Clinical Gastroenterology and Hepatology
Volume 6, Issue 4 , Pages 379-388, April 2008

Genetic Factors Affecting the Occurrence, Clinical Phenotype, and Outcome of Autoimmune Hepatitis

  • Albert J. Czaja

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Albert J. Czaja, MD, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. fax: (507) 284-0538.

published online 10 March 2008.

Article Outline

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.

Abbreviations used in this paper: anti-LKM1, antibodies to liver/kidney microsome type 1, MHC, major histocompatibility complex

 

Autoimmune hepatitis is a self-perpetuating liver inflammation of unknown cause that is characterized by interface hepatitis on histologic examination, hypergammaglobulinemia, and autoantibodies.1, 2, 3 The bases for the disease are unknown, but there is a presumed loss of self-tolerance after repeated exposure to foreign antigens that resemble self-antigens.4, 5, 6 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.4, 5, 6

Repeated exposures to a critical epitope may generate promiscuous T lymphocytes through molecular mimicry, and these activated lymphocytes may in turn overcome self-tolerance.4, 5, 7, 8 The antigen-sensitized immunocytes may be directed against anatomically distant organs in the same individual because their T-cell–antigen receptor is imprecise and the various self-antigens are similar to each other.7, 8, 9 This promiscuous behavior is enhanced by antigen-presenting molecules that can cradle different but similar peptides that continue to sensitize naive immunocytes.7 Active expansion of these immunocytes may in turn result in the development of concurrent immune diseases.5, 10

Molecular mimicry can occur when there are homologous amino acid sequences within peptides or similar conformational epitopes in structurally dissimilar peptides.5, 10 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.4, 5, 6, 7, 11, 12 Cross-reactivity also has been shown between hepatitis C virus antigens and host-derived smooth muscle and nuclear antigens.13 The association of HLA B51 with cross-reactive immune responses between viral and microsomal antigens suggests that molecular mimicry is favored by genetic predisposition.13

Recent studies have emphasized the importance of genetic factors in the occurrence, clinical expression, and behavior of autoimmune hepatitis.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 These genetic factors can affect autoantigen presentation and the activation, proliferation, and elimination of sensitized immunocytes. Autoimmune hepatitis is a complex polygenic immune disorder, and the perturbations in immune homeostasis that contribute to the disease only partially are understood.37 Recent clarification of the human genome38 and technologic advances in gene assessment promise to fill the knowledge gaps.25, 39, 40, 41

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Principal Genetic Drivers of Susceptibility 

Antigens are displayed within the binding groove of class II molecules of the major histocompatibility complex (MHC) (Figure 1).42, 43, 44 The alignment of the processed peptide within the binding groove and its ability to be recognized by uncommitted CD4 T-helper cells are affected mainly by the structure of the DRβ chain. The DRβ chain of the class II MHC molecule has polymorphic amino acid residues that are clustered in 3 hypervariable regions that line the binding groove.42, 43, 44 Hypervariable region 3 is on the α-helix of the DRβ polypeptide, and it orients the antigenic peptide for recognition by the CD4 T-helper cell. Amino acid sequences that are encoded genetically govern the configuration of the antigen-binding groove and influence the type of peptide that can be presented.8, 17, 42, 43, 44

  • View full-size image.
  • Figure 1. 

    Antigen binding groove of the class II molecule of the MHC containing autoantigen and showing the 6 amino acid core motif at positions DRβ67–72 that is associated with susceptibility to type 1 autoimmune hepatitis in white North American and northern European adult patients. The antigen-binding groove consists of 2 polypeptide chains (DRα and DRβ) which orient the autoantigen for immunocyte recognition. The autoantigen is connected by a salt bridge (encircled) to the ligation point at the lip of the DRβ polypeptide chain. The core motif of leucine (L), leucine (L), glutamic acid (E), glutamine (Q), lysine (K), and arginine (R) spans positions 67–72 on the DRβ polypeptide chain at the ligation point. Lysine (K) at position DRβ71 has been implicated as the principal susceptibility factor for type 1 autoimmune hepatitis in white North American and northern European adult populations.

Type 1 Autoimmune Hepatitis 

Type 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.45 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).14, 15, 22, 46 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).14, 46 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 DRβ71.14, 46

Table 1. Susceptibility Alleles of the MHC Associated With Type 1 Autoimmune Hepatitis
MHC alleleSusceptible populationEffects
DRB1*0301White North American, northern European, and ItaliansEncodes LLEQ-K-R at DRβ 67–72 with lysine (K) at DRβ71 as key factor
DRB1*0401White North American and northern EuropeanSame as DRB1*0301
DRB1*0404Mestizo MexicansEncodes LLEQ-R-R with arginine (R) at DRβ71
DRB1*0405Japanese, mainland Chinese, Argentine adultsSame as DRB1*0404
DRB1*1301Brazilians, Argentine childrenEncodes ILED-E-R with glutamic acid (E) at DRβ71; associated with protracted hepatitis A
DRB1*1501Northern EuropeanEncodes ILEQ-A-R with alanine at DRβ71; protective against type 1 autoimmune hepatitis

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).14, 46 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 mellitus47, 48 and rheumatoid arthritis.49, 50

Type 1 autoimmune hepatitis in Japan,20, 25, 51, 52 mainland China,53 and Mexico54 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.16, 17, 18, 55, 56

DRB1*1301 is associated with type 1 autoimmune hepatitis in Argentine children27, 28 and Brazilian patients,24, 29, 30, 32 and it encodes ILEDER at positions DRβ67–72 (Table 1). Isoleucine (I), leucine (L), and arginine (R) are not in critical locations within the antigen-binding groove of the class II MHC molecule. In contrast, aspartic acid (D) and glutamic acid (E) are at positions DRβ70 and 71 within the antigen-binding groove encoded by DRB1*1301.56 These negatively charged amino acid residues within the ILEDER motif would favor presentation of antigens different from those accommodated by the LLEQKR motif.56

