Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

David, Grégoire; Djaoud, Zakia; Willem, Catherine; Legrand, Nolwenn; Rettman, Pauline; Gagne, Katia; Cesbron, Anne; Retière, Christelle

doi:10.4049/jimmunol.1301580

Cited by 86 publications

(97 citation statements)

References 38 publications

(37 reference statements)

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“…The functional effects of KIR2DS5 diversity await additional investigation, but certain KIR2DS5 allotypes do show different expression levels in transfected cells, similar to findings for other KIR variants (30). For example, allelic variation of KIR2DL1 affects protein expression levels at the cell surface, NK repertoire, and affinity of binding (22,31,32). Furthermore, although no binding has been shown of the European allele KIR2DS5*002 to any HLA ligand, KIR2DS5*006 might bind to C2-bearing HLA-C allotypes common in Africans (C*04, C*02, C*17, and C*18) (15).…”

Section: Discussionmentioning

confidence: 64%

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

Nakimuli

Chazara²,

Hiby³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

135

146

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In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.Uganda | pre-eclampsia | NK cells | maternal mortality | KIR

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Section: Discussionmentioning

confidence: 64%

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

Nakimuli

Chazara²,

Hiby³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

135

146

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“…The "licensing" or NK cell education model predicts that NK cells with inhibitory KIR for self-HLA class I acquire effector function, whereas NK cells lacking inhibitory KIR for self-HLA class I are hyporesponsive (25), and this model has been supported and elaborated by findings of gene dose effects among receptors and ligands. Individual NK cells with multiple copies of inhibitory KIR for self-HLA class I acquire progressively increased effector function (26,27), and increasing copy number of HLA-Bw4 and HLA-C2 alleles confers increased antitumor responsiveness to cognate KIR3DL1-and KIR2DL1-expressing NK cells (28,29). Similarly, an increasing number of distinct MHCencoded ligands confers increased responsiveness, presumably through a collective increase in licensed NK cell subsets (27).…”

mentioning

confidence: 99%

“…Of the KIR3DL1 ligands, HLA-Bw4 molecules with threonine at position 80 (HLA-Bw4-80Thr) bind KIR3DL1 with lower affinity than HLA-Bw4 molecules with isoleucine at position 80 (HLA-Bw4-80Ile) (32,33,41), conferring lower responsiveness but weaker NK cell inhibition (32,33). Similarly, certain HLA-C1 alleles weakly bind KIR2DL2/3, although the clinical implications are unclear (29,30,42,43).…”

mentioning

confidence: 99%

KIR and HLA Genotypes Predictive of Low-Affinity Interactions Are Associated with Lower Relapse in Autologous Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Marra

Greene

Hwang

et al. 2015

The Journal of Immunology

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Killer cell Ig–like receptors (KIRs) bind cognate HLA class I ligands with distinct affinities, affecting NK cell licensing and inhibition. We hypothesized that differences in KIR and HLA class I genotypes predictive of varying degrees of receptor–ligand binding affinities influence clinical outcomes in autologous hematopoietic cell transplantation (AHCT) for acute myeloid leukemia (AML). Using genomic DNA from a homogeneous cohort of 125 AML patients treated with AHCT, we performed KIR and HLA class I genotyping and found that patients with a compound KIR3DL1+ and HLA-Bw4-80Thr+, HLA-Bw4-80Ile– genotype, predictive of low-affinity interactions, had a low incidence of relapse, compared with patients with a KIR3DL1+ and HLA-Bw4-80Ile+ genotype, predictive of high-affinity interactions (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06–0.78; p = 0.02). This effect was influenced by HLA-Bw4 copy number, such that relapse progressively increased with one copy of HLA-Bw4-80Ile (HR, 1.6; 95% CI, 0.84–3.1; p = 0.15) to two to three copies (HR, 3.0; 95% CI, 1.4–6.5; p = 0.005) and progressively decreased with one to two copies of HLA-Bw4-80Thr (p = 0.13). Among KIR3DL1+ and HLA-Bw4-80Ile+ patients, a predicted low-affinity KIR2DL2/3+ and HLA-C1/C1 genotype was associated with lower relapse than a predicted high-affinity KIR2DL1+ and HLA-C2/C2 genotype (HR, 0.25; 95% CI, 0.09–0.73; p = 0.01). Similarly, a KIR3DL1+ and HLA-Bw4-80Thr+, HLA-Bw4-80Ile– genotype, or lack of KIR3DL1+ and HLA-Bw4-80Ile+ genotype, rescued KIR2DL1+ and HLA-C2/C2 patients from high relapse (p = 0.007). These findings support a role for NK cell graft-versus-leukemia activity modulated by NK cell receptor–ligand affinities in AHCT for AML.

