title: Killer Immunoglobulin-like Receptors (KIR) haplogroups A and B track with Natural Killer Cells and Cytokine Profile in Aged Subjects: Observations from Octo/Nonagenarians in the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST).
abstract: BACKGROUND
  Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well.
  
  
  RESULTS
  In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99-1.09; p=0.027) and 14% higher levels for TGF-β (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99-1.09; p=0.002).
  
  
  CONCLUSIONS
  In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood.
authors: School of Medicine, Dentistry and Biomedical Science Queens University, Belfast, UK. i.rea@qub.ac.uk.
authors: Irene Maeve
authors: IM
authors: Rea
authors: Lynn D
authors: LD
authors: Maxwell
authors: Susan E
authors: SE
authors: McNerlan
authors: H Denis
authors: HD
authors: Alexander
authors: Martin D
authors: MD
authors: Curran
authors: Derek
authors: D
authors: Middleton
authors: Owen A
authors: OA
authors: Ross
references: Lancet. 2000 Nov 25;356(9244):1795-9
references: 11117911
references: Blood. 1994 Mar 1;83(5):1323-8
references: 7906963
references: PLoS One. 2011 Feb 17;6(2):e16103
references: 21379581
references: J Gerontol A Biol Sci Med Sci. 2003 Mar;58(3):232-7
references: 12634289
references: Transpl Immunol. 2005 Aug;14(3-4):135-42
references: 15982555
references: Mol Immunol. 2005 Feb;42(4):471-5
references: 15607801
references: Am J Epidemiol. 2010 May 15;171(10):1144-52
references: 20400465
references: PLoS One. 2011;6(9):e22842
references: 21909397
references: Clin Cancer Res. 1999 Jan;5(1):9-16
references: 9918197
references: J Leukoc Biol. 2009 Jan;85(1):88-97
references: 18820174
references: J Psychiatr Res. 1975 Nov;12(3):189-98
references: 1202204
references: Exp Gerontol. 2002 Jan-Mar;37(2-3):445-53
references: 11772532
references: J Clin Immunol. 2002 Jan;22(1):28-36
references: 11958591
references: Cell Immunol. 1994 Jul;156(2):480-92
references: 7912999
references: Curr Opin Immunol. 2010 Aug;22(4):529-34
references: 20685099
references: Blood. 2000 May 15;95(10):3183-90
references: 10807786
references: Hum Immunol. 2006 Jul;67(7):521-6
references: 16829306
references: J Clin Immunol. 1998 Jan;18(1):31-8
references: 9475351
references: Int J Oncol. 2004 Aug;25(2):487-91
references: 15254748
references: Tissue Antigens. 2005 Jun;65(6):556-63
references: 15896204
references: Clin Cancer Res. 2010 Aug 1;16(15):3901-9
references: 20542985
references: Clin Exp Immunol. 1993 Nov;94(2):297-305
references: 7693383
references: Semin Hematol. 2005 Apr;42(2):91-103
references: 15846575
references: Tissue Antigens. 2009 Jun;73(6):599-603
references: 19392800
references: Mech Ageing Dev. 1984 Nov;28(1):47-55
references: 6513613
references: Am J Epidemiol. 2008 Dec 15;168(12):1444-51
references: 18953059
references: Nucleic Acids Res. 1988 Feb 11;16(3):1215
references: 3344216
references: Gerontology. 1996;42(2):69-78
references: 9138976
references: Blood. 2002 Sep 15;100(6):1935-47
references: 12200350
references: N Engl J Med. 1989 Jun 29;320(26):1731-5
references: 2543925
references: Exp Gerontol. 2007 Aug;42(8):753-61
references: 17606347
references: J Immunol. 1995 Aug 1;155(3):1066-73
references: 7636180
references: Microbes Infect. 2002 Dec;4(15):1545-58
references: 12505527
references: Curr Top Microbiol Immunol. 2006;298:225-57
