Therapeutic Implications of the IL-21: IL-4 Receptor System in Children with Common Variable Immunodeficiency Syndrome

Objectives: Interleukin-21 (IL-21) has been shown to restore immunoglobulin production together with Interleukin-4 (IL-4) in common variable immunodeficiency syndrome (CVID). Here, we elucidate the functional and structural properties of the corresponding IL-21R : IL-4R system. Patients and Methods: An in vitro cell culture system was established to study the molecular effects of IL-21 and IL-4 on B cell differentiation, class-switch recombination (CSR) and immunoglobulin (Ig) production in 32 paediatric patients with CVID. MHC haplotypes and the IL21 and IL21R gene were analysed by genotyping. Ternary complexes of the IL-21 respectively IL-4 receptor were set-up by homology modeling and ligand-interaction was examined by molecular dynamics (MD) simulation. Results: Stimulation with IL-21,IL-4 and CD40L uniformly induced IgG and IgA production in B cells from all tested patients by initiation of both CSR and AID-independent Ig production. No mutations were found in the coding regions of the IL21 or IL21R genes and no distinct HLA allele or extended haplotype could be correlated with the amount of Ig production or the gene expression pattern induced by IL-21. MD simulations of the modelled receptor complexes showed that IL-4 and IL-21 are both able to bind to IL-4R and IL21R complexes in an interchangeable manner. Conclusions: The function of the IL-21R : IL-4R system seems not to be related to the aetiology of CVID in paediatric patients and might be suitable for a regenerative therapy.