Review
Abstract
Peptidyl arginine deiminases (PADs) catalyze the conversion of arginine residues into peptidyl citrulline, a posttranslational modification known as protein citrullination (or arginine deimination). This process alters the charge of proteins from positive to neutral, thereby affecting their folding, stability, conformation, and function. PAD2 and PAD4 can translocate into the nucleus and citrullinate both cytoplasmic and nuclear proteins. In this Review, we focus on PAD2- and PAD4-mediated citrullination in immune cell subsets within the tumor microenvironment. We discuss how citrullination regulates immune cell function and tumor immunity and explore the potential of targeting citrullination as a strategy for cancer immunotherapy.
Authors
Michael R. Pitter, Weiping Zou
Abstract
The increasing recognition of a new category of encephalitides that occur in association with antibodies against neuronal surface proteins has prompted the use of terms like “autoimmune psychosis” and “autoimmune psychiatric disorders.” However, although psychosis and other psychiatric symptoms can occur in autoimmune encephalitides and systemic autoimmune diseases, evidence for a distinct psychiatric entity beyond these conditions is lacking. A particularly defining condition is anti-NMDA receptor encephalitis, which has been central to promoting concepts such as autoimmune psychosis and autoimmune psychiatric disorders. While anti-NMDA receptor encephalitis can resemble primary psychiatric conditions, certain clinical features often suggest the specific diagnosis. This Review traces the development of the autoimmune psychosis concept and examines the implications of framing it as a separate entity. We discuss leading theories of psychosis and the convergence of the NMDA receptor hypofunction/glutamate hypothesis with anti-NMDA receptor encephalitis mechanisms. The interest generated by such disorders has driven uncontrolled antibody testing in psychiatric populations, often neglecting pretest probability and favoring prevalence over diagnostic specificity. Finally, we highlight the main limitations of current approaches and propose directions for future research.
Authors
José Maria Cabrera-Maqueda, Jesús Planagumà, Mar Guasp, Josep Dalmau
Abstract
Pancreatic cancer (PC) is a devastating disease, due in part to its diagnosis frequently being made at an advanced stage. Ongoing efforts are aimed at identifying early-stage PC in high-risk individuals, as early detection leads to downstaging of PC and improvements in survival. However, there are a myriad of challenges that arise when trying to optimize PC early detection strategies, including selection of the appropriate high-risk individuals and selection of the test or combination of tests that should be performed. Here, we discuss the populations that are the strongest candidates for PC screening and review professional PC screening guidelines. We also summarize the current state of imaging techniques for early detection of PC and further review many studied biomarkers — ranging from nucleic acid targets, proteins, and the microbiome — to highlight the current state of the field and the challenges that remain in the years to come.
Authors
Michael J. Shen, Arsia Jamali, Bryson W. Katona
Abstract
Chronic organ disease is often complicated by fibrosis, the excessive accumulation of extracellular matrix, as a consequence of dysfunctional wound healing responses. Fibrosis progressively distorts tissue architecture and eventually leads to loss of organ function, accounting for up to 45% of deaths in developed countries. Moreover, fibrosis is a major risk factor for tumor development. The few approved therapies aimed at preventing or resolving fibrosis show limited efficacy and safety. One reason for the lack of efficient antifibrotic therapies is the fact that the cell circuits driving the disease biology are still only partially understood. The circadian clock is known to regulate the physiological functions of critical organs, including the liver, kidneys, and lungs. Several experimental and clinical studies have established that circadian disruption plays an important role in the development of chronic diseases across organs involving fibrosis. These include metabolic dysfunction–associated steatotic liver disease, chronic kidney disease, and chronic obstructive pulmonary disease. Here, we provide an overview of the circadian mechanisms that play critical roles in mediating physiological functions in the liver, kidneys, and lungs and whose deregulations could predispose toward development of chronic disease of these organs, leading to fibrosis. We also highlight the possible opportunities of chronotherapy for chronic diseases and discuss future perspectives.
Authors
Atish Mukherji, Pierre-Louis Tharaux, David W. Ray, Thomas F. Baumert
Abstract
The gut microbiota plays a crucial role in maintaining intestinal homeostasis and influencing various aspects of host physiology, including immune function. Recent advances have highlighted the emerging importance of the complement system, particularly the C3 protein, as a key player in microbiota-host interactions. Traditionally known for its role in innate immunity, the complement system is now recognized for its interactions with microbial communities within the gut, where it promotes immune tolerance and protects against enteric infections. This Review explores the gut complement system as a possibly novel frontier in microbiota-host communication and examines its role in shaping microbial diversity, modulating inflammatory responses, and contributing to intestinal health. We discuss the dynamic interplay between microbiota-derived signals and complement activation, with a focus on the C3 protein and its effect on both the gut microbiome and host immune responses. Furthermore, we highlight the therapeutic potential of targeting complement pathways to restore microbial balance and treat diseases such as inflammatory bowel disease and colorectal cancer. By elucidating the functions of the gut complement system, we offer insights into its potential as a target for microbiota-based interventions aimed at restoring intestinal homeostasis and preventing disease.
