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Deliverables
CVID is a disease where diagnosis used to be mainly based on antibody deficiencies and recurrent infections. The cause of CVID was poorly understood up to now and this consortium contributed in several ways towards characterization and diagnosis of CVID clearly improving both. The following is a summary of the results obtained/contributed by partner 8 (BITg).
We have developed a new purification method to isolate pure sCD21 from human sera and used this to establish an ELISA. This was necessary because sCD21 was biochemically purely characterized and a high quality ELISA was and is not available on the market.
Determining the sedimentation coefficient, the partial specific volume, the diffusion coefficient and the frictional coefficient of the sCD21 protein we were able to conclude that sCD21 is an elongated rod-shaped molecule of 126 kDa. Using our ELISA we have analysed sCD21 content in > 400 healthy donors and from > 150 CVID patient´s sera. We found that CD21 in healthy donors is on average about 300ng/ml and declines with age (statistically significant). The sCD21 content varies significantly in the CVID subgroups. In rheumatoid arthritis, Soegren´s syndrome, scleroderma, systemic lupus erythomatosus and others we found a severe reduction of sCD21 and concluded that autoimmune processes act on the regulation of CD21 shedding. Mass spectrometrical analysis of sCD21 showed only fragments derived from the extracellular portion of the molecule and representing the short version of CD21. During our analysis of CD21 in activation processes, we found for the first time that two lipid microdomain resident proteins, flotillin-1 and -2 form pre-assembled platforms (PAPs) in haematopoietic cells. These platforms recruit signalling molecules such as CD21 upon activation through lipid rafts. We have shown that activation of lymphocytes via PMA and Ca2+ Ionophores or via crosslinking using anti-IgM/anti-CD40 antibodies induced the proteolytic cleavage of CD21.
Analyzing signalling pathways leading to CD21 shedding we found that CD21 is susceptible to BzATP induced shedding via purinergic receptors. Shedding could be inhibited with P2X7 receptor inhibitors oxATP and KN62. CD21-shedding is redox regulated. Oxidants and thiol-antioxidants operate at different sites of CD21-shedding induction and serine- and metalloproteases are involved in CD21-shedding. CVID patients differ in sCD21 comparing Bryant´s classification A and B groups.
Primary antibody deficiencies (PAD) are rare diseases caused by defects of the immune systerm. These defects result in an individual having problems fighting bacterial infections so that they suffer recurrent sinusitis, bronchitis or even pneumonia. This usually leads to permanent lung damage and other life-threatening situations.
Early diagnosis and better classification is essential to prevent disability. We have developed an improved rapid and reliable classification of CVID the most common form of PAD. It is based on B cell subset analysis taking into account a direct relationship between numbers of class-switched memory B cells and immunoglobulin synthesis in vitro. Thus 75% of all CVID patients (type I) lack class-switched memory B cells (easily measurable by cytofluorometry) in their peripheral blood and fail to produce IgG and IgA in vivo and in vitro. 25% of CVID patients (type II) have low serum IgG and IgA concentrations but do have class-switched memory B cells and produce switched isotypes (IgG, IgA) in vitro. Attempts have been made to subclassify type I CVID patients based on the observation that a subset of patients with splenomegaly and autoimmune phenomena often exhibits an expansion of CD21neg B cells. The group of E.Oksenhendler in Paris has identified among type I CVID patients a subset which lacks IgM memory B cells as well as class-switched memory B cells.Currently a European consensus study of >300 CVID patients is being finalized confirming basically the Freiburg classification but extending it in subclassifying type I patients.
This European consensus classification of CVID will considerably improve the speed of diagnosis and treatment decisions for CVID patients throughout the world.
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