The role of Natural Killer Cells in Human Disease
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P225
2025-12-15
53
Studies of individuals with impaired or dysfunctional NK cell activity have shed new light on the genes and mechanisms responsible for proper NK development and function. Several syndromes have been linked to increased susceptibility to infection, while others may predispose to autoimmune disease and possibly the development of malignancy.
Natural Killer Deficiency Syndromes Linked to Increased Infectious Risks
Pure NK cell deficiency syndromes may be the result of a pro found decrease in the number of circulating NK cells, or may reflect a serious defect in NK cell function but with normal numbers of NK cells in the peripheral blood. Patients with classical NK cell deficiency present with a history of severe, recur rent infections caused by members of the Herpesviridae and Papillomaviridae families that usually have a benign course in nor mal individuals. CD56+ NK cells are either absent or represent less than 1% of circulating lymphocytes. Biron and colleagues reported in 1989 on the case of a young patient who presented with life-threatening varicella infection who exhibited an absolute absence of CD56+CD16+ NK cells. This individual subsequently developed CMV pneumonia and cutaneous HSV (herpes simplex virus) infection. A second patient with a similar lack of peripheral blood NK cells presented with disseminated Mycobacterium avium infection and went on to die as a result of systemic varicella infection. Other patients have been described with an isolated deficiency of CD56+/CD3− lymphocytes but with normal or even increased populations of CD56+/CD3+ cells. One such patient presented with severe, recurrent condylomatous disease caused by the human papilloma virus. An example of a gene mutation causing a functional NK deficiency in NK cell cytotoxicity is the substitution of “T → A” at gene position 230 in FCGR3A (codes for FcγRIIIa) resulting in the replacement of a histidine residue with lysine. Affected patients experience increased susceptibility to severe and disseminated HSV infections as well as Epstein-Barr virus and varicella infections.
The Role of Natural Killer Cells in Autoimmunity
NK cells have been implicated in both the regulation and pathogenesis of autoimmune disorders. NK cells have been implicated in preventing the progression of paralysis in murine experimental models of MS. Recently, investigators have identified CD56bright NK cells as a possible biomarker of response in MS following treatment with interferon-beta. NK cells have also been shown to control inflammation in an experimental model of autoimmune colitis. Experimental evidence supports the idea that NK cells may promote development of type 1 diabetes mellitus through targeted elimination of pancreatic islet β cells after viral infection. This pathobiology may be mediated via an as yet unidentified NKp46 ligand located in the insulin granules of beta cells. Other studies suggest that NK cells can promote humorally mediated autoimmune diseases such as myasthenia gravis through potentiation of autoreactive B cells. Synoviocytes of patients with rheumatoid arthritis (RA) have been shown to express abnormally high levels of MICA, a ligand for NKG2D. NK cells present in acute RA joint effusions may perpetuate this autoimmune inflammatory response, and an analysis of synovial fluid NK cells in patients with severe RA revealed a marked expansion of a CD56bright population with high-level expression of CD69 and NKp46. There is also evidence for NK cell participation in the process of RA bone destruction.
Polymorphisms of the FcγRIIIA gene have been implicated in the pathogenesis and progression of autoimmune disease such as systemic lupus erythematosus (SLE) and RA. There is evidence for an association between NK cell KIR expression and the onset of several autoimmune diseases. The frequency of KIR2DS2 has been identified as being significantly elevated in individuals with SLE. The KIR2DS gene has also been associated with the onset of psoriatic arthritis. Behçet disease is a rare autoimmune disease affecting blood vessels. A comprehensive analysis of HLA and KIR genotypes in over 300 patients suggested that the NK cell KIR repertoire is very likely involved in Behçet disease pathogenesis. Particular KIR genes have also been linked to the development of RA, MS, type 1 diabetes, and ankylosing spondylitis, among others.
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