DRB1*1301 is associated with protracted hepatitis A virus infection,31 and hepatitis A virus has been associated with the development of autoimmune hepatitis.57, 58, 59 South Americans, especially children, with DRB1*1301 may be selected to have prolonged exposure to viral and liver antigens and thereby overcome self-tolerance.27, 28, 29, 30, 31, 32 Other geographic regions may have other susceptibility alleles for autoimmune hepatitis because their indigenous etiologic antigens are different.19, 21, 25, 60, 61

Clarification of the different susceptibility alleles for the same disease in different geographic regions may be a mechanism by which to deduce the triggering epitope. The presence of the LLEQKR or LLEQRR amino acid sequences at the DRβ positions 67–72 in white North American and northern European patients with autoimmune hepatitis restricts the range of peptides that can be bound to those containing negatively charged residues (aspartic acid or glutamic acid) opposite lysine or arginine at DRβ71. Knowing the conformational and electrostatic requirements for optimal presentation of the triggering epitope allows modeling of the ideal antigen and characterization of the etiologic trigger for the disease.16, 17, 18, 31

Similarly, recognition of different susceptibility alleles for the same disease in the same population may implicate different etiologic agents or epidemiologic risk factors within that region.62, 63 These risk factors may be age-related and reflect antigenic exposures specific for that age range.64, 65, 66, 67, 68, 69 They also may reflect differences in immune responsiveness or the imprecision of the T-cell–antigen receptor to recognize a specific epitope.8, 70, 71

Type 2 Autoimmune Hepatitis 

Type 2 autoimmune hepatitis has been described mainly in European children, and it is associated with antibodies to liver/kidney microsome type 1 (anti-LKM1).72, 73 Susceptibility to type 2 autoimmune hepatitis has been associated with DRB1*07 in Brazil,24, 29, 30, 32 Britain,73 and Germany,74 and with DRB1*03 in Spain75 (Table 2). DQB1*0201 is in strong linkage disequilibrium with DRB1*07 and DRB1*03, and it has been proposed as the principal genetic determinant of the disease.76 The association of a single disease with multiple alleles suggests that there may be different genetic determinants for various aspects of the condition.26, 76

Table 2. Susceptibility Alleles of the MHC Associated With Type 2 Autoimmune Hepatitis
MHC alleleSusceptible populationConsequences
DRB1*03Northern European (Spain)Associated with anti-LC1
DRB1*07Northern European (Brazil, Britain, Germany, Italy)Associated with anti-LKM1 in type 2 autoimmune hepatitis and in chronic hepatitis C
DQB1*0201Northern EuropeanPrincipal susceptibility factor for the disease in linkage disequilibrium with DRB1*03 and DRB1*07

Anti-LC1, antibodies against liver cytosol type 1.

DRB1*07 has been associated with the expression of anti-LKM1 in children with type 2 autoimmune hepatitis24, 29, 30 and in Italian patients with chronic hepatitis C (Table 2).77 In contrast, antibodies to liver cytosol type 1 are associated with DRB1*03.76 Both anti-LKM1 and antibodies to liver cytosol type 1 occur in type 2 autoimmune hepatitis, and each has genetic associations distinct from each other but occurring in the same disease.76 The disease in turn is driven mainly by DQB1*0201 (Table 2).76 The diversity of genetic associations with the same disease suggests that manifestations of the condition can vary between individuals depending on the haplotype of the patient and the antigenic stimuli provoking the immune response.26, 78, 79 The low occurrence of anti-LKM1 in North American patients with autoimmune hepatitis80 and in chronic hepatitis C77, 81 may reflect the lower frequency of HLA DRB1*07 in North America than in Europe.74, 77

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Ancillary Genetic Drivers of Susceptibility 

The propensity for autoimmune hepatitis also can be affected by nonspecific autoimmune modulators that exist outside the MHC.34, 35, 36, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 These may be genetic polymorphisms or point mutations that modify the autoimmune response, and they may or may not be associated closely with the principal susceptibility alleles of the MHC (Table 3). In white North American and northern European patients with autoimmune hepatitis, a polymorphism of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene appears to favor disease occurrence (Table 3).82 This polymorphism may result in deficient expression of the CTLA-4 molecule, which in turn can unbridle the immune response.

Table 3. Polymorphisms and Point Mutations Outside the MHC Associated With Autoimmune Hepatitis
Polymorphism or point mutationNatureClinical significance
TNFA*2Adenine for a guanine at position -308 of the tumor necrosis factor-α geneEarly age onset disease; treatment failure associated with DRB1*0301
CTLA-4Guanine for an adenine at position 49 in the first exon of the CTLA-4 geneImmune reactivity (thyroid antibodies); associated with DRB1*0301; also found in primary biliary cirrhosis
TNFRSF6Adenosine to guanine single nucleotide polymorphism at position -670 of the TNFRSF gene promoterEarly cirrhosis
VDR genePolymorphism of vitamin D receptor geneAssociated with autoimmune hepatitis
Tyrosine phosphatase CD451Point mutation of tyrosine phosphatase CD45 geneAssociated with autoimmune hepatitis
AIREPoint mutation of autoimmune regulator geneAssociated with APECED, which may include autoimmune hepatitis
Interleukin (IL)-2, IL-4, IL-6, IFN-γ, and TGF-βCytokine immune modulators undergoing active studyPolymorphisms may modify counter-regulatory cytokine milieu

AIRE, autoimmune regulator gene; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; IFN-γ, interferon gamma gene; TGF-β, transforming growth factor-beta gene; VDR, vitamin D receptor gene.

The same polymorphism of the CTLA-4 gene described in autoimmune hepatitis has been found in primary biliary cirrhosis,93 and it may be one of several autoimmune regulatory genes that are outside the MHC and not disease specific. The CTLA-4 polymorphism has not been shown in South American patients with autoimmune hepatitis,94 and this finding emphasizes the difficulty in extending observations from one ethnic group to another.

