Abstract
Idiopathic granulomatous mastitis (IGM) is a chronic inflammatory breast disease that predominantly affects parous women of reproductive age, with higher incidence in women of Latina, Middle Eastern, Asian, and African descent. Although its etiology remains controversial, accumulating clinical and molecular evidence supports classification of IGM as an organ-specific autoimmune disease modulated by hormonal and environmental factors. This review integrates immunologic, hormonal, genetic, molecular, and therapeutic data to evaluate this hypothesis. The review comprised two components: (1) a broad narrative synthesis of autoimmune and immunopathogenic mechanisms based on searches of PubMed, Google Scholar, and ClinicalTrials.gov (January 2000-April 2026), and (2) a prospectively registered (PROSPERO CRD420251106132) systematic analysis of IGM breast laterality. Results reveal consistent immune dysregulation, including elevated IL-6/Th17-axis cytokines, aberrant macrophage polarization, impaired regulatory T-cell function, and frequent polyautoimmunity (erythema nodosum, arthritis, and autoimmune thyroid disease). Genetic associations involve HLA class I/II alleles and variants in macrophage function and prolactin signaling. Single-cell RNA-sequencing studies confirm enrichment of IL-6/JAK/STAT3, TNF-α/NF-κB, and prolactin receptor pathways in lesional tissue. Clinically, IGM shows favorable responses to corticosteroids, methotrexate, azathioprine, anti-TNF agents, and JAK inhibitors. Laterality analysis of 3,973 patients demonstrated 93.9% unilateral disease with modest left-sided predominance (1.15:1 ratio), which remains hypothesis-generating. Collectively, evidence supports IGM as an organ-specific autoimmune disease. Convergence of prolactin and IL-6 signaling on the JAK/STAT3 pathway provides a plausible mechanistic node and rationale for targeted therapies. Future high-resolution immunoprofiling and prospective trials are needed to define disease subtypes and advance treatment modalities.