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

AG-014699 in vitro 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 MK-8669 order 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 see more 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.