Twenty distinct polymorphisms of the human Fas gene (tumor necrosis factor–receptor superfamily [TNFRSF] gene) have been described over a span of 26 kilobases of the chromosome 10q24.1, and 4 have been associated with the occurrence of autoimmune hepatitis in Japan (Table 3).83 In white North American and northern European patients with autoimmune hepatitis, an adenosine to guanine single nucleotide substitution in the Fas gene promoter at position -670 (TNFRSF6) has been associated with the early development of cirrhosis.84 Polymorphisms that disturb the homeostatic mechanisms of programmed cell death within liver and immune cells can be deleterious without being disease-specific.95

The substitution of an adenine for a guanine at position -308 of the tumor necrosis factor-α gene results in a polymorphism (TNFA*2) that is found in white North American and northern European patients with autoimmune hepatitis (Table 3).34 The TNFA*2 allele is associated with high inducible and constitutive levels of TNF-α, and it is carried on the 8.1 ancestral haplotype of white northern Europeans in association with the DRB1*0301 allele.96, 97, 98, 99 The TNFA*2 polymorphism occurs mainly in young white patients with autoimmune hepatitis, especially those who respond less well to corticosteroid therapy.35

Serum levels of B-cell activating factor, which is a constituent of the TNF superfamily, are higher in autoimmune hepatitis than in acute hepatitis, chronic hepatitis C, and normal individuals.100 These observations suggest that multiple genetic determinants outside the MHC may work in synergy (epistasis) with other drivers of the immune response (ie, DRB1*0301) to affect disease occurrence and severity. The -308 polymorphism of TNFA has not been associated with susceptibility to autoimmune hepatitis or with HLA DRB1*03 in Brazil.101

Other immune modulators also are under genetic control, and their occurrence and functional consequences in autoimmune hepatitis still are being defined (Table 3). Polymorphisms of interleukin (IL)-2, -4, and -6,36 interferon-γ,36 transforming growth factor-β,36 and the vitamin D receptor gene102, 103 are examples of nonspecific autoimmune promoters that can influence the occurrence and behavior of autoimmune hepatitis (Table 3). Point mutations of the tyrosine phosphatase CD45 gene104, 105 and the autoimmune regulator gene106, 107 also have been investigated, but only the mutated tyrosine phosphatase CD45 gene104, 105 has been implicated in autoimmune hepatitis that exists outside the syndrome of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

The MHC class III human complement genes,108, 109 the immunoglobulin constant region genes,110 adhesion molecule genes,111, 112 and genes encoding the T-cell–antigen receptor113 also are candidates for further study. The existence and variety of these genetic determinants have been underscored by studies in murine models of autoimmune hepatitis in which mouse strains with different genes inside and outside the MHC have responded differently to the same recipe for the induction of experimental hepatitis.114

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Genetic Effects on Clinical Phenotype 

The same genetic factors inside and outside the MHC that affect susceptibility also influence disease expression and behavior. Patients with DRB1*0301 develop autoimmune hepatitis at a younger age than patients with DRB1*0401,115 and they have more severe laboratory abnormalities.15, 115 In contrast, patients with DRB1*0401 are more commonly women, and they have a higher frequency of concurrent immunologic diseases, especially autoimmune thyroiditis.15, 115

In Japan, the B8-DRB1*0301 haplotype almost never is found, and the principal susceptibility allele is DRB1*0405.20, 25, 51, 52 Japanese patients with autoimmune hepatitis mainly are women who present late in life and who respond well to nonsteroidal treatments.116 In this respect, they resemble the white patients from North America and northern Europe with HLA DRB1*04.15, 115

In Brazil, patients with autoimmune hepatitis mainly are children with severe inflammatory activity and DRB1*1301,24, 29, 30, 32 whereas in Argentina, adults with autoimmune hepatitis are distinguished from children with the disease by having DRB1*03 in contrast to DRB1*1301.27, 28

Age-related differences in genetic susceptibilities and clinical phenotype also are evident in white North American and northern European patients.64, 65, 66, 67, 68 After the age of 40 years, the autoimmune hepatitis among white North Americans tends to be associated with DRB1*0401, whereas the disease in adults younger than 40 years old is associated with DRB1*0301.67 Elderly patients age 60 years and older have concurrent rheumatic diseases more commonly than young adults age 35 years and younger, and they respond better to corticosteroid therapy.67 Aging diminishes the cellular immune response, and it increases the number and type of antigenic exposures that might trigger loss of self-tolerance.117, 118, 119, 120

The genetic effects on clinical phenotype extend to genetic polymorphisms outside the MHC in white North American and northern European patients. The TNFA*2 allele is associated with an earlier age of disease onset and poorer response to corticosteroid treatment than other alleles,34, 35 the CTLA-4 gene polymorphism is associated with concurrent immune manifestations,82 and the TNFRSF6 allele is associated with early progression to cirrhosis.84 The strong association of TNFA*2 and CTLA-4 with DRB1*0301 suggests that DRB1*0301 is the principal driver of the clinical phenotype, whereas the polymorphisms are secondary modifiers of disease expression.34, 35, 82

Sex also modifies the clinical phenotype, and white North American women with autoimmune hepatitis have HLA DRB1*04 more commonly than men.115, 121 They also have a higher frequency of DRB1*04 alleles other than the DRB1*0401 allele than men.121 This allelic diversity in women may influence the occurrence and the range of the autoimmune response, and it may explain the predilection of women with autoimmune hepatitis to have concurrent immune diseases more commonly than men.115, 121

Ethnicity is another factor that may affect the clinical phenotype, and it may be a surrogate marker of a different genetic or etiologic basis for the disease. African American patients,122 Alaskan natives,123 Middle Eastern patients,124 Asian patients,51, 52, 116 South American patients,27, 28, 32 and Somalian patients125 have different clinical phenotypes and disease behaviors that may reflect their genetic predisposition or an indigenous etiologic agent.

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Genetic Effects on Serologic Phenotype 

Autoantibodies may be associated with certain clinical phenotypes or outcomes in autoimmune hepatitis, which in turn are associated with particular genetic risk factors.126, 127, 128, 129, 130, 131 The associations of anti-LKM1 with HLA DRB1*0729, 73, 74, 76, 77 and antibodies to liver cytosol type 1 with HLA DRB1*0376 in type 2 autoimmune hepatitis are examples of these relationships.

