Reviews & Analysis

Hyperactivation of the complement system has been implicated in the pathology of COVID-19. Here the authors bring together the latest information on the role of complement in COVID-19 and progress in targeting complement components for treatment of severe disease.

Although B cells represent only a minor cell population in the central nervous system (CNS), they can contribute to CNS pathology — most notably in multiple sclerosis — through antibody and effector molecule secretion and antigen presentation. Here, Jain and Yong discuss the roles of B cells in the CNS and examine the potential for targeting these cells in various neurological conditions.

Here, Lipsitch and colleagues assess the impact of breakthrough SARS-CoV-2 infections that occur in individuals who have been vaccinated against COVID-19. The authors explain how the rate of breakthrough infections can be measured, what the causes of these infections are and discuss other key questions that need to be considered in light of these infections.

In this Review, Brian Laidlaw and Ali Ellebedy outline our current understanding of the germinal centre response in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its importance for establishing protective immunity against the virus. They also consider the germinal centre responses seen following vaccination and how germinal centre responses may be modulated to induce broad protection against new variants of SARS-CoV-2.

In this Perspective, Lok-Yin Roy Wong and Stanley Perlman consider how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses are able to drive immune dysregulation and immunopathology. They provide an overview of the coronavirus-derived molecules that interfere with key innate immune responses, including interferon pathways and complement, NF-κB signalling and inflammasome activation, as well as with the activation of host adaptive immunity.

Current strategies for HIV-1 cure have not been successful in eliminating the latent reservoir. This Review highlights potential therapeutic strategies that engage the immunology of dendritic cells and natural killer cells in efforts to achieve HIV-1 cure.

Studying ageing at the single-cell level has provided insight into the changes that occur systemically and in tissues as we age. For example, we now have a greater appreciation of the heterogeneity and dynamic nature of immune cell ageing and of the impact of age-associated tissue remodelling on the immune system, together contributing to increased vulnerability to some diseases.

In this Review, Manabe and Heneka examine how the systemic inflammation associated with sepsis can lead to acute cerebral dysfunction known as sepsis-associated encephalopathy (SAE). Moreover, they suggest that some of the mechanisms involved in SAE may be relevant for understanding the cognitive impairments that develop in some patients with COVID-19.

The renin–angiotensin, complement and kallikrein–kinin systems comprise a multitude of mediators that modulate physiological responses during inflammatory and infectious diseases. This Review investigates the complex interactions between these systems and how these are dysregulated in various conditions, including cardiovascular diseases and COVID-19, as well as their therapeutic implications.

Non-alcoholic steatohepatitis (NASH) is a serious chronic liver disorder of increasing prevalence worldwide. Metabolic by nature, the disease also mobilizes the immune system. Here, Huby and Gautier discuss current knowledge regarding how diverse immune cell subsets affect NASH onset and progression.

In this Review, Trim and Lynch provide an overview of the adipose tissue immune system and discuss the functional roles of adipose immune structures, as well as focusing on recently discovered ‘non-immune’ functions of adipose tissue immune cells.

This Perspective chronicles the journey to the elimination of transmission of wild poliovirus in Africa, with a critical discussion of the global, continental, national and community actions that were required and the lessons learnt along the way.

This Review describes our current understanding of the functional and structural transitions that occurred during the evolution of the recombination activating gene 1 (RAG1)–RAG2 (collectively RAG) recombinase, yielding a RAG recombinase in jawed vertebrates with tightly regulated cleavage activity and strongly suppressed transposition activity.

The term ‘type I interferonpathy’ was coined 10 years ago to describe rare genetic diseases that are caused by an aberrant upregulation of type I interferon signalling. Here, Crow and Stetson discuss our current understanding of the type I interferonpathies, 10 years on.

Individuals with asymptomatic COVID-19 can transmit the virus and may be at risk of long-term disease. In this Progress article, Boyton and Altman present current insights into immune responses in asymptomatic SARS-CoV-2 infection and discuss the relevance of asymptomatic disease for public health strategies.

Besides neutralizing antibodies, viruses face a range of cell-intrinsic inhibitors that are specialized to limit virus entry into host cells. Majdoul and Compton describe the mechanisms of action of the cellular factors providing this important first line of defence against virus infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Kolkhir and colleagues discuss how therapies targeting human mast cells in both allergic and non-allergic disease settings have provided crucial insights into the functions of these cells.

The causative mechanisms of cachexia, a complex catabolic syndrome that can occur in the context of malignant or infectious diseases, are poorly understood. This Review examines the immunological context of cachexia and explores immunometabolic crosstalk both upstream and downstream of tissue catabolism.

In this Perspective, the authors propose that innate immune detection of oxidized phospholipids, which result from tissue injury, allows the immune system to assess the degree of danger; the detection of oxidized phosphocholines in the presence of pathogen-associated molecular patterns or damage-associated molecular patterns triggers a heightened immune response.

In this Perspective, McInnes and Gravallese highlight the remarkable progress made over the past 20 years in treating immune-mediated inflammatory diseases. The available therapies have progressed from broad-spectrum immune modulators to highly targeted biological and small-molecule agents as our understanding of disease mechanisms has advanced.