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Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis

2016; Elsevier BV; Volume: 138; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2016.07.011

1097-6825

Yuge Wang, Tracy Hwangpo, Maureen P. Martin, Nicolas Vince, Qi Ying, Richard J. Reynolds, Devin Absher, Xiaojiang Gao, Carol A. Ballinger, Peter D. Burrows, T. Prescott Atkinson, Elizabeth E. Brown, Ada Elgavish, Cunren Liu, Mary Carrington, Harry W. Schroeder,

T-cell and B-cell Immunology

Patients with common variable immune deficiency (CVID) display hypogammaglobulinemia, blunted antibody responses to bacterial polysaccharides, and recurrent sinopulmonary infections.1Schroeder Jr., H.W. Schroeder III, H.W. Sheikh S.M. The complex genetics of common variable immunodeficiency.J Invest Med. 2004; 52: 90-103PubMed Google Scholar MHC haplotypes associated with some autoimmune disorders are linked to CVID.1Schroeder Jr., H.W. Schroeder III, H.W. Sheikh S.M. The complex genetics of common variable immunodeficiency.J Invest Med. 2004; 52: 90-103PubMed Google Scholar However, inheritance of these haplotypes is insufficient for CVID development. We postulated a role for other immunogenetic factors that might interact with the MHC. Killer cell immunoglobulin-like receptors (KIRs) are expressed on natural killer (NK) cells and T-cell subsets. KIRs and HLA class I molecules are encoded by unlinked polymorphic gene families, and interactions between these molecules contribute to innate and adaptive immunity.2Lanier L.L. NK cell recognition.Ann Rev Immunol. 2005; 23: 225-274Crossref PubMed Scopus (2257) Google Scholar Significant associations of KIR and KIR/HLA compound genotypes with several immune diseases have been reported.3Kulkarni S. Martin M.P. Carrington M. The yin and yang of HLA and KIR in human disease.Semin Immunol. 2008; 20: 343-352Crossref PubMed Scopus (289) Google Scholar To our knowledge, there has been only 1 study, from Central Europe, testing for associations between CVID, HLA, and KIR. With 18 study subjects and 15 controls, statistical power was low.4Kartal O. Musabak U. Yesillik S. Sagkan R.I. Pekel A. Demirel F. et al.Killer-cell immunoglobulin-like receptor and human leukocyte antigen-C genes in common variable immunodeficiency.Wien Klin Wochenschr. 2015; PubMed Google Scholar We tested whether KIR/HLA genotypes influence the risk of CVID in patients from the Southeastern United States, which among the European-derived was mostly populated by people of British ancestry. We genotyped KIR and HLA, and performed an ImmunoChip assay5Eyre S. Bowes J. Diogo D. Lee A. Barton A. Martin P. et al.High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.Nat Genet. 2012; 44: 1336-1340Crossref PubMed Scopus (471) Google Scholar on 175 affected individuals (Table I) and on 72 spousal controls without evidence of immune dysfunction. Performed under guidelines of the UAB Institutional Review Board, informed consent was obtained from all study participants.Table IGrouped subjects (CHI) diseases phenotypeDiseases phenotype (CHI)∗Affected individuals were diagnosed after age 2 years, and other causes of antibody deficiency were excluded.SexAge at diagnosis (y), range (mean ± SD)DefinitionCase no. (Total 175)FemaleMaleCVID44254-71 (39.6 ± 18.1)IgG level < 500 mg/dL and either IgM or IgA level <2 SD below the mean (IgM level < 46 mg/dL, IgA level < 82 mg/dL)•Tested for isohemagglutinin titers•Low isohemagglutinin titers∗Affected individuals were diagnosed after age 2 years, and other causes of antibody deficiency were excluded.•Tested for antipneumococcal polysaccharide titers•Low antipneumococcal polysaccharide titers†•Tested for either isohemagglutinin or antipneumococcal polysaccharide titers•Low isohemagglutinin and/or low antipolysaccharides titers69483341325234 (65%)Hypogammaglobulinemia23510-70 (51.96 ± 13.8)IgG level < 500 mg/dL with normal IgA and IgM levels•Tested for isohemagglutinin titers•Low isohemagglutinin titers∗Affected individuals were diagnosed after age 2 years, and other causes of antibody deficiency were excluded.•Tested for antipneumococcal polysaccharide titers•Low antipneumococcal polysaccharide titers†Less than 70% of antipneumococcal polysaccharide titers achieved the protective range.•Tested for either isohemagglutinin or antipneumococcal polysaccharide titers•Low isohemagglutinin and/or low antipolysaccharides titers282231882211 (50%)ICR (intermediate CVID)552320-84 (51.0 ± 14.1)IgG level between 500 and 600 mg/dL with normal IgM and IgA levels, or IgG level between 600 and 751 mg/dL with either IgM or IgA level 2000 individuals). Disease phenotypes in relation to the European Society for Immunodeficiencies 2014 criteria are presented in Table I. Only patients with self-declared Northern European ancestry were studied. Their average age was 46.7 ± 16.5 years. For reasons unknown, we observed a sex preference for women (female:male, 2.3:1; P < .0001 when compared with the 1958 birth cohort). After correction for population stratification and adjusting to Eigen2, we used logistic regression to estimate odds ratios (ORs) and corresponding CIs. We examined HLA at the 2-digit level. HLA-B alleles can also be grouped as Bw4 or Bw6, with Bw4 alleles serving as ligand for the inhibitory KIR3DL1 and possibly for the activating KIR3DS1, both of which are alleles of the same locus. Likewise, HLA-C group 1 allotypes (C alleles with asparagine at position 80, C1) are ligands for the inhibitory KIR2DL2 and KIR2DL3, which are alleles of the same locus. All the remaining HLA-C allotypes (C2) have lysine at position 80 and are ligands for the inhibitory KIR2DL1 and the activating KIR2DS1.2Lanier L.L. NK cell recognition.Ann Rev Immunol. 