Natural Killer Cell Lymphocytosis Research Articles

Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia.

Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.

Natural Killer Cell Lymphocytosis as a Cause of Pulmonary Arterial Hypertension: A Case Report

Natural Killer Cell Lymphocytosis as a Cause of Pulmonary Arterial Hypertension: A Case Report

Clinicopathological and phenotypic features of chronic NK cell lymphocytosis identified among patients with asymptomatic lymphocytosis

Chronic natural killer (NK) cell lymphocytosis is currently a provisional entity. This study demonstrated NK cell lymphocytosis in patients with asymptomatic lymphocytosis and presented the hematological and phenotypic findings. Flow cytometry analysis was performed for investigation of unexplained peripheral lymphocytosis. NK cells were determined by the phenotype of CD3-/CD16+/CD56+. Chronic NK cell lymphocytosis was defined by a NK cell count of ≥ 2 × 10(9)/L, persistent for over 6 months, no evidence of B- or T-cell clonality and no hematologic disorders. Among 190 patients with peripheral lymphocytosis, 15(7.9%) patients, age 42-72 years, were identified to have NK cell lymphocytosis, with a median NK cell count of 3.1 × 10(9)/L (range 2.1-7.3 × 10(9)/L). Persistent NK cell lymphocytosis was confirmed with a median follow-up of 18 months. CD56(bright) NK cell populations were seen in eight patients and CD56(dim) NK cells in seven patients. CD57 co-expression was seen in both CD56(dim) and CD56(bright) cells. CD7, CD2, or CD8 expression was seen in some of the NK populations. The NK cell lymphocytosis appeared stable and no progression to NK cell leukemia during the follow-up period. This study demonstrated that chronic NK cell lymphocytosis, similar to monoclonal B lymphocytosis or T-cell clones, may account for asymptomatic lymphocytosis. There were no identifiable causes of the NK cell expansion. The variable phenotype may represent the heterogeneity and pathological features of NK lymphocytosis.

A Case of Hypersensitivity to Mosquito Bites without Peripheral Natural Killer Cell Lymphocytosis in a 6-Year-Old Korean Boy

Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by intense skin reactions such as bulla and necrotic ulcerations at bite sites, accompanied by general symptoms such as high-grade fever and malaise occurred after mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukemia/lymphoma. We describe here a Korean child who presented with 3-yr history of HMB without natural killer cell lymphocytosis. He has been ill for 6 yr with HMB. Close observation and examination for the development of lymphoproliferative status or hematologic malignant disorders is needed.

Scleritis and multiple systemic autoimmune manifestations in chronic natural killer cell lymphocytosis associated with elevated TCRα/β+CD3+CD4−CD8− double-negative T cells

Background/aimsChronic natural killer lymphocytosis (CNKL) has been associated with systemic autoimmunity; however, its association with scleritis or ocular autoimmunity has not been characterised. The natural killer (NK) cell function and...

A Case of Hypersensitivity to Mosquito Bite Associated with Epstein-Barr Viral Infection and Natural Killer Cell Lymphocytosis

Hypersensitivity to mosquito bites (HMB) is a disorder characterized by a necrotic skin reaction and generalized symptoms subsequent to mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer cell leukemia/lymphoma. We describe here a Korean child who had HMB associated with chronic EBV infection and natural killer cell lymphocytosis. A 5-yr-old boy was suffered from necrotic skin lesions on the right ear lobe. Type A EB virus was detected from hlood cells and bone marrow biospy recognized hemophagocyrosis.

A 61‐year‐old man with livedo reticularis

Cutaneous polyarteritis nodosa (PAN) is a rare form ofpolyarteritis involving the deep dermis and panniculus. Itis characterized by livedo reticularis, nodules, and ulcer-ations in more severe disease (1,2). The lower extremitiesare most commonly involved. Constitutional and muscu-loskeletal symptoms and polyneuropathy may be associ-ated findings (2). Underlying systemic disorders may beseen with cutaneous PAN, although in the majority ofcases, it occurs in isolation (2). Here we describe a case ofcutaneous PAN occurring in a patient with natural killer(NK) cell lymphocytosis, an exceedingly unusual combi-nation of two rare diseases.

