) and with other disease states, a series of synthetic peptides were prepared based on the DNA sequence encoding the EA-D molecule. One synthetic peptide (K7b) was reactive with the majority of sera from patients with acute IM. Anti-K7b activity was most readily detected among IgM and IgA antibodies and to a lesser extent among IgG antibodies. In contrast, significant elevations of anti-K7b activity were observed in less than 5% of healthy adults. Serial analysis of samples from individuals prior to and after exposure to EBV demonstrated increased anti-K7b reactivity associated with the symptoms of acute IM. Elevated anti-peptide K7b titers also were found in sera of patients with nasopharyngeal carcinoma and with Sjogren's syndrome (an autoimmune disease involving the salivary glands). Four different synthetic peptides from other regions of the EA-D molecule were not reactive with antibodies from these patients nor from IM patients. These results suggest that peptide K7b defines an antigenic epitope recognized during primary EBV infection and during viral reactivation occurring in patients with autoimmune and neoplastic disease.     

Immunogenetic analysis of variants of a clinical course and prognosis of chronic glomerulonephritis in the west Siberia

AIM: To analyze association of HLA antigens with clinical variants of chronic glomerulonephritis (CGN)in 106 patients. MATERIAL AND METHODS: HLA association with the time of development of terminal chronic renal failure (CRF) from the moment of detection of initial CRF was studied in 80 patients. Determination of HLA of class I was conducted in the lymphocytotoxic test. DRB1 genes specificity was determined with DNA polymerase chain reaction. The control group consisted of 341 healthy citizens of Novosibirsk. Common HLA associations of latent and hypertensive, latent and nephrotic CGN variants were found demonstrating their succession. HLA associations with a mixed CGN variant defining its genetic isolation were established. It is shown that development of terminal CRF at different time since the disease onset is associated with different HLA alleles. The findings allow prognosis of clinical CGN variants, time of development of terminal CRF.     

HLA-DQA1 and -DQB1 allele typing in southern Taiwanese women with breast cancer.

BACKGROUND: The pathogenesis of breast cancer is multifactorial. Genetic predisposition, environmental factors, hormones and even infection agents are thought to interact in the manifestation of breast cancer. In particular, human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. Regardless of the importance and functions of HLA genes in the evolution of cancer, the allele-specific association of HLA molecules in cancer patients has not been well established. Recently, a few studies have concentrated on the association between HLA and breast cancer, but the results of these studies are controversial. METHODS: We designed a study to evaluate the association between the genotype of HLA class II genes and breast cancer. HLA-DQA1 and -DQB1 polymorphisms were determined by PCR with sequence-specific primers (PCR-SSP) in 101 Taiwanese women patients with breast cancer and 115 matched control subjects. RESULTS: Using PCR-SSP typing, HLA-DQA1 and -DQB1 locus comparison of allele frequencies between breast cancer patients and healthy controls showed no significant difference. CONCLUSIONS: We have established a significant lack of HLA-DQA1 and -DQB1 association with breast cancer in southern Taiwanese women. The results of this study may provide information for further clarification of the etiology of breast cancer in this region.     

Epstein Barr Virus-specific Immune Defects in Patients with Persistent Symptoms Following Infectious Mononucleosis

In a number of patients recovery from infectious mononucleosis(IM) following primary Epstein Barr virus (EBV) infection, iscomplicated by the persistence of symptoms for months or years.Normally recovery from infectious mononucleosis is associatedwith the development of EBV-specific antibodies and memory cytotoxicT-cells, which are present in the peripheral blood of all normalseropositive individuals. We studied four patients who had persistentsymptoms for more than two years after infectious mononucleosisto determine if this abnormality was associated with a defectin EBV-specific or non-specific immune responses. All four patientshad normal immunoglobulin concentrations, T- and B-cell numbers,T-cell proliferate responses and natural killer cell activity.However three of the four had reduced or absent antibodies tothe EBV nuclear antigen (EBNA) although other EBV-specific antibodytitres were normal. All four also had reduced EBV-specific cytotoxicT-cell activity as measured by the EBV regression assay. Thisdefect was probably EBV-specific as alloreactive cytotoxic T-cellresponses were normal. In addition, three of three patientstested had reduced in vitro antibody synthesis following pokeweedmitogen stimulation. These studies indicate that the syndromeof persistent symptoms following EBV mononucleosis may be associatedwith a defect in EBV-specific immunity, and thus suggest a possibleimmunological basis for the syndrome     

