Microplastics and IgA nephropathy: a novel environmental hypothesis of immune dysregulation.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by a 4-hit pathogenesis primarily driven by mucosal immune dysregulation in the gut-associated lymphoid tissue (GALT). However, the specific environmental triggers initiating this cascade remain elusive. We propose a novel hypothesis that chronic exposure to ubiquitous micro- and nano-plastics (MNPs) serves as a primary environmental catalyst for IgAN. Through a proposed 5-step cascade, we outline how ingested MNPs directly degrade intestinal tight junctions, precipitating a 'leaky gut' that permits the synergistic influx of plastics and commensal bacterial antigens into the GALT. Acting as a 'Trojan horse,' MNP-corona complexes evade immune detection but trigger chronic inflammation and B-cell dysregulation upon internalization by phagocytes. This persistent immune stimulation drives the aberrant production of galactose-deficient IgA1. Furthermore, we hypothesize that circulating MNPs co-deposit in the renal mesangium alongside immune complexes, acting as a dual generator of both systemic immune complexes and direct structural kidney injury. This potential gene-environment interaction is supported by the intersecting high prevalence of environmental MNPs and IgAN in Asia. Finally, we delineate future