Polymorphism in the Human Complement C4 Genes and Genetic Susceptibility to Autoimmune Hepatitis

Doherty, Derek G.; Underhill, James A.; Donaldson, Peter; Manabe, Koji; Mieli‐Vergani, Giorgina; Eddleston, A. L. W. F.; Vergani, Diego; Demaine, Andrew; Williams, Roger

doi:10.3109/08916939409009525

Cited by 48 publications

(20 citation statements)

References 35 publications

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“…Rather, the deposition of C3 in the same liver tissues suggests that complement-mediated cell cytotoxicity might in fact be the responsible mechanism in this in vivo model. As has been previously reported, 23,24 many Caucasian AIH patients have deletions in C4A and C5B loci, resulting in a reduced C4 level in relatively younger AIH patients. A C4A loci deletion is known to be in strong linkage disequilibrium with HLA-A1, B8, DR3, DR52a, and DQ2, of all of which are associated with susceptibility to AIH in Caucasian AIH patients.…”

Section: Discussionsupporting

confidence: 58%

A Murine Model of Acute Liver Injury Induced by Human Monoclonal Autoantibody *

et al. 2005

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We have previously reported an immunoglobulin (Ig) M autoantibody to hepatocyte-related 190-kd molecules in patients with type 1 autoimmune hepatitis (AIH). This molecule was first isolated by hepatocyte-specific human monoclonal antibody (MoAb). To elucidate the role of this IgM autoantibody in hepatocyte injury, we examined the reactivity of this MoAb to murine hepatocytes and then questioned whether acute hepatic injury could be induced in mice via injection of this MoAb. The reactivity of MoAb was examined via both FACS analysis using murine hepatocytes and immunostaining of liver tissues. We then identified the murine hepatocyte membrane molecule recognized by this MoAb A utoimmune hepatitis (AIH) is a chronic disorder of hepatocytes that is accompanied by immunological abnormality as determined by serological examination. 1,2 Based on the observation of alterations in several T cell functions, AIH is generally thought to be a disorder mediated by T cells. [3][4][5][6] However, various types of hepatocyte-specific autoantibodies frequently found in AIH patients are also suspected of being involved in immune-mediated liver injury in this disease. This was supported by the following results: (1) Serum autoantibodies obtained from AIH patients were able to kill human hepatocytes, 7-12 (2) the titer of hepatocyte-specific autoantibody was tightly correlated with liver damage in AIH patients. 13,14 However, despite these important observations, because of the lack of an adequate in vivo system, the precise role of such autoantibodies in immunomediated liver injury has remained obscure.We have previously reported the hepatocyte-specific human monoclonal autoantibody (MoAb) produced by human clone established by peripheral blood mononuclear cells of patients with AIH. 15 This MoAb recognized a 190-kd molecule on the hepatocyte membrane and was able to kill human hepatocyte cell lines in a complementdependent manner. In addition, a similar 190-kd molecule-recognizing immunoglobulin M (IgM) autoantibody was also found in AIH patients, and its titer was Abbreviations: Ig, immunoglobulin; AIH, autoimmune hepatitis; MoAb, monoclonal autoantibody; MP, myeloma protein; TBS, C3, complement component 3; AST, asparate aminotransferase; ALT, alanine aminotransferase. From the

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Section: Discussionsupporting

confidence: 58%

A Murine Model of Acute Liver Injury Induced by Human Monoclonal Autoantibody *

et al. 2005

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“…HLA haplotypes associated with C4*BQ0 are B44; CS30;DR4, B35;CF320;DR1 and B18;CF130; DR3 [5]. A small proportion of C4*Q0 alleles in autoimmune diseases arises due to deletions at C4A or C4B loci or due to large deletions of C4A-21-OHA [15][16][17] In SSc, functional deficiencies of C4 and C2 have not been investigated. The occurrence of C4A*Q0 and C4B*Q0 and HLA alleles has been studied, but consensus has not yet been reached on their increased incidence in a particular subset of SSc [21][22][23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

“…C4A and C4B are highly polymorphic [20]. In many autoimmune diseases, patients with nonexpressed C4A carry the HLA-A1;B8; CS01;DR3 haplotype [5,[15][16][17]. HLA haplotypes associated with C4*BQ0 are B44; CS30;DR4, B35;CF320;DR1 and B18;CF130; DR3 [5].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Heterogeneity of Second and Fourth Components of Complement and Their Genes in Systemic Sclerosis and Association of HLA Alleles A1, B8 and DR3 with Limited and DR5 with Diffuse Systemic Sclerosis

Venneker¹,

Hoogen²,

Meegen³

et al. 1998

Exp Clin Immunogenet

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Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher’s exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

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“…On the contrary, the available evidence indicates that complement-mediated cytolysis is not involved in AIH, due to the frequent finding in patients of null alleles at either the C4A or C5B loci (often in linkage disequilibrium with HLA A1-B8-DR3), resulting in low complement levels which are positively associated with severity of disease. [35][36][37] Yamauchi et al point out, however, that this evidence comes from studies in caucasoids and that such complement gene deletions are not common in Japanese AIH patients. 29 Again, this has some merit, because there is no reason to suppose that what we see as the clinical expression of AIH necessarily arises through the same pathogenetic mechanisms in all individuals with the disease.…”

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confidence: 99%