IL22RA2 encodes IL-22 binding protein (IL-22BP), a soluble cytokine receptor that functions as an antagonist of interleukin-22 signaling. The gene produces three protein isoforms through alternative splicing 1. While isoforms IL-22BPi2 and IL-22BPi3 neutralize IL-22 in the extracellular space, isoform IL-22BPi1 is largely retained in the endoplasmic reticulum and uniquely activates the unfolded protein response by binding ER chaperones GRP78 and GRP94, rather than antagonizing IL-22 1. IL22RA2 plays critical roles in immune regulation and disease pathogenesis. In colorectal cancer, IL-22BP expression is suppressed by prostaglandin E2 from myeloid-derived suppressor cells, and increasing IL-22BP levels suppresses tumor development 2. In inflammatory skin diseases, SMAD7 transcriptionally upregulates IL22RA2 to blunt IL-22/STAT3 activation and attenuate dermatitis and psoriasis 3. IL22RA2 is expressed in specialized dendritic cell subsets in inflamed mesenteric lymph nodes of inflammatory bowel disease patients 4. Genetically, IL22RA2 variants affect disease susceptibility: a rare coding variant (p.Leu16Pro) in the signal peptide reduces secretion of all three isoforms by 40-50% and increases multiple sclerosis risk 5. IL22RA2 locates within the SM2 quantitative trait locus on chromosome 6 linked to schistosomiasis-induced hepatic fibrosis 6. Circulating IL22RA2 levels inversely correlate with pulmonary hypertension severity and right ventricular dysfunction 7.