Macrophage activation syndrome, a devastating complication of some rheumatic conditions, shows pathologic similarities to a rare hereditary condition. Genetic studies imply that their similarities may be more than coincidental.
Macrophage activation syndrome (MAS) is a serious, potentially fatal complication of rheumatic diseases caused by excessive activation and expansion of T lymphocytes and macrophages that exhibit hemophagocytic activity.1
In rheumatology, it occurs most frequently in patients with systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus . The excessive cellular activation and expansion in MAS leads to cytokine overproduction and a hyperinflammatory state associated with cytopenias, liver dysfunction, and coagulopathy that resemble disseminated intravascular coagulation.
Extreme hyperferritinemia is another striking laboratory feature of MAS. It is a life-threatening condition, and the reported mortality rates reach 20-30%.2
MAS bears striking clinical resemblance to a group of histiocytic disorders collectively known as hemophagocytic lymphohistiocytosis (HLH).3,4
HLH is further subdivided into primary or familial (FHLH) and secondary or reactive (ReHLH) lymphohistiocytosis.4 The familial form is a constellation of autosomal recessive immune disorders. Its clinical symptoms usually become evident early in life. Reactive HLH tends to occur in older children and more often is associated with an identifiable infectious episode.
Based on clinical similarities between MAS and ReHLH, some rheumatologists view MAS as ReHLH that occurs in a setting of a rheumatic disease.5 The distinctions between primary and secondary HLH, however, become increasingly blurred as new genetic variants are identified. Some of these are associated with somewhat distinct clinical presentations occurring later in life.6
FHLH is caused by various genetic defects that all lead to profoundly depressed cytolytic activity of natural killer (NK) cells and cytotoxic CD8+ lymphocytes (CTL).
In about 30% of these patients, decreased cytolytic activity is due to mutations in the gene encoding perforin (PRF1).7 Cytolytic cells utilize perforin to induce apoptosis of target cells such as tumor cells or cells infected by viruses. More recently, mutations in several other genes encoding proteins that facilitate granule fusion in intracellular trafficking events leading to the release of perforin have been linked to the development of primary HLH. These include MUNC13-4, Syntaxin 11 (STX11), and syntaxin binding protein 2 (STXBP2, known as MUNC18-2).8
Finally, there are several immunodeficiency syndromes that predispose to HLH which are caused by mutations in gene products involved in function of lytic granules. These include Griscelli syndrome type II (Rab27a) and Chediak Higashi syndrome (LYST).8
The exact mechanisms that would link cytolytic abnormalities with the expansion of T cells and macrophages are not known.
Normally, cytotoxic cells induce apoptosis of cells infected with intracellular microbes or cells undergoing malignant transformation. In some circumstances, cytotoxic cells may also be involved directly in inducing apoptosis of activated macrophages and T cells during the contraction stage of the immune response.
It has been proposed that in HLH, failure to induce apoptosis due to cytotoxic dysfunction leads to prolonged expansion of T cells and macrophages and escalating production of proinflammatory cytokines.9 Although familial cases of MAS in SJIA have not been reported, SJIA/MAS patients do have cytolytic dysfunction to some degree.2
Do rare gene sequence variants affecting the cytolytic pathway create a predisposition to MAS in SJIA?
To address this question, we performed whole exome sequencing in 14 SJIA patients with MAS and their parents, in search of rare sequence variants that might alter proteins in ways that affect the cytolytic pathway. We were able to identify a large number of interesting rare variants with the potential to affect various parts of this pathway.10
First, 5 of 14 patients (35.7%) had heterozygous protein-altering variants in the known genes associated with HLH. Two patients had the same splice-site variant in the STXBP2 gene that was observed previously in adult-onset FHLH,10 suggesting a role for this variant in the development of MAS. In addition, one patient had a protein-altering variant of unknown significance in MUNC13-4 and another patient had a protein altering variant in LYST. Altogether we found 9 variants in 14 patients with MAS, many of them with relevant effects, as opposed to only 4 variants of unknown significance in 4 of 29 (13.7%) SJIA patients who had no history of MAS.
Our analysis identified a large number of genes, encoding proteins important for intracellular vesicle transport.10 The functional significance of the variants in these “new candidate genes” need to be explored further. We are now studying the effects of these variants on the cytolytic function of NK cells to establish how they are pathogenic and contribute to the development of MAS and FHLH.
The “enrichment” for heterozygous variants in the genes implicated in hereditary hemophagocytic syndromes in our cohort of SJIA/MAS patients reinforces the concept that, in addition to striking clinical similarities, there is some pathophysiologic and genetic overlap between FHLH and MAS in SJIA.10
The study also suggests that the presence of such variants identifies SJIA/SLE patients at higher risk for MAS. Such patients may need closer monitoring so that MAS is diagnosed at its early stages, before it becomes life-threatening.