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Background <p>Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are potentially fatal cytokine storm syndromes with clinical features including fever, pancytopenia, hepatosplenomegaly, coagulopathy, and progressive multiorgan system dysfunction. Mechanistically, HLH / MAS are driven by persistent activation of lymphoid and myeloid cells, but our understanding of the pathogenic cell populations remains incomplete.</p> Main body <p>In this Perspectives article, we provide an overview of the biology of HLH / MAS and the critical role of interferon-g in disease pathogenesis. We discuss the recent discovery of cycling lymphocytes in HLH / MAS marked by expression of CD38 and HLA-DR, which are primary producers of IFN-γ. The expansion of cycling lymphocytes correlates with disease activity and helps to distinguish HLH / MAS from clinical mimics. We demonstrate an approach to quantify CD38<sup>+</sup>HLA-DR<sup>+</sup> cycling lymphocytes and evaluate their utility as a diagnostic biomarker for HLH / MAS. Lastly, we discuss the treatment of MAS, including potential therapeutic options to target these pathogenic lymphocytes.</p> Conclusion <p>Understanding of biology of cycling lymphocytes in HLH / MAS will facilitate the development of novel therapeutic approaches to overcome these fatal hyperinflammatory disorders.</p>

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T-ing up the storm: pathogenic cycling lymphocytes in the biology of macrophage activation syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月17日

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  • Michael T. Lam,
  • Connie L. Jiang,
  • Pui Y. Lee

摘要

Background

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are potentially fatal cytokine storm syndromes with clinical features including fever, pancytopenia, hepatosplenomegaly, coagulopathy, and progressive multiorgan system dysfunction. Mechanistically, HLH / MAS are driven by persistent activation of lymphoid and myeloid cells, but our understanding of the pathogenic cell populations remains incomplete.

Main body

In this Perspectives article, we provide an overview of the biology of HLH / MAS and the critical role of interferon-g in disease pathogenesis. We discuss the recent discovery of cycling lymphocytes in HLH / MAS marked by expression of CD38 and HLA-DR, which are primary producers of IFN-γ. The expansion of cycling lymphocytes correlates with disease activity and helps to distinguish HLH / MAS from clinical mimics. We demonstrate an approach to quantify CD38+HLA-DR+ cycling lymphocytes and evaluate their utility as a diagnostic biomarker for HLH / MAS. Lastly, we discuss the treatment of MAS, including potential therapeutic options to target these pathogenic lymphocytes.

Conclusion

Understanding of biology of cycling lymphocytes in HLH / MAS will facilitate the development of novel therapeutic approaches to overcome these fatal hyperinflammatory disorders.