Antibodies to soluble liver antigen/liver pancreas (anti-SLA/LP) characterize patients with severe inflammatory activity and a propensity to relapse after corticosteroid withdrawal.132, 133, 134, 135, 136 Furthermore, they have been associated strongly with DRB1*0301.133, 134 Antibodies to SLA/LP may reflect pathogenic mechanisms promoted by DRB1*0301 or other genetic factors working in epistasis with this principal genetic driver.

Antibodies to actin are serologic markers that also have been associated with HLA DRB1*03 and a poor prognosis.136, 137 Their clinical relevance, however, is highly dependent on the assay system used for their detection. Antibodies to actin assessed by certain assay systems identify patients with a poor outcome, and they are found more commonly in individuals with HLA DRB1*03.137 Other assay systems have shown the reliability of anti-actin as diagnostic markers of autoimmune hepatitis but not as prognostic indices.138

Recent studies using an enzyme-linked immunosorbent assay have suggested that antibodies to the α-actinin domain on the actin molecule identify patients with severe clinical and histologic disease when they are present with antibodies to filamentous actin.139 These observations suggest that assays that evaluate reactivity against select critical molecular targets may have greater prognostic value than those directed against larger epitopes. These refined assays also may have a tighter association with genetic risk factors.

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Genetic Effects on Severity 

The density of the class II MHC molecules that contain autoantigen is affected by the number of alleles that encode the amino acid motif favoring its presentation (gene dose).42, 43, 44 Multiple alleles can encode the same critical amino acid sequence within the antigen-binding groove of the class II MHC molecules, and the number of these alleles (gene dose) may affect the vigor of immunocyte activation.

Both DRB1*0301 and DRB1*0401 encode identical sequences at positions DRβ67-72 with lysine at position DRβ71.56 DRB1*0301 is in strong linkage disequilibrium with DRB3*0101, which also encodes a lysine at DRβ71, whereas DRB1*0401 is in strong linkage disequilibrium with DRB4*0103, which encodes an arginine at DRβ71 (Table 4).56 Patients with DRB1*0301 typically have 2 lysine-encoding DRB alleles per haplotype, whereas those with DRB1*0401 typically have 1. The reduced density of antigen-presenting molecules with lysine at DRβ71 in patients with DRB1*0401 may attenuate the immune response and lessen the severity of the disease.15, 115 The gene dose can be variable among individuals with the same principal susceptibility alleles because the critical motif with lysine at position DRβ71 can be encoded by other alleles within the haplotype (Table 4).56

Table 4. Gene Doses Encoding Lysine at DRβ71 and Clinical Phenotype
Susceptibility alleleDRβ67-72 motifGene dose encoding DRβ71 lysineClinical phenotype
DRB1*0301-DRB3*0101LLEQ-K-R * * * *-K-*2–4Early onset; associated with treatment failure, death from liver failure, or need for transplantation
DRB1*0401-DRB4*0103LLEQ-K-R * * * *-R-*1–3Late onset; commonly female; concurrent immune diseases; good treatment outcome
DRB1*0301- DRB1*0401LLEQ-K-R LLEQ-K-R2–4Variable according to concurrence of DRB3*0101 and other alleles encoding DRβ71 lysine
DRB1*0404LLEQ-R-R0–3Similar to DRB1*0401
DRB1*0405LLEQ-R-R0–3Similar to DRB1*0401
DRB1*1301ILED –E-R0–3Protracted hepatitis A infection; risk factor in South America
DRB1*1501ILEQ –A-R0–3Protective in white North Americans and northern Europeans

DRB1*0302

DRB1*0303

DRB1*0409

DRB1*0413

DRB1*0416

DRB1*1303

DRB3*0101

DRB3*0201

DRB3*0202 or DRB3*0301

* * * *-K-*1–4Variable clinical phenotype; other DRβ71 lysine encoding alleles that can extend susceptibility haplotype

The dosing effect also may reflect alleles that encode amino acids with structural and electrostatic properties similar to those of lysine (such as arginine), which substitute for lysine at the critical DRβ71 position. This substitution may attenuate but not prevent presentation of the triggering epitope, and the allele encoding the substitution may exist in constellation with other alleles that encode the same or similar substitutions. Alleles such as DRB1*0404 and DRB1*0405 encode arginine at the DRβ71 position, and they may be present as homozygous or heterozygous haplotypes (Table 4).56 These haplotypes in turn can be extended by other alleles that encode lysine or arginine residues at the DRβ71 location. The composite dosing effect thereby can be variable and unpredictable.

Gene dosing is a concept that is supported by clinical observations. Patients with type 1 autoimmune hepatitis and 3 to 4 alleles encoding lysine at the DRβ71 position have higher serum bilirubin concentrations at presentation, greater frequency of treatment failure during corticosteroid treatment, and higher occurrence of an adverse treatment result than patients with type 1 autoimmune hepatitis who have 0 to 1 alleles encoding lysine at the DRβ71 position.14, 15

These findings also were observed in patients with type 1 autoimmune hepatitis who had the HLA DRB1*03–DRB1*04 phenotype.140 Although there is only 1 DRB1*03 allele common in white North American patients (DRB1*0301), there are at least 38 alleles associated with HLA DRB1*04, and not all are lysine-encoding at position DRβ71.56 Consequently, patients with HLA DRB1*03–DRB1*04 can have variable clinical manifestations and treatment outcomes depending on the allelic combinations that govern the placement of a lysine residue at DRβ71 (Table 4).140

A hierarchy of haplotypes based on the number of alleles encoding lysine at DRβ71 also has been described that affects susceptibility to type 1 autoimmune hepatitis, ranging from low risk when alanine is at DRβ71, medium risk when arginine is at DRβ71, and high risk when lysine is at DRβ71.14, 46 The ability of multiple alleles to encode the same critical motif also may account for the occurrence of type 1 autoimmune hepatitis in individuals from the same geographic region who lack DRB1*0301 and DRB1*0401.62, 63, 140 Gene dosing also may explain variations in disease severity among individual patients.

