We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen.
In 32 patients and 48 healthy controls, polymerase chain reaction amplified with sequence-specific primers (PCR-SSP) was performed to elucidate the relevance of certain alleles or polymorphic sequences of HLA-DRB1 with autoimmune hepatitis.
American patients with type 1 autoimmune hepatitis had DRB1*03 alleles more commonly than the German patients with type 2 disease (51% vs 17%, p = 0.03) and DRB1*0301 occurred more frequently in the type 1 patients (51% vs 17%, p = 0.03).
Among the HLA DRB1 alleles, DRB1*0301 (20% vs 6.19%; P = 0.03), DRB1*1301 (15% vs 2.65%; P = 0.01), DRB1*14 (30% vs 11.5%; P = 0.02) and DRB1*1501 (40% vs 22.12%; P = 0.08) were increased in AIH patients when compared with the controls.
A polymorphism of the tumor necrosis factor gene occurs more commonly in patients with type 1 autoimmune hepatitis than in normal subjects; it is associated with a poorer response to corticosteroids.
In subtypes of DR4, there was a trend of increase in the gene frequency of DRB1 0405 in patients with AIH versus healthy controls (21.9% vs 6.3%, P=0.04, but P(c) =0.08).
Serum NFκB-p65 and TNF-α levels were measured using enzyme-linked immunosorbent assays (ELISAs). rs6000782 C and rs1799724 T alleles, separate or in combination, were significantly increased in pAIH patients compared to controls.
DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01.
Thus, the sera of patients with autoimmune hepatitis type II and patients with chronic hepatitis C recognize different antigenic epitopes of the CYP2D6 molecule.
The DRB1*0405-DQB1*0401 haplotype in autoimmune pancreatitis showed no significant association with any HLA class I antigens, in contrast to the B54-DRB1*0405-DQB1*0401 haplotype reported in autoimmune hepatitis.
Human leucocyte antigen typing revealed DRB1*03 heterozygosity, which has been associated with the occurrence of both autoimmune hepatitis and type 1 diabetes.
These findings suggest that the DR4-specific sequence (Val 11 and His 13 at amino acid positions 11 and 13, respectively), but not particular Dw-associated DR4 sequence, in the first domain of the DRB1 chain contributes to susceptibility to autoimmune hepatitis among Japanese.
This study showed that the direct and indirect effect of IL-37 on macrophages could reduce the hepatic TNF-α expression, and also modulate IL-1β/IL-12 and IL-10/IL-1Ra expression to suppress the hepatic IFN-γ expression, thus suppressing the development of T cell-dependent liver injury such as autoimmune hepatitis.
These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.
Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401.
These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.
In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc =.014 and second set: 26% vs. 56%, P =.00008).
American patients with type 1 autoimmune hepatitis had DRB1*03 alleles more commonly than the German patients with type 2 disease (51% vs 17%, p = 0.03) and DRB1*0301 occurred more frequently in the type 1 patients (51% vs 17%, p = 0.03).
The frequency of deleterious alleles in TNFAIP3 was higher in the AIH subset without the DRB1 risk alleles than that with (P = 0.0052, OR 5.10, 95%CI 1.55-16.74).