2005; 23: 225-274Crossref PubMed Scopus (2257) Google Scholar Consistent with our previous findings that patients with CVID have a higher frequency of HLA-B*0801,1Schroeder Jr., H.W. Schroeder III, H.W. Sheikh S.M. The complex genetics of common variable immunodeficiency.J Invest Med. 2004; 52: 90-103PubMed Google Scholar we observed a significant association between HLA-B*08 (Bw6) and increased risk of disease. HLA-B*0801 is in linkage disequilibrium with HLA-C*07 (C1). Also increased were HLA-B*44 (Bw4-80T) and HLA-C*16 (C1). However, individual associations between HLA-B*44, HLA-C*07, and HLA-C*16 did not achieve statistical significance due to population size. KIR genes associated with disease risk included activating KIR2DS1 (OR, 1.45; P = .03) and KIR3DS1 (OR, 1.54; P = .01) and inhibitory KIR2DL5 (OR, 1.43; P = .04) (Fig 1). All 3 genes are found on KIR “B” haplotypes in linkage disequilibrium.6Uhrberg M. Valiante N.M. Shum B.P. Shilling H.G. Lienert-Weidenbach K. Corliss B. et al.Human diversity in killer cell inhibitory receptor genes.Immunity. 1997; 7: 753-763Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar KIR2DL5 confers susceptibility to the autoimmune disease psoriasis vulgaris,7Suzuki Y. Hamamoto Y. Ogasawara Y. Ishikawa K. Yoshikawa Y. Sasazuki T. et al.Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris.J Invest Derm. 2004; 122: 1133-1136Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar and KIR2DS1 is associated with both PV and psoriatic arthritis.7Suzuki Y. Hamamoto Y. Ogasawara Y. Ishikawa K. Yoshikawa Y. Sasazuki T. et al.Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris.J Invest Derm. 2004; 122: 1133-1136Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 8Martin M.P. Nelson G. Lee J.H. Pellett F. Gao X. Wade J. et al.Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles.J Immunol. 2002; 169: 2818-2822Crossref PubMed Scopus (304) Google Scholar We tested the effect of KIR/HLA receptor-ligand combinations on disease risk, focusing on Bw or C allotype. CHI risk with the compound genotype KIR3DS1+HLA−Bw4 was similar to that with KIR3DS1 alone (OR, 1.57 vs 1.54). Surprisingly, the effect was significantly stronger when the analysis was restricted to Bw4 alleles with threonine at position 80 (Bw4-80T) (OR, 1.79; P = .002), given that KIR3DS1+Bw4−80I (Ile80) was previously shown to associate with delayed progression to AIDS.3Kulkarni S. Martin M.P. Carrington M. The yin and yang of HLA and KIR in human disease.Semin Immunol. 2008; 20: 343-352Crossref PubMed Scopus (289) Google Scholar KIR2DL1+C2 was protective (OR, 0.58; P = .002), whereas homozygosity for KIR2DL3+C1 was associated with increased CHI risk (OR, 1.88; P = .002). We tested the significance of the nominally significant associations by a permutation test, which yielded empirical P values of .03 for the most significant association and .007 for the combined significance of the observed associations. Overall, the data suggest that CVID risk increases in patients in whom NK cell activation can be facilitated, as evidenced by the association with the activating receptors KIR2DS1 and KIR3DS1, as well as KIR3DS1+Bw4, and decreases in patients with the strongly inhibitory KIR2DL1+C2. Homozygosity for KIR2DL3/C1, which has a relatively weak inhibitory potential relative to KIR2DL1+C2,9Winter C.C. Gumperz J.E. Parham P. Long E.O. Wagtmann N. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition.J Immunol. 1998; 161: 571-577PubMed Google Scholar was also associated with increased risk. The mechanism by which KIR could influence the development of CVID is unknown. Upon activation, NK cells become cytotoxic, produce inflammatory cytokines, and interact with dendritic cells and macrophages. Emerging data suggest that KIR may help to control certain viruses including HIV and hepatitis C virus, while also increasing the risk for some inflammation-mediated conditions, for example, cancers and autoimmune diseases.3Kulkarni S. Martin M.P. Carrington M. The yin and yang of HLA and KIR in human disease.Semin Immunol. 2008; 20: 343-352Crossref PubMed Scopus (289) Google Scholar The CVID/hypogammaglobulinemia/intermediate CVID/recurrent sinopulmonary infection phenotype is frequently acquired. Many patients associate the onset of symptoms with an inflammatory event. It is possible that enhanced NK activation could be advantageous for patients exposed to infection, but detrimental in a disease such as CVID in which enhancement of an inflammatory response to an antigen, either environmental or pathogen derived, could set up a regulatory cascade that results in a variable block in B-cell development and antibody production. Our study identifies an unappreciated association between KIR and CVID, which will need to be confirmed in a second, independent cohort. KIR may have discordant roles, either protective or exacerbating in CVID, which suggests a new mechanism for the pathogenesis of this immunodeficiency. These findings warrant functional studies to define the role of KIR-bearing cells in the development of CVID, and suggest the possibility of applying both KIR and HLA ligand genotyping to predict disease risk.