In type 2 autoimmune hepatitis, the proliferative T-cell response to the target antigen, CYP2D6, is against multiple antigenic regions.73 These antigenic regions differ in patients with and without DRB1*07, presumably because of differences in the peptide-binding affinity of the class II MHC molecules. T- and B-cell responses can be induced by the same overlapping antigenic sequences, and disease activity relates to the number of epitopes involved in the T- and B-cell responses and the amount of cytokines produced from these responses.73 Gene dosing related to the presence or absence of DRB1*07 may affect the density of epitope presentation, vigor of immunocyte activation, and the severity of the disease in the same fashion as in type 1 autoimmune hepatitis.73

Theoretically, the dosing of polymorphisms and point mutations of genes outside the MHC and the effects of genes in different regions of the MHC (HLA C locus) also could have a cumulative effect on disease severity. They may constitute a genetic network that is highly variable among patients, and they may be able to influence disease severity and outcome in an unpredictable and highly individualized fashion.

The HLA C genes lie between the HLA A and B genes, and they are part of the extended haplotype. Cw*0701 occurs more frequently in autoimmune hepatitis than in normal subjects,141 and studies in primary sclerosing cholangitis have indicated that it is in linkage disequilibrium with the B8-DRB1*03 haplotype.142 The impact of Cw*0701 within the haplotype of patients with autoimmune hepatitis is unclear, but its occurrence may be another example of a subsidiary genetic determinant that can contribute to the immune response and help shape the clinical phenotype.

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Genetic Effects on Outcome 

The same genetic factors that influence disease severity also affect outcome. In white North American and northern European patients with type 1 autoimmune hepatitis, treatment failure, relapse after corticosteroid withdrawal, and need for liver transplantation occur more often in patients with the DRB1*0301 allele.15, 115, 143, 144 The presence of the TNFA*2 polymorphism in white North American and northern European patients also augurs a poor treatment response,34, 35 and the TNFRSF6 polymorphism is associated with early progression to cirrhosis.84 Gene dosing effects on autoantigen presentation,14, 15, 140 individual predilections for the loss of self-tolerance through protracted or repeated antigen exposures,31 and the cumulative actions of non-MHC genes on apoptotic mechanisms of programmed cell death,83, 84 counter-regulatory cytokine pathways,34, 35, 36 and other homeostatic mechanisms of the immune response85, 86, 87, 88 also may contribute to prognosis.

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Future Directions 

The elucidation of the human genome38 and the development of technologies that can assess the structure, function, and evolution of genes25, 39, 40, 41, 145 promise to clarify the genetic bases for autoimmune hepatitis. Genome-wide DNA microsatellite techniques already have been applied to Japanese patients with autoimmune hepatitis,25 and multiple candidate regions outside the HLA class II loci have been identified that may confer susceptibility or resistance to the disease. These findings not only show the power of the new research techniques to dissect the human genome, but they also support earlier concepts that multiple genes interact to affect development of the disease.

Crystallography studies are necessary to confidently associate the density of class II MHC dimers on the surface of APC with disease susceptibility and severity.42, 43, 44 Whole-genome microarray screening can identify chromosome imbalances not detected previously,40 and integrative characterization of full-length complementary DNAs can capture gene transcripts as complete functional cassettes.146 In this fashion, gene interactions and the structure and function of diverse individual genes can be determined. The clinical observations that have supported the genetic bases for autoimmune hepatitis and that have emerged over decades are the current primitive starting points from which to seek new knowledge.

