T Helper Cell Dysfunction in ANCA Associated Vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is an autoimmune disease characterised by inflammation of small blood vessels that leads to organ dysfunction. Auto-reactive B cells produce pathogenic antibodies against the neutrophil enzymes, myeloperoxidase (MPO) and proteinase 3 (PR3). Genome-wide association studies that identified the relationship between MHC class II genes and ANCA specificity strongly support the role of CD4 T helper cells in the pathogenesis of AAV. Recently a new subset of T cells called peripheral T helper (PTH) cells, characterised by the PD1+CXCR5- phenotype, was described in the context of auto-immune diseases, driving organ inflammation. These pathogenic cells were shown to infiltrate sites of inflammation and have the necessary machinery to provide B cell help in the peripheral tissues. This thesis is aimed at establishing the role of these cells in systemic AAV and their potential role in disease pathogenesis. PTH cells have been studied by flow cytometry, transcriptomic and functional assays across multiple compartments of lymph node, peripheral blood, kidney tissue and urine of AAV patients. A newer angle is the use of single cell transcriptomic technology to understand the clonal and transcriptomic relationship of these cells to the traditional T follicular helper (TFH) cells. This thesis established that PTH cells were expanded within the circulatory compartment of AAV patients irrespective of their disease status and were seen in the urine and kidney tissue of AAV patients with nephritis. Transcriptomic analysis revealed them to express cytotoxic and chemokine receptor signatures that could aid their migration to sites of inflammation. T cell receptor analysis identified the clonal relationship between different subsets, giving newer insight into the development of these cells. Furthermore, possible targets for therapeutic intervention were identified.
Experimental Medicine Initiative (EMI) - a GSK/University of Cambridge collaboration