Loss of T follicular regulatory cell-derived IL-1R2 augments germinal center reactions via increased IL-1.

Inappropriate immune activity is key in the pathogenesis of multiple diseases, and it is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector owing to its powerful role in both innate and adaptive immunity, and, thus, it is tightly controlled at multiple levels. IL-1R2 antagonizes IL-1, but effects of losing this regulation are unknown.

SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries.

Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission.

Significant differences exist in the availability of healthcare worker (HCW) SARS-CoV-2 testing between countries, and existing programmes focus on screening symptomatic rather than asymptomatic staff. Over a 3 week period (April 2020), 1032 asymptomatic HCWs were screened for SARS-CoV-2 in a large UK teaching hospital. Symptomatic staff and symptomatic household contacts were additionally tested.

Resolving mechanisms of immune-mediated disease in primary CD4 T cells.

Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms.

Genome-wide association studies in Crohn's disease: Past, present and future.

Over the course of the past decade, genome-wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL-17/IL-23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development - a realisation that is now being incorporated into the design of new treatments.

NBEAL2 is required for neutrophil and NK cell function and pathogen defense.

Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice.

T cell exhaustion and immune-mediated disease-the potential for therapeutic exhaustion.

T cell exhaustion represents a continuous spectrum of cellular dysfunction induced during chronic viral infection, facilitating viral persistence and associating with poor clinical outcome. Modulation of T cell exhaustion can restore function in exhausted CD8 T cells, promoting viral clearance. Exhaustion has also been implicated as playing an important role in anti-tumour responses, whereby exhausted tumour-infiltrating lymphocytes fail to control tumour progression.

T-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases.

During acute viral infection CD8 T cells rapidly expand before contracting down to a persistent memory population that confers long-lasting immunity. However when the antigen persists, such as during chronic viral infection, a dysfunctional process termed 'exhaustion' limits the antiviral response, facilitating ongoing viraemia and poor clinical outcome. CD8 T-cell exhaustion was originally identified in lymphocytic choriomeningitis virus infection of mice; however, new evidence has shown that exhaustion is associated with the control of a wide range of human chronic inflammatory states, including chronic viral infection, autoimmunity and cancer.

Leucocyte subset-specific type 1 interferon signatures in SLE and other immune-mediated diseases.

Objectives: Type 1 interferons (IFN-1) are implicated in the pathogenesis of systemic lupus erythematosus (SLE), but most studies have only reported the effect of IFN-1 on mixed cell populations. We aimed to define modules of IFN-1-associated genes in purified leucocyte populations and use these as a basis for a detailed comparative analysis.

Methods: CD4+ and CD8+ T cells, monocytes and neutrophils were purified from patients with SLE, other immune-mediated diseases and healthy volunteers and gene expression then determined by microarray.

Modules, networks and systems medicine for understanding disease and aiding diagnosis.

Many common diseases, such as asthma, diabetes or obesity, involve altered interactions between thousands of genes. High-throughput techniques (omics) allow identification of such genes and their products, but functional understanding is a formidable challenge. Network-based analyses of omics data have identified modules of disease-associated genes that have been used to obtain both a systems level and a molecular understanding of disease mechanisms.

Genetic variation, Fcγ receptors, KIRs and infection: the evolution of autoimmunity.

Recent work has emphasised the marked genetic variability that exists in the Fc receptor locus. This variation can contribute to the risk of autoimmune disease in both mice and humans, but can also have a profound impact on defence against infection. Using FcγRIIB and FcγRIIIB as examples, we demonstrate that variations associated with increased susceptibility to autoimmunity may be maintained in populations for their beneficial effect against infection.