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References 

  1. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938
  2. Czaja AJ, Freese DK. Diagnosis and treatment of autoimmune hepatitis. Hepatology. 2002;36:479–497
  3. Krawitt EL. Autoimmune hepatitis. N Engl J Med. 2006;354:54–66
  4. Czaja AJ. Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol. 2001;96:1224–1231
  5. Vergani D, Choudhuri K, Bogdanos DP, et al. Pathogenesis of autoimmune hepatitis. Clin Liver Dis. 2002;6:727–737
  6. Czaja AJ. Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance. Liver Transpl. 2002;8:505–513
  7. Hammer J, Valsasnini P, Tolba K, et al. Promiscuous and allele-specific anchors in HLA-DR-binding peptides. Cell. 1993;74:197–203
  8. Doherty DG, Penzotti JE, Koelle DM, et al. Structural basis of specificity and degeneracy of T cell recognition: pluriallelic restriction of T cell responses to a peptide antigen involves both specific and promiscuous interactions between the T cell receptor, peptide, and HLA-DR. J Immunol. 1998;161:3527–3535
  9. Lohr H, Manns M, Kyriatsoulis A, et al. Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis. Clin Exp Immunol. 1991;84:297–302
  10. Bogdanos DP, Choudhuri K, Vergani D. Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences. Liver. 2001;21:225–232
  11. Manns MP, Griffin KJ, Sullivan KF, et al. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest. 1991;88:1370–1378
  12. Kerkar N, Choudhuri K, Ma Y, et al. Cytochrome P4502D6193-212: a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease. J Immunol. 2003;170:1481–1489
  13. Bogdanos DP, 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;17:83–92
  14. Strettell MDJ, Donaldson PT, Thomson LJ, et al. Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology. 1997;112:2028–2035
  15. Czaja AJ, Strettell MDJ, Thomson LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology. 1997;25:317–323
  16. Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev. 2000;174:250–259
  17. Czaja AJ, Doherty DG, Donaldson PT. Genetic bases of autoimmune hepatitis. Dig Dis Sci. 2002;47:2139–2150
  18. Donaldson PT. Genetics in autoimmune hepatitis. Semin Liver Dis. 2002;22:353–364
  19. Amarapurkar DN, Patel ND, Amarapurkar AD, et al. HLA genotyping in type-1 autoimmune hepatitis in western India. J Assoc Physicians India. 2003;51:967–969
  20. Yoshizawa K, Ota M, Katsuyama Y, et al. Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis. J Hepatol. 2005;42:578–584
  21. Shankarkumar U, Amarapurkar DN, Kankonkar S. Human leukocyte antigen allele associations in type-1 autoimmune hepatitis patients from western India. J Gastroenterol Hepatol. 2005;20:193–197
  22. Teufel A, Worns M, Weinmann A, et al. Genetic association of autoimmune hepatitis and human leukocyte antigen in German patients. World J Gastroenterol. 2006;12:5513–5516
  23. Czaja AJ. Evolving concepts in the diagnosis, pathogenesis and treatment of autoimmune hepatitis. Minerva Gastroenterol Dietol. 2007;53:43–78
  24. Goldberg AC, Bittencourt PL, Oliveira LC, et al. Autoimmune hepatitis in Brazil: an overview. Scand J Immunol. 2007;66:208–216
  25. Yokosawa S, Yoshizawa K, Ota M, et al. A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology. 2007;45:384–390
  26. Czaja AJ, Dos Santos RM, Porto A, et al. Immune phenotype of chronic liver disease. Dig Dis Sci. 1998;43:2149–2155
  27. Fainboim 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;41:146–150
  28. Pando M, Larriba J, Fernandez GC, et al. Pediatric and adult forms of type 1 autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology. 1999;30:1374–1380
  29. Bittencourt PL, Goldberg AC, Cancado ELR, et al. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol. 1999;94:1906–1913
  30. Goldberg AC, Bittencourt PL, Mougin B, et al. Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus. Hum Immunol. 2001;62:165–169
  31. Fainboim L, Velasco VCC, Marcos CY, et al. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB1*1301, a marker for pediatric autoimmune hepatitis. Hepatology. 2001;33:1512–1517
  32. Czaja AJ, Souto EO, Bittencourt PL, et al. Clinical distinctions and pathogenic implications of type 1 autoimmune hepatitis in Brazil and the United States. J Hepatol. 2002;37:302–308
  33. Czaja AJ, Santrach PJ, Moore SB. Shared genetic risk factors in autoimmune liver disease. Dig Dis Sci. 2001;46:140–147
  34. Cookson S, Constantini PK, Clare M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology. 1999;30:851–856
  35. Czaja AJ, Cookson S, Constantini PK, et al. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology. 1999;117:645–652
  36. Fan L-Y, Tu X-Q, Zhu Y, et al. Genetic association of cytokine polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. World J Gastroenterol. 2005;11:2768–2772
  37. Juran BD, Lazaridis KN. Genomics and complex liver disease: challenges and opportunities. Hepatology. 2006;44:1380–1390
  38. Little PF. Structure and function of the human genome. Genome Res. 2005;15:1759–1766
  39. Honda M, Kawai H, Shirota Y, et al. cDNA microarray analysis of autoimmune hepatitis, primary biliary cirrhosis and consecutive disease manifestation. J Autoimmun. 2005;25:133–140
  40. Kepischi-Santos AC, Vianna-Morgante AM, Jehee FS, et al. Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndrome revisited and new alterations. Cytogenet Genome Res. 2006;115:254–261
  41. Schumacher A, Kapranov P, Kaminsky Z, et al. Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res. 2006;34:528–542
  42. Brown JH, Jardetsky T, Saper MA, et al. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988;332:845–850
  43. Stern LJ, Brown JH, Jardetzky TS, et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994;368:215–221
  44. Dessen A, Lawrence CM, 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;7:473–481
  45. Czaja AJ, Manns MP. The validity and importance of subtypes of autoimmune hepatitis: a point of view. Am J Gastroenterol. 1995;90:1206–1211
  46. Doherty DG, Donaldson PT, Underhill JA, et al. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology. 1994;19:609–615
  47. Becker KG. Comparative genetics of type 1 diabetes and autoimmune disease. Diabetes. 1999;48:1353–1358
  48. Corper AL, Stratmann T, Apostolopoulos V, et al. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science. 2000;288:505–511
  49. Singal DP, Li J, Zhu Y. Genetic basis for rheumatoid arthritis. Arch Immunol Ther Exp. 1999;47:307–311
  50. Toussirot E, Auge B, Tiberghien P, et al. HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis. J Rheumatol. 1999;26:1446–1451
  51. Seki T, Kiyosawa K, Inoko H, et al. Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology. 1990;12:1300–1304
