Casimiro Castillejo-López,
Angélica M Delgado-Vega,
Jerome Wojcik,
Sergey V Kozyrev,
Elangovan Thavathiru,
Ying-Yu Wu,
Elena Sánchez,
David Pöllmann, Juan R López-Egido,
Serena Fineschi, [......],
Johan Frostegård,
Bernardo A Pons-Estel,
Sandra D'Alfonso,
Torsten Witte,
José Luis Callejas,
John B Harley,
Patrick M Gaffney,
Javier Martin,
Joel M Guthridge,
Marta E Alarcón-Riquelme
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ABSTRACT: Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis.
The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK.
Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies.
This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.
Annals of the rheumatic diseases 01/2012; 71(1):136-42. · 8.11 Impact Factor
