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Chediak-Higashi syndrome (CHS) is a rare inherited disorder that inflicts a diversity of maladies on those afflicted by it. Identifying features of the disease include progressive neurological dysfunction, an increased tendency to develop leukemia and lymphoma, and depigmentation of hair, skin and eyes. Almost 90% of those afflicted have severe immunological deficiency, displaying defective natural-killer-cell function and deficits in neutrophil activity. These abnormalities in the leukocyte population are reflected in a greatly heightened susceptibility to infection, traceable in part to neutrophils that are deficient in chemotactic and bactericidal activities, and to dysfunctional populations of natural killer cells. The result is a greatly shortened life span; many Chediak-Higashi patients succumb to the disease in childhood. Microscopic examination of leukocytes from CHS patients reveals giant lysozomes that are characteristic of this disease.

Only those homozygous for a mutant form of a gene known as CHS-1/LYST (/ysosomal trafficking regulator) develop Chediak-Higashi syndrome. A corresponding mutation has been found in beige mice and the mouse analogue of human CHS-1/LYST. The mouse and human homologues both encode a very large polypeptide of 2,186 amino acids. Beige mice display a pattern of symptoms very much like those seen in humans, and their granulocytes, like those of afflicted humans, display the huge cytoplasmic granules that are a morphological hallmark of the disease. Studies of the disease in beige mice complement those in humans, and have led to the conclusion that severe defects in the formation, fusion, or trafficking of intracellular vesicles probably underlie its devastating pathology.

Bone marrow transplantation (BMT) is the only effective therapy for the defective natural killer activity, aberrant macrophage activation, and susceptibility to bacterial infections that plague those afflicted with Chediak-Higashi syndrome. However, this is a risky and complex therapy. A look at the experience of 10 CHS children who underwent BMT for their disease is informative. BMT is best done with marrow from a donor whose HLA type is identical to that of the recipient. Unfortunately, it may be difficult or impossible to obtain HLA-matched bone marrow, and 3 of the patients had to settle for HLA-non-identical marrow. After a median interval of 6.5 years post-transplantation, 6 of the 7 patients who had received marrow from HLA-identical donors were alive, but only 1 of the 3 recipients of HLA-nonidentical marrow survived. The clinical picture in the survivors was markedly improved. They were no longer hypersusceptible to bacterial infection, displayed significant NK-cell activity, and did not suffer from uncontrolled and pathological macrophage activation. However, the albinism and lack of eye pigmentation were not improved by BMT. HLA-identical BMT is thus accepted as a curative treatment for Chediak-Higashi syndrome, but reliance on HLA-nonidentical transplantation is experimental and carries very high risk.

Chediak Higashi Syndrome

A neutrophil with the giant lysozomes characteristic of Chediak-Higashi syndrome. (Courtesy of American Society of Hemotology Slide Bank, 3rd edition.)

C-type-lectin-inhibitory receptor is CD94/NKG2, a disulfide-bonded heterodimer made up of two glycoproteins, one of which is CD94 and the other a member of the NKG2 family. The CD94/NKG2 receptors recognize HLA-E on potential target cells. Because HLA-E is not transported to the surface of a cell unless it has bound a peptide derived from HLA-A,

HLA-B, or HLA-C, the amount of HLA-E on the surface serves as indicator of the overall level of class I MHC biosynthesis in the cells. These inhibitory CD94/NKG2 receptors are thus not specific for a particular HLA allele and will send inhibitory signals to the NK cell, with the net result that killing of potential target cells is inhibited if they are express ing adequate levels of class I. In contrast, KIR receptors, of which more than 50 family members have been found, are specific for one or a limited number of polymorphic products of particular HLA loci. Unlike B and T cells, NK cells are not limited to expressing a single KIR, but may express several, each specific for a different MHC molecule or for a set of closely related MHC molecules. For example, individual clones of human NK cells expressing a CD94/NKG2 receptor and as many as six different KIR receptors have been found. Because signals from inhibitory receptors have veto power over signals from activating receptors, a negative signal from any inhibitory receptor, whether of the CD94/NKG2 or KIR type, can block the lysis of target cells by NK cells. Thus, cells expressing normal levels of unaltered MHC class I molecules tend to escape all forms of NK-cell-mediated killing.

In the opposing-signals model of NK-cell regulation that is emerging from studies of NK cells (Figure 14-14), activating receptors engage ligands on the target cell. These ligands may be abnormal patterns of glycosylation on the surface of tumor or virus-infected cells. Recognition of these determinants by ARs on NK cells would signal NK cells to kill the target cells. Ligand engagement by NKR-P1-type lectin receptors, or a number of other ARs, such as CD16, or in some cases CD2, generates signals that direct the NK cell to kill the target cell. Any of these killing signals can be overridden by a signal from inhibitory receptors. As we have already seen, members of the inhibitory superfamily of receptors (ISRs) provide a signal that decisively overrides activation signals when these inhibitory receptors detect normal levels of MHC class I expression on potential target cells. This prevents the death of the target cell. It also prevents NK-cell proliferation and the induction of secretion of cytokines such as IFN-y and TNF-a. The overall consequence of the opposing-signals model is to spare cells that express critical indicators of normal self, the MHC class I molecules, and to kill cells that lack indicators of self (absence of normal levels of class I MHC).

Class I MHC CD94/NKG2

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