Connecting clinical and molecular disease features in Common Variable Immunodeficiency Disorder

Common Variable Immunodeficiency (CVID) disorder is the most prevalent symptomatic primary immunodeficiency in children and adults. Typically, a patient presents with recurrent pulmonary and/or gastrointestinal infections (with or without infection related complications), due to diminished immunoglobulin levels and insufficient specific antibody responses to encapsulated bacteria. Some patients present with autoimmune manifestations related to immune dysregulation. In order to reach the diagnosis of CVID patients must meet certain diagnostic criteria as formulated by the American and European Society for Immunodeficiencies (ESID): A patient should have a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and all of the following criteria: 1) Onset of immunodeficiency at > 2 years of age 2) Absent isohemagglutinins and/or poor response to vaccines and 3) Defined causes of hypogammaglobulinemia have been excluded. Treatment of CVID patients consists of Ig replacement therapy, with the purpose to prevent recurrent infections and subsequent complications. Other treatment options to prevent recurrent pulmonary bacterial infections include antibiotic prophylaxis, while for treatment of autoimmune manifestations immunosuppressive therapy (e.g. systemic corticosteroids) may be considered. The first part of this thesis focuses on possible new gene mutations and molecular mechanisms contributing to the B- and T-cell defects in CVID patients. To this end, we screened 30 primary immunodeficiency patients with a next gen sequencing technique for 170 known PID genes and 300 candidate genes. We found three potentially pathogenic new gene mutations of BLK, PSTPIP1 and STAT3 and performed functional experiments in an attempt to prove disease association. The second part of this thesis looks further into the local pulmonary and gastrointestinal homeostasis of CVID patients and evaluates the use of pneumococcal polysaccharide vaccination responses as a diagnostic criterium for CVID. We found that anti-pneumococcal polysaccharide IgA responses may be of use to differentiate transient antibody deficiency disease from persistent CVID. Secondly, for the assessment of anti-pneumococcal polysaccharide IgG responses, we believe individual measurement of serotypes is superior to combined serotype measurement. Thirdly, we found that CVID patients are more often carrying gastrointestinal viruses than healthy controls. Furthermore, viral presence correlated to signs of inflammation and low secretory IgA levels in feces in CVID patients and not in healthy controls. Finally, this thesis ends with a prospective study on the progression of pulmonary disease on CT scans op CVID patients. Silent progression of pulmonary disease occurred in almost all patients and higher IgG trough levels seemed to correlate to less progression of pulmonary disease. A randomized controlled study should be performed to confirm these findings.