The expanding spectrum of Hemophagocytic lymphohistiocytosis: pathogenic mechanisms and therapeutic implications

Hemophagocytic lymphohistiocytosis (HLH, a condition characterized by an altered immune response that combines defective viral clearance and uncontrolled inflammation) is one of the most life-threatening hyperinflammatory diseases. At present, the diagnosis of HLH is based on a clearly delineated set of clinical and laboratory criteria. Rather than being a single entity, however, the HLH phenotype is the point of convergence of a genetically heterogeneous group of diseases with various underlying mechanisms.

Thanks to the use of next-generation sequencing technologies, the number of novel genetic defects underlying HLH has dramatically increased. Furthermore, HLH has recently emerged as a rare, extreme manifestation of Coronavirus 19 infection; this observation emphasizes the importance of a balance between initial immune activation (to stop a virus from spreading) and subsequent immune downregulation (to prevent harmful inflammation).
Known and newly reported genetic inflammatory syndromes have been positioned within a spectrum that ranges from impaired cytotoxicity (as observed in primary HLH) to the intrinsic activation of macrophages (as found in autoinflammatory disorders). Other forms of HLH may fall within this spectrum, although the exact positions within this spectrum are not clear.

This Research Topic aims to understand how single disease entities are embedded in the HLH spectrum. With a view to describing the full spectrum of HLH, we encourage contributions that explore genetic, immunological and molecular mechanisms leading to HLH, and their translational implications. We welcome articles addressing, but not limited to, the following topics:

- Known and novel monogenic defects underlying HLH;

- Multifactorial disorders (such as malignant, autoimmune and rheumatological diseases) predisposing to HLH;

- Clinical and laboratory characterization, diagnostic markers, and personalized immune profiling of HLH;

- HLH mechanisms and immunopathology;

- Targetable pathways of HLH;

- Precision medicine therapeutic approaches for HLH.

By investigating these aspects, this Research Topic will contribute to the fundamental understanding of HLH while potentially paving the way for novel therapeutic strategies.