Immunogenetic aspects of duodenal ulcer in Helicobacter pylori positive Europeans in Western Siberia

AIM: To study HLA associations with HP-positive duodenal ulcer (DU). MATERIAL AND METHODS: A total of 47 Europeoid DU and 680 healthy subjects were examined for class I and II HLA antigens. Typing of class I antigens was conducted in the microlymphocytotoxicity test, of class 2 antigens--by polymerase chain reaction. RESULTS: The study has found associations of duodenal ulcer with HLA-A10, -B41 and different combinations of these alleles whereas HLA-A9 was protective. A relative risk of peptic ulcer was 3.03 in HLA-A10 (pcor < 0.05) and 7.78 in HLA-B41 (p < 0.001). The allele A9 occurred more frequently in healthy controls (30.15%) than in Helicobacter pylori-positive patients with DU (10.64%, RR = 3.50, pcor < 0.05). Frequencies of alleles HLA-DR7 and HLA-A1/B12 were higher in HP-positive DU patients with family history of peptic ulcer (RR = 4.00 and RR = 11.92, respectively, p < 0.05). CONCLUSION: These data suggest that HLA may influence duodenal ulcer susceptibility and resistance. The relationships help prognosticate not only development of the disease in HP infection but also the age of the infection manifestation.     

Epitope focusing in the primary cytotoxic T cell response to Epstein- Barr virus and its relationship to T cell memory

The relationship between primary and memory cytotoxic T lymphocyte (CTL) responses, and the factors influencing entry into memory, are poorly understood. Here we address this in the context of Epstein-Barr virus (EBV), a persistent human herpesvirus in which memory CTL responses in long-term virus carriers are highly focused on epitopes preferentially drawn from just three of the eight available virus latent proteins, EBNAs 3A, 3B, and 3C. To determine whether this unusual level of focusing is a consequence of long-term virus challenge, we carried out a detailed analysis of EBV antigen/epitope specificities in the primary virus-induced CTL response in 10 infectious mononucleosis (IM) patients of different HLA types. Primary effectors, studied in ex vivo assays and by limiting dilution cloning in vitro, were again highly skewed toward a small number of viral epitopes, almost all derived from the EBNA3 proteins, with CTL to the immunodominant epitope accounting for at least 1% of the circulating CD8+ IM T cell pool. This is the first unequivocal demonstration of an EBV-specific CD8+ CTL response in IM. Prospective studies on individual patients showed that, whereas all of the EBV reactivities found in CTL memory had been detectable earlier during primary infection, the memory population was not simply a scaled down version of the primary response. In particular (a) differences in the relative frequencies of CTL to immunodominant versus subdominant epitopes appeared to be much less marked in memory than in primary populations, and (b) we found at least one clear example in which a significant virus-specific reactivity within the primary response was never detectable in memory.     

Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis.

The present study was designed to determine if highly conserved hepatitis B virus (HBV)-derived peptides that bind multiple HLA class I alleles with high affinity are recognized as cytotoxic T lymphocyte (CTL) epitopes in acutely infected patients. Peripheral blood mononuclear cells from 67 patients with acute hepatitis B, and 12 patients convalescent from acute hepatitis B, were stimulated with three panels of peptides, each of which bind with high affinity to several class I alleles from the HLA-A2-, HLA-A3-, or HLA-B7-supertypes. In these patients, 8 of the 19 peptides tested were found to represent CTL epitopes recognized by two or more alleles in each supertype. Two sets of nested peptides were recognized in the context of alleles with completely unrelated peptide binding specificities. Finally, promiscuous recognition by the same CTL of a given peptide presented by target cells expressing different A2 subtypes was also commonly observed. In conclusion, several HBV-specific CTL epitopes, recognized by acutely infected or convalescent patients in the context of a wide range of HLA alleles have been identified. These results demonstrate the functional relevance of the supertype grouping of HLA class I molecules in a human viral disease setting. Furthermore, they represent a significant advance in the development of a totally synthetic vaccine to terminate chronic HBV infection and support the feasibility of a systematic approach to development of similar vaccines for prevention and treatment of other chronic viral infections.     