  52. Seki T, Ota M, Furuta S, et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology. 1992;103:1041–1047
  53. Qiu D-K, Ma X. Relationship between human leukocyte antigen-DRB1 and autoimmune hepatitis type I in Chinese patients. J Gastroenterol Hepatol. 2003;18:63–67
  54. Vazquez-Garcia MN, Alaez C, Olivo A, et al. MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis. J Hepatol. 1998;28:985–990
  55. Donaldson PT, Czaja AJ. Genetic effects on susceptibility, clinical expression, and treatment outcome of type 1 autoimmune hepatitis. Clin Liver Dis. 2002;6:707–725
  56. Schreuder GM, Hurley CK, Marsh SG, 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;62:826–849
  57. Vento S, Garofano T, Di Perri G, et al. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet. 1991;337:1183–1187
  58. Huppertz H-K, Treichel U, Gassel AM, et al. Autoimmune hepatitis following hepatitis A virus infection. J Hepatol. 1995;23:204–208
  59. Tanaka H, Tujioka H, Ueda H, et al. Autoimmune hepatitis triggered by acute hepatitis A. World J Gastroenterol. 2005;11:6069–6071
  60. Kosar Y, Kacar S, Sasmaz N, et al. Type 1 autoimmune hepatitis in Turkish patients: absence of association with HLA B8. J Clin Gastroenterol. 2002;35:185–190
  61. Muratori P, Czaja AJ, Muratori L, et al. Genetic distinctions between autoimmune hepatitis in Italy and North America. World J Gastroenterol. 2005;11:1862–1866
  62. Czaja AJ, Carpenter HA, Moore SB. Clinical and HLA phenotypes of type 1 autoimmune hepatitis in North America outside DR3 and DR4. Liver Int. 2006;26:552–558
  63. Czaja AJ, Carpenter HA, Moore SB. HLA DRB1*13 as a risk factor for type 1 autoimmune hepatitis in North American patients. Dig Dis Sci (in press).
  64. Schramm C, Kanzler S, Meyer zum Buschenfelde K-H, et al. Autoimmune hepatitis in the elderly. Am J Gastroenterol. 2001;96:1587–1591
  65. Granito A, Muratori L, Pappas G, et al. Clinical features of type 1 autoimmune hepatitis in elderly Italian patients. Aliment Pharmacol Ther. 2005;21:1273–1277
  66. Verslype C, George C, Buchel E, et al. Diagnosis and treatment of autoimmune hepatitis at age 65 and older. Aliment Pharmacol Ther. 2005;21:695–699
  67. Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology. 2006;43:532–538
  68. Al-Chalabi T, Boccato S, Portmann BC, et al. Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral center. J Hepatol. 2006;45:575–583
  69. Miyake T, Miyaoka H, Abe M, et al. Clinical characteristics of autoimmune hepatitis in older aged patients. Hepatol Res. 2006;36:139–142
  70. Chicz RM, Urban RG, Gorga JC, et al. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med. 1993;178:27–47
  71. Czaja AJ. Autoimmune hepatitis—part A (Pathogenesis). Exp Rev Gastroenterol Hepatol. 2007;1:113–228
  72. Homberg J-C, Abuaf N, Bernard O, et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis. Hepatology. 1987;7:1333–1339
  73. Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology. 2006;130:868–882
  74. Czaja AJ, Kruger M, Santrach PJ, et al. Genetic distinctions between types 1 and 2 autoimmune hepatitis. Am J Gastroenterol. 1997;92:2197–2200
  75. Jurado A, Cardaba B, Jara P, et al. Autoimmune hepatitis type 2 and hepatitis C virus infection: study of HLA antigens. J Hepatol. 1997;26:983–991
  76. Djilali-Saiah I, Fakhfakh A, Louafi H, et al. HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis. J Hepatol. 2006;45:844–850
  77. Muratori P, Czaja AJ, Muratori L, et al. Evidence of a genetic basis for the different geographical occurrences of liver/kidney microsomal antibody type 1 in hepatitis C. Dig Dis Sci. 2007;52:179–184
  78. Czaja AJ, Carpenter HA, Santrach PJ, et al. Genetic predispositions for the immunological features of chronic active hepatitis. Hepatology. 1993;18:816–822
  79. Czaja AJ, Carpenter HA, Santrach PJ, et al. Genetic predispositions for immunological features in chronic liver diseases other than autoimmune hepatitis. J Hepatol. 1996;24:52–59
  80. Czaja AJ, Manns MP, Homburger HA. Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. Gastroenterology. 1992;103:1290–1295
  81. Reddy KR, Krawitt EL, Homberg JC, et al. Absence of anti-LKM1 antibody in hepatitis C viral infection in the United States of America. J Viral Hepat. 1995;2:175–179
  82. Agarwal K, Czaja AJ, Jones DEJ, et al. CTLA-4 gene polymorphism and susceptibility to type 1 autoimmune hepatitis. Hepatology. 2000;31:49–53
  83. Hirade A, Imazeki F, Yokosuka O, et al. Fas polymorphisms influence susceptibility to autoimmune hepatitis. Am J Gastroenterol. 2005;100:1322–1329
  84. Agarwal K, Czaja AJ, Donaldson PT. A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis. Tissue Antigens. 2007;69:227–235
  85. Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35:126–131
  86. Vogel A, Strassburg CP, Manns MP. 77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence of a genetic link. Genes Immun. 2003;4:79–81
  87. Esteghamat F, Noorinayer B, Sanati MH, et al. C77G mutation in protein tyrosine phosphatase CD45 gene and autoimmune hepatitis. Hepatol Res. 2005;32:154–157
  88. Lankisch TO, Strassburg CP, Debray D, et al. Detection of autoimmune regulator gene mutations in children with type 2 autoimmune hepatitis and extrahepatic immune-mediated diseases. J Pediatr. 2005;146:839–842
  89. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7 in interleukin-2 production and immunotherapy. Cell. 1992;71:1065–1068
  90. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445–450
  91. Schiepers P, Reiser H. Role of the CTLA-4 receptor in T cell activation and immunity: physiologic function of the CTLA-4 receptor. Immunol Res. 1998;18:103–115
  92. McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol. 1999;77:1–10
  93. Agarwal K, Jones DE, Daly AK, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol. 2000;32:538–541
  94. Bittencourt PL, Palacios SA, Cancado ELR, et al. Cytotoxic T lymphocyte antigen-4 gene polymorphisms do not confer susceptibility to autoimmune hepatitis types 1 and 2 in Brazil. Am J Gastroenterol. 2003;98:1616–1620
  95. Fox CK, Furtwaengler A, Nepomuceno RR, et al. Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver. 2001;21:272–279
  96. Pociot F, Briant L, Jongeneel CV, et al. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol. 1993;23:224–231
  97. Wilson AG, de Vries N, Pociot F, et al. An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles. J Exp Med. 1993;177:557–560
  98. Wilson AG, Symons JA, McDowell TL, et al. Effects of a tumor necrosis factor (TNF-alpha) promoter base transition on transcriptional activity. Br J Rheumatol. 1994;33:89–92
  99. Tsikrikoni A, Kyriakou DS, Rigopoulou EI, et al. Markers of cell activation and apoptosis in bone marrow mononuclear cells of patients with autoimmune hepatitis type 1 and primary biliary cirrhosis. J Hepatol. 2005;42:393–399
