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Chapter 119 : Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation

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Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation, Page 1 of 2

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Abstract:

Both in hematopoietic stem cell transplantation (HSCT) and in solid-organ transplantation (SOT), T and B cell-mediated immunity toward nonshared HLA alleles can have a detrimental outcome. In the past decade, many studies have investigated whether natural killer (NK) cell-mediated immunity might also play a role in clinical transplantation. This work has focused on killer cell immunoglobulin-like receptors (KIRs), as these NK cell receptors interact with HLA class I molecules in an allele-specific manner. In this chapter, we describe the genetics and functions of KIRs and discuss their role in HSCT and SOT.

Citation: Rajalingam R, Cooley S, van Bergen J. 2016. Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation, p 1150-1160. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch119
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Image of FIGURE 1
FIGURE 1

NK cell recognition. NK cells are fast-acting effector lymphocytes that provide the first line of defense against an array of viral pathogens by their ability to spontaneously kill infected cells, as well as to rapidly secrete proinflammatory cytokines. Because NK cells circulate in a state that can rapidly deliver effector functions, NK cells express multiple inhibitory receptors that engage specific HLA class I molecules of healthy cells to prevent harmful autoreactivity. By expressing HLA-A, -B, and -C molecules, the healthy cells become resistant to NK cell surveillance. An essential part of NK cell development is that each functionally competent NK cell expresses at least one inhibitory receptor for a self-HLA class I determinant. As a consequence of this self-tolerance mechanism, NK cells can attack cells in which HLA class I expression is downregulated, a common property of cells that are virally infected or malignantly transformed, a phenomenon first described as the missing-self hypothesis. Other pathological perturbations of human cell surfaces might also trigger NK cell attack through the activating receptors that recognize either induced-self (such as MICA and MICB), altered-self (HLA class I molecule loaded with a foreign peptide), or nonself (either pathogen-encoded HLA class I-like molecules or allogeneic HLA class I).

Citation: Rajalingam R, Cooley S, van Bergen J. 2016. Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation, p 1150-1160. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch119
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Image of FIGURE 2
FIGURE 2

Killer cell immunoglobulin-like receptors (KIRs). Fourteen distinct KIRs have been characterized in humans that comprise either two or three (2D or 3D) extracellular Ig-like domains and either a long (L) or short (S) cytoplasmic tail. Six KIRs are activating types, and the remaining KIRs are inhibitory types. The immunoreceptor tyrosine-based inhibition motifs in the cytoplasmic tails of inhibitory KIRs are shown as blue boxes, and positively charged residues in the transmembrane regions of activating KIRs are shown as yellow circles. The inhibitory KIRs bind to distinct HLA class I allotypes, and the ligands for the activating KIRs are not known.

Citation: Rajalingam R, Cooley S, van Bergen J. 2016. Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation, p 1150-1160. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch119
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Image of FIGURE 3
FIGURE 3

KIR haplotypes have varied gene contents. Map of KIR haplotypes as determined by family segregation analyses. The first haplotypes on the top represent the group A KIR haplotype, and the remainder represent the group B haplotype. A stretch of 14 kb enriched with L1 repeats upstream of KIR2DL4 divides the KIR haplotype into halves. The centromeric half is delimited by 3DL3 and 3DP1, while the telomeric half is delimited by 2DL4 and 3DL2. Multiple reciprocal meiotic recombination events between 3DP1 and 2DL4 shuffled the centromeric and telomeric motifs and thus diversified gene content KIR haplotypes across individuals and populations. The framework genes, present in all haplotypes, are shown in yellow, genes encoding activating KIRs are in orange, and those for inhibitory receptors are in blue. KIR2DP1 and -3DP1 are pseudogenes that do not express a receptor.

Citation: Rajalingam R, Cooley S, van Bergen J. 2016. Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation, p 1150-1160. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch119
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Image of FIGURE 4
FIGURE 4

KIR-HLA effects on kidney transplantation. + indicates the presence and − indicates the absence of a particular genetic association. act, activator; inh, inhibitor.

Citation: Rajalingam R, Cooley S, van Bergen J. 2016. Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation, p 1150-1160. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch119
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