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“…62 It is known that KIR2DS1/HLA-C2 receptor/ligand interaction contributes to functional NK cell education; KIR2DS1pos NK cells from C2 negative individual demonstrated strong alloreactive activity against HLA-C2 targets, in contrast to low or absent alloreactivity if the NK cells were from a C2-positive individual. 63,64 Additional studies would be helpful to evaluate whether there is a genetic susceptibility to RPL in KIR2DS1/HLA-C2 co-expression cases.…”

Section: Kir and Hla-c Regulates The Immune Responsiveness Of Nk Cellmentioning

confidence: 99%

Future directions of clinical laboratory evaluation of pregnancy

et al. 2014

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In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss (RPL) or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant. New understanding leads to the concept that the activated innate response is vital for pregnancy and this can result in more effective testing and treatment to prevent an abnormal pregnancy in the future. We describe here only three such areas for future testing: one area involves sperm and semen and factors necessary for successful fertilization; another area would determine conditions for production of growth factors necessary for implantation in the uterus; finally, the last area would be to determine conditions necessary for the vascularization of the placenta and growing fetus by activated natural killer (NK) cells (combinations of killer cell immunoglobulin-like receptor (KIR) family genes with HLA-C haplotypes) that lead to capability of secreting angiogenic growth factors. These areas are novel but understanding their role in pregnancy can lead to insight into how to maintain and treat pregnancies with complicating factors. Keywords: male factor; preterm labor; recurrent pregnancy loss; seminal plasma; sperm INTRODUCTIONWhen utilizing clinical immunological testing in recurrent pregnancy loss (RPL) or preterm delivery, it should be considered that the primary function of the immune system in pregnancy is angiogenesis and its secondary function is to function as a system to kill and remove foreign pathogens. Alterations in the immune system can affect angiogenesis or the blood flow, which is necessary to maintain placental growth and thereby may divert the immune system from its non-pregnant primary function. At present, the most commonly performed tests to monitor and treat women with RPL are tests for autoantibodies such as antiphospholipid antibodies, antinuclear antibodies and anti-thyroid antibodies.1-3 In addition, assays for lymphocyte subsets and their functions, determination of HLA histocompatibility genes and genes related to thrombophilic conditions are used by some physicians to aid in treatment. Some physicians test women to determine if their RPL are due to an inappropriate inflammatory immune response, which may be treated by anti-inflammatory drug regimens. Some of the tests that are performed have been a matter of controversy but one might consider that women with histories of RPL should be tested to determine if a reason for the repeated miscarriages can be identified. Finally, women with preterm delivery usually are tested for infections or fetal fibronectin which can be helpful in the treatment. 4 The immune system is an endocrine-like system capable of producing numerous peptide hormones (cytokines and chemokines). These hormones are key in the vascularization necessary for pla...

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Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

Cited by 86 publications

References 38 publications

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

KIR and HLA Genotypes Predictive of Low-Affinity Interactions Are Associated with Lower Relapse in Autologous Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Future directions of clinical laboratory evaluation of pregnancy

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