It is possible that their reduced inflammatory responsiveness is beneficial in protecting the host from collateral damage that could otherwise result from the presence of large numbers of inflammatory cells. Alternatively, suppression of macrophage responsiveness by targeting TLRs on the HSPCs from which they are produced could be an immune evasion strategy employed by invading organisms. Future

studies will also be required to dissect the mechanisms underlying the specification of myeloid differentiation and function. One key question will be whether TLR signal transduction pathways in HSPCs are similar see more to those in differentiated cells such as macrophages and neutrophils. It is likely that TLR signaling pathways in HSPCs are at least partially overlapping with differentiated cells, but since TLR signaling in HSPCs uniquely controls myeloid differentiation, it is possible that HSPC TLRs may induce distinct signals in these cells, for example to activate transcription factors and induce KU-57788 ic50 chromatin modifications that specify myeloid

cell fate choice. Our studies on the functional consequences of exposure of HSPCs to Pam3CSK4, showed that exposed HSPCs produce soluble factors that can act in a paracrine manner to influence the function of macrophages produced by unexposed HSPCs [49]. The identity of these factors is not currently known, but candidates include several cytokines known to be induced by TLRs in differentiated cells, such as type I and II IFNs, TNF-α and IL-6, which have previously been reported to have myelopoietic properties [5, 7, 9, 10]. Thus, it is possible that myeloid differentiation may be specified second by TLRs in HSPCs without the activation of unique signal transduction pathways. The answers to all these questions will provide new insights into the role of TLRs in host–pathogen interactions, emergency myelopoiesis, and the development of immunity against infection,

which may reveal novel targets for antimicrobial intervention. Research in the M. L. Gil laboratory is supported by grants SAF2010–18256 (Ministerio de Economía y Competitividad, Spain) and ACOMP/2013/168 (Generalitat Valenciana, Valencia, Spain). H. S. Goodridge received a Scientist Development Grant from the American Heart Association and an R21 (AI082379) from the NIH. The authors declare no financial or commercial conflict of interest. “
“Citation Iwasawa Y, Kawana K, Fujii T, Schust DJ, Nagamatsu T, Kawana Y, Sayama S, Miura S, Matsumoto J, Adachi K, Hyodo H, Yamashita T, Kozuma S, Taketani Y. A possible coagulation-independent mechanism for pregnancy loss involving β2glycoprotein 1-dependent antiphospholipid antibodies and CD1d. Am J Reprod Immunol 2012; 67: 54–65 Problem  β2glycoprotein1 (β2GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss.