Immune checkpoint receptors are key players in regulating the immune response. They are responsible for both generating an immune response sufficient to kill invading pathogens, balancing the same response, and protecting against tissue destruction or the development of autoimmune events. The central role of the co-inhibitory receptors also referred to as inhibitory immune checkpoints, including PD-1 and CTLA-4 has become especially evident with the cancer treatments targeting these receptors. Blocking these pathways enhances the immune activity, resulting in both an increased chance of cancer clearance, at the same time induction of immune-related adverse events (irAE). Some of these irAE progress into actual autoimmune diseases with autoantibodies and symptoms, undistinguished from the naturally occurring diseases. This review will take advantage of the lessons learned from immune checkpoint blockade and relate this knowledge to our understanding of the same pathways in naturally occurring autoimmune diseases, mainly focusing on rheumatic diseases.

Fibroblasts like synoviocytes (FLS) play several significant roles in rheumatoid arthritis (RA) pathophysiology. This chapter will describe known roles of FLS in disease initiation, joint inflammation, disease persistence and joint destruction. It will describe the newly characterized subsets of FLS based on single cell RNA sequencing studies, and their association to specific aspects of the disease. Finally, we will discuss the future of targeting FLS in the treatment of RA. The FLS in the synovial lining layer are identified by surface complement decay-accelerating factor (CD55) along with lubricin and metallopeptidase expression. Pathological activation of this lining layer subset result in bone and cartilage damage in mice. FLS of the sublining layer are often characterized by THY1 expression, but recent studies have highlighted a heterogeneity where several distinct subsets are identified by additional markers. Sublining FLS expressing human leukocyte antigen-DRA (HLA-DRA) produce C-X-C motif chemokine 12 (CXCL12) and receptor activator of nuclear factor-κB ligand (RANKL) and seems to constitute a pro-inflammatory subset that is associated with inflammation and tertiary lymphoid structures. Another subset of FLS characterized by CD34 expression may discriminate a common progenitor fibroblast subset. Taken together, studies isolating and characterizing gene expression in synovial FLS report both associations of unknown importance and markers that may impose protective or destructive features. This supports evidence of FLS as active players in RA pathology capable of cellular recruitment, local cellular crosstalk and promotion of joint destruction. These discoveries may serve as an atlas for synovial activation in RA and have identified several potential fibroblast markers for the development of targeted treatment.

The aim was to examine anti‐tumor necrosis factor α (anti‐TNFα) therapy influence changes on Th17 and Th22 cells in patients with spondyloarthritis (SpA), and its correlation with changes in clinical and magnetic resonance imaging (MRI) activity and chronicity scores. The Th17 and Th22 cells were assessed at baseline, after 12 and 52 weeks of anti‐TNFα therapy by flow cytometry (ClinicalTrials.gov NCT4682724). The percentages of both Th17 and Th22 cells were increased by 70% at baseline compared with healthy controls (both p < 0.01). During treatment, these two subsets increased further to be 170% (Th17) and 123% (Th22) above levels in healthy controls (both p < 0.01). The same subsets decrease their expression of IL‐23R significantly during the observation period (p < 0.05). High levels of Th17 and Th22 cells at baseline were associated with the degree of chronic changes in the sacroiliac joints on MRI and a good clinical response to anti‐TNFα treatment after one year. Plasma levels were not associated with clinical changes. Th17 cells, and Th22 subsets, increased during one year of anti‐TNF‐α therapy in SpA, regardless of their clinical improvement. This supports that both the Th17 and Th22 subsets could be involved in the progression in SpA.

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BackgroundPulmonary fibrosis is one of the major manifestations in Systemic Sclerosis (SSc) associated with high mortality. Mesenchymal transformation of the airway epithelial cells has been implicated as one of the causes for developing pulmonary fibrosis. Though several animal models shed light towards some of these aspects, an in vitro airway epithelial model would provide a novel experimental platform for the understanding and molecular and genetic changes that occur in SSc associated pulmonary fibrosis.ObjectivesTo establish a functional model for airway epithelium from patient with diffuse cutaneous SSc (dSSc)and healthy volunteers derived nasal stem cells. Subsequently to induce Epithelial Mesenchymal transformation (EMT).MethodsNasal stem cells harvested from healthy volunteers(HV) and dSSc patients were differentiated into ciliated airway epithelium in an Air -Liquid Interface (ALI) using a transwell system. 4 HV cultures were then stimulated with TGF beta (5ug/ml) for 10 days at a basal stage and when differentiated. Markers of mesenchymal transformation including loss of E cadherin, and gain of N cadherin, fibronectin and vimentin were analysed by flow cytometry and image stream, and mean expression intensities given as (MFI). Secreted Type 1 collagen and fibronectin were measured by ELISA.ResultsCiliated epithelial cultures could successfully be established from nasal stem cells (Figure 1).TGF beta induced a phenotypic change in the epithelial cells towards a mesenchymal one in HV cultures. This was observed by significantly increased expression of fibronectin and vimentin and loss of expression of E cadherin on the ciliated cells with 7 days of stimulation with TGF beta at a basal stage (Figure 1b). When cells, stimulated with TGF beta for 7 days, were analysed at Day 35 a similar trend was seen in their Delta MFI (Figure 1c). Stimulating the ALI cultures with TGF beta for 20 days completely repressed epithelial cell growth and disrupted their microstructure.Figure 1.ConclusionThis novel ALI differentiated Airway epithelial model serves as a functional organoid to test various pulmonary manifestations of Systemic Sclerosis. The ability to induce Epithelial Mesenchymal Transformation of these cultures provides a proof of concept for TGF beta mediated fibrosis in dSSc. Moreover, this model can be utilized to explore, at the cell and molecular level, the impact of various autoantibodies and therapeutics on epithelial cells.References[1]Mehmet Kesimer,1 Sara Kirkham,2 Raymond J. Pickles,3 Ashley G. Henderson,4 Neil E. Alexis,5 Genevieve DeMaria,1 David Knight,2 David J. Thornton,2 and John K. Sheehan1 Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways?; Am J Physiol Lung Cell Mol Physiol 296: L92–L100, 2009Disclosure of InterestsNone declared.