IFNG and Granuloma: Consistently, hypercalcemia related to IRIS is known to be caused by overproduction of 1, 25-dihdroxyvitamin D3 (1, 25[OH2]D3) secreted from disease-activated macrophages together with Th1 cytokines, e.g., interferon-gamma (IFN-γ) and granuloma formation [28].