Genetic and non-genetic drivers of immune dysregulation: Beyond autoinflammation and autoimmunity

Immune dysregulation spans a continuum from autoinflammation to autoimmunity and primary immune disorders, and arises from the interplay between genetic lesions and multiple layers of biological regulation. Monogenic diseases have provided critical models to dissect this complexity, yet phenotype is not determined by DNA sequence alone. The same gene can give rise to distinct clinical entities depending on variant functional class, position within functional domains, residual activity, isoform usage and cell- or tissue-specific effects, while carriers of identical variants may have variable phenotype due to somatic mosaicism, clonal dynamics, allelic expression bias, modifier genetics or environmental buffering. This review examines the major determinants of penetrance and variable expressivity across mechanistically informative immune disorders. We first analyze variant-intrinsic mechanisms using archetypal genes including MEFV, NLRP3, PLCG2 and UBA1, highlighting how distinct functional classes reshape disease identity. We then discuss how cellular context, somatic variation, allelic expression and X-linked regulation modify effective gene dosage in vivo. We further integrate multilocus inheritance, common and rare modifiers, interferonopathies, monogenic lupus-like diseases and primary immune disorders characterized by blended autoimmunity, autoinflammation and host-defense defects. Finally, we examine epigenetic, environmental and life-course drivers and their implications for diagnosis, counseling and precision therapy. Together, these data support a model in which genotype defines a framework rather than a fixed outcome. A mechanism-based view of immune dysregulation is therefore required to move from genetic diagnosis to meaningful prediction of disease expression and therapeutic response.