Mast Cells as Central Hubs of Immune Dysregulation: Decoding Novel Pathogenic Circuits and Pioneering Therapeutics in Autoimmunity

Abstract

Context: Mast cells are increasingly recognized as central orchestrators of immune dysregulation in autoimmune and inflammatory diseases, extending their established role as histaminergic effector cells in allergy. Evidence Acquisition: This review synthesizes recent evidence positioning mast cells as key regulators of chronic inflammation, tissue remodeling, and neuroinflammation. Studies published between 1997 and 2026 have identified mast cells as focal points of immune dysregulation and helped define novel pathogenic pathways and develop therapeutic approaches for various autoimmune conditions. Results: We describe the multifaceted roles of mast cells in breaching immune-privileged sites, amplifying autoantibody production through interactions with B and T cells, and promoting pathology in rheumatoid arthritis, lupus, and juvenile dermatomyositis through IgE-independent pathways involving receptors such as MRGPRX2. We also explore their contributions to neurodegenerative processes, including Alzheimer's disease, through disruption of the blood-brain barrier and facilitation of leukocyte infiltration. Beyond these mechanisms, we critically evaluate emerging therapeutic strategies designed to precisely modulate mast cell activity. These strategies include targeting FcεRI signaling with Bruton's tyrosine kinase inhibitors, engaging inhibitory checkpoints such as CD300a, and depleting mast cells through KIT receptor inhibition. Conclusions: By reframing mast cells as dynamic cellular rheostats and actionable therapeutic nodes, this review outlines approaches for translating these insights into targeted therapies for refractory autoimmune conditions.