Genetically Determined Low C4: A Predisposing Factor to Autoimmune Chronic Active Hepatitis

Vergani, Diego; Larcher, VictorF; Davies, E T; Wells, L.; Nasaruddin, Ba; Mieli‐Vergani, Giorgina; Mowat, A P

doi:10.1016/s0140-6736(85)90348-4

Cited by 116 publications

(35 citation statements)

References 30 publications

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“…Alternatively, C4 proteins may be involved in immune clearance mechanisms and in this way contribute to the pathogenesis of Type 1 diabetes as of other autoimmune disorders characterised by C4A and/or C4B null alleles [29,30].…”

Section: Discussionmentioning

confidence: 99%

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in Type 1 (insulin-dependent) diabetes

et al. 1988

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Summary. Heterogeneity between two haplotypes in linkage disequilibrium with DR3: B8, C4AQOBt,BfS,DR3 and B18,C4A3BQO,BfF1,DR3, with regard to age at onset of Type 1 (insulin-dependent) diabetes mellitus, was investigated in 325 unrelated French patients (146 males and 179 females, age at onset 1 month to 29 years) who were genotyped for HLA-A, B, C, DR and Bf and 225 of whom were typed for the C4A, B complement components. A subgroup of 82 patients and 75 control subjects were tested for DR[3 and DQ[~ DNA restriction fragment length polymorphism. The distribution according to age at onset and the mean ages at onset were compared between patients bearing B8, DR3 (n=58), B18,DR3 (n=62) or other DR3 haplotypes (Bx, DR3, n=70), the haplotype segments C4AQOB1,DR3 (n=41) or C4A3BQO,DR3 (n=52) and the C4 null alleles C4AQO (N=48) or C4BQO (n= 112) alone. The BS,DR3 haplotype, its smaller segment C4AQOB1,DR3 or C4AQO alone were associated with age at onset after 6 years (p<0.01, <0.08 and < 0.02 respectively); on the other hand, the B18,DR3 haplotype, its segment C4A3BQO,DR3 or C4BQO alone were significantly more frequent in patients aged less than 6 years at onset (t9< 0.02, < 0.01 and < 0.01 respectively). Accordingly, the mean age of onset was significantly lower in the latter compared with the former pattens (p< 0.02, < 0.02 and < 0.01 respectively). No age-related variation was observed in BX,DR3 patients and their mean age of onset was intermediate. The observed age distributions were sex dependent: that of C4AQO was mainly observed in males, that of C4BQO in females. Restriction fragment length polymorphism analysis in 37 patients and 32 control subjects positive for DR3 showed distinct patterns which correlated with DR3 and/or DQW2 borne by the B8 (n= 11) and the B18 (n= 18) haplotypes, respectively. BX,DR3 subjects exhibited either one or the other of these patterns. In the patients, the B18 associated fragments were found in most cases; whereas the B8 associated pattern was more frequent in the control subjects. These results provide evidence that a heterogeneous genetic background associated with two subsets of DR3 and/or silent alleles of the fourth component of complement could account for differences in the clinical expression of Type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in Type 1 (insulin-dependent) diabetes

et al. 1988

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“…Oligonucleotides of human C4 and RCCX constituents were designed based on published DNA sequences (51)(52)(53) 1,3,4,5,6,8,9,10,11,12,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,31,32,33,34,35,37,38,39,40, and 41. The primers were designed based on the genomic DNA sequence of C4A3a (51).…”

Section: Synthetic Dna Primersmentioning

confidence: 99%

“…For examples, deficiency of C4A or C4B is associated with type 1 diabetes (25)(26)(27). Complete or partial deficiency of C4A is linked to systemic lupus erythematosus (SLE) (28 -31), autoimmune hepatitis (32,33), and disease manifestation and rapid progression of AIDS in HIV-infected patients (34,35). Deficiency of C4B increases the vulnerability to bacterial (36,37) and viral (38,39) infections.…”

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confidence: 99%

The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

Rupert

Moulds

Yang

et al. 2002

The Journal of Immunology

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The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75–96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.

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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%

Of Mice and Women: Toward a Mouse Model of Autoimmune Hepatitis * #

Heneghan

McFarlane

2005

Hepatology

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Genetically Determined Low C4: A Predisposing Factor to Autoimmune Chronic Active Hepatitis

Cited by 116 publications

References 30 publications

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in Type 1 (insulin-dependent) diabetes

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in Type 1 (insulin-dependent) diabetes

The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

Of Mice and Women: Toward a Mouse Model of Autoimmune Hepatitis * #

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