Common variable immunodeficiency to solve the variable of the equation

Abstract

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency requiring treatment. Despite significant progress in fundamental research and treatment strategies, many issues in the origins of CVID still need to be addressed. Some disease-causing monogenetic defects in e.g. B cell co-receptors were found, but a molecular diagnosis remains limited to a neglible fraction of patients. Despite improvements in therapy, morbidity remains high. This thesis provides various insights on the pathogenesis and complications of CVID, which were obtained by studies in children with CVID and related antibody deficiencies. As current literature is mainly based on research in adult CVID patients, it had thus far been uncertain whether pediatric CVID is the same disease displayed a younger population, or a dissimilar disease entity. We show that pediatric CVID disorders are analogous to adult CVID regarding lymphocyte characteristics, with increased numbers of transitional B cells accompanied by low memory populations, in comparison to age-related reference values. As a result, CVID classifications show a different patient distribution when applied to children and are thus inapt for this population. The etiology of CVID remains to be elucidated. We have investigated early B cell activation upon triggering of the B cell receptor (BCR). and demonstrate that BCR-mediated calcium signaling is disturbed in a significant proportion of pediatric CVID patients. The defect correlates with disturbed plasmablast differentiation in vitro. These data suggest that defective plasma membrane lateral interaction of the BCR with its co-molecules is a pivotal pathogenetic mechanism in CVID, and is supported by our finding of defective B cell surface dissociation of CD20 and the BCR. Pulmonary abnormalities are the most frequent complications in CVID. We describe for the first time in pediatric CVID patients comparative data on interstitial or parenchymal lung disease. While pulmonary abnormalities in pediatric CVID are common but generally mild as rated by HRCT, they may occur despite what we consider optimal treatment regimens and despite the lack of pulmonary symptoms. We additionally report the first HRCT scoring method and its validation that is specifically designed for CVID. CVID-related lung abnormalities develop via different pathogenetic mechanisms. Accordingly, the separation of complications into two categories revealed that the patients concerned display dissimilar clinical and immunological characteristics. Enteropathy is the most lethal non-malignant intrinsic complication in CVID. We illustrate that human parechovirus is nearly impossible to eradicate in the agammaglobulinemic patients, and may persist in the gastrointestinal tract for many years. Whether there is a relation between persistent enteric virus infections and enteropathy in immunodeficiency remains to be elucidated. To this end, a longitudinal study has been initiated and promising preliminary data are described in this thesis. Children with CVID suffered more often from gastrointestinal discomfort than healthy children. These symptoms were associated with intestinal inflammation. In addition, common enteric infections were numerous and associated with intestinal inflammation in pediatric CVID. This thesis involved the phenotypic and mechanistic clarification of CVID disease and its complications, which should eventually facilitate molecular diagnoses, prevention of complications and optimalization of therapeutic options.