references: 16329188
references: Exp Gerontol. 1999 Jan;34(1):79-93
references: 10197730
references: J Exp Med. 1985 Jun 1;161(6):1464-82
references: 3159818
references: Mol Med Today. 1999 Apr;5(4):178-86
references: 10203751
references: J Exp Med. 1989 Sep 1;170(3):827-45
references: 2504877
references: Curr Opin Immunol. 2004 Oct;16(5):626-33
references: 15342010
references: Int J Immunogenet. 2013 Feb;40(1):39-45
references: 23280119
references: Exp Gerontol. 2004 Aug;39(8):1223-32
references: 15288696
references: Aging (Albany NY). 2012 Aug;4(8):535-46
references: 22935594
references: Age (Dordr). 2009 Dec;31(4):261-7
references: 19496022
references: Immunogenetics. 2002 Nov;54(8):543-50
references: 12439616
references: Semin Immunol. 2001 Feb;13(1):41-9
references: 11289798
references: Front Immunol. 2013 Jan 29;4:8
references: 23372569
references: J Immunol. 2002 Nov 1;169(9):5118-29
references: 12391228
references: PLoS One. 2010 Aug 26;5(8):e12381
references: 20865034
references: Cytokine. 2000 Feb;12(2):156-9
references: 10671301
references: Dis Markers. 2012;33(4):201-6
references: 22960345
references: J Exp Med. 1996 Nov 1;184(5):1781-90
references: 8920866
references: Blood. 2011 May 12;117(19):5152-6
references: 21415265
references: Immunity. 1997 Dec;7(6):753-63
references: 9430221
references: J Immunol. 2011 Jun 15;186(12):6753-61
references: 21555534
references: J Exp Med. 1990 Dec 1;172(6):1589-98
references: 2147946
references: J Immunol. 2006 Feb 15;176(4):2645-53
references: 16456027
references: Viruses. 2009;1(3):362
references: 20151027
references: Immun Ageing. 2010 May 27;7:6
references: 20507630
references: Immunogenetics. 2002 Jul;54(4):221-9
references: 12136333
references: Vaccine. 2000 Feb 25;18(16):1613-20
references: 10689137
references: Immunol Rev. 2006 Dec;214:186-201
references: 17100885
references: Eur J Clin Nutr. 1997 Feb;51(2):102-6
references: 9049569
references: Br J Haematol. 2013 Apr;161(2):294-6
references: 23346960
references: Blood. 2010 Nov 11;116(19):3865-74
references: 20733159
references: Nat Immunol. 2012 Sep;13(9):843-50
references: 22863752
references: Nature. 1997 Apr 3;386(6624):514-7
references: 9087413
references: Genes Immun. 2007 Dec;8(8):678-83
references: 17882223
references: Eur J Immunol. 2001 Oct;31(10):3121-7
references: 11592089
references: Cytotherapy. 2011 Jan;13(1):98-107
references: 20849361
references: J Clin Invest. 1998 May 1;101(9):1835-42
references: 9576746
references: Nat Rev Immunol. 2005 Mar;5(3):201-14
references: 15719024
references: Blood. 1990 Dec 15;76(12):2421-38
references: 2265240
references: Infect Immun. 2005 Aug;73(8):4913-21
references: 16041005
references: Nature. 1981 May 28;291(5813):335-8
references: 6164929
references: Proc Natl Acad Sci U S A. 1986 Aug;83(15):5688-92
references: 2426704
references: Blood. 2010 Nov 11;116(19):3853-64
references: 20696944
references: Tissue Antigens. 2007 Jun;69(6):577-82
references: 17498267
references: Cancer Biol Ther. 2009 Dec;8(23):2211-20
references: 19923897
references: Nat Rev Immunol. 2013 Feb;13(2):133-44
references: 23334245
references: Gene. 2004 Jun 23;335:121-31
references: 15194195
references: J Am Geriatr Soc. 1994 Sep;42(9):978-83
references: 8064108
references: Eur J Immunol. 2010 Aug;40(8):2289-95
references: 20540115
references: Immunogenetics. 2007 Feb;59(2):145-58
references: 17200871