Abstract
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti-platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP.
Highlights
Immune thrombocytopenia (ITP) is an autoimmune disease manifested by immune-mediated platelet destruction and suppression of platelet production
Elevated levels of TLR7 in ITP mice An ITP mouse model was developed according to Musaji [18]
To investigate whether TLR7 is activated in Antigen-presenting cell (APC), splenic mononuclear cells (SMCs) were isolated from ITP mice and controls to determine the levels of TLR7
Summary
Immune thrombocytopenia (ITP) is an autoimmune disease manifested by immune-mediated platelet destruction and suppression of platelet production. Several abnormalities involving the cellular mechanisms of immune modulation have been identified, development of autoantibodies against platelet glycoproteins remains central in the pathogenesis of ITP [1]. Increasing evidence suggests an important role of deviant APC in the pathophysiology of autoimmune diseases [2]. Targeting APC shows promising therapeutic effects in an animal model of rheumatoid arthritis (RA) [3]. In ITP patients, changes in number and function of APC have been indicated [4]. Activation of APC is found to play a critical role in the pathogenic anti-platelet autoantibody response [4,5]. How activation of APC affects autoantibody producing B cells is not well elucidated
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