Primary immunodeficiency patients suffer from monogenetic or polygenetic defects in the immune system that render them susceptible to a variety of infections. 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 to provide tailored health care. For example, the development of classification systems has enabled distinction of patients prone to develop disease-related complications such as autoimmune cytopenia and granulomatous disease, but the the origination of these presumed causal relations remains to be established. Further, disease causing monogenetic defects in e.g. B cell co-receptors were found, which have provided important clues for understanding human immunology, but a molecular diagnosis remains limited to a neglible fraction of patients. And finally, treatment has improved significantly in the recent decades, but nevertheless, many patients suffer on a daily basis from the consequences of their disease.
Phenotypic and functional B cell abnormalities in CVID
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. In chapter 2-3, 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. Akin to adults, CVID-related complications are associated with severely decreased percentages of class-switched memory B cells; their incidence is however lower in children.
The etiology of CVID remains to be elucidated, but probably originates in the B lymphocyte for the majority of patients (chapter 4). We have investigated early B cell activation upon triggering of the B cell receptor (BCR). In chapter 5, we demonstrate that BCR-mediated calcium signaling is disturbed in a significant proportion of pediatric CVID(-like) patients. The defect correlates with disturbed plasmablast differentiation in vitro and appears to occur upstream in the BCR signaling cascade, i.e. endoplasmic reticulum Ca2+ storage and depletion were normal, as well as calcium influx via plasma membrane channels. 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. The complexity of studying heterogeneous multifactorial disorders such as CVID is further demonstrated in chapter 6, describing three siblings with identical mutations in the TACI susceptibility gene, but with clinical phenotypes ranging from completely asymptomatic to severe CVID with refractory autoimmune symptoms.
Pulmonary complications in pediatric CVID disorders
Pulmonary abnormalities are the most frequent complications in CVID, causing significant morbidity and at times mortality. Consequently, accurate detection is of major importance, and preferably performed early in the course of disease development when adequate treatment options are still available. Scientific literature unambiguously shows that HRCT is the most sensitive non-invasive method to detect pulmonary anomalies in CVID (chapter 7). Though most research was performed in adult CVID patients, a few studies show that structural abnormalities such as bronchiectasis can already occur in childhood CVID. In chapter 8, 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. In this chapter, we additionally report the first HRCT scoring method that is specifically designed for CVID and related antibody deficiencies. In chapter 9, we report the validation of the HRCT scoring system, which revealed that this diagnostic method has sensitivity and discriminative potential superior to conventional chest X-ray and pulmonary function tests. This chapter furthermore confirms that CVID-related lung abnormalities develop via different pathogenetic mechanisms. Accordingly, the separation of complications into two categories (structural airway disease and interstitial or parenchymal lung disease) revealed that the patients concerned display dissimilar clinical and immunological characteristics. Pneumonias occurred more often and had a relatively longer disease duration in patients with structural airway disease, suggesting that structural lung complications probably result from structural damage due to cumulative infectious events. Concerning pathogenesis of interstitial lung disease, pathology appears to result from a broader immune-related dysregulation: these patients more often suffer from autoimmune and lymphoproliferative disorders, and display several lymphocyte alterations; most notably a severe decrease of memory B cells and a trend towards increased CD8+ cytotoxic memory and effector T cells.
Gastrointestinal manifestations in CVID and related antibody disorders
Enteropathy is the most lethal non-malignant intrinsic complication in CVID, with typically an unsatisfactory response to treatment. The case of CVID enteropathy described in chapter 10 demonstrates the exceeding challenges in reaching complete disease remission: a combinatory regimen of steroids and tacrolimus only accomplished partial remission. Second, it illustrates that human parechovirus is nearly impossible to eradicate in the agammaglobulinemic patients, and may persist in the gastrointestinal tract for many years. Review of the literature confirmed that persistent viral shedding occurs occasionally in the immunocompromised individual, and very sporadically in immunocompetent subjects (chapter 11). Several cases of chronic enteroviral infections in humoral immunodeficiency have been reported; cohort studies however show that this does not occur on a regular basis. 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 chapter 12. Children with CVID and related antibody deficiencies suffered significantly more often from gastrointestinal discomfort than healthy children. These symptoms were not merely functional, but associated with intestinal inflammation. In addition, common enteric infections were numerous and associated with intestinal inflammation in pediatric CVID, but not in healthy children.
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. Future studies to consecutively address these issues are suggested in the discussion.