Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura.
BACKGROUND
Immune thrombocytopenic purpura (ITP) is an autoimmune disease primarily caused by IgG anti-platelet autoantibodies. Activation of autoreactive CD4(+) T cells upon recognition of cryptic GPIIb/IIIa peptides presented by antigen-presenting cells (APCs) is a critical step for triggering and maintaining the pathogenic anti-platelet autoantibody response.


OBJECTIVE
We investigated which APCs carry the cryptic peptides of GPIIb/IIIa that activate autoreactive CD4(+) T cells in ITP patients.


METHODS
GPIIb/IIIa-reactive T-cell lines generated from ITP patients were cultured with autologous freshly isolated splenic macrophages, B cells or dendritic cells. To further investigate how the macrophages presented the antigenic GPIIb/IIIa peptides, we prepared macrophages from the peripheral blood monocytes of the same patients during remission.


RESULTS
Macrophages induced the proliferation of GPIIb/IIIa-reactive T-cell lines without an exogenous antigen, but B cells and dendritic cells required GPIIb/IIIa peptides to stimulate the T cells. Macrophages derived from peripheral blood during remission required an exogenous antigen to induce the GPIIb/IIIa-reactive T-cell line response, but could elicit a response without added antigen if they were preincubated with platelets from ITP patients with platelet-associated anti-GPIIb/IIIa antibodies or healthy platelets pretreated with ITP platelet eluates. The T-cell response was inhibited by anti-FcgammaRI antibody. Finally, cultured macrophages that captured opsonized platelets promoted anti-GPIIb/IIIa antibody production in mixed cultures of autologous GPIIb/IIIa-reactive T-cell lines and B cells.


CONCLUSIONS
Splenic macrophages that take up opsonized platelets via FcgammaRI are major APCs for cryptic GPIIb/IIIa peptides, and are central to the maintenance of anti-platelet autoantibody production in ITP patients.
Kuwana
M
M
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. kuwanam@sc.itc.keio.ac.jp
Okazaki
Y
Y
Ikeda
Y
Y
D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes; D001792:Blood Platelets / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D009895:Opsonin Proteins / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D013154:Spleen; D013601:T-Lymphocytes
C489017:FCGR1A protein, human; D009895:Opsonin Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017452:Receptors, IgG