Abstract
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a low platelet count and the production of anti-platelet antibodies. The majority of ITP patients have antibodies to platelet integrin αIIbβ3 (GPIIbIIIa) which can direct platelet phagocytosis by macrophages. One effective treatment for patients with ITP is intravenous immunoglobulin (IVIg) which rapidly reverses thrombocytopenia. The exact mechanism of IVIg action in human patients is unclear, although in mouse models of passive ITP, IVIg can rapidly increase platelet counts in the absence of adaptive immunity. Another antibody therapeutic that can similarly increase platelet counts independent of adaptive immunity are CD44 antibodies. Toll-like receptors (TLRs) are pattern recognition receptors which play a central role in helping direct the innate immune system. Dendritic cells, which are notable for their expression of TLRs, have been directly implicated in IVIg function as an initiator cell, while CD44 can associate with TLR2 and TLR4. We therefore questioned whether IVIg, or the therapeutic CD44 antibody KM114, mediate their ameliorative effects in a manner dependent upon normal TLR function. Here, we demonstrate that the TLR4 agonist LPS does not inhibit IVIg or KM114 amelioration of antibody-induced thrombocytopenia, and that these therapeutics do not ameliorate LPS-induced thrombocytopenia. IVIg was able to significantly ameliorate murine ITP in C3H/HeJ mice which have defective TLR4. All known murine TLRs except TLR3 utilize the Myd88 adapter protein to drive TLR signaling. Employing Myd88 deficient mice, we found that both IVIg and KM114 ameliorate murine ITP in Myd88 deficient mice to the same extent as normal mice. Thus both IVIg and anti-CD44 antibody can mediate their ameliorative effects in murine passive ITP independent of the Myd88 signaling pathway. These data help shed light on the mechanism of action of IVIg and KM114 in the amelioration of murine ITP.
Highlights
Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by the production of platelet-reactive autoantibodies which can induce platelet clearance, resulting in thrombocytopenia
In the case of ITP, we have shown that intravenous immunoglobulin (IVIg) increases platelet counts in mice with severe combined immune deficiency (SCID), indicating that IVIg likely mediates its effects in murine ITP at the level of the innate immune system [6,7]
Acute exposure to the TLR4 agonist LPS does not interfere with IVIg or KM114 mediated amelioration oif murine ITP
Summary
Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by the production of platelet-reactive autoantibodies which can induce platelet clearance, resulting in thrombocytopenia. One efficacious treatment for ITP and many other autoimmune diseases is intravenous immunoglobulin (IVIg), an IgG fraction prepared from large pools of human plasma. There are many theories as to the mechanism of action of IVIg in the treatment of autoimmune disease and the exact pathway by which IVIg functions remains incompletely understood. One innate cell population which has been directly implicated in the IVIg pathway are dendritic cells [8], which we [9,10,11] and others [8,12,13,14,15,16,17] have shown can play a key role as initiators of IVIg effects
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call