Nature Reviews Rheumatology

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including ?? T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.

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Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases

Ivona Aksentijevich,Oskar Schnappauf

doi : 10.1038/s41584-021-00614-1

Nature Reviews Rheumatology volume 17, pages405–425 (2021)

Monogenic autoinflammatory diseases are a group of rheumatologic disorders caused by dysregulation in the innate immune system. The molecular mechanisms of these disorders are linked to defects in inflammasome-mediated, NF-?B-mediated or interferon-mediated inflammatory signalling pathways, cytokine receptors, the actin cytoskeleton, proteasome complexes and various enzymes. As with other human disorders, disease-causing variants in a single gene can present with variable expressivity and incomplete penetrance. In some cases, pathogenic variants in the same gene can be inherited either in a recessive or dominant manner and can cause distinct and seemingly unrelated phenotypes, although they have a unifying biochemical mechanism. With an enhanced understanding of protein structure and functionality of protein domains, genotype–phenotype correlations are beginning to be unravelled. Many of the mutated proteins are primarily expressed in haematopoietic cells, and their malfunction leads to systemic inflammation. Disease presentation is also defined by a specific effect of the mutant protein in a particular cell type and, therefore, the resulting phenotype might be more deleterious in one tissue than in another. Many patients present with the expanded immunological disease continuum that includes autoinflammation, immunodeficiency, autoimmunity and atopy, which necessitate genetic testing.

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The role of HIF proteins in maintaining the metabolic health of the intervertebral disc

Elizabeth S. Silagi,Ernestina Schipani,Makarand V. Risbud

doi : 10.1038/s41584-021-00621-2

Nature Reviews Rheumatology volume 17, pages426–439 (2021)

The physiologically hypoxic intervertebral disc and cartilage rely on the hypoxia-inducible factor (HIF) family of transcription factors to mediate cellular responses to changes in oxygen tension. During homeostatic development, oxygen-dependent prolyl hydroxylases, circadian clock proteins and metabolic intermediates control the activities of HIF1 and HIF2 in these tissues. Mechanistically, HIF1 is the master regulator of glycolytic metabolism and cytosolic lactate levels. In addition, HIF1 regulates mitochondrial metabolism by promoting flux through the tricarboxylic acid cycle, inhibiting downsteam oxidative phosphorylation and controlling mitochondrial health through modulation of the mitophagic pathway. Accumulation of metabolic intermediates from HIF-dependent processes contribute to intracellular pH regulation in the disc and cartilage. Namely, to prevent changes in intracellular pH that could lead to cell death, HIF1 orchestrates a bicarbonate buffering system in the disc, controlled by carbonic anhydrase 9 (CA9) and CA12, sodium bicarbonate cotransporters and an intracellular H+/lactate efflux mechanism. In contrast to HIF1, the role of HIF2 remains elusive; in disorders of the disc and cartilage, its function has been linked to both anabolic and catabolic pathways. The current knowledge of hypoxic cell metabolism and regulation of HIF1 activity provides a strong basis for the development of future therapies designed to repair the degenerative disc.

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