Alterations of dendritic cells and monocytes contribute to disease process in Sjögren Syndrome

A population of rare immune cells (type 2 conventional dendritic cells) are altered in Sjögren patients as well as in non-Sjögren sicca patients, and they have an important contribution to the disease. In addition, it was found that monocytes are affected and reshaped by the disease environment. These are the main findings of the PhD research by Ana Pinheiro Lopes at UMC Utrecht who defended her thesis on November 1, 2022.

Sjögren syndrome is a chronic systemic autoimmune disease whose main features are dryness of eyes and mouth as consequence of abnormal function and destruction of the secretory glands. For unknown reasons, the immune system overreacts and attacks the patient’s own body as well as invades the salivary and lacrimal glands, causing dry eyes and mouth. As current treatments mainly focus on relieving symptoms, Sjögren patients are therefore in need of better therapeutic options. By improving the knowledge of the key processes involved in this disease, it is considered that patients will have a better chance of receiving optimal treatment. Therefore, Ana Pinheiro Lopes (Center for Translational Immunology and Department of Rheumatology & Clinical Immunology, UMC Utrecht) investigated systemic and epigenetic regulators in primary Sjogren Syndrome (pSS), their contribution to various immune cells and molecular mechanisms that drive immune cell activation.

Key findings:

• circulating microRNAs may aid to identify subclusters of patients with pSS as they seem to reflect the systemic inflammatory profile.
• the microRNA-130a-MSK1 axis is dysregulated in cDC2s from patients with pSS and can contribute to enhance IL-12 and TNF-α production.
• Long non-coding RNA HCP5 expression is increased in inflamed tissues and circulating cDC2s from patients with pSS and positively regulates crucial cDC2s functions, like interferon (IFN)-β and chemokine production, B cell survival and T cell cytokine production.
• cDC2s from patients with pSS are transcriptionally altered, and show an aberrant antigen uptake and processing, including (auto-)antigens, together with an increased proliferation of tissue-homing CD4+ T cells.
• monocytes from patients with pSS have an altered transcriptome enriched for intermediate and non-classical monocyte profiles which seems to be modulated by the circulating inflammatory mediators, including type-I IFNs, and thus contributes to their activation in pSS.

In this thesis, Ana Pinheiro Lopes aimed to identify and explore novel paths behind the abnormal immune system activation observed in patients with pSS or non-Sjögren’s sicca. Her studies mainly focused on a rare immune cell population (type 2 conventional dendritic cells or cDC2s), which is an important initiator of immune activation. In addition, her studies confirmed that monocytes are also affected, and reshaped by the disease environment.

Dysregulated immune cells

The insights of this work 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.

“The results of my studies bring us one step closer to understand how the immune system is altered in patients with Sjögren Syndrome and give us new clues to develop novel therapeutics. Moreover, an adequate patient characterization is essential and it will eventually contribute to effective personalized medicine”, concluded Ana Pinheiro Lopes.