Study of killer immunoglobulin-like receptor genes and human leukocyte antigens class I ligands in a Caucasian Brazilian population with Crohn's disease and ulcerative colitis

Wilson, Timothy J.; Jobim, Mariana; Jobim, Luiz Fernando Job; Portela, Pâmela; Salim, Patrícia Hartstein; Rosito, Mário Antonello; Damin, Daniel C.; Flores, Cristina; Peres, Alessandra; Machado, Marta Brenner; Chies, José Artur Bogo; Schwartsmann, Gilberto; Roesler, Rafaël

doi:10.1016/j.humimm.2009.12.006

Cited by 24 publications

(19 citation statements)

References 48 publications

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“…We and others have previously identified associations between IBD and genetic variation at the killer cell immunoglobulin-like receptor (KIR) locus. (13, 14, 39) KIR genes are predominantly expressed by NK cells, and are one element of the receptor repertoire controlling NK cell activation, proliferation, and effector functions that mediate surveillance and host defense for microbial infection and malignancy. (10, 11) The relevance of this locus together with the role of NK cells in the development of IBD has recently been further highlighted with the publication of the IBD genome-wide association studies/Immunochip study.…”

Section: Discussionmentioning

confidence: 99%

Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

Lin

Wei

et al. 2014

The Journal of Immunology

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Natural killer (NK) cells are innate immune cells known for their cytolytic activities towards tumors and infections. They are capable of expressing diverse killer immunoglobulin receptors (KIRs), and KIRs are implicated in susceptibility to Crohn’s disease (CD), a chronic intestinal inflammatory disease. However, the cellular mechanism of this genetic contribution is unknown. Here we show that the ‘licensing’ of NK cells, determined by the presence of KIR2DL3 and homozygous HLA-C1 in host genome, results in their cytokine reprogramming, which permits them to promote CD4+ T cell activation and TH17 differentiation ex vivo. Microfluidic analysis of thousands of NK single cells and bulk secretions established that licensed NK cells are more polarized to pro-inflammatory cytokine production than unlicensed NK cells, including production of IFN-γ, TNF-α, CCL-5, and macrophage inflammatory protein (MIP)-1β. Cytokines produced by licensed NK augmented CD4+ T cell proliferation and IL-17A/IL-22 production. Antibody blocking indicated a primary role for IFN-γ, TNF-α, and IL-6 in the augmented T cell proliferative response. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel NK cytokine program that activates and induces pro-inflammatory CD4+ T cells, thereby providing a potential biologic mechanism for KIR-associated susceptibility to CD and other chronic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

Lin

Wei

et al. 2014

The Journal of Immunology

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“…Specific KIR-HLA combinations have been associated with differential responses to infection [5–7] and susceptibility to autoimmune disorders including Crohn’s disease [8–10], ulcerative colitis [10, 11], systemic lupus erythematosus [12, 13], type I diabetes [14], and psoriatic arthritis [15]. In the case of autoimmunity, the presence of an activating KIR and/or absence of ligands for inhibitory KIR is commonly associated with disease susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-α therapy

et al. 2011

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The identification of patients who will respond to anti-tumor necrosis factor alpha (anti-TNF-α) therapy will improve the efficacy, safety, and economic impact of these agents. We investigated whether killer cell immunoglobulin-like receptor (KIR) genes are related to response to anti-TNF-α therapy in patients with rheumatoid arthritis (RA). Sixty-four RA patients and 100 healthy controls were genotyped for 16 KIR genes and human leukocyte antigen-C (HLA-C) group 1/2 using polymerase chain reaction sequence-specific oligonucleotide probes (PCR-SSOP). Each patient received anti-TNF-α therapy (adalimumab, etanercept, or infliximab), and clinical responses were evaluated after 3 months using the disease activity score in 28 joints (DAS28). We investigated the correlations between the carriership of KIR genes, HLA-C group 1/2 genes, and clinical data with response to therapy. Patients responding to therapy showed a significantly higher frequency of KIR2DS2/KIR2DL2 (67.7% R vs. 33.3% NR; P = 0.012). A positive clinical outcome was associated with an activating KIR–HLA genotype; KIR2DS2+HLA-C group 1/2 homozygous. Inversely, non-response was associated with the relatively inhibitory KIR2DS2–HLA-C group 1/2 heterozygous genotype. The KIR and HLA-C genotype of an RA patient may provide predictive information for response to anti-TNF-α therapy.

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“…KIR genotypes and HLA ligand patterns have been recognized for diseases and disease conditions such as hepatitis C [18], psoriasis vulgaris [19,20], psoriatic arthritis [21,22], rheumatoid arthritis [23], celiac disease [24], ulcerative colitis [25,26], Crohn's disease [27], human immunodeficiency virus [28], recurrent miscarriage [29], and leprosy [30], as well as in T1D [31][32][33][34][35][36][37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Association of killer cell immunoglobulin-like receptors and human leukocyte antigen–C genotypes in South Brazilian with type 1 diabetes

et al. 2010

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Study of killer immunoglobulin-like receptor genes and human leukocyte antigens class I ligands in a Caucasian Brazilian population with Crohn's disease and ulcerative colitis

Cited by 24 publications

References 48 publications

Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

Human NK Cells Licensed by Killer Ig Receptor Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-α therapy

Association of killer cell immunoglobulin-like receptors and human leukocyte antigen–C genotypes in South Brazilian with type 1 diabetes

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