Influence of C4A deficiency on nonresponse to HBsAg vaccination: a new immune response gene

Milich, David R.

doi:10.1016/s0168-8278(02)00237-4

Cited by 9 publications

(5 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice that were genetically identical except within the MHC indicated a strong influence of at least 2 MHC-linked class II genes and 1 MHC class III gene (in particular the C4 gene) on this response. C4 deficiency affects antibody production, because antigen recognition by follicular dendritic cells is diminished in the absence of activation of the classical complement pathway [51]. The influence of MHC class II genes on the response to specific epitopes on the HBsAg was studied in detail.…”

Section: Laboratory Animal Differences In the Response To Vaccinationmentioning

confidence: 99%

Genetic Variation in the Response to Vaccination

Kimman¹,

Vandebriel

Hoebee

2007

Public Health Genomics

View full text Add to dashboard Cite

Vaccines are the most powerful means to prevent and diminish the burden of infectious disease. However, there are limitations to their use: vaccines are not yet available for all infectious diseases (including human immunodeficiency virus and respiratory syncytial virus), they sometimes lack efficacy, the response to vaccination is limited by maternal antibodies in very young infants, and the response to vaccination is variable or may even be absent in some individuals. This review focuses on genetic factors that determine the variable response to vaccination. The highly polymorphic human leukocyte antigen system, which is involved in antigen presentation, has been researched most in this aspect, and clearly affects the response to vaccination. Other, but less polymorphic pathways involved are the Toll-like receptor pathway, which is involved in antigen recognition and stimulation of the immune system, and the cytokine immunoregulatory network. The heritability, or the proportion of total variance that is due to additive genetic factors, appears to be particularly large for vaccine-induced antibody responses in young infants compared with cell-mediated responses and antibody responses in older, immunologically more mature individuals. Both antibody and cell-mediated responses are not only affected by loci within, but also strongly by loci outside the human leukocyte antigen system. Because most genes that are important in influencing immune responses to vaccination are still unknown, clearly more work is required. A better understanding of the factors that determine an effective response to vaccination may lead to the identification of specific genes and pathways as targets for the development of novel more uniformly effective vaccines.

show abstract

Section: Laboratory Animal Differences In the Response To Vaccinationmentioning

confidence: 99%

Genetic Variation in the Response to Vaccination

Kimman¹,

Vandebriel

Hoebee

2007

Public Health Genomics

View full text Add to dashboard Cite

show abstract

“…Complete deficiencies of C4 in humans or guinea pigs have impairments in the secondary immune response and switching of IgM to IgG (32)(33)(34). In an immunization process, it has been shown that low concentrations of C4 in mice (35) or partial deficiencies of C4A in humans are associated with higher frequencies of nonresponders to hepatitis B Ags (36,37). Therefore, an accurate account of the phenotypic and genotypic diversities of C4A and C4B in a human population both qualitatively and quantitatively is critically important for epidemiological studies of disease associations with C4.…”

mentioning

confidence: 99%

Diversity in Intrinsic Strengths of the Human Complement System: Serum C4 Protein Concentrations Correlate withC4Gene Size and Polygenic Variations, Hemolytic Activities, and Body Mass Index

Yang

Chung

Zhou

et al. 2003

The Journal of Immunology

112

110

View full text Add to dashboard Cite

Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein concentrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system.

show abstract

“…Although the MHC contributes 40% of the genetic effect to HBsAg responsiveness, there is strong evidence that other genes than HLA class II antigens are also important. Observations in mice and in humans strongly suggest that complete and partial deficiencies for complement factor C4A, which is encoded telomeric to the class II region, is responsible for nonresponsiveness particularly in HLA‐DRB1*0301 individuals [21–23]. Most of these individuals carry a deletion of the C4A gene on the HLA A1/B8/DRB1*0301 haplotype.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B surface antigen presentation and HLA-DRB1*– lessons from twins and peptide binding studies

Krüger

Adams

Hammer

et al. 2005

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryThe aim of this study was to investigate the underlying mechanisms of the genetic association between certain HLA-DRB1* alleles and the immune response to HBsAg vaccination. Therefore, HBsAg peptide binding to HLA-DR molecules was measured in vitro by peptide binding ELISAs. Additionally, HBsAg-specific T cell reaction and cytokine profile of immune response were analysed ex vivo in ELISPOT assays and DR-restriction of T-cell proliferative responses was investigated with HBsAg specific T cell clones. In addition, we compared HBsAg specific T cell responses of 24 monozygotic and 3 dizygotic twin pairs after HBsAg vaccination. Our results showed that the peptide binding assays did not reflect antigen presentation in vivo . DR alleles associated with vaccination failure like DRB1*0301 and 0701 efficiently presented HBsAg peptides. In 11 of 24 investigated monozygotic twin pairs we observed pronounced differences in the recognition of HBsAg peptides. This study indicates that HLA-DR associations with HBsAg vaccination response are not caused by differences in peptide binding or by a shift in the Th1/Th2 profile. Our findings strongly argue for differences in the T cell recognition of peptide/MHC complexes as the critical event in T cell responsiveness to HBsAg.

show abstract

Influence of C4A deficiency on nonresponse to HBsAg vaccination: a new immune response gene

Cited by 9 publications

References 27 publications

Genetic Variation in the Response to Vaccination

Genetic Variation in the Response to Vaccination

Diversity in Intrinsic Strengths of the Human Complement System: Serum C4 Protein Concentrations Correlate withC4Gene Size and Polygenic Variations, Hemolytic Activities, and Body Mass Index

Hepatitis B surface antigen presentation and HLA-DRB1*– lessons from twins and peptide binding studies

Contact Info

Product

Resources

About