title: NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome.
abstract: Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a key regulator of the innate immune system, particularly in the skin where, in response to molecular triggers such as pathogen-associated or damage-associated molecular patterns, the NLRP1 inflammasome promotes caspase-1-dependent processing of bioactive interleukin-1β (IL-1β), resulting in IL-1β secretion and downstream inflammatory responses. NLRP1 is genetically associated with risk of several autoimmune diseases including generalized vitiligo, Addison disease, type 1 diabetes, rheumatoid arthritis, and others. Here we identify a repertoire of variation in NLRP1 by deep DNA resequencing. Predicted functional variations in NLRP1 reside in several common high-risk haplotypes that differ from the reference by multiple nonsynonymous substitutions. The haplotypes that are high risk for disease share two substitutions, L155H and M1184V, and are inherited largely intact due to extensive linkage disequilibrium across the region. Functionally, we found that peripheral blood monocytes from healthy subjects homozygous for the predominant high-risk haplotype 2A processed significantly greater (P < 0.0001) amounts of the IL-1β precursor to mature bioactive IL-1β under basal (resting) conditions and in response to Toll-like receptor (TLR) agonists (TLR2 and TLR4) compared with monocytes from subjects homozygous for the reference haplotype 1. The increase in basal release was 1.8-fold greater in haplotype 2A monocytes, and these differences between the two haplotypes were consistently observed three times over a 3-mo period; no differences were observed for IL-1α or TNFα. NLRP1 RNA and protein levels were not altered by the predominant high-risk haplotype, indicating that altered function of the corresponding multivariant NLRP1 polypeptide predisposes to autoimmune diseases by activation of the NLRP1 inflammasome.
authors: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors: Cecilia B
authors: CB
authors: Levandowski
authors: Christina M
authors: CM
authors: Mailloux
authors: Tracey M
authors: TM
authors: Ferrara
authors: Katherine
authors: K
authors: Gowan
authors: Songtao
authors: S
authors: Ben
authors: Ying
authors: Y
authors: Jin
authors: Kimberly K
authors: KK
authors: McFann
authors: Paulene J
authors: PJ
authors: Holland
authors: Pamela R
authors: PR
authors: Fain
authors: Charles A
authors: CA
authors: Dinarello
authors: Richard A
authors: RA
authors: Spritz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000070576:NLR Proteins; D014820:Vitiligo / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000070576:NLR Proteins; C427903:NLRP1 protein, human
references: Autoimmunity. 2012 Jun;45(4):271-8
references: 22235789
references: J Allergy Clin Immunol. 2007 Apr;119(4):991-6
references: 17320940
references: N Engl J Med. 2007 Mar 22;356(12):1216-25
references: 17377159
references: Pigment Cell Res. 2005 Aug;18(4):300-5
references: 16029422
references: J Biol Chem. 2012 Jul 20;287(30):25030-7
references: 22665479
references: Trends Immunol. 2011 Mar;32(3):110-6
references: 21333600
references: Nat Med. 2001 Aug;7(8):899-905
references: 11479621
references: J Biol Chem. 2011 Apr 1;286(13):10889-96
references: 21296874
references: Hum Immunol. 2010 May;71(5):530-4
references: 20152874
references: J Invest Dermatol. 2012 Jun;132(6):1730-3
references: 22402439
references: N Engl J Med. 2006 Aug 10;355(6):581-92
references: 16899778
references: Immunity. 2012 Dec 14;37(6):1009-23
references: 23219391
references: PLoS One. 2011;6(11):e27396
references: 22087307
references: Semin Immunopathol. 2007 Sep;29(3):213-29
references: 17703304
references: Ann Rheum Dis. 2011 Apr;70(4):668-74
references: 21149496
references: J Invest Dermatol. 2007 Nov;127(11):2558-62
references: 17637824
references: J Histochem Cytochem. 2007 May;55(5):443-52
references: 17164409
references: J Clin Gastroenterol. 2011 Jan;45(1):e1-7
references: 20697295
references: J Exp Med. 2009 May 11;206(5):1029-36
references: 19364880
references: Annu Rev Immunol. 2011;29:707-35
references: 21219188
references: Curr Opin Immunol. 2012 Oct;24(5):571-5
references: 23017373
references: Curr Opin Immunol. 2012 Oct;24(5):538-43
references: 23026397
references: Immunity. 2004 Mar;20(3):319-25
references: 15030775
references: Arthritis Rheum. 2012 Mar;64(3):647-54
references: 21976003
references: Blood. 2011 Apr 7;117(14):3720-32
references: 21304099
references: Nat Rev Drug Discov. 2012 Aug;11(8):633-52
references: 22850787
references: Genes Immun. 2009 Mar;10(2):120-4
references: 18946481
references: Clin Immunol Immunopathol. 1997 Sep;84(3):223-43
references: 9281381
references: Hum Immunol. 2012 Jun;73(6):654-60
references: 22507623
references: Trends Immunol. 2013 Jan;34(1):22-6
references: 23031829
references: Am J Gastroenterol. 2011 Mar;106(3):539-44
references: 21245836