Therapeutic implications of the IL-21: IL-4 receptor system in children with common variable immunodeficiency syndrome.
OBJECTIVE
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.


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 IL-21R 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.
Department of Clinical Immunology and Transfusion Medicine, University of Leipzig, Johannisallee 30, Leipzig, Germany. stephan.borte@medizin.uni-leipzig.de
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Borte
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Lanig
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Borte
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Fasshauer
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Sack
D000293:Adolescent; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000378:metabolism; D053738:Interleukin-21 Receptor alpha Subunit / Q000187:drug effects* / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000187:drug effects* / Q000235:genetics; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D056004:Molecular Dynamics Simulation; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D000098546:Interleukin-21
C508117:IL21R protein, human; C508598:IL4 protein, human; C504000:IL4R protein, human; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D053738:Interleukin-21 Receptor alpha Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D007378:Interleukins; D011994:Recombinant Proteins; D015847:Interleukin-4; D000098546:Interleukin-21