B-cell differentiation defects and clinical complications in antibody deficiency syndromes with a focus on Common Variable Immunodeficiency

Antibody deficiency syndromes (ADS) are defects in the quantity or quality of
antibody secretion a crucial adaptive defence mechanism against infections. ADS
cause recurrent bacterial upper and lower respiratory tract infections
resulting in bronchiectasis, pulmonary fibrosis and eventually respiratory
failure. Furthermore, auto-immune diseases and malignancies can complicate the
course of these diseases. In a minority of patients the genetic defect can be
established. The clinical course of these conditions is very variable and
difficult to predict. Despite immunoglobulin replacement, ADS patients have a
decreased life expectancy and a significantly worse health-related quality of
life than patients with other chronic disorders.

To detect B-cell differentiation and maturation defects in patients with
antibody deficiency syndromes of unknown origin (CVID, SAD), which are
predictive for clinical complications

To detect and sequence candidate genes in subgroups of patients with similar
B-cell differentiation defects by using gene expression profiles.

To investigate whether abnormalities in antibody production are present in
patients with bronchiectasis of unknown origin or chronic ENT infections of
unknown origin.

The patients will be clinically classified and prospectively monitored using
predefined clinical parameters. Peripheral blood samples of the patients will
be analyzed using a novel integrated immunological approach, which aims for the
identification of the defective step in B-cell differentiation and maturation.
The clinical information will be combined with the defined defective step in
B-cell differentiation to see which clinical parameters are specific for each
of the newly defined subgroups and to see whether a subgroup is immunological
and clinical homogenous. Within one (or more) homogenous subgroup, genetic
searches will be initiated in order to identify genetic defects that explain
the causes of the disease.

The benefits of the study are the possibility of detecting clinical significant
prognostic parameters, like certain B-cell differentiation defects. Insight in
the ethiology of ADS might lead to new modes of treatment in the future.
Taking blood samples will not impose a significant risk, no extra venous
punctures are required. Diagnostic vaccination with rabies is safe in
immunocompromized patients, but can in a minority of the cases give temporary
side effects, like local reactions or fever of short duration. The study
requires extra time of the patients. Nasopharyngeal swabs might be
inconvenient.