Abstract
In Spondyloarthropathies (SpA), a common group of immune-mediated diseases characterised by excessive inflammation of musculo-skeletal structures and extra-articular organs, T helper 17 (Th17) cells are widely considered the main drivers of the disease. Th17 are able to modulate their genes according to the immune environment: upon differentiation, they can adopt either housekeeping, anti-bacterial gene modules or inflammatory, pathogenic functions, and only the latter would mediate immune diseases, such as SpA. Experimental work aimed at characterising Th17 heterogeneity is largely performed on murine cells, for which the in vitro conditions conferring pathogenic potential have been identified and replicated. Interestingly, Th17 recognising different microorganisms are able to acquire specific cytokine signatures. An emerging area of research associates this heterogeneity to the preferential metabolic needs of the cell. In summary, the tissue environment could be determinant for the acquisition of pathogenetic features; this is particularly important at barrier sites, such as the intestine, considered one of the key target organs in SpA, and likely a site of immunological changes that initiate the disease. In this review, we briefly summarise genetic, environmental and metabolic factors that could explain how homeostatic, anti-microbial Th17 could turn into disease-causing cells in Spondyloarthritis.
Highlights
T helper lymphocytes, characterised by the expression of CD4 on their surface, are the central cell subset of adaptive immunity
The central transcription factor (TF) are as: T-box protein expressed in T cells (T-bet) in Th1, GATA-binding protein 3 in Th2, retinoic acid-related orphan receptor gamma-t (ROR-ɣt) in T helper 17 (Th17) and Forkhead box P3 in Tregs (Zheng and Flavell, 1997; Szabo et al, 2000; Fontenot et al, 2003; Harrington et al, 2005)
Other genetic events leading to unrestrained, diseasecausing differentiation are still not clear: ex vivo single-cell sequencing led to identify novel pathogenic genes (Gpr65, Toso and Plzp) promoting Th17-mediated CNS inflammation in EAE mice (Gaublomme et al, 2015; Wang et al, 2015), but none of which, as of today, have been validated in humans, with the partial exception of GPR65, an important TF in human GM-CSF + Th17 (Al-Mossawi et al, 2017)
Summary
T helper lymphocytes, characterised by the expression of CD4 on their surface, are the central cell subset of adaptive immunity. The lineage-specific (‘master’) TF controls the transcriptional programme of the cell, including specific cytokine production and the expression of chemokine receptors that mediate trafficking to the organs: this network helps each T-cell subset to exert specific functions in response to antigens, and in the tissues.
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