Evidence in animal models that beta2-glycoprotein I (beta 2GPI), the principal target of autoimmune antiphospholipid antibodies, is involved in the initiation and progression of atherosclerosis, prompted us to investigate the possible role of this self protein as a target autoantigen of immune reactions in patients with carotid atherosclerosis. Plaque-infiltrating T lymphocytes from patients, and circulating T lymphocytes from patients and healthy subjects were tested by cell proliferation assay and by flow cytometry for intracellular cytokine expression in response to beta 2GPI. ELISA was used to detect cytokine production in culture supernatants and anti-beta 2GPI/anti-cardiolipin antibodies in serum samples. Eight of 35 PBMC samples and 1 of 5 plaque-infiltrating T lymphocyte samples from patients proliferated in response to beta 2GPI, whereas PBMC from healthy subjects did not. Patients' PBMC samples that proliferated in response to beta 2GPI produced significantly higher IFN-gamma and TNF-alpha than non-proliferating PBMC. beta 2GPI-specific plaque-derived T lymphocytes expressed IFN-gamma, TNF-alpha and IL-4, suggesting concomitant Th1 and Th2 activation. Only one patient's serum was positive for anti-beta 2GPI and anti-cardiolipin IgM antibodies. These new findings indicate that beta 2GPI induces a cellular immune response in a subpopulation of patients with carotid atherosclerosis thus contributing to the inflammatory responses involved in carotid atherosclerotic disease.