Immunopathology of and potential therapeutics for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a translational perspective

Abstract

Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a life-threatening immune disorder triggered by rheumatic disease, infections, malignancies, or medications. Characterized by the presence of hemophagocytic macrophages and a fulminant cytokine storm, sHLH/MAS leads to hyperferritinemia and multiorgan failure and rapidly progresses to death. The high mortality rate and the lack of specific treatments necessitate the development of a new drug. However, the complex and largely unknown immunopathologic mechanisms of sHLH/MAS, which involve dysfunction of various immune cells, diverse etiologies, and different clinical contexts make this effort challenging. This review introduces the terminology, diagnosis, and clinical features of sHLH/MAS. From a translational perspective, this review focuses on the immunopathological mechanisms linked to various etiologies, emphasizing potential drug targets, including key molecules and signaling pathways. We also discuss immunomodulatory biologics, existing drugs under clinical evaluation, and novel therapies in clinical trials. This systematic review aims to provide insights and highlight opportunities for the development of novel sHLH/MAS therapeutics. In the intricate realm of health issues, there's a serious inflammation-related disorder known as secondary hemophagocytic lymphohistiocytosis, which can escalate to a potentially fatal situation called a cytokine storm. This condition involves the excessive activation of immune cells named macrophages and can lead to signs like constant fever, irregularities in blood cells, and organ enlargement. While sHLH can emerge from various infections and diseases, its precise causes and processes are not completely known, creating a void in our capability to diagnose and treat it effectively. This review is a thorough analysis of sHLH, concentrating on the immune system's role in the disease and potential treatments. The significance of this research lies in its potential to enhance the diagnosis and management of sHLH, which could result in improved patient outcomes.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.