Enrichment of Variations in KIR3DL1/S1 and KIR2DL2/L3 among H1N1/09 ICU Patients: An Exploratory Study

Abstract

BackgroundInfection by the pandemic influenza A (H1N1/09) virus resulted in significant pathology among specific ethnic groups worldwide. Natural Killer (NK) cells are important in early innate immune responses to viral infections. Activation of NK cells, in part, depend on killer-cell immunoglobulin-like receptors (KIR) and HLA class I ligand interactions. To study factors involved in NK cell dysfunction in overactive immune responses to H1N1 infection, KIR3DL1/S1 and KIR2DL2/L3 allotypes and cognate HLA ligands of H1N1/09 intensive-care unit (ICU) patients were determined.Methodology and FindingsKIR3DL1/S1, KIR2DL2/L3, and HLA -B and -C of 51 H1N1/09 ICU patients and 105 H1N1-negative subjects (St. Theresa Point, Manitoba) were characterized. We detected an increase of 3DL1 ligand-negative pairs (3DL1/S1+ Bw6+ Bw4−), and a lack of 2DL1 HLA-C2 ligands, among ICU patients. They were also significantly enriched for 2DL2/L3 ligand-positive pairs (P<0.001, Pc<0.001; Odds Ratio:6.3158, CI95%:2.481–16.078). Relative to St. Theresa aboriginals (STh) and Venezuelan Amerindians (VA), allotypes enriched among aboriginal ICU patients (Ab) were: 2DL3 (Ab>VA, P = 0.024, Pc = 0.047; Odds Ratio:2.563, CI95%:1.109–5.923), 3DL1*00101 (Ab>VA, P<0.001, Pc<0.001), 3DL1*01502 (Ab>STh, P = 0.034, Pc = 0.268), and 3DL1*029 (Ab>STh, P = 0.039, Pc = 0.301). Aboriginal patients ligand-positive for 3DL1/S1 and 2DL1 had the lowest probabilities of death (Rd) (Rd = 28%), compared to patients that were 3DL1/S1 ligand-negative (Rd = 52%) or carried 3DL1*029 (Rd = 52%). Relative to Caucasoids (CA), two allotypes were enriched among non-aboriginal ICU patients (NAb): 3DL1*00401 (NAb>CA, P<0.001, Pc<0.001) and 3DL1*01502 (CA<NAb, P = 0.012, Pc = 0.156). Non-aboriginal patients with ligands for all three KIRs (3DL1/S1, 2DL2/L3, and 2DL1) had the lowest probabilities of death (Rd = 36%), compared to subjects with 3DL1*01502 (Rd = 48%) and/or 3DL1*00401 (Rd = 58%).ConclusionsSpecific KIR3DL1/S1 allotypes, 3DL1/S1 and 2DL1 ligand-negative pairs, and 2DL2/L3 ligand-positive pairs were enriched among ICU patients. This suggests a possible association with NK cell dysfunction in patients with overactive immune responses to H1N1/09, leading to severe disease.

The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface

“…Interestingly however a combination of the activating receptor KIR2DS3 in combination with a single nucleotide polymorphism of the IL28B gene, significantly increased the risk of chronic disease in hepatitis C virus infection, possibly through a IL28 mediated inhibition of IFNÈ by NK cells (127). Other studies also demonstrated that diminished inhibitory responses through KIR2D and HLA-C interactions, confers protection against HCV (128)(129)(130) and influences the development of severe influenza (131). Many HLA-C independent interactions between NK cells and EVT may contribute to inhibition and activation of dNK cytotoxicity, e.g., HLA-G and KIR2DL4 interaction favors IFN production but inhibits NK cytotoxicity (Figure 2D) (132), NKG2 receptors mediate responses through HLA-E as well as cellular stress ligands (133).…”

Killer Cell Immunoglobulin-Like Receptor Gene Associations with Autoimmune and Allergic Diseases, Recurrent Spontaneous Abortion, and Neoplasms

“…Several KIR genes were found to be associated with H1N1 influenza 2009 pandemics (La et al, 2011; Aranda-Romo et al, 2012). …”

Altered natural killer cells' response to herpes virus infection in multiple sclerosis involves KIR2DL2 expression

“…Since KIR2DL2 is an inhibitory receptor that was associated with a greater viral infection severity (La et al, 2011) and an overrepresentation of two copies for KIR2DL2 gene was observed in MS patients (Jelcic et al, 2012), we evaluated the possible effect of CpG and HSV-1 infection on NK cell KIR2DL2 expression.…”