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Concept and project objectives

Primary Antibody Deficiencies (PAD) represent a collection of rare inborn diseases having in common the inability of the affected individuals to produce sufficient antibody titres in response to infections or immunizations.
The most severe form is termed agammaglobulinemia in which a block in B cell development in the bone marrow prevents the development of peripheral B cells. Hence no or very few antibody producing B cells or plasma cells can be found in these individuals. Agammaglobulinemias can be either autosomal recessive or x-linked (XLA).
Second forms are defects in class switch recombination (CSR). Following the initial production of immunoglobulin (Ig) M after antigenic stimulation, B cells switch their immunoglobulin isotype to produce highly specific neutralizing antibodies of the IgG or IgA isotype. Patients with a defect in class switch recombination may mount IgM responses, but lack the production of protective IgG and IgA isotypes.
A third form is the collection of syndromes termed common variable immunodeficiency. This diagnosis represents a grab-bag of different conditions, having in common the disability to maintain IgG and IgA responses. 75% of the patients are characterized by the lack of class switched memory B cells, the remaining have them, but may produce the antibodies insufficiently or catabolise them abnormally.
A fourth form encompasses the lack if specific antibody isotypes, such as selective IgA deficiency, selective IgG2 deficiency etc.

Prevalence:

The exact prevalence of primary antibody disorders (PADs) is unknown. Moreover, since there are several different types of PADs, their prevalence in the population varies. Estimations range between one in 25.000 to one in 100.000 for the most common disorder, which is termed common variable immunodeficiency (CVID); and about one in 1x10^6 for rare class switch recombination defects [1].

[1] Eades-Perner AM, Gathmann B, Knerr V, Guzman D, Veit D, Kindle G, Grimbacher B; ESID Registry Working Party. The European internet-based patient and research database for primary immunodeficiencies: results 2004-06. Clin Exp Immunol. 2007 Feb;147(2):306-12.

Current state-of-the-art knowledge

Research in our groups in recent years have elucidated the genetic etiologies of a few of the antibody deficiency disorders such as the tyrosine kinase Btk being deficient in the x-linked form of agammaglobulinemia [1]; mutations in the co-stimulatory T cell molecule CD40 ligand (which account for the majority of patients with class switch recombination defects, but the genetic cause in 60% of the B cell intrinsic CSR defects is, however, despite the identification of mutations in CD40, AID and UNG still unknown) [2]; and ICOS, CD19, TACI, and BAFFR being defective in about 10% of patients with common variable immunodeficiency (CVID) [3-5]. For selective Ig isotype deficiencies no genetic defects have been so far described.
The identification of these defects led to the better understanding of the pathophysiology of these diseases. As example serves the discovery that the x-linked form of a class switch recombination defect, also termed hyper-IgM syndrome type 1 is caused by a lack of a co-stimulatory T cell molecule (CD40L). This prompted investigators to more closely study the T cell function in these patients which was found to be defective, rendering patients susceptible to opportunistic infections [6]. This finding explained that some patients had suffered of Pneumocystis jirovecii (PCP) infections and led to the introduction of a PCP-prophylaxis regimen in all patients with the x-linked form of hyper-IgM syndrome since about yr 2000. This example serves as an illustration how the identification of the genetic origin of a given defect and the following basic research findings improve patient management preventing morbidity and mortality.

[1] Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarstrom L, Kinnon C, Levinsky R, Bobrow M, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993; 361:226-33.
[2] Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol. 2006;18:369-76. Review.
[3] Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005; 37:820-8.
[4] Grimbacher B., A. Hutloff, M. Schlesier, E. Glocker, K. Warnatz, R. Dräger, H. Eibel, B. Fischer, A. Schäffer, H.W. Mages, R.A. Kroczek, H.H. Peter. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nature Immunol. 2003; 4:261-268.
[5] Van Zelm MC, Reisli I, an der Burg M, Castaño D, van Noesel CJM, van Tol MJD, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJM, Franco JL. Novel antibody deficiency in patients with CD19 gene defects. New Engl. J. Med., 2006; 354:1901-1912.
[6] Korthauer et al., Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993;361:539-41.

Current state-of-the-art patient management

Patients with antibody deficiency syndromes lack immunoglobulins. Therefore, the current treatment strategy is to replace those missing immunoglobulins by a substitution regimen using pooled serum immunoglobulins from healthy donors. This Ig replacement has been shown to effectively reduce the severe complications of the disease such as sepsis, pneumonia, or acute otitis media, but is not capable of preventing a) local infections such as chronic sinusitis, and b) more importantly, the long term deterioration of the respiratory tract leading to e.g. the formation of bronchiectases. Ongoing local infections of the mucosa reduce the patients? quality of life, the structural damage of the lungs however directly reduces life expectancy as shown by our groups and others in patients with x-linked agammaglobulinemia [1] and patients with common variable immunodeficiency (CVID) [2].
Therefore, an increased knowledge on the (genetic) etiology (WP2), pathophysiology (WPs3-5), and natural course of the disease (WP1), as well as the improvement of diagnostic monitoring (project 4 in WP1), and the treatment regimens of those patients is very much warranted.

[1] Plebani et al., Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104:221-30.
[2] Quinti et al., Long-Term Follow-Up and Outcome of a Large Cohort of Patinets with Common Variable Immunodeficiency. J. Clin. Immunol. 2007, in press.

Translating research for human health

The EU-PADnet consortium aims at increasing knowledge of the cause and the biological mechanisms leading to an impaired immune system. In this application we propose to focus on Primary Antibody Deficiencies (PAD). We will transpose this knowledge into clinical applications including disease monitoring, disease control and treatment. We will develop new classification schemes, and diagnostic protocols. We will also work towards new therapeutic and management protocols for patients with PAD. WP1 will ensure that clinical (including epidemiological) data will guide our research.
EU-PADnet represents a Europe-wide multidisciplinary consortium of clinician scientists and basic researchers focussing on the documentation of the genetic and molecular cause, the natural history, and the pathophysiology of Primary Antibody Deficiencies (PADs). Most PADs are considered to be Mendelian disorders. In this proposal, we will work towards the development of novel preventive, diagnostic and therapeutic interventions. We will:
- Document and monitor the course of the disease in a clinical and research online database linked to a repository (WP1)
- Develop new diagnostic tools and tests, including genetic and in vitro tests (WPs 2-5)
- Address preventive medicine (WPs 1 and 5)
- Work towards new therapeutic approaches (WP5)
- Measure the quality of life from patients with PAD and their families (WP1)
- Develop in vitro models for PAD (WP3)
- Develop animal models for PAD (WP4)
The acquired knowledge will provide the bases for future development of diagnostic, therapeutic and preventive approaches.

Child Health and Health of the Ageing Population

About 50% of patients with PAD are children or adolescents. Thus, our research addresses the special need for children in this FP7 call. Implications for child health and paediatric PAD will be taken into account whenever appropriate in all research projects of this proposal, and especially in project 4 of WP1.
Some researchers hypothesize that PAD in adults represent a premature ageing of the immune system. This will be addressed in WP2, where we aim at identifying the genetic contributions to the condition. It is indisputable, however, that the immune system of the elderly is more susceptible to infections and that hypogammaglobulinemia develops over the decades. What we will learn from the proposed project may then be used for the understanding of the ageing of the immune system in the elderly, e.g. by pinpointing biomarkers for the ageing of the immune system. The ageing immune system, however, is not a central part of this proposal, but results of this work programme may feed into a follow-up proposal within FP7 at a later stage.