  100. Migita K, Abiru S, Maeda Y, et al. Elevated serum BAFF levels in patients with autoimmune hepatitis. Hum Immunol. 2007;68:586–591
  101. Bittencourt PL, Palacios SA, Cancado EL, et al. Autoimmune hepatitis in Brazilian patients is not linked to tumor necrosis factor alpha polymorphisms at position -308. J Hepatol. 2001;35:24–28
  102. Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology. 2002;35:126–131
  103. Fan L, Tu X, Zhu Y, et al. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in China. J Gastroenterol Hepatol. 2005;20:249–255
  104. Vogel A, Strassburg CP, Manns MP. 77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence of a genetic link. Genes Immun. 2003;4:79–81
  105. Esteghamat F, Noorinayer B, Sanati MH, et al. C77G mutation in protein tyrosine phosphatase CD45 gene and autoimmune hepatitis. Hepatol Res. 2005;32:154–157
  106. Lankisch TO, Strassburg CP, Debray D, et al. Detection of autoimmune regulator gene mutations in children with type 2 autoimmune hepatitis and extrahepatic immune-mediated diseases. J Pediatr. 2005;146:839–842
  107. Djilali-Saiah I, Renous R, Caillat-Zucman S, et al. Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients. J Hepatol. 2004;40:904–909
  108. Scully LJ, Toze C, Sengar DPS, et al. Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Gastroenterology. 1993;104:1478–1484
  109. Doherty DG, Underhill JA, Donaldson PT, et al. Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis. Autoimmunity. 1994;18:243–249
  110. Dugoujon JM, Cambon-Thomsen A. Immunoglobulin allotypes (Gm and Km) and their interactions with HLA antigens in autoimmune diseases: a review. Autoimmunity. 1995;22:245–260
  111. Ajuebor MN, Aspinall AI, Zhou F, et al. Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells. J Immunol. 2005;174:8027–8037
  112. Heydtmann M, Lalor PF, Eksteen JA, et al. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed liver. J Immunol. 2005;174:1055–1062
  113. Manabe K, Hibberd ML, Donaldson PT, et al. T-cell receptor constant β germline polymorphisms and susceptibility to autoimmune hepatitis. Gastroenterology. 1994;106:1321–1325
  114. Lapierre P, Beland K, Djilali-Saiah I, et al. Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development. J Autoimmun. 2006;26:82–89
  115. Czaja AJ, Carpenter HA, Santrach PJ, et al. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology. 1993;105:1502–1507
  116. Nakamura K, Yoneda M, Yokohama S, et al. Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis. J Gastroenterol Hepatol. 1998;13:490–495
  117. Villanueva JL, Solana R, Alonso MC, et al. Changes in the expression of HLA class II antigens on peripheral blood monocytes from aged humans. Dis Markers. 1990;8:85–91
  118. Murasko DM, Goonewardene IM. T cell function in aging: mechanisms of decline. Ann Rev Gerontol Geriatr. 1990;10:71–96
  119. Currie MS. Immunosenescence. Compr Ther. 1992;18:26–34
  120. Talor E, Rose NR. Hypothesis: the aging paradox and autoimmune disease. Autoimmunity. 1991;8:245–249
  121. Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97:2051–2057
  122. Lim KN, Casanova RL, Boyer TD, et al. Autoimmune hepatitis in African Americans: presenting features and responses to therapy. Am J Gastroenterol. 2001;96:3390–3394
  123. Hurlburt KJ, McMahon BJ, Deubner H, et al. Prevalence of autoimmune liver disease in Alaska natives. Am J Gastroenterol. 2002;97:2402–2407
  124. Zolfino T, Heneghan MA, Norris S, et al. Characteristics of autoimmune hepatitis in patients who are not of European Caucasoid ethnic origin. Gut. 2002;50:713–717
  125. D’Souza R, Sinnott P, Glynn MJ, et al. An unusual form of autoimmune hepatitis in young Somalian men. Liver Int. 2005;25:325–330
  126. Czaja AJ, Homburger HA. Autoantibodies in liver disease. Gastroenterology. 2001;120:239–249
  127. Czaja AJ, Norman GL. Autoantibodies in the diagnosis and management of liver disease. J Clin Gastroenterol. 2003;37:315–329
  128. Czaja AJ. Autoantibodies in autoimmune liver disease. Adv Clin Chem. 2005;40:127–164
  129. Czaja AJ. The role of autoantibodies as diagnostic markers of autoimmune hepatitis. Exp Rev Clin Immunol. 2006;2:33–48
  130. Muratori L, Cataleta M, Muratori P, et al. Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis. Gut. 1998;42:721–726
  131. Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol. 1999;30:394–401
  132. Baeres M, Herkel J, Czaja AJ, et al. Establishment of standardized SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut. 2002;51:259–264
  133. Czaja AJ, Donaldson PT, Lohse AW. Antibodies to soluble liver antigen/liver pancreas and HLA risk factors in type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97:413–419
  134. Ma Y, Okamoto M, Thomas MG, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology. 2002;35:658–664
  135. Czaja AJ, Shums Z, Norman GL. Frequency and significance of antibodies to soluble liver antigen/liver pancreas in variant autoimmune hepatitis. Autoimmunity. 2002;35:475–483
  136. Czaja AJ, Shums Z, Norman GL. Nonstandard antibodies as prognostic markers in autoimmune hepatitis. Autoimmunity. 2004;37:195–201
  137. Czaja AJ, Cassani F, Cataleta M, et al. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology. 1996;24:1068–1073
  138. Granito A, Muratori L, Muratori P, et al. Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis. J Clin Pathol. 2006;59:280–284
  139. Gueguen P, Dalekos G, Nousbaum JB, et al. Double reactivity against actin and alpha-actinin defines a severe form of autoimmune hepatitis. J Clin Immunol. 2006;26:495–505
  140. Montano-Loza A, Carpenter HA, Czaja AJ. Clinical significance of HLA DRB1*03-DRB1*04 in type 1 autoimmune hepatitis. Liver Int. 2006;26:1201–1208
  141. Strettell MDJ, Thomson LJ, Donaldson PT, et al. HLA-C genes and susceptibility to type 1 autoimmune hepatitis. Hepatology. 1997;26:1023–1026
  142. Moloney MM, Thomson LJ, Strettell MJ, et al. Human leukocyte antigen-C genes and susceptibility to primary sclerosing cholangitis. Hepatology. 1998;28:660–662
  143. Sanchez-Urdazpal L, Czaja AJ, van Hoek B, et al. Prognostic features and role of liver transplantation in severe corticosteroid-treated autoimmune chronic active hepatitis. Hepatology. 1992;15:215–221
  144. Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end stage liver disease. Hepatology. 2007;46:1138–1145
  145. Wolfsberg TG, McEntyre J, Schuler GD. Guide to the draft human genome. Nature. 2001;409:824–826
  146. Imanishi T, Itoh T, Suzuki Y, et al. Integrative annotation of 21,037 human genes validated by full length cDNA clones. PLoS Biol. 2004;2:e162

PII: S1542-3565(07)01251-7

doi:10.1016/j.cgh.2007.12.048

Clinical Gastroenterology and Hepatology
Volume 6, Issue 4 , Pages 379-388, April 2008