Homozygosity for the IgG2 Subclass Allotype G2M(n) Protects against Severe Infection in Hereditary C2 Deficiency

Abstract

Homozygous C2 deficiency (C2D) is the most common deficiency of the classical complement pathway in Western countries. It is mostly found in patients with autoimmune disease or susceptibility to bacterial infections and in healthy persons. We wished to assess to what extent other immunological factors might explain differences of susceptibility to infections in C2D. For this reason, 44 Swedish patients with C2D were stratified with regard to the severity of documented infections. Investigations of IgG subclass levels, IgG subclass-specific GM allotypes, concentrations of factor B, properdin, and factor H, and polymorphisms of mannan-binding lectin and the Fc receptors FcγRIIa and FcγRIIIb were performed. Homozygosity for the G2M*n allele, which is known to promote Ab responses to polysaccharide Ags, was strongly associated with the absence of severe infections (p < 0.001) in the patients, suggesting a major protective role. The combination of mannan (or mannose)-binding lectin and C2 deficiency was found to be a minor susceptibility factor for invasive infection (p = 0.03). Low concentrations of IgG2 and factor B might sometimes contribute to susceptibility to infection. Other factors investigated did not appear to be important. In conclusion, the findings indicated that efficient Ab responses to polysaccharides are protective against severe infection in C2D. Implications with regard to vaccination should be considered.

Vaccination against encapsulated bacteria in hereditary C2 deficiency results in antibody response and opsonization due to antibody-dependent complement activation

“…These findings are in line with previous vaccine responses found in humans and in animal models with early complement deficiency states [16]. In a previous study [20], we found that almost all of the C2D persons without previously documented infections also carried the favorable G2M(n) allotype. The possibility that the GM*b,f,n haplotype contributes to early antibody diversification in CD27 + memory B cells might be considered [52].…”

“…One explanation to the variation may be difference in IgG heavy chain allotypes (GM) as suggested by our previous findings that absence of infections in C2D is found in carriers of the G2M*n allele [20], which is known to promote antibody responses to polysaccharide antigens. Other factors may be involvement of other antibodies or recognition molecules such as MBL that contributes to complement activation also involving amplification by the alternative pathway.…”

“…In a follow-up study of 44 C2D persons, we found that the G2M*n/G2M*n genotype was associated with protection against severe infections suggesting the involvement of an immunoglobulin (Ig)-dependent defense mechanism [20].…”

Impaired Opsonization with C3b and Phagocytosis ofStreptococcus pneumoniaein Sera from Subjects with Defects in the Classical Complement Pathway

“…However, recent data obtained using mice genetically modified to be deficient in one or more complement components have identified a vital role for classical pathway activity in innate immunity to S. pneumoniae and other pathogens and have demonstrated the classical pathway to be activated by a variety of innate immune mediators, including pentraxins, natural IgM, and the cell surface lectin SIGN-R1 (7,11,18,29,41,44,48,49). An important role for the classical pathway in immunity to S. pneumoniae is also supported by the limited clinical data available on infections in patients with complement deficiencies, as patients with defects in the classical pathway are at high risk of S. pneumoniae infections (10,27,28). In contrast, patients with complement deficiencies affecting the alternative pathway have a massively increased incidence of infections with Neisseria species rather than S. pneumoniae (10).…”

Complement C2 deficiency disarranging innate and adaptive humoral immune responses in a pediatric patient: Treatment with rituximab

“…Consequently, bacterial sepsis and meningitis predominantly caused by Streptococcus pneumoniae are common in C2D (1,7). Homozygosity for the IgG2 allotype G2M(n) has been reported to be a protective factor in C2D, suggesting a possible compensation for the innate humoral immunodeficiency by the adaptive humoral immunity (8). However, our C2D patient displayed a marked IgG2 and modest IgG4 subclass deficiency and experienced pneumococcal sepsis shortly after oral steroids were given.…”