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Introduction:

This medium-sized collaborative project will document and monitor the natural course and study the pathophysiology of Primary Antibody Deficiencies (PAD). PADs are rare inborn errors of the immune system with an estimated incidence of <1:25.000. The defective immunity in patients with PAD causes an increased susceptibility to recurrent infections of the respiratory- and gastro-intestinal tract as well as ill defined co-morbidity including granulomatous disease, lymphocytic organ infiltration and (paradoxically) autoimmunity.
Our consortium cares for more than 1000 PAD patients, representing approx. 50% of the patients registered in Europe, many of them being children. This project will:
1. Combine clinical and research data in a central online registry, complemented by a sample repository (WP1)
2. Elucidate the genetic cause of PADs by linkage analysis and candidate gene approaches (WP2)
3. Establish in vitro models for B cell differentiation steps that are defective in PADs such as in vitro class switch recombination, and siRNA knockdown models for PAD screening (WP3)
4. Create mouse models of PAD by using several technology platforms including knock-in and knock-out mice, shRNA mediated gene knock-down and humanised mice (WP4)
5. Perform translational research by taking the observations from the patients into the basic research projects and transfer these results back to the patients (WP5)
The study of these immunodeficiencies represent an "experiment of nature", uniquely enabling researchers to study the detrimental effects of mutations in specific genes involved in the immune system. Basic research results are translated into the development of new technologies, new knowledge, and new therapeutic tools. The clinical results will improve the diagnosis, management and quality of life of PAD patients, leading to future developments of new tests, preventive measures and treatment protocols.

Project duration: 36 months

Participants:

1 (Coordinator) University College London, United Kingdom
2 Karolinska Institute, Sweden
3 University Hospital Freiburg, Germany
4 Sapienza University Rome, Italy
5 Hanover Medical School, Germany
6 Universiy of Brescia, Italy
7 Hôpital Necker – INSERM U768, France
8 The Chancellor, Masters and Scholars of the University of Oxford, United Kingdom
9 Masaryk University, Brno, Czech Republic
10 VU University Medical Centre Amsterdam, The Netherlands
11 The Binding Site (SME), Germany
12 Ospedale Pediatrico Bambino Gesù, Italy
13 Universitätsmedizin Göttingen, Germany