Clonal haematopoiesis (CH) extends beyond a pre-leukaemic state to a systemic process that may influence immunity and inflammation. We suggest the term Clonal Haematopoiesis of Immune Significance (CHIS) to describe situations in which genetic lesions within haematopoietic clones could contribute to immune-mediated disease. Mutant myeloid cells may remodel cytokine signaling, inflammasome activity and tissue-level immune responses, generating a wide spectrum of immunological phenotypes. Based on current evidence, we propose that CHIS could be tentatively organized into four overlapping categories: CHIS associated with syndromic mutations, CHIS associated with myeloid neoplasms with systemic inflammation, CHIS associated with common immunoinflammatory diseases and CHIS associated with chronic inflammation. Recognizing CHIS may help reframe systemic inflammation as a clone-modulated process, with potential implications for diagnosis, risk stratification and therapy. While causality, pathogenic thresholds and clinical impact remain to be clarified, CHIS should be viewed as a flexible and evolving concept that might guide future mutation-based clinical studies.

Consortium of European experts to classify CHIS.

To provide an overview of the main features of this proposed classification, Table 1 summarizes the principal genetic abnormalities, inflammatory phenotypes and representative publications associated with each category.

Table 1 Comparative overview of proposed CHIS entities.

The validation of CHIS as a clinical framework will depend on close collaboration across disciplines. Shared registries, integrated haematology-immunology clinics and mutation-driven basket trials will be essential to establish causal links and therapeutic relevance. Beyond its immediate applications, CHIS offers a paradigm for understanding how somatic evolution within the bone marrow influences systemic immunity and lifelong disease susceptibility. Integrating genomic, immunologic and clinical data will be key to translating this concept into a practical tool for diagnosis, risk assessment and targeted intervention in inflammatory diseases. Although uncertainties persist regarding causality, pathogenic thresholds and optimal treatment strategies, CHIS should be regarded as a dynamic and evolving model, although its boundaries and clinical implications will require further validation.