Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms.

Macrophage Activation Syndrome (MAS) is a severe, potentially fatal condition associated with excessive activation of macrophages and T cells leading to an overwhelming inflammatory reaction. The main manifestations of MAS include fever, hepatosplenomegaly, lymphadenopathy, severe cytopenias, serious liver disease, and disseminated intravascular coagulation [1,2]. The pathognomonic feature of MAS is often found in bone marrow: numerous, well-differentiated macrophages phagocytosing hematopoietic elements. Although MAS has been reported in patients with different rheumatic diseases, it is most strongly associated with Systemic Juvenile Idiopathic Arthritis (SJIA). In fact, it accounts for much of the morbidity and mortality seen in this form of JIA. At least 10% of the patients with SJIA develop MAS [3]. The true incidence of MAS might be much higher since there are no validated diagnostic criteria and mild instances of MAS are not always recognized [4,5]. It is now recognized that MAS bears close resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH) [2,6]. HLH is a term that describes a spectrum of disease processes characterized by accumulations of well-differentiated mononuclear cells with a macrophage phenotype [7]. In the contemporary classification of histiocytic disorders, HLH is further subdivided into primary, or familial HLH, and secondary, or reactive HLH (ReHLH) [7]. Clinically, however, they may be difficult to distinguish from each other [9]. Familial hemophagocytic lymphohistiocytosis (FHLH) is a constellation of rare autosomal recessive immune disorders. The clinical symptoms of FHLH usually become evident within the first 2 months of life although initial presentation as late as 22 years of age has been reported [8]. Secondary HLH tends to occur in older children and more often is associated with an identifiable infectious episode, most notably Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection. The exact pathophysiological relationship between MAS and HLH is not understood. Some pediatric rheumatologists view MAS as ReHLH occurring in a setting of a rheumatologic disease [6]. The pathological mechanisms of HLH/MAS are not fully understood. In HLH, there is uncontrolled proliferation of T cells and macrophages that has been linked to decreased NK-cell and cytotoxic T-cell function [10] often due to mutations in the gene encoding perforin [11]. Perforin is a protein which cytolytic cells utilize to induce apoptosis of target cells such as tumor cells or cells infected by viruses. It has been hypothesized by some authors that abnormal cytotoxic cells may fail to provide appropriate apoptotic signals for removal of activated macrophages and T cells during the contraction stage of certain immune responses [12]. Our recent observations suggest that as in HLH, MAS patients have profoundly depressed NK-cell function, often associated with abnormal perforin expression [13]. More recently, mutations in another gene, MUNC13-4, have been implicated in the development of hemophagocytic lymphohistiocytosis in about 10-30% of patients with inherited HLH [14]. The protein encoded by the MUNC13-4 gene is an essential effector of the cytolytic secretory pathway. MUNC13-4 protein is involved in vesicle priming function which follows granule docking and precedes plasma granule membrane fusion [14]. Therefore, it is an important player in the intracellular transport of perforin. Although the cytolytic cells of the patients with FHLH caused by MUNC13-4 mutations produce sufficient amounts of perforin, the poor ability to deliver perforin to the surface of the cells leads to profoundly decreased cytolytic activity against target cells. Here we present new data that suggests an association between MAS in SJIA and specific mutations and/or haplotypes in MUNC13-4 gene.