Allogeneic HLA antibodies can be produced in response to exposure to foreign HLA through blood transfusion, pregnancy or transplantation. Allogeneic antibodies are produced in response to foreign HLA when B cell surface immunoglobulin receptors specifically bind the foreign HLA and the B cell is triggered by armed CD4+ T cells into activation and differentiation into antibody secreting plasma cells. The antibodies secreted have the same specificity as the surface immunoglobulin of the activated B cell.
When a B cell immunoglobulin receptor binds to allogeneic HLA, the bound HLA is internalised, processed and presented on the cell surface as peptides bound to HLA class II molecules. The peptide-MHC class II complex can be recognised by antigen specific armed T cells, resulting in activation of the B cells, leading to proliferation and differentiation into plasma cells. The T cells are armed in the direct and indirect pathways of allorecognition by presentation of peptide from the same allogeneic HLA by professional antigen presenting cells. The direct pathway involves donor derived dendritic cells presenting allogeneic HLA peptides to host CD4+ helper T cells. The indirect pathway involves allogeneic HLA being internalised, processed and presented to host CD4+ helper T cells as peptide-MHC complexes by host dendritic cells. Both the direct and indirect routes result in antigen specific activated CD4+ T cells which are capable of providing the second signal that the B cell requires, along with binding of antigen, in order to become activated. The trapping of B cells in the T cell zone of secondary lymphoid tissues raises the probability that the otherwise low frequency of armed T cells of the right specificity would make such as encounter.
T cell are triggered to synthesis and secrete a number of cytokines such as IL-4 and other effector molecules including CD40 ligand which binds the B cell CD40 receptor and helps drive the resting B cell into the cell cycle, by the recognition of the allogeneic HLA peptide in the context of HLA class II on the B cell by the armed T cell triggers.
The activated B cells proliferate for several days before eventually differentiating into Plasma cells capable of secreting antibodies. Plasma cells can have a wide range of life span with some living for only days to weeks but others are long lived and result in persist antibody production.
Allogeneic antibodies produced following transfusion can be IgG or IgM and are not generally long lasting. Antibodies developed as a result of pregnancy or transplantation are however generally IgG and are long lasting.
Other allogeneic antibodies that be produced include anti-HPA antibodies, anti endothelial cell antibodies and anti MICA antibodies.
Female transplant recipients who subsequently have children are at risk of developing anti-paternal antibodies and need to be carefully managed if these antibodies are also donor specific.
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