Clinical and Virological Characterization of Persistent Human Infection with Simian Foamy Viruses

Persons occupationally exposed to nonhuman primates (NHPs) can be persistently infected with simian foamy virus (SFV). The clinical significance and person-to-person transmissibility of zoonotic SFV infection is unclear. Seven SFV-infected men responded to annual structured interviews and provided whole blood, oral, and urogenital specimens for study. Wives were tested for SFV infection. Proviral DNA was consistently detected by PCR in PBMCs of infected men and inconsistently in oral or urogenital samples. SFV was infrequently cultured from their PBMCs and throat swabs. Despite this and a long period of intimate exposure (median 20 years), wives were SFV negative. Most participants reported nonspecific symptoms and diseases common to aging. However, one of two persons with mild thrombocytopenia had clinically asymptomatic nonprogressive, monoclonal natural killer cell lymphocytosis of unclear relationship to SFV. All participants worked with NHPs before 1988 using mucocutaneous protection inconsistently; 57% described percutaneous injuries involving the infecting NHP species. SFV likely transmits to humans through both percutaneous and mucocutaneous exposures to NHP body fluids. Limited follow-up has not identified SFV-associated illness and secondary transmission among humans.

Close Resemblance between Chemokine Receptor Expression Profiles of Lymphoproliferative Disease of Granular Lymphocytes and Their Normal Counterparts in Association with Elevated Serum Concentrations of IP-10 and MIG

T-cell large granular lymphocyte (T-LGL) leukemia and chronic natural killer (NK) cell lymphocytosis (CNKL) are major subtypes of lymphoproliferative disease of granular lymphocytes (LDGL). To clarify the mechanism of LGL proliferation and the relationship with the chemokine system in LDGL, we enrolled 22 T-LGL leukemia patients and 8 CNKL cases, analyzed the expression profiles of chemokine receptors, and measured the serum concentrations of the corresponding chemokines. There were no significant differences in chemokine receptor expression profiles between T-LGL leukemia patients and healthy donors. An association of CCR5 and CXCR3 expression levels on LGLs was recognized in T-LGL leukemia patients (r = 0.84; P < .001). Among the chemokines, serum IP-10 and MIG levels were significantly higher in LDGL patients than in healthy donors (P < .05, and P < .001, respectively), and MIG expression was associated with the number of circulating LGLs (r = 0.73; P < .01). The chemokine receptor phenotypes of LDGL cells are essentially similar to those of normal T-cells and NK cells. The roles of IP-10 and MIG in the pathophysiology of LDGL need further examination.

Chronic lymphocytosis of functionally immature natural killer cells

The development of natural killer (NK) cells in the bone marrow is not well characterized. We recently described a mouse (referred to as an NK cell-deficient [NKD] mouse) with a selective deficiency in NK cells caused by the insertion of a transgene construct into the genetic locus for the basic leucine zipper transcription factor ATF-2. NK cells in this mouse were both phenotypically and functionally immature and accumulated in the bone marrow at a stage at which constitutive NK cell proliferation occurs in wild-type mice. We hypothesized that excess IL-15 could potentially overcome this developmental block, allowing normal emigration of mature NK cells from the bone marrow to the periphery. Double-transgenic mice were generated by crossing the NKD mice with transgenic mice overexpressing IL-15. The double-transgenic mice had a dramatic accumulation of phenotypically immature NK cells in the bone marrow and subsequently in the blood, liver, and spleen. NK cells from these double-transgenic mice manifested functional deficits similar to those observed in NK cells from NKD mice, as assessed by decreased cytokine production and cytotoxicity. Rather than bypass the observed developmental defect in NKD mice, excess IL-15 drove a massive accumulation of phenotypically and functionally immature NK cells in the bone marrow and periphery. We propose that these double-transgenic mice will serve as a murine model of chronic NK cell lymphocytosis in human patients.

Atypical Hypersensitivity to Mosquito Bites without Natural Killer Cell Proliferative Disease in an Adult Patient

Hypersensitivity to mosquito bites (HMB) is a rare disorder that occurs in the first 2 decades of life and is considered to be associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukemia/lymphoma. EBV-encoded small nuclear RNA (EBER)-positive NK cells infiltrate the skin lesion at the site of the mosquito bite. In this report, we present the case of an adult patient with mantle cell lymphoma complicated by atypical HMB. The anti-EBV antibody titer of the patient indicated reactivation of chronic infection with this virus, and EBV DNA in the peripheral blood mononuclear cells was detected after chemotherapy by quantitative polymerase chain reaction analysis. However, an in situ hybridization analysis did not detect EBER-positive cells in the skin lesion at the bite site or in the lymph node. Peripheral NK cell lymphocytosis and EBV-associated lymphoproliferative disease did not develop. These findings suggest that some patients with chronic EBV infection may develop HMB without NK cell proliferative disease.