Authors
Xianbin Tian, Lan Zhang, Xinyang Qian, Yangqing Peng, Fengyixin Chen, Sarah Bengtson, Zhiqing Wang, Meng Wu
Abstract
The complement system has emerged as a critical regulator of intestinal homeostasis, inflammation, and cancer. In this Review, we explore the multifaceted roles of complement in the gastrointestinal tract, highlighting its canonical and noncanonical functions across intestinal epithelial and immune cells. Under homeostatic conditions, intestinal cells produce complement that maintains barrier integrity and modulates local immune responses, but complement dysregulation contributes to intestinal inflammation and promotes colon cancer. We discuss recent clinical and preclinical studies to provide a cohesive overview of how complement-mediated modulation of immune and nonimmune cell functions can protect or exacerbate inflammation and colon cancer development. The complement system plays a dual role in the intestine, with certain components supporting tissue protection and repair and others exacerbating inflammation. Intriguingly, distinct complement pathways modulate colon cancer progression and response to therapy, with novel findings suggesting that the C3a/C3aR axis constrains early tumor development but may limit antitumor immunity. The recent discovery of intracellular complement activation and tissue-specific complement remains vastly underexplored in the context of intestinal inflammation and colon cancer. Collectively, complement functions are context- and cell-type-dependent, acting both as a shield and a sword in intestinal diseases. Future studies dissecting the temporal and spatial dynamics of complement are essential for leveraging its potential as a biomarker and therapeutic in colon cancer.
Authors
Carsten Krieg, Silvia Guglietta
Abstract
The complement system is an evolutionarily conserved host defense system that has evolved from invertebrates to mammals. Over time, this system has become increasingly appreciated as having effects beyond purely bacterial clearance, with clinically relevant implications in transplantation, particularly lung transplantation. For many years, complement activation in lung transplantation was largely focused on antibody-mediated injuries. However, recent studies have highlighted the importance of both canonical and noncanonical complement activation in shaping adaptive immune responses, which influence alloimmunity. These studies, together with the emergence of FDA-approved complement therapeutics and other drugs in the pipeline that function at different points of the cascade, have led to an increased interest in regulating the complement system to improve donor organ availability as well as improving both short- and long-term outcomes after lung transplantation. In this Review, we provide an overview of the when, what, and how of complement in lung transplantation, posing the questions of: when does complement activation occur, what components of the complement system are activated, and how can this activation be controlled? We conclude that complement activation occurs at multiple stages of the transplant process and that randomized controlled trials will be necessary to realize the therapeutic potential of neutralizing this activation to improve outcomes after lung transplantation.
Authors
Hrishikesh S. Kulkarni, John A. Belperio, Carl Atkinson
Abstract
Rheumatoid arthritis (RA) has a preclinical period of 5–10 years preceding the appearance of joint pain and swelling characteristic of clinical RA. Preclinical RA has been characterized by circulating IgA and IgG classes of autoantibodies targeting citrullinated protein antigens (ACPAs) that are highly specific for future clinical RA, circulating IgA plasmablasts, and autoantibody production at mucosal sites, all of which point toward mucosal tissues as the origin of immune dysregulation. In individuals at risk for developing and with established RA, oral and gut microbial shifts correlate with immune activation. Specific bacterial taxa such as Segatella copri, Subdoligranulum didolesgii, Eggerthella lenta, and Streptococcal species have been shown to contribute to the development and/or perpetuation of RA through mechanisms that include molecular mimicry, antigen citrullination, and disruption of mucosal immunity. Furthermore, microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune homeostasis and offer potential therapeutic avenues. The gut microbiome also influences therapeutic responses by modulating conventional disease-modifying antirheumatic drugs. This Review synthesizes current knowledge on the bacterial microbiome’s role in RA pathogenesis and treatment responses, highlighting microbiome-targeted interventions as potential strategies for disease prevention and management.
Authors
Jing Li, Kristine A. Kuhn
Abstract
Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.
Authors
Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD), now the most common cause of chronic liver disease, is estimated to affect around 30% of the global population. In MASLD, chronic liver injury can result in scarring or fibrosis, with the degree of fibrosis being the best-known predictor of adverse clinical outcomes. Hence, there is huge interest in developing new therapies to inhibit or reverse fibrosis in MASLD. However, this has been challenging to achieve, as the biology of fibrosis and candidate antifibrotic therapeutic targets have remained poorly described in patient samples. In recent years, the advent of single-cell and spatial omics approaches that can be applied to human samples have started to transform our understanding of fibrosis biology in MASLD. In this Review, we describe these technological advances and discuss the new insights such studies have provided, focusing on the role of epithelial cell plasticity, mesenchymal cell activation, scar-associated macrophage accumulation, and inflammatory cell stimulation as regulators of liver fibrosis. We also consider how omics techniques can enhance our understanding of evolving concepts in the field, such as hot versus cold fibrosis and the mechanisms of liver fibrosis regression. Finally, we touch on future developments and how they are likely to inform a more mechanistic understanding about how fibrosis might differ between patients and how this could influence optimal therapeutic approaches.
Authors
Fabio Colella, Neil C. Henderson, Prakash Ramachandran
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