Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the X-chromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.
Abstract The importance of lymphotoxin (LT) βR (LTβR) as a regulator of lymphoid organogenesis is well established, but its role in host defense has yet to be fully defined. In this study, we report that mice deficient in LTβR signaling were highly susceptible to infection with murine CMV (MCMV) and early during infection exhibited a catastrophic loss of T and B lymphocytes, although the majority of lymphocytes were themselves not directly infected. Moreover, bone marrow chimeras revealed that lymphocyte survival required LTα expression by hemopoietic cells, independent of developmental defects in lymphoid tissue, whereas LTβR expression by both stromal and hemopoietic cells was needed to prevent apoptosis. The induction of IFN-β was also severely impaired in MCMV-infected LTα−/− mice, but immunotherapy with an agonist LTβR Ab restored IFN-β levels, prevented lymphocyte death, and enhanced the survival of these mice. IFN-αβR−/− mice were also found to exhibit profound lymphocyte death during MCMV infection, thus providing a potential mechanistic link between type 1 IFN induction and lymphocyte survival through a LTαβ-dependent pathway important for MCMV host defense.
Background/Purpose:
Localized myositis is rarely reported in patients with systemic-onset JIA (sJIA), despite common symptoms of myalgia. We describe sJIA patients with the manifestation of localized myositis.
Methods:
We reviewed the charts of 6 pediatric patients with sJIA who developed localized myositis during their disease course.
Results:
The age at presentation with myositis ranged from 5 to 19 years. 4 were males and 2 were females. Races included Caucasian (4), Caucasian/Mayan (1), and African-American (1). Three patients had localized myositis with initial presentation of sJIA, and 3 patients developed localized myositis during disease flares. For the disease flare group, the time from diagnosis of sJIA until development of myositis ranged from 3 to 6 years, and 2 of 3 patients were on immunosuppressive agents: methotrexate (MTX) (1), anakinra and MTX (1). All 6 patients complained of localized swelling and pain in a localized muscle group. Accompanying symptoms included arthralgia, arthritis, fever and rash. Three patients had localized erythema of the skin overlying myositis areas on exam. Sites of myositis included unilateral biceps (3), bilateral biceps (1), quadriceps (1), and flexor pollicis longus and flexor digitorum superficialis and profundus (1). All patients had at least one muscle enzyme obtained, and all were normal. Five patients had imaging studies demonstrating evidence of myositis: 2 by ultrasound, 2 by ultrasound and MRI, and 1 by MRI. All 6 patients had laboratory evidence of systemic inflammation, including elevated ESR (41–172 mm/hr) and CRP (54–269 mg/L). Four patients had thrombocytosis (462,000–834,000/μL). Two patients transferred care to another hospital, thus we had no information on follow-up. The remaining 4 patients responded well to prednisone, with resolution of their symptoms within 4 weeks. One patient underwent incision and drainage for a fluid collection and myositis of biceps muscle. He was initially treated with antibiotics and started on anakinra after negative cultures. Duration of follow-up since onset of myositis was 6–14 months, and no patients had recurrent myositis. The current treatment of the 4 patients includes infliximab (1), MTX (1), canakinumab and leflunomide (1), and canakinumab and MTX (1).
Conclusion:
Localized myositis is a rare extraarticular manifestation of sJIA and can present either as an initial manifestation or during a disease flare. Patients usually present with unilateral or bilateral localized swelling, overlying warmth and erythema, and pain of one muscle group, most commonly the biceps in our series of patients. Our subjects' muscle enzymes were normal, likely secondary to the focal nature of muscle inflammation. Imaging studies are helpful in establishing the diagnosis. To our knowledge, this study represents the largest series to date of sJIA patients with localized myositis.
Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation.
NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell–mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy.
Abstract NK cells have important functions in cancer immunosurveillance, bone marrow allograft rejection, fighting infections and reproduction. NK cell-based therapies are promising blood cancer treatments. Overcoming their currently limited efficacy requires a better understanding of the molecular mechanisms controlling NK cell development and dampening their effector functions. NK cells recognize pathogen-infected or tumor cells through invariant NK cell receptors (NKR), and then kill such stressed cells. Two second-messenger pathways downstream of NKRs are required for NK cell maturation and effector responses: PIP3-generation by PI3K, and generation of DAG and IP3 by PLCγ. IP3 plays a key signaling role by mobilizing Calcium, but can also be converted into soluble inositol(1,3,4,5)tetrakisphosphate (IP4). We and others previously showed that IP4 can act as a soluble analog of the PI3K lipid-product phosphatidylinositol(3,4,5) trisphosphate (PIP3) and control PIP3-mediated signaling protein membrane recruitment and activation in thymocytes and granulocytes. Here, we show data which suggest a novel IP4 function in promoting NK cell terminal differentiation and acquisition of a mature NKR repertoire. However, in mature NK cells, IP4 limits NKR induced IFNγ secretion, granule exocytosis and target-cell clearance, in part by inhibiting the PIP3 effector-kinase Akt. This identifies IP4 as an important novel regulator of NK cell development and function, and expands our understanding of the therapeutically important mechanisms dampening NK cell responses. Our results further suggest that PI3K regulation by soluble IP4 is a broadly important signaling paradigm.
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