The pathogenesis of celiac disease (CD) is associated with polymorphisms in human leukocyte antigen (HLA) genes; however, compelling evidence suggests that additional non-HLA genes are associated with CD and related complications. The present study investigated whether killer cell immunoglobulin-like receptor (KIR)/HLA gene combinations are associated with CD and its clinical complications in the population of northeast Italy. The study included 61 adults affected by CD: 48 patients were at first diagnosis and 13 patients had CD-related complications (8 with refractory CD and 5 with cancer). Controls were 69 blood donors genotyped for KIR and HLA. Several statistically significant differences emerged between CD patients and blood donors. The results herein presented show that susceptibility to CD with refractory disease or cancer is associated with various genotypes including the 2DS2/2DL2+C1, 2DS3, 3DL1, and 2DL5B genes. In addition, the absence of the Bw4 ligand may be a predisposing factor for cancer. These results suggest that a KIR haplotype and HLA ligands may be involved in the susceptibility to important clinical CD complications such as tumors or refractoriness as a result of a gluten-free diet.
Di SabatinoA, CorazzaGR. Coeliac disease. Lancet2009; 373: 1480–93.
2.
TackGJ, VerbeekWH, SchreursMW, MulderCJ. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nat Rev Gastroenterol Hepatol2010; 7: 204–13.
3.
De ReV, SimulaMP, NotarpietroA, CanzonieriV, CannizzaroR, ToffoliG.Do gliadin and tissue transglutaminase mediate PPAR downregulation in intestinal cells of patients with coeliac disease?Gut2010; 59: 1730–1.
4.
BiagiF, LorenziniP, CorazzaGR. Literature review on the clinical relationship between ulcerative jejunoileitis, coeliac disease and enteropathy-associated T-cell. Scand J Gastroenterol2003; 5: 785–90.
5.
CatassiC, BearziI.HolmesG.K.Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology2005; 128: S79–S86.
6.
EkstromSK, VajdicCM, FalsterM, Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood2008; 111: 4029–38.
7.
FarstadIN, LundinKE. Gastrointestinal intraepithelial lymphocytes and T cell lymphomas. Gut2003; 52: 163–4.
8.
GreenP, CellierC.Celiac Disease. N Engl J Med2007; 357: 1731–43.
9.
MeresseB, ChenZ, CiszewskiC, Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity2004; 21: 357–66.
10.
Di SabatinoA, CiccocioppoR, CupelliF, Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut2006; 55: 469–77.
11.
SimulaMP, CannizzaroR, CanzonieriV, PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage. Mol Med2010; 16: 199–209.
12.
CarringtonM, NormanP.The KI. gene cluster. NCBI Bookshelf, 2003.
13.
ParhamP.MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol2005; 5: 201–14.
14.
CullifordA, DalyJ, DiamondB, RubinM, GreenPH. The value of wireless capsule endoscopy in patients with complicated celiac disease. Gastrointest Endosc2005; 62: 55–61.
15.
OberhuberG, GranditschG, VogelsangH.The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol1999; 11: 1185–94.
16.
De ReV, SimulaMP, CannizzaroR, Galectin-10, eosinophils, and celiac disease. Ann N Y Acad Sci2009; 1173: 357–64.
17.
CordovadoSK, HancockLN, SimoneAE, HendrixM, MuellerPW. High-resolution genotyping of HLA-DQA1 in the GoKinD study and identification of novel alleles HLA-DQA1*040102, HLA-DQA1*0402 and HLA-DQA1*0404. Tissue Antigens2005; 65: 448–58.
18.
MartinMP, NelsonG, LeeJH, Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol2002; 169: 2818–22.
19.
HibySE, WalkerJJ, O'shaughnessyKM, Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med2004; 200: 957–65.
20.
Gomez-LozanoN, GardinerCM, ParhamP, VilchesC.Some human KIR haplotypes contain two KIR2DL5 genes: KIR2DL5A and KIR2DL5B. Immunogenetics2002; 54: 314–9.
21.
PowisSH, VaughanRW. MHC protocols. In: Methods in molecular biology, Volume 210. Totowa, NJ: Humana Press, 2003; 143–71.
22.
KotschK, WehlingJ, KohlerS, BlasczyKR. Sequencing of HLA class I genes based on the conserved diversity of the noncoding regions sequencing-based typing of the HLA-A gene. Tissue Antigens1997; 50: 178–91.
23.
DuZ, SharmaSK, SpellmanS, ReedEF, RajalingamR.KIR2DL5 alleles mark certain combination of activating KIR genes. Genes Immun2008; 9: 470–80.
24.
MaiuriL, CiacciC, RicciardelliI, Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet2003; 5: 30–7.
25.
HarrisKM, FasanoA, MannDL. Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol2010; 135: 430–9.
26.
BeziatV, DescoursB, ParizotC, DebreP, VieillardV.NK cell terminal differentiation: correlated stepwise decrease of NKG2A and acquisition of KIRs. PLoS One2010; 5: e11966.
CarringtonM, MartinMP. The impact of variation at the KIR gene cluster on human disease. Curr Top Microbiol Immunol2006; 298: 225–57.
29.
KhakooSI, CarringtonM.KIR and disease: a model system or system of models?Immunol Rev2006; 214: 186–201.
30.
RauchA, LairdR, McKinnonE, Influence of inhibitory killer immunoglobulin-like receptors and their HLA-C ligands on resolving hepatitis C virus infection. Tissue Antigens2007; 69: 237–40.
31.
KhakooSI, ThioCL, MartinMP, HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science2004; 6: 872–4.
32.
QiY, MartinMP, GaoX, KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog2006; 2: 79.
33.
BashirovaAA, MartinMP, McVicarDW, CarringtonM.The killer immunoglobulinlike receptor gene cluster: tuning the genome for defense. Annu Rev Genomics Hum Genet2006; 7: 277–300.
34.
AlterG, AltfeldM.NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J Intern Med2009; 265: 29–42.
35.
KulkarniS, MartinMP, CarringtonM.The Yin and Yang of HLA and KIR in human disease. Semin Immunol2008; 20: 343–52.
