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 α(IIb)β₃ (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.