Activity and Phenotype of Natural Killer Cells in Peptide Transporter (TAP)-deficient Patients (Type I Bare Lymphocyte Syndrome)

In this paper we describe the function and phenotype of natural killer (NK) lymphocytes from HLA class I–deficient patients. These cells are, as has been previously reported, unable to lyse HLA class I⁻ K562 cells, but are able to perform antibody-dependent cellular cytotoxicity (ADCC), although with lower efficiency as compared to NK cells from normal individuals. Transporter associated to antigen processing (TAP)⁻ NK cells proliferate when cultured in the presence of lymphoblastoid B cells (B-LCs) and interleukin 2 and develop a spectrum of cytotoxicity similar to that of activated normal NK cells. Importantly, activation of the TAP⁻ NK cells induces strong cytotoxicity to autologous B-LCs. Analysis of the phenotype of circulating TAP⁻ NK lymphocytes showed them to display a normal diverse repertoire of HLA class I–specific NK receptors. These receptors were expressed at normal levels, apart from the CD94–NKG2A complex, which appeared to be overexpressed. This latter finding could reflect an adaptation to the low expression of HLA class I molecules. Finally, functional analyses indicated that the inhibitory receptors in TAP⁻ individuals can transduce inhibitory signals. Our results suggest that in vivo, the NK cells of TAP⁻ patients could participate in immune defense, at least through ADCC, but upon activation, may be involved in autoimmune processes.Type I bare lymphocyte syndrome is a rare disease characterized by a strong reduction in the cell surface expression of HLA class I molecules. The patients are not reported to suffer from severe viral infections, which suggests that cell-mediated cytotoxic immune responses are efficient to some extent. However, chronic lung inflammation develops in late childhood. A few years ago we described two siblings, EMO and EFA, who are homozygous for a stop mutation in the gene encoding the TAP2 subunit of the peptide transporter associated to antigen processing (TAP; 1). As a result of this deficiency, most HLA class I molecules remain peptide-free and cannot reach the cell surface. Thus, the TAP-deficient cells from these patients express <3% of HLA class I molecules as compared to normal cells. Nevertheless, CD8⁺ α/β T cells are present among their PBMCs. Recent observations (2) suggest that some of these cells may recognize TAP-independent HLA class I–restricted viral antigens and participate in the development of the immune response, thus explaining the absence of a greater susceptibility to viral infection in these patients.Immune responses are also controlled by NK cells. These lymphocytes are cytotoxic to certain tumor cells, HLA class I⁻ cells, and virus-infected cells and mediate antibody-dependent cellular cytotoxicity (ADCC; 3). The importance of these cells in human immune responses is indicated by the association of severe infections with herpesvirus and EBV with an absence of NK cells or with a reduction of their activity (4, 5).Several molecules expressed at the surface of NK cells are involved in the recognition of target cells and control their cytotoxic activity (6). Some are activating receptors; among these is the type III low affinity receptor for IgG, or CD16, which is involved in ADCC. Other receptors, called killer inhibitory receptors (KIRs), block the cytotoxic process when they interact with the HLA class I molecules expressed on normal cells. In humans, these receptors may be classified in two main families. The receptors specific for subsets of the alleles of HLA-C (p58), HLA-B (p70), and HLA-A (p140) belong to the Ig superfamily (Ig-SF; 6). In contrast, the CD94–NKG2A (or -B) receptor complex is composed of proteins homologous to C-type lectins and displays a broader specificity for different HLA class I alleles (7). More recently, receptors have been described that are homologous to KIRs, but activate the cytotoxicity of NK cells (6, 7).In a previous paper, we reported that NK cells from TAP-deficient patients were unable to lyse HLA class I⁻ K562 tumor cells, suggesting that these cells were not functional (1). However, since the patients do not seem to suffer from severe herpesvirus or EBV infections, this may indicate that their NK cells possess immunological functions. The cytotoxic activity of NK cells from TAP-deficient patients was therefore reexamined in the present study. In a second step, we investigated whether a defective expression of class I molecules could affect the repertoire of HLA class I–specific receptors on NK cells. Finally, we explored the functionality of the inhibitory receptors of these cells.     

