DeCoding the molecular regulation of Antigen Presenting Cells in Sjögren’s Syndrome

Primary Sjögren’s syndrome (pSS) is a chronic, systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands, associated with glandular destruction and dysfunction. The immune mechanisms behind the self-directed damage of exocrine gland tissue are still not fully understood, however the composition of the tissue lesions observed in pSS patients suggests an altered crosstalk between the innate, adaptive immunity and salivary epithelial cells. Type 2 conventional dendritic cells (cDC2s) and monocytes are important activators of these cells, either by direct interaction or through the production of inflammatory mediators, but their contribution to pSS immunopathology has been poorly studied. In this thesis, we aimed to investigate systemic and cellular epigenetic regulators in pSS, their contribution to cDC2s function and to study the key mediators and molecular mechanisms that drive cDC2s and monocyte activation in pSS. The results presented in this thesis demonstrate that epigenetic regulators such as circulating miRNAs may aid to identify subclusters of pSS patients as they seem to reflect their systemic inflammatory profile. In line, we found that miR-130a-MSK1 axis is dysregulated in cDC2s of pSS patients and can contribute to their enhanced IL-12 and TNF-α production. The long non-coding RNA HCP5 expression is increased in inflamed tissues and circulating cDC2s of pSS patients and positively regulates crucial cDC2s functions, like interferon (IFN)-β and chemokine production, B cell survival and T cell cytokine production. In addition, the transcriptomic profile of cDC2s from pSS patients is altered, displaying an aberrant antigen uptake and processing, including self-antigens derived from salivary gland epithelial cells linked with an abnormal IFN signalling. cDC2s from pSS patients also induce an increased proliferation of tissue-homing CD4+ T cells. Moreover, monocytes from pSS patients have an altered transcriptome enriched for intermediate and non-classical monocyte profiles and the circulating inflammatory mediators, including type-I IFNs, partly underly the transcriptional alterations in monocytes from patients with pSS, contributing to their activation. As such, the insights presented in this thesis reveal different levels of epigenetic, transcriptomic and functional dysregulation in cDC2s and monocytes from pSS patients which significantly increases the understanding of their contribution to immune cell activation and salivary gland dysfunction. Thus, disclosing novel opportunities to halt inflammation and supports the need of adequate patient characterization which is essential to effective personalized medicine