Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication.
Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased toward nucleolar antigens because of increased expression of TLR7, a single-stranded RNA-binding innate immune receptor. The TLR7 gene is duplicated in Yaa mice because of a 4-Megabase expansion of the pseudoautosomal region. These results reveal high divergence in mouse Y chromosomes and represent a good example of gene copy number qualitatively altering a polygenic disease manifestation.
Pisitkun
Prapaporn
P
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Rockville, MD 20852, USA.
Deane
Jonathan A
JA
Difilippantonio
Michael J
MJ
Tarasenko
Tatyana
T
Satterthwaite
Anne B
AB
Bolland
Silvia
S
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D000918:Antibody Specificity; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D002466:Cell Nucleolus / Q000276:immunology*; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D000077271:Imiquimod; D017404:In Situ Hybridization, Fluorescence; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics* / Q000276:immunology; D014960:X Chromosome / Q000235:genetics; D014998:Y Chromosome / Q000235:genetics
D000634:Aminoquinolines; D000974:Antibodies, Antinuclear; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D012313:RNA; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000077271:Imiquimod