Infectious mononucleosis

Infectious mononucleosis (IM) is the manifestation of primary infection with Epstein-Barr virus (EBV). EBV persisting after infection for a life-time infects > 90% of the adult population. Primary infection mostly asymptomatic in young children manifests in teenagers and young adults in about 50% as IM with fever, sore throat, generalized lymphadenopathy, frequently hepatosplenomegaly and blood lymphocytosis with the characteristic atypical lymphocytes. Clinical presentation, typical lymphocytosis and heterophile antibodies are diagnostic. Atypical cases may need to be confirmed by specific serology. IM is a self-limiting lymphoproliferation regressing within 2-3 weeks. Complications are rare and may involve many different organs. Severe cases are very uncommon, except in patients with inborn or acquired immunodeficiency carrying a substantially higher risk for severe courses, pogredient lymphoproliferation and lymphoma.     

Infectious mononucleosis with atypical manifestations accompanied by transient IgM antibody response for cytomegalovirus

Infectious mononucleosis (IM) is a clinical syndrome caused by primary infection with Epstein–Barr virus (EBV) that is common in adolescents. In adults, particularly in elderly people, the clinical picture of IM tends to be atypical, often leading to a diagnostic challenge. Diagnosis is also complicated because infection with EBV can induce the synthesis of cross-reacting immunoglobulin M antibodies for other herpesviruses. We report an unusual case of infectious mononucleosis in a 34-year-old immunocompetent adult. Epidemiological studies indicate that the average age of primary EBV infection in developed countries is increasing. IM with atypical presentation will be a diagnostic challenge in the future as the number of EBV-naïve adults increases.     

Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer

The nature and frequency of human histocompatibility leukocyte antigen (HLA) class I loss mechanisms in primary cancers are largely unknown. We used flow cytometry and molecular analyses to concurrently assess allele-specific HLA phenotypes and genotypes in subpopulations from 30 freshly isolated cervical tumor cell suspensions.Tumor-associated HLA class I alterations were present in 90% of the lesions tested, comprising four altered pheno/genotype categories: (a) HLA-A or -B allelic loss (17%), mostly associated with gene mutations; (b) HLA haplotype loss, associated with loss of heterozygosity at 6p (50%). This category included cases with additional loss of a (third) HLA-A or -B allele due to mutation, as well as one case with an HLA class I-negative tumor cell subpopulation, caused by a beta2-microglobulin gene mutation; (c) Total HLA class I antigen loss and retention of heterozygosity (ROH) at 6p (10%); and (d) B locus or HLA-A/B downregulation associated with ROH and/or allelic imbalance at 6p (10%). Normal HLA phenotypes and ROH at 6p were observed in 10% of the cases. One case could not be classified (3%).Altered HLA class I antigen expression occurs in most cervical cancers, is diverse, and is mainly caused by genetic changes. Combined with widespread tumor heterogeneity, these changes have profound implications for natural immunity and T cell-based immunotherapy in cervical cancer.     

Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).

