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Genetic Defects in Cytolysis in Macrophage Activation Syndrome

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
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Abstract

Macrophage activation syndrome (MAS), typically presenting beyond the first year of life, is an often lethal cousin of familial hemophagocytic lymphohistiocytosis (fHLH). Defects in natural killer (NK) cell and CD8 T cell cytotoxicity result in a pro-inflammatory cytokine storm, cytopenia, coagulopathy, and multi-organ system dysfunction. MAS can occur in association with infections (herpes viruses), cancer (leukemia), immune deficient states (post-transplantation), and in autoimmune (systemic lupus erythematosus) and autoinflammatory conditions (systemic juvenile idiopathic arthritis). The distinction between fHLH, the result of homozygous defects in cytolytic pathway genes, and MAS is becoming blurred with the identification of single or multiple mutations in the same cytolytic pathway genes in patients with later onset MAS. Here, we review the literature and present novel cytolytic pathway gene mutations identified in children with MAS. We study the inhibitory effect of one these novel mutations on NK cell function to suggest a direct link between fHLH and MAS.

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Conflict of Interest

Randy Q. Cron has received < $5,000 each as consulting fees from Genentech, Novartis, and Swedish Orphan Biovitrum. Alexei A. Grom has received < $5,000 each as consulting fees from Novartis and Roche. Mingce Zhang, Edward M. Behrens, T. Prescott Atkinson, and Bita Shakoory declare that they have no conflict of interest. The work used to generate the data in Fig. 1 was supported by a grant from the Kaul Pediatric Research Institute to Randy Q. Cron.

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This article does not contain any studies with animals. Institutional Review Board approval was obtained for human subjects studies.

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Authors and Affiliations

  1. University of Alabama at Birmingham, 1825 University Blvd., Shelby 306, Birmingham, AL, 35294, USA

    Mingce Zhang

  2. University of Pennsylvania, 3615 Civic Center Blvd., ARC 1102B, Philadelphia, PA, 19107, USA

    Edward M. Behrens

  3. University of Alabama at Birmingham, 1600 7th Avenue S., CPP #M210, Birmingham, AL, 35233-1711, USA

    T. Prescott Atkinson & Randy Q. Cron

  4. Temple University, 3322 N. Broad St., MOB 200D, Philadelphia, PA, 19104, USA

    Bita Shakoory

  5. University of Cincinnati, 3333 Burnet Ave., MLC 4010, Cincinnati, OH, 45229-3026, USA

    Alexei A. Grom

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  1. Mingce Zhang
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Correspondence to Randy Q. Cron.

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Zhang, M., Behrens, E.M., Atkinson, T.P. et al. Genetic Defects in Cytolysis in Macrophage Activation Syndrome. Curr Rheumatol Rep 16, 439 (2014). https://doi.org/10.1007/s11926-014-0439-2

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