title: Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells.
abstract: OBJECTIVE
  B lymphoid kinase (BLK) is associated with rheumatoid arthritis (RA) and several other B cell-associated autoimmune disorders. BLK risk variants are consistently associated with reduced BLK expression, but the mechanisms by which reduced expression alters human B cell function to confer autoimmune disease susceptibility are unknown. This study was undertaken to characterize the BLK risk haplotype and to determine associated B cell functional phenotypes involved in autoimmunity.
  
  
  METHODS
  The BLK risk haplotype association with RA (determined using whole-genome sequencing data) was confirmed in 2,526 RA cases and 2,134 controls. Peripheral blood mononuclear cells (PBMCs) from RA patients, healthy adults, and umbilical cord blood were used to study B cell functional phenotypes associated with the BLK risk genotype. Association of the BLK haplotype with B cell phenotypes was analyzed using cell culture and flow cytometry.
  
  
  RESULTS
  Two insertion/deletions were found on the RA risk haplotype in BLK, and the reduction in BLK expression associated with the risk haplotype was confirmed in primary B lymphocytes. Carriers of the RA-associated haplotype had evidence of lower basal B cell receptor (BCR) signaling activity, yet their B cells were hyperactivatable, with enhanced up-regulation of CD86 after BCR crosslinking and greater T cell stimulatory capacity. The number of isotype-switched memory B cells was also significantly increased in subjects carrying the risk haplotype.
  
  
  CONCLUSIONS
  A major mechanism underlying the BLK association with autoimmune disease involves lowered thresholds for BCR signaling, enhanced B cell-T cell interactions, and altered patterns of isotype switching.
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Kim R
authors.initials: KR
authors.lastname: Simpfendorfer
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Armstead
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shih
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.affiliation: Janssen Pharmaceuticals, Springhouse, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Curran
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Nataly
authors.initials: N
authors.lastname: Manjarrez-Orduño
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007132:Immunoglobulin Isotypes; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D007132:Immunoglobulin Isotypes; C584409:BLK protein, human; D019061:src-Family Kinases