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Chapter 22 Natural Killer Cell Immunity 243

MHC-dependent processing termed licensing, NK cells that express and responsiveness to cytokine stimulation. Population studies have
receptors for self MHC exhibit greater responsiveness to stimulation; subsequently suggested that the H48 allele may be necessary but not
however, their effector function against normal cells is blocked by sufficient to produce clinical disease. 86
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engagement of inhibitory receptors for self MHC. Whether respon- Clinical examples of patients entirely lacking any CD56
siveness is determined by interaction with cells expressing ligands lymphocyte subsets have been reported. The first report was of a
for NK cell receptors (so-called arming) or hyporesponsiveness is young patient who presented with life-threatening varicella infec-
induced via encounters with normal cells lacking MHC ligands tion. She subsequently developed CMV pneumonia and cutaneous
(“disarming” or “anergy”) is unclear; however, experimental data HSV infection. Analysis of her lymphocyte subsets demonstrated a
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suggest that persistent stimulation results in hyporesponsiveness but striking and selective absolute absence of CD56 or CD16 cells.
persistent stimulation with concomitant inhibition leads to NK cell The patient went on to develop aplastic anemia and died as a result
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responsiveness. 78,79 Studies such as these and others suggest that NK of complications of stem cell transplant. A second patient who
cells may be sensitive to changes in the microenvironment and may presented with disseminated Mycobacterium avium went on to die
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modulate responsiveness to stimuli. as a result of disseminated varicella. Other patients have been
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described with an isolated deficiency of CD56 /CD3 lymphocytes
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but with normal or even increased populations of CD56 /CD3
Natural Killer Cell Memory cells. One such patient presented with severe, recurrent human papil-
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loma virus–related condylomatous disease. Although the genetic
Immunologic memory has long been reserved as a process of the mechanisms of these diseases remain unknown, they highlight the
adaptive immune system; however, recent data suggest that NK cells functional role of NK cells in providing immunity toward infectious
possess a form of memory as well. This idea was first demonstrated pathogens.
in a recombinase-activating gene 1 (RAG-1)-deficient mouse lacking NK cell deficiencies have been described as a component of other
T and B cells. Hapten-induced hypersensitivity was mediated by NK disease processes affecting multiple hematopoietic and immune lin-
cells in this model, and “memory” NK cells were described as residing eages. The genetic deficiencies responsible for many of these disorders
in the liver and bearing Thy1 and CXCR6 on their surfaces. 80 have been described and can be found in Table 22.2.
This concept has also been demonstrated in the setting of viral
infection in mice with vesicular stomatitis virus, HIV-1, influenza,
and murine CMV (MCMV). 80,81 In regard to MCMV, for instance, The Role of Natural Killer Cells in Autoimmunity
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Ly49H NK cells recognize MCMV m157 glycoprotein, resulting
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in NK cell–mediated control of the disease. These Ly49H NK Interestingly, NK cells have been implicated in both the regula-
cells preferentially expand in the setting of infection and contract tion and the pathogenesis of autoimmune disorders. For example,
after infection is controlled. However, “memory” NK cells could in a murine experimental autoimmune encephalomyelitis model of
be detected months after infection, and, upon restimulation, these multiple sclerosis in which disease is induced with myelin oligo-
NK cells exhibited augmented cytotoxicity and cytokine production dendrocyte glycoprotein (MOG), NK depletion leads to enhanced
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against MCMV. Although a unique marker of memory is unclear, T-cell response to MOG. Similarly, in human multiple sclerosis,
these NK cells stably express KLRG1, a cadherin-recognizing inhibi- NK cells have been implicated in the maintenance of disease remis-
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tory receptor, and could be detected 2 months after infection control sion. NK cells have also been shown to control inflammation in
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even in adoptive transfer models. 81 an experimental model of autoimmune colitis. NK cells may exert
A third demonstration of functional NK cell memory has been this effect through recognition and elimination of T cells activated
reported whereby human NK cells preactivated after brief exposure against autoantigens. 91
to IL-12, IL-15, and IL-18. These cells showed an enhanced response There are also examples of NK cells promoting autoimmune dis-
to restimulation up to 3 weeks later that also was retained in divid- orders. For instance, experimental evidence supports the idea that NK
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ing NK cells. This subset was associated with CD94, NKG2A, cells may promote development of type 1 diabetes mellitus through
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NKG2C, and CD69 expression and lacked KIR and CD57. targeted elimination of pancreatic islet β cells after viral infection.
This pathobiology may be mediated via an as yet unidentified NKp46
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THE ROLE OF NATURAL KILLER CELLS IN ligand located in the insulin granules. Other studies suggest that
NK cells can promote humorally mediated autoimmune diseases such
HUMAN DISEASE as myasthenia gravis through potentiation of autoreactive B cells.
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Synoviocytes of patients with rheumatoid arthritis (RA) have been
NK cell deficiencies are rare; however, such conditions provide insight shown to express abnormally high levels of MICA, the previously
into the role NK cells play in response to infectious pathogens, described ligand for NKG2D. 95,96 In fact, NK cells present in acute
autoimmune disorders, and the development of malignancy. Selec- RA joint effusions may perpetuate this autoimmune inflammatory
tive NK cell deficiency has not been associated with a particular response. 97
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Mendelian disorder ; however, studies have shed new light on the Finally, NK cell receptor polymorphisms have been implicated in
genetic mechanisms responsible for proper NK development and the pathogenesis and progression of autoimmune disease. For example,
function. Many syndromes have been linked to increased suscep- a T → G substitution at position 559 in the FcγRIIIA (CD16) gene
tibility to infection, and others may predispose to autoimmune leads to a phenylalanine-to-valine substitution at residue 176 of the
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disease. FcγRIIIA protein. Although the receptors are expressed similarly
on the cell membrane, the V/V homozygous state is associated with
Natural Killer Deficiency Syndromes Linked to a higher affinity for immunoglobulin G (IgG) binding than the F/F
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state. The low binding state (F/F) is associated with lupus nephritis.
Increased Infectious Risks Others have confirmed this observation by genetic linkage studies in
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patients with systemic lupus erythematosis. Another polymorphism
The first gene directly implicated in NK deficiency was FCGR3A, in the FcγRIIIA receptor (158V/F) has been associated with RA in
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which codes for FcγRIIIa (CD16) expressed on NK cells. A “T → A” certain ethnic groups. This mutation may also be associated with
substitution at position 230 leads to coding of a lysine residue at posi- the development of subcutaneous rheumatoid nodules in patients
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tion 48, normally a histidine. Although the protein expressed appears with established RA. Because CD16 is expressed on a number of
phenotypically normal, patients present with increased susceptibility immune cells, the specific role of NK cells contributing to pathology
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to severe and disseminated herpes simplex virus (HSV) infections. is unclear; however, as discussed later, these polymorphisms have
Other patients present with progressive Epstein-Barr virus and vari- also been linked to an enhanced response to monoclonal antibody
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cella infections. Patients have variable deficits in NK cytotoxicity therapy for cancer.