Specificity and HLA-restriction of CD4 T Cells Associated with Neonatal Alloimmune Thrombocytopenia

Abstract

The immune system is efficiently protecting us against infections by recognizing foreign structures; however it can occasionally cause complications during pregnancy by eliciting immune responses against foetal blood cells. Blood platelets have surface proteins that exist in different variants in the population. Those that are known to be a target for alloimmune responses are referred to as human platelet antigens (HPA). In cases where the foetus has inherited an HPA-determinant from its father that differs from the mother’s own, there is a risk of immunisation. Maternal antibodies are transferred over the placenta to the foetus during pregnancy, where platelet-reactive antibodies can cause depletion of foetal platelets and increase the risk of bleeding – a condition defined as neonatal alloimmune thrombocytopenia (NAIT). There is currently no treatment that can prevent immunisation. The vast majority of NAIT cases are due to incompatibility in the HPA-1 system, defined by a single amino acid difference (Leu33/Pro33) in β3-integrin on platelets. The knowledge of the underlying cellular mechanisms that result in production of maternal platelet-reactive antibodies has been limited. This thesis sheds light on cellular mechanisms, by characterizing HPA-1a-specific T cells isolated from HPA-1a-immunised women who have given birth to a child affected by NAIT. Formal evidence for these cells is important, as antigen-specific T cells are generally orchestrating any given antigen-specific immune response. Furthermore, the characteristics of these HPA-1a-specific T cells were studied; both regarding specific recognition and HLA-restriction. The MHC class II allele HLA-DRB3*01:01 is known to be associated with alloimmunisation with HPA-1a. However, the HLA class II genes are located in close proximity on the chromosome, and are therefore inherited in confined entities defined as haplotypes. The DRB3*01:01 allele seen in HPA-1a immunised women are associated with only a few DR-DQ haplotypes. The results indicate that other properties of the DR3-DQ2, additional to the HLA-DRB3*01:01, can influence immunisation. The understanding of the cellular reactions that results in production of anti-HPA-1a antibodies and subsequent NAIT, are important for potential treatment strategies to prevent immunisation.