Mosquito Salivary Gland Extracts Induce EBV-Infected NK Cell Oncogenesis Via CD4+ T Cells in Patients with Hypersensitivity to Mosquito Bites

Severe hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. Patients with HMB often have natural killer (NK) cell lymphocytosis associated with Epstein-Barr virus (EBV) infection. Here we investigated whether mosquito bites have any influence on the oncogenesis of EBV-infected NK cells. We examined six HMB patients with EBV-infected NK cell lymphocytosis. We first demonstrated that CD4+ T cells, but not NK cells, proliferated well in response to mosquito salivary gland extracts (SGE), especially to SGE of Aedes albopictus. When NK cells were cocultured with autologous CD4+ T cells stimulated by mosquito SGE, the expression of viral oncogene latent membrane protein 1 (LMP1) was remarkably enhanced. Next, we stimulated mononuclear cells of the patients with mosquito SGE, and NK cell counts were monitored for 28 d. The counts changed little from initial levels in the culture with mosquito SGE, whereas they decreased steadily in the culture without the extracts. Furthermore, we detected LMP1 mRNA in the skin lesion induced by mosquito SGE. These results suggest that mosquito bites can induce expression of the viral oncogene LMP1 in NK cells via mosquito antigen-specific CD4+ T cells, which is involved in the oncogenesis of NK cells in vivo.

Characterization of Epstein-Barr virus–infected natural killer lymphocytes in a patient with hypersensitivity to mosquito bites

To the Editor: Hypersensitivity to mosquito bites is characterized by severe skin reactions associated with fever and liver damage1 and is often complicated by the presence of other Epstein-Barr virus (EBV)–related disorders2 and natural killer (NK) cell lymphocytosis.3 We report a cytologic profile of EBV-infected NK cells isolated from a 15-year-old Japanese boy with chronic active EBV infection associated with hypersensitivity to mosquito bites of 12 years' duration.

Persistence of Natural Killer (NK) cell lymphocytosis with hyposplenism without development of leukaemia

BackgroundNatural killer (NK) cell lymphocytosis usually has an indolent course and can progress into massive lymphocytosis with development of cytopenias and neoplastic diseases. NK-cells usually express one or more "NK-associated" antigens (CD16, CD56, CD57). Reactive expansions are seen in autoimmune diseases, viral infections, solid tumours and non-Hodgkin's lymphoma.Case presentationWe report a lady with a benign clinical course over 10 years and persistent CD8+/CD3-/CD57+/CD16+ LGL proliferation with presence of Howell-Jolly bodies (functional hyposplenism), an association not previously described.ConclusionWe discuss the possible causes of clonal expansion and conclude that this may be part of the spectrum of immune dysregulation associated with NK-cell lymphocytosis.

Significance of chemokine receptor expression in aggressive NK cell leukemia

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.

Peripheral neuropathy associated with chronic natural killer cell lymphocytosis

We report a patient with steroid-responsive peripheral neuropathy which developed with chronic natural killer cell lymphocytosis (CNKL). A 70-year-old female with a 2-week history of progressive motor and sensory neuropathy showed a marked increase of natural killer (NK) cells in the blood, and was diagnosed as having CNKL. Nerve conduction studies (NCS) revealed a mixed axonal and demyelinating neuropathy. A sural nerve biopsy revealed infiltration of NK cells into the nerve fascicles, and demyelinating changes with axonal degeneration. The infiltrating NK cells were adjacent to myelinated fibers, showing damage of Schwann cell membrane. Treatment with oral prednisolone resulted in rapid improvement of the sensory disturbance and weakness with a significant decrease of NK cells in the blood and disappearance of the conduction blocks in NCS. This is the first case of CNKL associated neuropathy in which infiltration of NK cells was demonstrated in the nerve fascicles. Our observations suggest that the infiltrating NK cells may directly damage myelin and Schwann cells, thus causing demyelination.

Chronic Natural Killer Cell Lymphocytosis Is Associated With Elevated Cytotoxic Activity of Natural Killer Cells

The authors describe a 16-year-old girl who has suffered from chronic natural killer cell lymphocytosis (CNKL) for 12 years. From age 4 years, she has shown a persistent lymphadenopathy and lymphocytosis. Clinically, she developed allergic skin involvement, thrombocytopenia, and peripheral polyneuropathy. Annual flow cytometry analyses of lymphocyte subsets revealed persistently elevated NK cell levels (55-75% of the lymphocyte fraction and 0.7-10 x 10(3) NK cells per microliter of blood). Furthermore, IgE serum concentrations were markedly increased. Based on CD16, CD161, and CD94 surface antigen expression, the NK cell population was characterized as mature NK cells. Functional analysis of these cells showed a 2-fold increase of intrinsic cytotoxic activity toward K-562 cells compared with NK cells from healthy controls. The authors present a clinical case of rare CNKL. The patient's NK cells possess significantly increased cytotoxic activity. These findings are discussed in context with elevated IgE concentrations.

