Genetic Factors Affecting the Occurrence, Clinical Phenotype, and Outcome of Autoimmune Hepatitis
2008; Elsevier BV; Volume: 6; Issue: 4 Linguagem: Inglês
10.1016/j.cgh.2007.12.048
ISSN1542-7714
Autores Tópico(s)Systemic Lupus Erythematosus Research
ResumoAutoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67–72 in the DRβ polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRβ71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRβ71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-α gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor–receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general. Autoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67–72 in the DRβ polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRβ71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRβ71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-α gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor–receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general. Autoimmune hepatitis is a self-perpetuating liver inflammation of unknown cause that is characterized by interface hepatitis on histologic examination, hypergammaglobulinemia, and autoantibodies.1Alvarez F. Berg P.A. Bianchi F.B. et al.International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis.J Hepatol. 1999; 31: 929-938Abstract Full Text Full Text PDF PubMed Scopus (1363) Google Scholar, 2Czaja A.J. Freese D.K. 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Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.Liver Transpl. 2002; 8: 505-513Crossref PubMed Scopus (60) Google Scholar This hypothesis holds that the triggering epitope is a short, commonly shared, amino acid sequence, and it is founded on the observations that diverse viruses and medications can cause similar immune manifestations and liver dysfunction.4Czaja A.J. Understanding the pathogenesis of autoimmune hepatitis.Am J Gastroenterol. 2001; 96: 1224-1231Crossref PubMed Google Scholar, 5Vergani D. Choudhuri K. Bogdanos D.P. et al.Pathogenesis of autoimmune hepatitis.Clin Liver Dis. 2002; 6: 727-737Abstract Full Text Full Text PDF PubMed Google Scholar, 6Czaja A.J. Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.Liver Transpl. 2002; 8: 505-513Crossref PubMed Scopus (60) Google ScholarRepeated exposures to a critical epitope may generate promiscuous T lymphocytes through molecular mimicry, and these activated lymphocytes may in turn overcome self-tolerance.4Czaja A.J. Understanding the pathogenesis of autoimmune hepatitis.Am J Gastroenterol. 2001; 96: 1224-1231Crossref PubMed Google Scholar, 5Vergani D. Choudhuri K. Bogdanos D.P. et al.Pathogenesis of autoimmune hepatitis.Clin Liver Dis. 2002; 6: 727-737Abstract Full Text Full Text PDF PubMed Google Scholar, 7Hammer J. Valsasnini P. Tolba K. et al.Promiscuous and allele-specific anchors in HLA-DR-binding peptides.Cell. 1993; 74: 197-203Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 8Doherty D.G. Penzotti J.E. 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Tolba K. et al.Promiscuous and allele-specific anchors in HLA-DR-binding peptides.Cell. 1993; 74: 197-203Abstract Full Text PDF PubMed Scopus (275) Google Scholar Active expansion of these immunocytes may in turn result in the development of concurrent immune diseases.5Vergani D. Choudhuri K. Bogdanos D.P. et al.Pathogenesis of autoimmune hepatitis.Clin Liver Dis. 2002; 6: 727-737Abstract Full Text Full Text PDF PubMed Google Scholar, 10Bogdanos D.P. Choudhuri K. Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences.Liver. 2001; 21: 225-232Crossref PubMed Scopus (94) Google ScholarMolecular mimicry can occur when there are homologous amino acid sequences within peptides or similar conformational epitopes in structurally dissimilar peptides.5Vergani D. Choudhuri K. Bogdanos D.P. et al.Pathogenesis of autoimmune hepatitis.Clin Liver Dis. 2002; 6: 727-737Abstract Full Text Full Text PDF PubMed Google Scholar, 10Bogdanos D.P. Choudhuri K. Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences.Liver. 2001; 21: 225-232Crossref PubMed Scopus (94) Google Scholar Homologies between various viral genomes (hepatitis C virus, cytomegalovirus, and herpes simplex type 1 virus) and recombinant CYP2D6, which is the target antigen associated with one form of autoimmune hepatitis, suggest that multiple exposures to these or similar viruses may be one mechanism by which to break self-tolerance.4Czaja A.J. Understanding the pathogenesis of autoimmune hepatitis.Am J Gastroenterol. 