Clinical and molecular characterization of Factor I and C5 complement deficienciesfrom diagnosis to pupulation studies /

Resumen

The Complement System is a part of the humoral immune response that, among other functions, is responsible for the defense against pathogens and elimination of immune complexes. It is composed of more than thirty soluble and membrane-bound proteins, which are activated as a proteolytic cascade to be able to exert their function. Congenital defects in complement proteins increase susceptibility to infections by encapsulated pathogens and increase the risk of recurrence of infections by bacteria of the genus Neisseria meningitidis. Despite being considered rare diseases, the hypothesis of the work is that they are underdiagnosed by the lack of awareness and laboratory techniques for the study of this part of the immune system. In addition, we consider that an early diagnosis of this type of defects allows adopting preventive therapeutic measures that improve the quality of life of patients. In this work, 10 new techniques are implemented for the study of the complement system in the routine of the Immunology Department of the Hospital Universitario Vall d'Hebron. This fact allowed the diagnosis and molecular characterization of nine cases of complement defects (three families with defects of C5 and three families with defects of Factor I). Two of the diagnosed cases were in newborns, siblings of index patients. This fact allowed the early vaccination and the indication of antibiotic prophylaxis to avoid future infections. Due to the geographic variability described in the frequency of defects in molecules of the complement (C5-C9) terminal pathway, we studied the presence of alleles that presented the p.A252T mutation in 2710 samples from representative populations of the different continental regions. According to our hypothesis, we observe that there is an over-representation of this mutation in countries of Sub-Saharan Africa, coinciding in part with the countries included in the African meningitis belt. In contrast, we also identified two samples that were carriers of the mutated allele in regions outside of Africa (Israel and Pakistan). In order to answer the question of whether it is necessary to study the complement system in the cases of invasive meningococcal disease, in this thesis we present a new algorithm in which they are added to the presence of recurrences, the fact that there is consanguinity, that Infection is determined by a rare serotype or the patient is from Africa or the Middle East.