It is now becoming clear that inhibitor development is a complex,

multi-factorial immune response involving both patient-specific and treatment-related factors [1–3]. It has been shown that patients with severe defects in the FVIII gene, p38 MAPK inhibitors clinical trials such as large deletions, inversions (most commonly intron 22 inversion) and stop mutations are significantly more likely to develop inhibitors than are those with more minor defects such as missense mutations, small deletions or insertions and splice site mutations [1]. Severe mutations in the FVIII gene are predicted to cause a complete deficit of any endogenous FVIII production. In these circumstances, FVIII cannot be presented to the immune system during negative selection of high-affinity autoreactive T cells in the thymus [4,5] and central immune Z-IETD-FMK cost tolerance against FVIII cannot establish itself. FVIII in FVIII products that are given for replacement therapy to patients who carry such mutations

would be seen as a foreign protein by their immune system. Why some of these patients develop FVIII inhibitors while others do not is far from clear. For many years immunologists believed that the immune system’s primary goal was to discriminate between self and non-self [6,7]. Matzinger introduced the concept that the primary driving force of the immune system is the need to detect and protect against danger [8]. If a foreign or a self-antigen is not dangerous, immune tolerance is the expected outcome [8]. In recent years, it has been suggested that the ability of the immune system to sense danger is part of a more general surveillance, defence and repair system that enables multicellular organisms to control whether their cells are alive or dead and to recognize when micro-organisms intrude [9–12]. Danger is transmitted by various signals that are associated either with pathogens or with

tissue and cell damage [9–12]. Pathogens express pathogen-associated molecular patterns (PAMPS) that are recognized by pattern recognition receptors such as toll-like receptors (TLR), Nod1-like receptors (NLRs) or Rig-I like receptors (RLRs) that are expressed on a range of cells of the click here innate and the adaptive immune system. Once these receptors are triggered, several signaling pathways are activated that can induce inflammatory responses and the activation of specific anti-pathogen immune responses. Evidence is accumulating that trauma, ischemia and tissue damage can cause inflammatory responses that are very similar to responses induced by pathogens [9–12]. Damaged cells release so called damage-associated molecular patterns (DAMPs) that recruit and activate receptor-expressing cells of the innate immune system, including dendritic cells, granulocytes, monocytes or eosinophils, and thus directly or indirectly promote adaptive immune responses [9–12].