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Weyand and Goronzy discuss how aging increases the risk for autoimmune disease. They propose that the inappropriate endurance of immune stemness predisposes older individuals to autoimmunity, as exemplified in patients with giant cell arteritis.

In this Review, Cornelia Weyand and Jörg Goronzy introduce the key role that T cells have in the pathogenesis of rheumatoid arthritis and discuss the development and application of T-cell-targeted therapies for this disease, focusing on approaches that block T-cell co-stimulation.

Pathogenic human CD4⁺ T cells in rheumatoid arthritis have hyperactivated metabolism. Weyand and colleagues show that this phenotype is associated with less myristoylation of the energy sensor AMPK and dysregulated metabolic sensor mTORC1.

Homeostasis of memory T cells is modulated by each antigen encounter, thereby creating a heterogeneous population preventing precise tracking. Here, the authors use barcode-assisted tracing of Epstein-Barr virus-specific CD8⁺ memory T cells of young and older individuals to find antigen-guided, clonally divergent aging trajectories.

Previous studies have defined a state of metabolic reprogramming in rheumatoid arthritis (RA) T cells. Here Weyand and colleagues show that the rewiring of cellular metabolism renders RA T cells tissue invasive, directly promoting disease-inducing effector functions.

Giant cell arteritis (GCA) is the most frequent form of large-vessel vasculitis. In this Review, Weyand and Goronzy discuss the aberrant immune pathways that underlie medium and large-vessel vasculitis, focusing on new understanding of the IL-6–IL-17 and IL-12–IFN-γ cytokine clusters in the development of GCA. Immunostromal interactions are introduced as mechanisms of tissue tropism and disease amplification, and therapeutic interventions targeting vascular instead of immune cells are considered.

Metabolic reprogramming of immune cells in disease has functional consequences and presents potential therapeutic opportunities. In this Review, Weyand & Goronzy examine the role of immunometabolism in rheumatoid arthritis, looking particularly at the different metabolic pathways used in early and late stages of disease.

Zhao et al. show that, in patients with coronary artery disease, CD4⁺ T cells present a blunted response to SARS-CoV-2 and Epstein–Barr viral antigens, due to the overexpression of the immune checkpoint CD155 in macrophages, primed by the exposure to low-density lipoprotein and its oxidized form. The experiments show that CD155 overexpression is due to stabilizing post-translational modifications mediated by the mRNA methylase MTTL3.

Chronic inflammation is a sign of immune system aging. Here the authors show that T cells from older adults contribute to inflammation due to CISH-mediated enhanced proteasomal degradation of a component of the proton pump V-ATPase, resulting in reduced lysosome function and the release of mtDNA and other amphisomal content.

Goronzy and colleagues examine differences in naive CD4⁺ T cells from young and older adults to TCR stimulation. They find reduced HELIOS expression in the elderly, resulting in increased CD25 expression and activation of pSTAT5 in FOXP3⁻ T cells. This scenario favors generation of short-lived effector T cells over memory cell populations.

Rheumatological diseases can have a broad spectrum of cardiovascular manifestations that, whilst sometimes mild or clinically silent, can often increase morbidity and mortality. In this Review, Prasad et al. explore the underlying pathophysiology and available management strategies of cardiovascular complications in patients with autoimmune rheumatic diseases, and focus on the vascular aspects of the emerging field of 'cardiorheumatology'.

Hu and Zhao et al. identify a mechanism mediated by CCL18 and RFX5, through which tissue macrophages adapt their metabolic programme to nutrient stress in the context of autoimmune diseases.

ORAI3 is part of pore forming calcium channels involved in T cell activation. Here the authors show that there is increased expression of ORAI3 in T cells from patients with rheumatoid arthritis and that the transcription factor IKAROS negatively regulates the ORAI3 promoter, indicating a regulatory loop that can control auto-reactivity of T cells in these patients.

Mitochondrial aspartate regulates ER morphology and co-translational translocation via BiP ADP ribosylation. In T cells from patients with rheumatoid arthritis, mitochondrial aspartate is deficient, resulting in ER expansion and excessive production of the pro-inflammatory cytokine TNF.

Human T cell function declines with age, reducing the ability of vaccines to protect the elderly against infectious disease. In this issue, Jörg Goronzy and his colleagues shed light on the mechanism by which naive CD4⁺ T cell responses are impaired in elderly individuals. The researchers show that miR-181a is reduced in these cells in older individuals. This results in increased expression of DUSP6, a phosphatase that dampens ERK signaling, which is necessary for optimal T cell receptor sensitivity to antigen.

MicroRNA miR-181a has been implicated in the regulation of T cell activation and development. Here the authors show that miR-181a is regulated by a transcription factor, YY1, with reduced YY1 expression linked to reduced miR-181a in old individuals, while silencing YY1 impairs T cell functions largely through influencing the expression of miR-181a targets.

Weyand and Goronzy discuss how the progressive loss of immune cell tolerance underlies the immunopathology associated with rheumatoid arthritis.

Premature aging of the immune system, driven by defective DNA maintenance and repair, could be responsible for the pathogenesis of RA. The authors discuss the phenomenon of premature immunosenescence in RA, and suggest that 'resetting' the immune system could be a novel therapeutic concept.

Large-vessel vasculitis is the most common primary vasculitis in adults, manifesting as inflammation of the aorta and its major branches. This Primer reviews the epidemiology, pathophysiology, diagnosis and management of this disease, highlights its effects on patient quality of life, and discusses future research questions.

This Review describes how the body attempts to maintain a functional T cell compartment with advancing age. It explores whether T cell ageing reflects cellular senescence or the failure to maintain quiescence and instead undergo differentiation.

Systemic chronic inflammation increases with age and is linked to the development of several diseases, as presented in this Perspective.