title: Concordance of increased B1 cell subset and lupus phenotypes in mice and humans is dependent on BLK expression levels.
abstract: Polymorphisms in the B lymphoid tyrosine kinase (BLK) gene have been associated with autoimmune diseases, including systemic lupus erythematosus, with risk correlating with reduced expression of BLK. How reduced expression of BLK causes autoimmunity is unknown. Using Blk(+/+) , Blk(+/-) , and Blk(-/-) mice, we show that aged female Blk(+/-) and Blk(-/-) mice produced higher anti-dsDNA IgG Abs and developed immune complex-mediated glomerulonephritis, compared with Blk(+/+) mice. Starting at young age, Blk(+/-) and Blk(-/-) mice accumulated increased numbers of splenic B1a cells, which differentiated into class-switched CD138(+) IgG-secreting B1a cells. Increased infiltration of B1a-like cells into the kidneys was also observed in aged Blk(+/-) and Blk(-/-) mice. In humans, we found that healthy individuals had BLK genotype-dependent levels of anti-dsDNA IgG Abs as well as increased numbers of a B1-like cell population, CD19(+)CD3(-)CD20(+)CD43(+)CD27(+), in peripheral blood. Furthermore, we describe the presence of B1-like cells in the tubulointerstitial space of human lupus kidney biopsies. Taken together, our study reveals a previously unappreciated role of reduced BLK expression on extraperitoneal accumulation of B1a cells in mice, as well as the presence of IgG autoantibodies and B1-like cells in humans.
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; ying-yu-wu@omrf.org alarconm@omrf.org.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada 18016, Spain;
authors.forename: Ina
authors.initials: I
authors.lastname: Georg
authors.affiliation: Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada 18016, Spain;
authors.forename: Alejandro
authors.initials: A
authors.lastname: Díaz-Barreiro
authors.affiliation: Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada 18016, Spain;
authors.forename: Nieves
authors.initials: N
authors.lastname: Varela
authors.affiliation: Pôle de Pathologies Rhumatismales, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium; and.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lauwerys
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;
authors.forename: Harini
authors.initials: H
authors.lastname: Bagavant
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martín
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Fadi
authors.initials: F
authors.lastname: El Salem
authors.affiliation: Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada 18016, Spain;
authors.forename: Concepción
authors.identifier: http://orcid.org/0000-0002-7827-6301
authors.initials: C
authors.lastname: Marañón
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada 18016, Spain; ying-yu-wu@omrf.org alarconm@omrf.org.
authors.forename: Marta E
authors.identifier: http://orcid.org/0000-0002-7632-4154
authors.initials: ME
authors.lastname: Alarcón-Riquelme
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D001706:Biopsy; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013154:Spleen / Q000276:immunology; D053668:Syndecan-1 / Q000378:metabolism; D055815:Young Adult; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D053668:Syndecan-1; C000592904:B lymphoid kinase, mouse; C584409:BLK protein, human; D019061:src-Family Kinases