Beta2-Glycoprotein I is a Target of T Cell Reactivity in Patients with Advanced Carotid Atherosclerotic Plaques

Abstract

Evidence in animal models that beta2-glycoprotein I (beta2GPI), 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 beta2GPI. ELISA was used to detect cytokine production in culture supernatants and anti-beta2GPI/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 beta2GPI, whereas PBMC from healthy subjects did not. Patients PBMC samples that proliferated in response to beta2GPI produced significantly higher IFN-gamma and TNF-alpha than non-proliferating PBMC. beta2GPI-specific plaque-derived T lymphocytes expressed IFN-gamma, TNF-alpha and IL-4, suggesting concomitant Th1 and Th2 activation. Only one patients serum was positive for anti-beta2GPI and anti-cardiolipin IgM antibodies. These new findings indicate that beta2GPI induces a cellular immune response in a subpopulation of patients with carotid atherosclerosis thus contributing to the inflammatory responses involved in carotid atherosclerotic disease.

Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

“…The signal peptide [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] is underlined in the figure. The protein was further subjected to PROSITE and ASC analyses (see "Bioinformatic analysis"), which indicated that the following cysteine residues are likely to be involved in disulfide bond formation and to be responsible for the Sushi domain secondary structure: C23-C66, C51-C79, C84-C124, C110-C137, C142-C188, C174-C200, C205-C248, and C234-C260.…”

“…This Th2 bias is consistent with the presence of ␤ 2 GPI-autoreactive T cells with a Th2 profile determined in the peripheral blood of patients with APS 14 and in patients with advanced carotid atherosclerotic plaques. 17 In addition, G-␤ 2 GPI enhanced the capacity of DCs to stimulate T-cell proliferation in an allogenic mixed-lymphocyte reaction. Further studies will be needed to verify whether protein glycation may modify DC uptake and presentation of ␤ 2 GPI, thus inducing Tand B-cell immunogenicity.…”

“…16 Recently, we showed that ␤ 2 GPI is a T-cell target in patients with advanced carotid atherosclerotic plaques. 17 Although much is known about ␤ 2 GPI as a cofactor in autoimmune diseases, crucial information is still lacking to clarify why this abundant self-plasma protein is the target of autoimmune responses.…”

“…16 Recently, we showed that ␤ 2 GPI is a T-cell target in patients with advanced carotid atherosclerotic plaques. 17 Although much is known about ␤ 2 GPI as a cofactor in autoimmune diseases, crucial information is still lacking to clarify why this abundant self-plasma protein is the target of autoimmune responses.The molecular structure and location of the major epitopic region(s) on the ␤ 2 GPI molecule are controversial. Several studies have investigated whether the immune response is directed to native ␤ 2 GPI 8,9,18 or to cryptic or neoepitopes.…”

Tumor Necrosis Factor-Alpha and Mast Cells: Revisited Study

“…Various cellular anti-self responses are mediated by chronic over-expression of tumor necrosis factor (14), along with some other cytokines as key factors in autoimmune processes. Mice that lack mast cells (W/Wv mice) are resistant to inflammatory and erosive arthritis induced by arthritogenic serum (41)(42)(43).…”