Mutations such as stop codons may lead to no FVIII expression, or possibly to expression of a non-functional truncated FVIII, and in these cases the haemophilia patient’s immune system may be exposed to additional FVIII epitopes

Alpelisib upon FVIII infusion. Moreover, the amino acid sequence homology between factors V and VIII may lead to partial tolerance to FVIII, as the immune system will not respond to potential epitopes that are also present in circulating factor V and are thus ‘tolerized’ by developmental exposure. This may help to explain why only a minority (~25%) of patients with haemophilia A form inhibitors, while generally the larger the mutation, the more likely a patient will respond to FVIII. Thus, in central tolerance, lymphocytes are exposed to self antigens in the bone marrow or thymus for B cells and T cells respectively. In the marrow, B cells that recognize ubiquitous self molecules are deleted or rearrange their receptors so that they no longer recognize a self protein. In the thymus, T cells must be able Sirolimus cost to recognize self MHC molecules plus the self peptides being presented. Those that recognize self peptides with high affinity are preferentially deleted. However, some lower affinity self-reactive lymphocytes may escape central tolerance and enter the periphery. These must be subjected to elimination or functional inactivation via a variety of mechanisms including

peripheral anergy, deletion, or suppression by regulatory T cells (Tregs) [2-4]. Approaches to manipulate inhibitor responses, discussed below, involve medchemexpress some of these mechanisms. The antibody response to proteins involves an interaction and collaboration between three cells: thymus-derived (T) helper cells, B cells and antigen-presenting cells (APCs), such as dendritic cells. Protein antigens are taken up by dendritic cells

which process and present peptide epitopes that bind in a defined manner to a groove on the major histocompatibility complex (MHC) class II. This complex may then be recognized by T-cell receptors (TCR) on the T helper cells of an individual, providing the first biochemical signal (called signal 1) to the T cells. However, this signal is insufficient to drive these T cells to divide and produce the cytokines that lead to help for B cells to mature into antibody forming cells. Rather, the presence of additional signals via the CD80/CD86 (also known as B7) complex provides signal 2 to drive full T-cell activation. Further signals may also be necessary to fully activate T-cell help and cytokine production. In the context of this two-signal model, it is clear that T-cell help is necessary for antibody formation against most protein antigens. What evidence is there, then, that the immune response to FVIII is T-cell-dependent in such a scenario? The data supporting this process come from both human case histories in HIV-infected patients with haemophilia A, and from studies in mice.