2001; 96: 1224-1231Crossref PubMed Google Scholar, 5Vergani D. Choudhuri K. Bogdanos D.P. et al.Pathogenesis of autoimmune hepatitis.Clin Liver Dis. 2002; 6: 727-737Abstract Full Text Full Text PDF PubMed Google Scholar, 6Czaja A.J. Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.Liver Transpl. 2002; 8: 505-513Crossref PubMed Scopus (60) Google Scholar, 7Hammer J. 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Okamoto M. et al.Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients associated with the possession of HLA B51.Int J Immunopathol Pharmacol. 2004; 17: 83-92PubMed Google Scholar The association of HLA B51 with cross-reactive immune responses between viral and microsomal antigens suggests that molecular mimicry is favored by genetic predisposition.13Bogdanos D.P. Lenzi M. Okamoto M. et al.Multiple viral/self immunological cross-reactivity in liver kidney microsomal antibody positive hepatitis C virus infected patients associated with the possession of HLA B51.Int J Immunopathol Pharmacol. 2004; 17: 83-92PubMed Google ScholarRecent studies have emphasized the importance of genetic factors in the occurrence, clinical expression, and behavior of autoimmune hepatitis.14Strettell M.D.J. Donaldson P.T. 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Cupo S. et al.X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II.Immunity. 1997; 7: 473-481Abstract Full Text Full Text PDF PubMed Google ScholarType 1 Autoimmune HepatitisType 1 autoimmune hepatitis is the most common form of autoimmune hepatitis, and it is characterized by the presence of antinuclear antibodies and/or smooth muscle antibodies.45Czaja A.J. Manns M.P. The validity and importance of subtypes of autoimmune hepatitis: a point of view.Am J Gastroenterol. 1995; 90: 1206-1211PubMed Google Scholar The susceptibility alleles for type 1 autoimmune hepatitis in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401 (Table 1).14Strettell M.D.J. Donaldson P.T. Thomson L.J. et al.Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis.Gastroenterology. 1997; 112: 2028-2035Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 15Czaja A.J. Strettell M.D.J. Thomson L.J. et al.Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis.Hepatology. 1997; 25: 317-323Crossref PubMed Google Scholar, 22Teufel A. Worns M. Weinmann A. et al.Genetic association of autoimmune hepatitis and human leukocyte antigen in German patients.World J Gastroenterol. 2006; 12: 5513-5516PubMed Google Scholar, 46Doherty D.G. Donaldson P.T. Underhill J.A. et al.Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis.Hepatology. 1994; 19: 609-615Crossref PubMed Google Scholar Analyses of amino acid sequence variations encoded by these alleles indicate that the core motif associated with type 1 autoimmune hepatitis in these populations is a 6 amino acid sequence, encoded as L (leucine), L (leucine), E (glutamic acid), Q (glutamine), K (lysine), and R (arginine), at positions DRβ67–72 within the antigen-binding groove (Figure 1).14Strettell M.D.J. Donaldson P.T. Thomson L.J. et al.Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis.Gastroenterology. 1997; 112: 2028-2035Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 46Doherty D.G. Donaldson P.T. Underhill J.A. et al.Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis.Hepatology. 1994; 19: 609-615Crossref PubMed Google Scholar Lysine (K) at position DRβ71 is at the lip of the antigen-binding groove, and it is at a critical contact point between the antigen, the class II MHC molecule, and the T-cell–antigen receptor. In white North American and northern European patients with type 1 autoimmune hepatitis, the optimal presentation of antigens by the class II MHC molecules depends on lysine at position DRβ71.14Strettell M.D.J. Donaldson P.T. Thomson L.J. et al.Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis.Gastroenterology. 1997; 112: 2028-2035Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 46Doherty D.G. Donaldson P.T. Underhill J.A. et al.Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis.Hepatology. 1994; 19: 609-615Crossref PubMed Google ScholarTable 1Susceptibility Alleles of the MHC Associated With Type 1 Autoimmune HepatitisMHC alleleSusceptible populationEffectsDRB1*0301White North American, northern European, and ItaliansEncodes LLEQ-K-R at DRβ 67–72 with lysine (K) at DRβ71 as key factorDRB1*0401White North American and northern EuropeanSame as DRB1*0301DRB1*0404Mestizo MexicansEncodes LLEQ-R-R with arginine (R) at DRβ71DRB1*0405Japanese, mainland Chinese, Argentine adultsSame as DRB1*0404DRB1*1301Brazilians, Argentine childrenEncodes ILED-E-R with glutamic acid (E) at DRβ71; associated with protracted hepatitis ADRB1*1501Northern EuropeanEncodes ILEQ-A-R with alanine at DRβ71; protective against type 1 autoimmune hepatitis Open table in a new tab In contrast, DRB1*1501 protects against type 1 autoimmune hepatitis in white adult North Americans and northern Europeans, and this allele encodes an isoleucine (I) for leucine (L) at position DRβ67 and an alanine (A) for lysine (K) at position DRβ71 (Table 1).14Strettell M.D.J. Donaldson P.T. Thomson L.J. et al.Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis.Gastroenterology. 1997; 112: 2028-2035Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 46Doherty D.G. Donaldson P.T. Underhill J.A. et al.Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis.Hepatology. 1994; 19: 609-615Crossref PubMed Google Scholar Alanine is a neutral, nonpolar amino acid whose substitution for lysine would greatly affect antigen presentation and immunocyte activation. The substitution of this single amino acid at a critical location in the antigen-binding groove of the class II MHC molecule may prevent disease occurrence by altering antigen recognition. The impact of select changes in critical regions of the antigen-binding groove already have been shown in insulin-dependent diabetes mellitus47Becker K.G. 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Katsuyama Y. et al.Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis.J Hepatol. 2005; 42: 578-584Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 25Yokosawa S. Yoshizawa K. Ota M. et al.A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1.Hepatology. 2007; 45: 384-390Crossref PubMed Scopus (25) Google Scholar, 51Seki T. Kiyosawa K. Inoko H. et al.Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients.Hepatology. 1990; 12: 1300-1304Crossref PubMed Scopus (104) Google Scholar, 52Seki T. Ota M. Furuta S. et al.HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients.Gastroenterology. 1992; 103: 1041-1047Abstract PubMed Google Scholar mainland China,53Qiu D.-K. Ma X. Relationship between human leukocyte antigen-DRB1 and autoimmune hepatitis type I in Chinese patients.J Gastroenterol Hepatol. 2003; 18: 63-67Crossref PubMed Scopus (28) Google Scholar and Mexico54Vazquez-Garcia M.N. Alaez C. Olivo A. et al.MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis.J Hepatol. 1998; 28: 985-990Abstract Full Text PDF PubMed Scopus (60) Google Scholar is associated with the susceptibility alleles DRB1*0404 and DRB1*0405, which encode an arginine (R) for lysine (K) at the DRβ71 position (Table 1). Arginine (R) is a polar amino acid that is structurally similar to lysine, and its substitution for lysine at position DRβ71 would not greatly alter the steric and electrostatic properties of the class II MHC molecule.16Czaja A.J. Donaldson P.T. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis.Immunol Rev. 2000; 174: 250-259Crossref PubMed Google Scholar, 17Czaja A.J. Doherty D.G. Donaldson P.T. Genetic bases of autoimmune hepatitis.Dig Dis Sci. 2002; 47: 2139-2150Crossref PubMed Scopus (60) Google Scholar, 18Donaldson P.T. Genetics in autoimmune hepatitis.Semin Liver Dis. 2002; 22: 353-364Crossref PubMed Scopus (49) Google Scholar, 55Donaldson P.T. Czaja A.J. Genetic effects on susceptibility, clinical expression, and treatment outcome of type 1 autoimmune hepatitis.Clin Liver Dis. 2002; 6: 707-725Abstract Full Text Full Text PDF PubMed Google Scholar, 56Schreuder G.M. Hurley C.K. Marsh S.G. et al.The HLA dictionary 2001: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and –DQ antigens.Hum Immunol. 2001; 62: 826-849Crossref PubMed Scopus (23) Google ScholarDRB1*1301 is associated with type 1 autoimmune hepatitis in Argentine children27Fainboim L. Marcos Y. Pando M. et al.Chronic active autoimmune hepatitis in children Strong association with a particular HLA DR6 (DRB1*1301) haplotype.Hum Immunol. 1994; 41: 146-150Crossref PubMed Google Scholar, 28Pando M. Larriba J. Fernandez G.C. et al.Pediatric and adult forms of type 1 autoimmune hepatitis in Argentina: evidence for differential genetic predisposition.Hepatology. 1999; 30: 1374-1380Crossref PubMed Google Scholar and Brazilian patients,24Goldberg A.C. Bittencourt P.L. Oliveira L.C. et al.Autoimmune hepatitis in Brazil: an overview.Scand J Immunol. 2007; 66: 208-216Crossref PubMed Scopus (9) Google Scholar, 29Bittencourt P.L. Goldberg A.C. Cancado E.L.R. et al.Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2.Am J Gastroenterol. 1999; 94: 1906-1913Crossref PubMed Scopus (83) Google Scholar, 30Goldberg A.C. Bittencourt P.L. Mougin B. et al.Ana
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