The Impact of Variation at the KIR Gene Cluster on Human Disease

Carrington, Mary; Martin, Maureen P.

doi:10.1007/3-540-27743-9_12

Cited by 119 publications

(143 citation statements)

References 153 publications

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“…37 Segregation analysis of families suggests that KIR haplotypes can vary widely in gene content with a range of 4-14 genes per haplotype. 38 Why is there so much variation in NK cell receptor repertoires within species? At least two separate factors are driving the evolution of these gene clusters: (1) recognition of self by the inhibitory receptors and (2) recognition of non-self by the activating receptors.…”

Section: Discussionmentioning

confidence: 99%

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Dewar

Ml³

et al. 2005

Genes Immun

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The BALB/c inbred mouse is widely used in models of infectious disease, transplantation, and cancer. The differences in the immune responses of BALB/c compared to C57BL/6 mice are especially valuable for the identification of immune regulation genes. One striking immune variance between these mice is in the function of natural killer (NK) cells, and there is strong evidence implicating differential expression of Ly49 genes. In this study, the complete BALB/c Ly49 gene cluster has been sequenced and found to contain six functional genes and two pseudogenes. Compared to C57BL/6 mice, there is a 200 kb region absent in the BALB/c cluster including a complete lack of Ly49h-related genes, which explains the increased susceptibility of BALB/c to cytomegalovirus infection. In addition, there is no BALB/c Ly49d allele, explaining the inability of BALB/c NK cells to kill certain tumor cells. The Ly49 region has now been sequenced in three different inbred mouse strains, and comparisons indicate that the evolution of each haplotype is not straightforward and has involved large-scale deletions/ insertions, gene recombination, and unequal crossing over between divergent haplotypes. This study confirms that relatively small murine class I MHC receptor haplotypes exist, analogous to observations made of human killer cell Ig-like receptor gene haplotypes.

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Section: Discussionmentioning

confidence: 99%

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Dewar

Ml³

et al. 2005

Genes Immun

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“…Thus, KIR/HLA-C compound genotypes contribute to susceptibility or resistance to a variety of infectious diseases and cancer (20). In particular, homozygosity for HLA-C1 and KIR2DL3 may be advantageous in viral infections, but detrimental in chronic inflammatory conditions that play a role in carcinogenesis (21).…”

Section: Introductionmentioning

confidence: 99%

Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses

Ahlenstiel¹,

Martin²,

Gao³

et al. 2008

J. Clin. Invest.

120

145

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“…Whether Ly49H-m157 constitutes a prototypical example of recognition of infectious non-self ligand for the other activating Ly49 and KIR-S molecules is still not known. Genetic epidemiological studies have revealed that activating KIR genotypes are associated with protection against two infectious diseases (HIV-1 and hepatitis C virus) as well as against pre-eclampsia, but they also represent genetic risk factors for developing autoimmune diseases [22]. NKp44 is another KARAP/DAP12-dependent receptor belonging to the natural cytotoxicity receptor (NCR) family, which is selectively expressed on activated human NK cells and rare cd T cells [23].…”

Section: Introductionmentioning

confidence: 99%

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

2005

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The signaling adaptor protein KARAP/DAP12/TYROBP (killer cell activating receptorassociated protein / DNAX activating protein of 12 kDa / tyrosine kinase binding protein) belongs to the family of transmembrane polypeptides bearing an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). This adaptor, initially characterized in NK cells, is associated with multiple cell-surface activating receptors expressed in both lymphoid and myeloid lineages. We review here the main features of KARAP/DAP12, describing findings from its identification to recently published data, showing its involvement in a broad array of biological functions. KARAP/DAP12 is a wiring component for NK cell anti-viral function (e.g. mouse cytomegalovirus via its association with mouse Ly49H) and NK cell anti-tumoral function (e.g. via its association with mouse NKG2D or human NKp44). KARAP/DAP12 is also involved in inflammatory reactions via its coupling to myeloid receptors, such as the triggering receptors expressed by myeloid cells (TREM) displayed by neutrophils, monocytes/ macrophages and dendritic cells. Finally, bone remodeling and brain function are also dependent upon the integrity of KARAP/DAP12 signals, as shown by the analysis of KARAP/DAP12-deficient mice and KARAP/DAP12-deficient Nasu-Hakola patients. IntroductionPolypeptides that bear at least one immunoreceptor tyrosine-based activation motif (ITAM; YxxL-x 7 -YxxL) in their intracytoplasmic domain constitute family of various signaling molecules ( Fig. 1A and B). ITAM were first identified in the immune system, where they are required for the expression and signaling of several activating immunoreceptors, thus playing a key role in immune responses. ITAM-bearing proteins can also be detected in non-hematopoietic tissues, such as the brain, and they can also be produced by several viruses (Fig. 1A and B). The latest ITAM-bearing polypeptide to be identified [1][2][3][4][5] protein (TYROBP); here we refer to it as KARAP/DAP12. As previously described for other ITAM-bearing polypeptides, tyrosine residues present in KARAP/DAP12 ITAM, once phosphorylated, are both required for the recruitment and the activation of Syk and ZAP70, which are SH2-domain-containing protein tyrosine kinases (PTK) [3]. KARAP/DAP12 transcripts are present in bony fishes, rodents, swine and humans, showing the broad conservation of this signaling component in vertebrates [2, 3, 6, 7]. KARAP/DAP12 expression is detectable in both lymphoid and myeloid cells, where it can associate with several activating immunoreceptors, contributing to several biological functions [8].In this review, we will correlate KARAP/DAP12 broad expression in both hematopoietic and non-hematopoietic tissues with pleiotropic functions of this signaling , protein G1 of hantavirus (sequence indicated corresponds to substrain NY1, but G1 proteinITAM sequences of several other hantavirus substrains' have also been reported) [59]. All the ITAM motifs reported here, except for viral molecules, are derived from human sequenc...

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The Impact of Variation at the KIR Gene Cluster on Human Disease

Cited by 119 publications

References 153 publications

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

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