Previous studies in Caucasians with progressive systemic sclerosis (PSS) have suggested associations of antitopoisomerase I (antitopo I) autoantibodies with either serologically defined HLA-DR2 or DR5. To better define class II HLA associations with the antitopo I response, 161 PSS patients (132 Caucasians and 29 American blacks) were studied for antitopo I autoantibodies by immunodiffusion and immunoblotting, and their HLA-DRB1, DRB3, DQA1, and DQB1 alleles were determined by restriction fragment length polymorphic analysis and DNA oligotyping. Among Caucasians with antitopo I, HLA-DR5(DRB1*1101-*1104), DRB3*0202 and DQw3 (DQw7,8,9) were significantly increased in frequency. In American blacks, however, only HLA-DQB1*0301(DQw7) was significantly increased. The presence of HLA-DQB1*0301(DQw7) and other HLA-DQB1 alleles bearing the uncharged polar amino acid residue tyrosine at position 30 of the outermost domain was found in all antitopo I-positive Caucasian PSS patients compared with 66% of antitopo I-negative PSS patients (pc = 0.007) and 70% of normal controls (pc = 0.008), as well as all antitopo I-positive black patients. The association with HLA-DQB1 was independent of HLA-DR5(DRB1*1101-*1104) or any other HLA-DRB1, DRB3, or DQA1 alleles. Alternative or additional candidate epitopes for this autoimmune response include alanine at position 38 and threonine at position 77 of these same DQB1 alleles. These data suggest that genetic predisposition to the antitopo I response in PSS is associated most closely with the HLA-DQB1 locus.     

MICA polymorphism is associated with type 1 diabetes in the Korean population

OBJECTIVE: Recent studies have demonstrated that MICA (major histocompatibility complex class I chain-related genes) on the short arm of the chromosome 6 are associated with susceptibility to various autoimmune diseases in Caucasians. The aim of our study was to investigate the role of MICA in type 1 diabetes susceptibility independent of the HLA DR-DQ polymorphism in genetically distinct Koreans. RESEARCH DESIGN AND METHODS: A total of 119 patients selected from Korean Seoul type 1 diabetes registry and 134 nondiabetic unrelated control subjects were typed for exon 5 polymorphism of MICA in addition to HLA DR-DQ typing. A total of 52 simplex families of type 1 diabetes were also studied. RESULTS: The MICA microsatellite allele consisting of six repetitions of GCT/AGC (A6) was present at a significantly lower frequency in the diabetic patient group (Pc < 0.01; Pc = P value after Bonferroni correction) than in the control population. The MICA microsatellite allele consisting of four repetitions (A4) was present at a higher frequency in diabetic patients (P < 0.05). This deviated distribution was not changed even after controlling for the HLA DRB1-DQB1 haplotype. Transmission/disequilibrium test revealed significant deviation of transmission for alleles at the A6 polymorphism within the MICA gene (P < 0.05). CONCLUSIONS: We could assess that the MICA gene might be associated with type 1 diabetes transracially independent of the HLA gene.     

Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I.

14 gorilla class I major histocompatibility complex (MHC) alleles have been isolated, sequenced, and compared to their counterparts in humans and chimpanzees. Gorilla homologues of HLA-A, -B, and -C were readily identified, and four Gogo-A, four Gogo-B, and five Gogo-C alleles were defined. In addition, an unusual Gogo class I gene with features in common with HLA-A and its related pseudogene, HLA-H, is described. None of the gorilla alleles is identical or even closely related to known class I alleles and each encodes a unique antigen recognition site. However, the majority of polymorphic substitutions and sequence motifs of gorilla class I alleles are shared with the human or chimpanzee systems. In particular, elements shared with HLA-A2 and HLA-B27 are found in Gogo-A and -B alleles. Diversity at the Gogo-B locus is less than at the Gogo-A locus, a trend the opposite of that seen for HLA-A and -B. The Gogo-C locus also appears to have limited polymorphism compared to Gogo-A. Two basic Gogo-C motifs were found and they segregate with distinctive sets of HLA-C alleles. HLA-A allels are divided into five families derived from two ancient lineages. All chimpanzee A alleles derived from one of these lineages and all gorilla alleles derive from the other. Unlike chimpanzee Patr-A alleles, the Gogo-A alleles do not clearly partition with one of the HLA-A families but have similarities with two. Overall, gorilla class I diversity appears from this sampling to show more distinctions from class I HLA than found for chimpanzee class I.