Clinicobiological, Immunophenotypic, and Molecular Characteristics of Monoclonal CD56 −/+dim Chronic Natural Killer Cell Large Granular Lymphocytosis

Indolent natural killer (NK) cell lymphoproliferative disorders include a heterogeneous group of patients in whom persistent expansions of mature, typically CD56(+), NK cells in the absence of any clonal marker are present in the peripheral blood. In the present study we report on the clinical, hematological, immunophenotypic, serological, and molecular features of a series of 26 patients with chronic large granular NK cell lymphocytosis, whose NK cells were either CD56(-) or expressed very low levels of CD56 (CD56(-/+dim) NK cells), in the context of an aberrant activation-related mature phenotype and proved to be monoclonal using the human androgen receptor gene polymerase chain reaction-based assay. As normal CD56(+) NK cells, CD56(-/+dim) NK cells were granzyme B(+), CD3(-), TCRalphabeta/gammadelta(-), CD5(-), CD28(-), CD11a(+bright), CD45RA(+bright), CD122(+), and CD25(-) and they showed variable and heterogeneous expression of both CD8 and CD57. Nevertheless, they displayed several unusual immunophenotypic features. Accordingly, besides being CD56(-/+dim), they were CD11b(-/+dim) (heterogeneous), CD7(-/+dim) (heterogeneous), CD2(+) (homogeneous), CD11c(+bright) (homogeneous), and CD38(-/+dim) (heterogeneous). Moreover, CD56(-/+dim) NK cells heterogeneously expressed HLA-DR. In that concerning the expression of killer receptors, CD56(-/+dim) NK cells showed bright and homogeneous CD94 expression, and dim and heterogeneous reactivity for CD161, whereas CD158a and NKB1 expression was variable. From the functional point of view, CD56(-/+dim) showed a typical Th1 pattern of cytokine production (interferon-gamma(+), tumor necrosis factor-alpha(+)). From the clinical point of view, these patients usually had an indolent clinical course, progression into a massive lymphocytosis with lung infiltration leading to death being observed in only one case. Despite this, they frequently had associated cytopenias as well as neoplastic diseases and/or viral infections. In summary, we describe a unique and homogeneous group of monoclonal chronic large granular NK cell lymphocytosis with an aberrant activation-related CD56(-/+dim)/CD11b(-/+dim) phenotype and an indolent clinical course, whose main clinical features are related to concomitant diseases.

Cutaneous findings associated with chronic natural killer cell lymphocytosis.

Chronic Natural Killer Cell Lymphocytosis (CNKL) is a recently described rare proliferative disorder. We noted an association of cutaneous disorders with CNKL in our clinical experience. We reviewed the medical records of all known patients with CNKL at our institution. Five of 14 patients (36%) with CNKL had associated chronic cutaneous disease: two had livedoid vasculopathy; one, urticarial vasculitis; one, peripheral T-cell lymphoma; and one had complex recurrent aphthous stomatitis. In each case, except the one with lymphoma, the cutaneous disease was present before CNKL was diagnosed and CNKL persisted for the duration of the cutaneous disease. All five patients had increased numbers of large granular lymphocytes on a peripheral blood smear and three or four in the bone marrow (one patient did not undergo bone marrow biopsy). Although CNKL and the reported skin diseases have occurred in the same patients, a causal link cannot yet be established. With CNKL, dermatologists must recognize associated cutaneous diseases, monitor patients for systemic disorders and cytopenias, and appropriately refer patients to a hematologist.

Natural Killer Cells and the Syndrome of Chronic Natural Killer Cell Lymphocytosis

Natural killer (NK) cells provide anti-infectious, anti-neoplastic, and immunomodulatory function effected by both cytokine production and direct cellular cytotoxicity that is not major histocompatibility complex-restricted. NK cells lack truly specific cell surface determinants as well as antigen-specific receptors. Recent information suggests a variety of receptor-ligand interactions that underlie recognition and treatment of target cells by NK cells. Primary NK cell disorders in humans are currently classified into NK cell lymphomas and chronic NK cell lymphocytosis (CNKL). In this review, we summarize current understanding of the biology of NK cells and describe the clinical manifestations of CNKL.