In order to clarify intraglomerular cellular activation and cytokine involvement in IgA nephropathy, the glomerular expression of MHC class II antigens (HLA-DR and DQ) and cellular proliferative nuclear antigen (Ki-67), and serum γ-interferon (γ-IFN) levels were evaluated in 49 patients with IgA nepropathy. HLA-DR was detected in all but 4 patients in whom glomerular sclerosis was present. HLA-DQ and Ki-67 were observed in 51 and 38% of the patients, respectively. Proteinuria, recent macroscopic hematuria, mesangial proliferation, and extracapillary and endocapillary lesions were more frequent and more severe in HLA-DQ-positive than in HLA-DQ-negative patients. In 10 patients with acute exacerbation, endocapillary lesions and HLA-DQ and Ki-67 expression were present in 70,80 and 88%, respectively. Serum γ-IFN levels were high in the patients (2.0 ± 0.3 U/ml, n = 40), especially during acute exacerbation (3.4 ± 1.1 U/ml, n = 9). Glomerular HLA-DQ and Ki-67 expression correlated with serum γ-IFN levels (r = 0.73, p < 0.01 for HLA-DQ; r = 0.75, p < 0.01 for Ki-67). Renal biopsy specimens taken before and after prednisolone and/or urokinase therapy were available from 4 patients. There was strong reactivity to HLA-DQ in the glomerular tufts of all 4 pretreatment samples. However, HLA-DQ reactivity disappeared after treatment in 3 samples, concomitant with normalization of serum γ-IFN levels. We conclude that serum γ-IFN levels are related to glomerualr HLA-DQ and Ki-67 expression and acute exacerbation in patients with IgA nephropathy. These data suggest that γ-IFN and MHC class II antigens play an important role in the immune-mediated glomerular injury of IgA nep