Specific Human Leukocyte Antigen Alleles Research Articles

Mechanisms of autoimmune hepatitis

Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease with a female preponderance, responsive to immunosuppressive treatment. Two types of AIH are described: type 1 AIH is characterized by positivity for smooth muscle and/or antinuclear antibody, while type 2 AIH is positive for liver kidney microsomal type 1 antibody. The putative mechanisms leading to the development of this condition include genetic predisposition to autoimmunity through possession of specific human leukocyte antigen alleles, immune reactions to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, where immune responses to external pathogens, e.g. viruses, become directed toward structurally similar self-components, and an impairment in immune regulation. AIH has been described to arise de novo after liver transplantation. The mechanisms leading to post-transplant autoimmunity remain to be defined.

HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease.

Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequence-specific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P =.002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P =.001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P =.003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P =.0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage.

Human leukocyte antigen class II immune response genes, female gender, and cigarette smoking as risk and modulating factors in abdominal aortic aneurysms

Objective: Aortic inflammation and the genes that regulate the immune response play an important role in abdominal aortic aneurysm pathogenesis. However, the modulating effects of such genetic and other environmental factors on the severity on aneurysm inflammation is not known. The objective of this study was to determine the influence of the human leukocyte antigen (HLA) class II genes, gender, and environmental factors on degree of abdominal aortic aneurysm tissue inflammation. Methods: Aneurysm specimens were obtained at the time of operation from 96 consecutive patients who underwent abdominal aortic aneurysm repair and were graded for degree of histologic inflammation. Multivariate analysis was used to determine the association of genetic and environmental factors with degree of inflammation and to determine the HLA-associated disease risk for aneurysm. Results: Active cigarette smoking and female gender were independently associated with high-grade tissue inflammation identified histologically (odds ratio [OR], confidence interval [CI]: 5.6, 1.6 to 19.3; and 6.0, 1.4 to 26.2, respectively), and a specific HLA allele (DR B1*01) was inversely associated with inflammation (OR, CI: 0.2, 0.04 to 0.7). Overall, the HLA-DR B1*02 and B1*04 alleles were significantly associated with disease risk, more than doubling risk for abdominal aortic aneurysm (OR, CI: 2.5, 1.4 to 4.3; and 2.1, 1.2 to 3.7, respectively). Conclusion: Active cigarette smoking and female gender are significant disease-modulating factors associated with increased abdominal aortic aneurysm inflammation. In addition, the HLA class II immune response genes possess both disease modulating and disease risk properties, which may be useful in early aneurysm detection and surveillance. (J Vasc Surg 2002;35:988-93.)

Atopy and asthma genes--where do we stand?

Atopy and asthma genes--where do we stand?

Immunodominance Across HLA Polymorphism: Implications for Cancer Immunotherapy

Recent advances in the understanding of the mechanisms leading to tumor recognition by the immune system have shown that, at least in the case of human melanoma, the majority of cytotoxic T lymphocytes (CTL) identified in association with in vivo tumor regression after interleukin-2 therapy recognize nonmutated molecules expressed by most melanoma cells. For this reason, peptide-based or whole protein vaccination protocols against melanoma-associated antigens (MAA) are ongoing in several institutions, with the goal of inducing tumor regression by enhancing in vivo specific antitumor CTL reactivity. The rationale for the use of such vaccines is supported by: (a) preclinical evidence that vaccination with major histocompatibility complex class I restricted epitopes can enhance effectively cellular immunity, (b) evidence that potent antimelanoma CTL reactivity can be generated by repetitive in vitro stimulation of peripheral blood monocytes with MAA, and (c) evidence that the systemic administration of the same MAA can elicit antitumor CTL reactivity in vivo. As strategies are being developed for the development of sound vaccines, two basic approaches are investigated: one vaccination strategy is based on the administration of the specific amino acid sequence recognized by the CTL in association with a particular human leukocyte antigen (HLA) restriction element, and the other is based on the administration of the whole antigenic molecule, which relies on the organism's antigen-processing capabilities to render suitable the antigen for induction of HLA class I restricted CTL reactivity in vivo. Among the various factors complicating T-cell-based vaccination approaches stands the polymorphism of the HLA molecules. HLA are the most polymorphic of human genes, and because such polymorphism is clustered in the functional peptide-binding region, the binding of antigenic peptides is necessarily restricted to specific HLA alleles. This limits the interactions between CTL and antigen to specific sequences for each HLA allele. For this reason, the ability of an individual antigen to function as a T-cell immunogen in the context of different HLA allele restriction elements is an open question. It seems logical that whole-molecule vaccines have the potential advantage of broader use across patient populations. In particular, large antigenic molecules may contain multiple peptide sequences with putative binding properties for different HLA alleles, which in turn may elicit T-cell reactivity across the polymorphism of HLA. Such a concept, however, relies on the assumption that the same antigen may function with similar efficiency as an immunogen in association with different HLA alleles, independently from the epitopic sequence recognized in the various situations. This concept has been challenged recently by several practical observations and remains, in our opinion, an open question. This review will address the practical question of immunogenicity of molecules across the HLA polymorphism. We postulate that the complexity and success of the development of peptide-based vaccination strategies depend on the severity of this restriction, which is currently only incompletely studied and understood. Although no solutions are offered to the problem, emphasis is placed on the importance of this question, hopefully to stimulate the interest of other researchers, particularly in clinical settings, toward the investigation of this type of problem.

