Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis
1Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. alexi.grom@cchmc.org.
Abstract:
Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation driven by excessive activation and expansion of T cells (mainly CD8) and hemophagocytic macrophages producing proinflammatory cytokines. MAS has been reported in association with almost every rheumatic disease, but it is by far most common in systemic juvenile idiopathic arthritis (SJIA). Clinically, MAS is similar to familial or primary hemophagocytic lymphohistiocytosis (pHLH), a group of rare autosomal recessive disorders linked to various genetic defects all affecting the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. Decreased cytolytic activity in pHLH patients leads to prolonged survival of target cells associated with increased production of proinflammatory cytokines that overstimulate macrophages. The resulting cytokine storm is believed to be responsible for the frequently fatal multiorgan system failure seen in MAS. Whole exome sequencing as well as targeted sequencing of pHLH-associated genes in patients with SJIA-associated MAS demonstrated increased "burden" of rare protein-altering variants affecting the cytolytic pathway compared to healthy controls, suggesting that as in pHLH, genetic variability in the cytolytic pathway contributes to MAS predisposition. Functional studies of some of the novel variants have shown that even in a heterozygous state, their presence partially reduces cytolytic activity that may lead to increased cytokine production.
Insights
Genetic factors in the cytolytic pathway may predispose individuals to Macrophage Activation Syndrome (MAS), a severe hyperinflammatory condition. Rare variants in this pathway, even when inherited from one parent, can impair immune cell function and increase MAS risk.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Macrophage Activation Syndrome (MAS) is a life-threatening hyperinflammatory condition often associated with rheumatic diseases, particularly systemic juvenile idiopathic arthritis (SJIA).
- MAS shares clinical similarities with primary hemophagocytic lymphohistiocytosis (pHLH), a group of genetic disorders affecting immune cell cytotoxicity.
- The underlying mechanism involves excessive immune cell activation, cytokine overproduction, and subsequent multiorgan failure.
Purpose of the Study:
- To investigate the genetic contribution of the perforin-mediated cytolytic pathway to MAS predisposition in patients with SJIA.
- To identify rare genetic variants within the cytolytic pathway that may increase susceptibility to MAS.
Main Methods:
- Whole exome sequencing and targeted gene sequencing were performed on patients with SJIA-associated MAS.
- Genetic data were compared to healthy controls to identify an increased burden of rare variants.
- Functional studies were conducted on identified novel variants to assess their impact on cytolytic activity.
Main Results:
- Patients with SJIA-associated MAS exhibited a higher burden of rare, protein-altering variants in genes of the cytolytic pathway compared to healthy individuals.
- Some novel variants, even in a heterozygous state, were found to partially reduce immune cell cytolytic activity.
- This reduced activity may contribute to increased pro-inflammatory cytokine production, a hallmark of MAS.
Conclusions:
- Genetic variability in the perforin-mediated cytolytic pathway contributes to the predisposition to MAS in patients with SJIA.
- Heterozygous variants affecting cytotoxicity can increase MAS susceptibility by promoting a pro-inflammatory state.
- These findings highlight the role of inherited immune dysregulation in the pathogenesis of MAS.
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