Oxford open immunology最新文献

Malaria and tuberculosis remain highly prevalent infectious diseases and continue to cause significant burden worldwide. Endemic regions largely overlap, and co-infections are expected to occur frequently. Surprisingly, malaria-tuberculosis co-infection is relatively understudied. Malaria has long been known to have immunomodulatory effects, for example resulting in reduced vaccination responses against some pathogens, and it is conceivable that this also plays a role if co-infection occurs. Data from animal studies indeed suggest clinically important effects of malaria-tuberculosis co-infection on the immune responses with potential consequences for the pathophysiology and clinical course of both infections. Specifically, rodent studies consistently show reduced control of mycobacteria during malaria infection. Although the underlying immunological mechanisms largely remain unclear, an altered balance between pro- and anti-inflammatory responses may play a role. Some observations in humans also support the hypothesis that malaria infection skews the immune responses against tuberculosis, but data are limited. Further research is needed to unravel the underlying immunological mechanisms and delineate possible implications of malaria-tuberculosis co-infection for clinical practice.

'Exhaustion' is a term used to describe a state of native and redirected T-cell hypo-responsiveness resulting from persistent antigen exposure during chronic viral infections or cancer. Although a well-established phenotype across mice and humans, exhaustion at the molecular level remains poorly defined and inconsistent across the literature. This is, in part, due to an overreliance on surface receptors to define these cells and explain exhaustive behaviours, an incomplete understanding of how exhaustion arises, and a lack of clarity over whether exhaustion is the same across contexts, e.g. chronic viral infections versus cancer. With the development of systems-based genetic approaches such as single-cell RNA-seq and CRISPR screens applied to in vivo data, we are moving closer to a consensus view of exhaustion, although understanding how it arises remains challenging given the difficulty in manipulating the in vivo setting. Accordingly, producing and studying exhausted T-cells ex vivo are burgeoning, allowing experiments to be conducted at scale up and with high throughput. Here, we first review what is currently known about T-cell exhaustion and how it's being studied. We then discuss how improvements in their method of isolation/production and examining the impact of different microenvironmental signals and cell interactions have now become an active area of research. Finally, we discuss what the future holds for the analysis of this physiological condition and, given the diversity of ways in which exhausted cells are now being generated, propose the adoption of a unified approach to clearly defining exhaustion using a set of metabolic-, epigenetic-, transcriptional-, and activation-based phenotypic markers, that we call 'M.E.T.A'.

Neutralizing monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein have been developed for the treatment of COVID-19. Whilst antibody therapy has been shown to reduce the risk of COVID-19-associated hospitalization and death, there is limited understanding of the endogenous immunity to SARS-CoV-2 generated in mAb-treated patients and therefore ongoing susceptibility to future infections. Here we measure the endogenous antibody response in SARS-CoV-2-infected individuals treated with REGN-COV2 (Ronapreve). We show that in the majority of unvaccinated, delta-infected REGN-COV2-treated individuals, an endogenous antibody response is generated, but, like untreated, delta-infected individuals, there was a limited neutralization breadth. However, some vaccinated individuals who were seronegative at SARS-CoV-2 infection baseline and some unvaccinated individuals failed to produce an endogenous immune response following infection and REGN-COV2 treatment demonstrating the importance of mAb therapy in some patient populations.

Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells (SnCs) using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target SnCs, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting SnCs are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful SnCs could have great potential to promote healthy immune function in ageing populations.

Orthostatic intolerance and other autonomic dysfunction syndromes are emerging as distinct symptom clusters in Long Covid. Often accompanying these are common, multi-system constitutional features such as fatigue, malaise and skin rashes which can signify generalized immune dysregulation. At the same time, multiple autoantibodies are identified in both Covid-related autonomic disorders and non-Covid autonomic disorders, implying a possible underlying autoimmune pathology. The lack of specificity of these findings precludes direct interpretations of cause and association, but their prevalence with its supporting evidence is compelling.

Myalgic encephalomyelitis (ME) previously also known as chronic fatigue syndrome is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection. The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here, we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation targeting nerve endings in the nasal cavity, likely from the trigeminal nerve, possibly activating additional centers in the brainstem of ME patients and correlating with a ∼30% reduction in overall symptom scores after 8 weeks of treatment. By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover signs of chronic immune activation in ME, as well as immunological correlates of improvement that center around gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remain to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We believe that these results are suggestive of ME as a condition explained by a maladaptive disease tolerance response following infection.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by a breakdown of immune tolerance and the development of autoantibodies against nucleic self-antigens. Immunometabolism is a rapidly expanding scientific field investigating the metabolic programming of cells of the immune system. During the normal immune response, extensive reprogramming of cellular metabolism occurs, both to generate adenosine triphosphate and facilitate protein synthesis, and also to manage cellular stress. Major pathways upregulated include glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle and the pentose phosphate pathway, among others. Metabolic reprogramming also occurs to aid resolution of inflammation. Immune cells of both patients with SLE and lupus-prone mice are characterized by metabolic abnormalities resulting in an altered functional and inflammatory state. Recent studies have described how metabolic reprogramming occurs in many cell populations in SLE, particularly CD4⁺ T cells, e.g. favouring a glycolytic profile by overactivation of the mechanistic target of rapamycin pathway. These advances have led to an increased understanding of the metabolic changes affecting the inflammatory profile of T and B cells, monocytes, dendritic cells and neutrophils, and how they contribute to autoimmunity and SLE pathogenesis. In the current review, we aim to summarize recent advances in the field of immunometabolism involved in SLE and how these could potentially lead to new therapeutic strategies in the future.