Immunogenetics and IDDM

Comparison of genetic determinants associated with susceptibility to IDDM in different countries remains important for understanding disease epidemiology and aetiology. The strong association of the human leukocyte antigens (HLA) with IDDM continues to be demonstrated in different populations. Genetic heterogeneity of HLA is always encountered in different ethnic groups and in the patients with varying clinical manifestations. Detailed studies by molecular design help to unify the hypothesis that the structural and functional changes in HLA class 11 molecules leads to autoimmune processes. Our studies in the Chinese living in Taiwan reveal that certain HLA class II alleles confer predisposition to or protection from IDDM. Moreover, some of them contribute to the clinical heterogeneity among IDDM subjects, eg. the presence or absence of thyroid autoantibodies. Although the specific HLA alleles might not be the true pathogenic factor(s) for IDDM or thyroid autoimmunity, the inference from the structural biology of the HLA molecules suggests that the amino acid residue 57 of the HLA DQβ chain might play a role in antigen presentation and T cell recognition. This hypothesis is almost correct through tests so far inmost of the populations except in the Japanese. However, the single HLA-DQB-57 locus is not sufficient to explain the difference in the world-wide incidence of IDDM. In complementation with HLA-DQα chain, HLA-DQα, β heterodimers strongly influence the risk to IDDM in Chinese population as well as in other ethnic groups, suggesting the direct role of HLA-DQ genes in IDDM. There are many genes resided within the MHC region on the short arm of chromosome 6. The presence of the linkage disequilibrium between these loci render it difficult to establish the role of individual genes. We have characterized a diallelic polymorphism of heat shock protein 70 gene on the chromosome 6 (HSP70-2 and HLA loci contribute to IDDM independently although these loci are in linkage disequilibrium. In conclusion, molecular typing of HLA class II genes allows us to re-examine the role of HLA in IDDM. Other genetic and environmental factors also contribute to the pathogenesis of IDDM.

Sharing of human leukocyte antigens in couples with unexplained infertility affects the success of in vitro fertilization and tubal embryo transfer

<b>Objective:</b> The purpose was to test further our hypothesis that genes, or genetic defects, linked to the major histocompatibility complex affect reproduction by correlating human leukocyte antigen sharing with the success or failure of in vitro fertilization and tubal embryo transfer in couples having unexplained infertility. <b>Study Design:</b> Seventy-six couples with unexplained infertility who failed superovulation and intrauterine insemination at least three times were typed for human leukocyte antigens and treated by in vitro fertilization and tubal embryo transfer. The results were correlated with the sharing of human leukocyte antigens in the couples. <b>Results:</b> Thirty-four of the women had successful pregnancies, 36 did not become pregnant, and six became pregnant but aborted shortly thereafter. There was a highly significant excess of human leukocyte antigen sharing in the couples who failed treatment: three of the A, B, DR, and DO antigens (<i>p</i> = 0.015) or two of the B, DR, and DO antigens (<i>p</i> = 0.015). No specific human leukocyte antigen alleles were present in excess. <b>Conclusions:</b> Genes, or genetic defects, linked to the major histocompatibility complex significantly affect the success of in vitro fertilization and tubal embryo transfer just as they affect the prevalence of recurrent spontaneous abortion, cancer, and congenital anomalies. It appears as if the critical genes, or genetic defects, are located in the B-DR-DO region of the major histocompatibility complex.

Sharing of human leukocyte antigens in couples with unexplained infertility affects the success of in vitro fertilization and tubal embryo transfer

OBJECTIVE: The purpose was to test further our hypothesis that genes, or genetic defects, linked to the major histocompatibility complex affect reproduction by correlating human leukocyte antigen sharing with the success or failure of in vitro fertilization and tubal embryo transfer in couples having unexplained infertility. STUDY DESIGN: Seventy-six couples with unexplained infertility who failed superovulation and intrauterine insemination at least three times were typed for human leukocyte antigens and treated by in vitro fertilization and tubal embryo transfer. The results were correlated with the sharing of human leukocyte antigens in the couples. RESULTS: Thirty-four of the women had successful pregnancies, 36 did not become pregnant, and six became pregnant but aborted shortly thereafter. There was a highly significant excess of human leukocyte antigen sharing in the couples who failed treatment: three of the A, B, DR, and DQ antigens (p = 0.015) or two of the B, DR, and DQ antigens (p = 0.015). No specific human leukocyte antigen alleles were present in excess. CONCLUSIONS: Genes, or genetic defects, linked to the major histocompatibility complex significantly affect the success of in vitro fertilization and tubal embryo transfer just as they affect the prevalence of recurrent spontaneous abortion, cancer, and congenital anomalies. It appears as if the critical genes, or genetic defects, are located in the B-DR-DQ region of the major histocompatibility complex. (AM J OBSTET GYNECOL 1994;170:63-71.)

Differences between white and Chinese populations in human leukocyte antigen sharing and gestational trophoblastic tumors

The prevalence of gestational trophoblastic tumors varies widely among different populations: it is lowest in whites (3 to 6/100,000) and highest in Chinese (68 to 202/100,000). This observation suggests that the origin of the disease is different in the two populations. To test this hypothesis, we examined couples in whom the woman developed a gestational trophoblastic tumor in a white population (Pittsburgh) and a Chinese population (Taiwan) for sharing of human leukocyte A, B, DR, and DQ antigens, which we consider markers for sharing of major histocompatibility complex-linked recessive genes affecting both embryogenesis and carcinogenesis. No human leukocyte antigen sharing occurred between partners in Pittsburgh, but there was significant human leukocyte antigen sharing in Taiwan. The latter couples shared human leukocyte antigen B ( p < 0.04) and human leukocyte antigen DQ ( p < 0.007) and shared three or more human leukocyte A, B, DR, and DQ antigens ( p < 0.02) significantly more frequently than did normal couples. However, there was no increased sharing of any specific human leukocyte antigen allele. These findings support the hypothesis that gestational trophoblastic tumors occur on a sporadic basis in whites and on a genetic basis in Chinese.