The CFH-CFHR3-CFHR1 aHUS-risk haplotype seems to be the same as was previously associated with protection against meningococcal infections, suggesting that the genetic variability in this region is limited to a few extended haplotypes, each with opposite effects in various human diseases.
The CFH-CFHR3-CFHR1 aHUS-risk haplotype seems to be the same as was previously associated with protection against meningococcal infections, suggesting that the genetic variability in this region is limited to a few extended haplotypes, each with opposite effects in various human diseases.
Genetic variations in the gene cluster encoding IL-1 and in key genes including TNF, SP-A2 and CFH have been associated with susceptibility to meningococcal disease.
The role of properdin in regulating complement in health and disease has not received as much appraisal as the many negative AP regulators, such as factor H. Historically, properdin deficiency has been strongly associated with an increased risk for meningococcal disease.
Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.
The prevention of meningococcal disease may be improved by recombinant vaccines such as 4CMenB and rLP2086 that target the factor H binding protein (fHbp), an immunogenic surface component of Neisseria meningitidis present as one of three variants.
This study shows that C-496T is both associated and linked with MD and that individuals possessing the fHC-496T C/C genotype are more likely to have increased serum fH protein levels, have reduced bactericidal activity against meningococci and be at an increased risk of contracting MD.
The absence (deletion, D) rather than the presence (insertion, I) of a 287 base pair fragment in the ACE gene is associated with higher circulating and tissue ACE activity, with excess mortality in critical illness (including adult acute respiratory distress syndrome and paediatric meningococcal infection) and with worse functional outcome from traumatic brain injury.
Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections.
The findings suggest that MBL2 supports innate immune defence against meningococcal disease in the early months of life, before acquired immunity is sufficiently robust for effective natural protection.
The MBL pathway is a critical determinant of meningococcal-disease susceptibility, and genetic variants of MBL might account for a third of all disease cases.
Genetic variants associated with severity of meningococcal disease, including the IgG Fc receptor (FCγRII)-A484T, interleukin-10 (IL-10)-A1082G, -C819T, and -C627A, IL-4-C589T, mannose binding lectin-2 (MBL2)-A/O, -H/L, -P/Q, and -X/Y, toll-like receptor 2 (TLR2)-G2408A, TLR4-A12874G and -C13174T, and TLR9-T1237C and -T1486C were determined by real-time PCR (RT-PCR) for 271 HIV-infected subjects (median, 17 years).
These results suggest that MBLnot only is involved in complement activation but also is a potent regulator of inflammatory pathways and, as such, may affect the severity of meningococcal disease.
Hence, the deletion polymorphism (4G) within the promoter region of the plasminogen activator inhibitor-1 gene leads to impaired fibrinolysis and influences the severity and outcome of meningococcal disease and the susceptibility to severe sepsis and multiple organ failure after trauma.
Because we had no information on genotypes of patients who died, we also genotyped 183 first-degree relatives of a consecutive series of patients with meningococcal infection for the 4G/5G deletion/insertion polymorphism in the promoter region of the plasminogen-activator-inhibitor-1 gene (PAI-1).
Our data show a correlation between the 4G/4G genotype in the plasminogen activator inhibitor-1 gene and poor outcome in children with meningococcal infection.
To assess the relevance of genetically determined host factors for the prognosis of meningococcal disease, Fc gamma receptor IIA (FcgammaRIIA), the tumor necrosis factor alpha (TNF-alpha) gene promoter region, and plasminogen-activator-inhibitor-1 (PAI-1) gene polymorphisms were studied in 145 patients with meningococcal disease and in 290 healthy controls matched by sex.