C4B Deficiency: A Risk Factor for Bacteremia with Encapsulated Organisms

Bishof, Nancy A.; Welch, Thomas R.; Beischel, Linda

doi:10.1093/infdis/162.1.248

Cited by 98 publications

(58 citation statements)

References 6 publications

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“…Heterozygous C2 deficiency occurs in 1%-1.5% of the general population (8 ). Homozygous deficiency of either C4A or C4B occurs in 3% of the population (9 ). Mannose-binding lectin (MBL2) binds to carbohydrates present on the surface of a variety of microorganisms.…”

Section: Streptococcus Pneumoniae and Haemophilus Influenzae Are Impomentioning

confidence: 99%

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

Bossuyt¹,

Moens²,

Hoeyveld³

et al. 2007

Clinical Chemistry

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Background: Respiratory infections are major causes of morbidity and mortality, but determinants of susceptibility are poorly defined. We studied whether and to what extent immunologic and genetic factors are associated with increased susceptibility to respiratory infections. Methods: We evaluated the prevalence of IgA, IgM, IgG, and IgG subclass deficiencies, impairment in the antibody response against pneumococcal polysaccharides, G2m(n) allotypes, Fc␥RIIa polymorphisms, partial C2 and partial C4 deficiency, promoter polymorphisms in MBL2, and lymphocyte subset deficiencies in a control population and in consecutive children with recurrent respiratory infections. Results: IgA and/or IgG subclass deficiency was found in 27 of 55 patients (49%) and 6 of 43 controls (14%) (P ‫؍‬ 0.0006). An impaired antibody response to polysaccharides was found in 7 patients (19%) and in 0 of 37 controls (P ‫؍‬ 0.002). The Gm(n)marker was absent in 25 of 55 patients (45%) and 6 of 42 controls (14%) (P ‫؍‬ 0.009). The MBL2 variants O/O, A/O, and A/A occurred in 9, 14, and 32 of the 55 patients, respectively, and in 1, 19, and 23 of the 43 controls, respectively (P ‫؍‬ 0.05). There was no increase in the prevalence of partial C4 deficiency, C2 deficiency, lymphocyte subset deficiency, or Fc␥RIIa polymorphism in the patients compared to the controls. A combination of at least 2 immune defects was found in 31 of 55 patients (56%) and in 4 of 42 controls (11.6%) (P <0.0001). Conclusion: Specific antipolysaccharide antibody deficiency, IgA and/or IgG subclass deficiency, Gm(n) allotype, and MBL2 genotype are susceptibility factors for recurrent respiratory infections, and coexistence of sev-

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Section: Streptococcus Pneumoniae and Haemophilus Influenzae Are Impomentioning

confidence: 99%

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

Bossuyt¹,

Moens²,

Hoeyveld³

et al. 2007

Clinical Chemistry

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“…Complete deficiency of complement C4 (i.e., both C4A and C4B) is one of the most penetrant genetic risk factors in autoimmune disease such as systemic lupus erythematosus (28,29). Complete or partial deficiencies of C4B are related to vulnerability and severity of microbial infections (30,31). 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).…”

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

114

110

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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.

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“…Increased susceptibility to infection has been described in patients with complete C4 deficiency, as well as in patients with isolated C4B deficiency (7,10,11 The autoimmune disease seen in this family, however, has also been reported in association with both complete C4 deficiency and heterozygous as well as homozygous C4A deficiency (7,8,9). The mechanisms by which C4 deficiency predisposes to rheumatic disorders is unclear.…”

Section: Discussionmentioning

confidence: 64%

“…Heterozygous and homozygous C4A deficiencies have been reported in association with systemic lupus erythematosus (SLE) and other autoimmune diseases (8,9). Homozygous C4B deficiency has been reported in association with bloodborne bacterial infections (1O, 11), Henoch-Schonlein purpura ( 12,13) and IgA nephropathy ( 13,14). Null alleles at C4 loci have been attributed to deletions, gene conversions, and nonexpressed alleles; however, the mechanisms by which the C4A * QO,C4B* QO double null haplotype arise have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

A unique recombination event resulting in a C4AQ0,C4BQ0 double null haplotype.

Fasano

Winkelstein²,

LaRosa³

et al. 1992

J. Clin. Invest.

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The fourth component of complement (C4) is encoded by two closely linked genes (C4A and C4B) within the MHC. Null alleles at either locus (C4AQO or C4BQO) are relatively common, occurring at the C4A locus in -10% of normal individuals and at the C4B locus in -16% of normal individuals. However, the presence of the double null haplotype (C4A * QO,B * QO) on the same chromosome is extremely rare. We recently studied a 7-yr-old patient with recurrent sinopulmonary infections in whom we documented the mechanism by which the C4A * QO,B * QO double null haplotype arose. Evaluation revealed significantly reduced levels of both C4 antigen and C4 hemolytic activity. Analysis of extended haplotypes in the family was performed using MHC typing and genomic DNA

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C4B Deficiency: A Risk Factor for Bacteremia with Encapsulated Organisms

Cited by 98 publications

References 6 publications

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

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

A unique recombination event resulting in a C4AQ0,C4BQ0 double null haplotype.

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C4B Deficiency: A Risk Factor for Bacteremia with Encapsulated Organisms

Cited by 98 publications

References 6 publications

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

Coexistence of (Partial) Immune Defects and Risk of Recurrent Respiratory Infections

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

A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype.

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A unique recombination event resulting in a C4AQ0,C4BQ0 double null haplotype.