The Role of Natural Killer Cells in Inflammation in Active Adult-onset Still Disease

Abstract

Adult-onset Still disease (AOSD) is a systemic inflammatory disease characterized by spiking fever, arthralgia, rash, leukocytosis, and hepatosplenomegaly, similar to systemic-onset juvenile idiopathic arthritis (sJIA)1,2. The etiology of AOSD is unclear but the disease is thought to result from a combination of genetic and environmental factors. The disease pathology is characterized by widespread immune dysregulation, involving cytokines and their receptors, immune cells, and tissues. Activation of the innate immune system plays a major role in the systemic inflammation that characterizes AOSD and sJIA3. Activated macrophages and neutrophils induce increased levels of proinflammatory cytokines, such as interleukin (IL)-1β, IL-18, IL-6, and interferon (IFN)-γ. These proinflammatory cytokines provoke activation of macrophages and neutrophils, and differentiation of T cells. Decreased numbers and functional impairment of natural killer (NK) cells have also been implicated in the pathogenesis of AOSD and sJIA4,5.\n\nNK cells are an important lymphocytic component of the innate immune system, providing a cytotoxicity defense against malignant, infected, and autoreactive cells6,7. NK cells exert their effects by secreting cytolytic granules such as perforin, granzyme, and serine proteases, and induce caspase-dependent apoptosis through death receptors including Fas/FasL. Impaired cytotoxic function of NK cells leads to excessive activation of macrophages and T cells, as seen in macrophage activation syndrome (MAS), and is a major, life-threatening complication of AOSD and sJIA8,9. Primary hemophagocytic lymphohistiocytosis (HLH), a hereditary disorder of MAS, occurs as a result of genetic defects in the perforin- or granzyme-dependent pathways of NK cells or cytotoxic T cells10. Additional genetic mutations associated with inhibitory or stimulatory NK cell receptors have also been observed in secondary HLH. The resulting failure of NK cells to lyse activated antigen-presenting cells results in sustained stimulation of lymphocytes … \n\nAddress correspondence to Dr. H.A. Kim, Department of Rheumatology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea. E-mail: nakhada{at}naver.com