Complement Biology and Therapeutics
Series edited by Claudia Kemper
The complement system executes an evolutionarily ancient innate immune response with important roles in many human diseases, including a variety of conditions involving the kidney, autoimmune disorders, age-related macular degeneration, and more. This series of reviews, curated by Dr. Claudia Kemper, highlights the latest discoveries in complement biology and examines ongoing efforts to target complement therapeutically. From the relatively newly uncovered functions of intracellular complement (complosome) to the complexities involved in using animal models of complementopathies, these reviews convey the challenges of studying complement and developing complement-targeted therapeutics as well as call attention to recent findings that supply momentum to the field.
Articles in series
Abstract
The complement system is an important component of the innate immune system involved in host defense and maintaining homeostasis. While the liver is the main source of complement proteins in the bloodstream, recent research has shown that various tissues, including the kidneys, can produce complement components locally in response to both acute and chronic inflammation. This Review highlights evidence from animal models of glomerular and tubulointerstitial kidney disease showing increased expression of intracellular complement in the kidneys. Studies using knockout mice for complement and complement receptors, along with complement inhibitors, have demonstrated that reduced complement activation in animal models of kidney fibrosis led to reduced inflammation and fibrosis, thereby supporting the pathogenic role of complement activation. Data from single-cell RNA-sequencing, spatial transcriptomics, and proteomics studies further demonstrate that alterations in local complement levels contribute to the fibrotic microenvironment observed in these models. Additionally, kidney biopsy results from patients with acute kidney injury and chronic kidney disease (CKD) indicate an increased expression of intracellular complement components as disease progresses. Developing drugs aimed at diminishing the expression and activation of local complement in glomerular and tubulointerstitial kidney disease could provide a novel approach to managing CKD.
Authors
Didier Portilla, Vikram Sabapathy, Daniel Chauss
Abstract
Animal experiments have long been a cornerstone of advancements in biomedical research, particularly in developing novel therapeutic strategies for inflammatory and autoimmune diseases. However, these historically important approaches are now facing growing scrutiny for ethical reasons, concerns about translational limitations to human biology, and the rising availability of animal-free research methods. This shift raises a critical question: How relevant and effective are animal models for driving future advancements in today’s research landscape? This Review aims to explore this question within the field of biomedical research on the complement system, critically evaluating the contribution of animal models to the recent advancements and clinical successes of complement-targeted therapies. Specifically, we assess areas where animal studies have been indispensable for elucidating disease mechanisms and conducting preclinical evaluations, alongside instances where findings from animal models failed to translate successfully to human trials. Furthermore, we discuss similarities and differences in the complement system between animals and humans and explore innovations in animal research designed to improve translatability to human biology. By assessing the contributions of animal studies to complement therapeutics, this Review aims to provide insights into animal models’ strengths, limitations, and evolving role in complement research.
Authors
Felix Poppelaars, V. Michael Holers, Joshua M. Thurman
Abstract
The complement system is a highly conserved and essential immune component with pivotal roles in innate and adaptive immunity. It is increasingly recognized that the complement system has a profound impact on disease. Current complement-targeting therapeutics for clinical use almost exclusively target the complement system in circulation. However, recent discoveries have demonstrated that complement is not only liver derived and plasma operative, but also synthesized and activated inside many cells locally within tissues, performing noncanonical, cell-autonomous intracellular functions, collectively referred to as the complosome. These intracellular complement pathways are distinct from the classical plasma-based system and critical for regulating fundamental cellular processes, including metabolism, gene transcription, autophagy, and the activation and resolution of inflammation. This Review explores the emerging roles of the complosome and current knowledge regarding its relation to human diseases, highlighting evidence across organ systems and disease states, including the kidneys, digestive tract, lungs, heart, CNS, musculoskeletal system, skin, and cancer. We also review current scientific approaches for detecting and functionally investigating the complosome, addressing challenges such as technological limitations and the need for advanced experimental models to delineate its tissue-specific roles. Finally, we discuss central unanswered questions critical for developing innovative therapeutic strategies targeting intracellular complement pathways. These strategies hold potential to modulate disease-specific mechanisms while preserving systemic complement activity.
Authors
Tilo Freiwald, Behdad Afzali
Abstract
Kidney cancer poses unique clinical challenges because of its resistance to conventional treatments and its tendency to metastasize. The kidney is particularly susceptible to dysfunction of the complement system, an immune network that tumors often exploit. Recent discoveries have highlighted that the complement system not only plays a crucial role in immune surveillance and defense in the circulatory system, but also functions intracellularly and autonomously. This concept has shifted the focus of investigation toward understanding how complement proteins influence cancer progression by regulating the tumor microenvironment (TME), cell signaling, proliferation, metabolism, and the immune response. With the complement system and its inhibitors emerging as a promising new class of immunotherapeutics and potential complement-targeted treatments advancing through development pipelines and clinical trials, this Review provides a timely examination of how harnessing the complement system could lead to effective tumor treatments and how to strategically combine complement inhibitors with other cancer treatments, offering renewed hope in the fight against kidney cancer.
Authors
Ravikumar Aalinkeel, Richard J. Quigg, Jessy Alexander
Abstract
Type 2 (Th2) allergic diseases are chronic conditions characterized by a Th2-polarized immune response to allergens. These diseases can be categorized by affected barrier sites: skin (atopic dermatitis, allergic contact dermatitis), gut (food allergy), and respiratory tract (e.g., asthma, chronic rhinosinusitis). The global prevalence of Th2 allergic diseases has increased the need for a deeper understanding of their pathophysiology. Several associations have been identified between genetic variants in the genes encoding components of the complement system and allergic disease. Moreover, levels of several complement proteins are elevated in patients with allergy. Experimental evidence demonstrates that the complement system plays a critical role in the development of these diseases across barrier sites. While site-specific differences exist in the complement components involved, key pathways, particularly C3 and C5, are prominent across the skin, gut, and lung.
Authors
Sarah A. Thomas, Stephane Lajoie
Abstract
Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.
Authors
Diana I. Jalal, Joshua M. Thurman, Richard J.H. Smith
Abstract
Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a “pathogen” magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer biology. Numerous studies provide evidence of the association among elevated CD46 expression, malignant transformation, and metastasizing potential. These features, along with its roles as pathogen receptor, have made CD46 a target for cancer therapeutics. Thus, modified viral vectors (such as strains of adenovirus and measles virus) targeting CD46 currently are being exploited against a wide range of cancers. Another oncologic treatment utilizes a CD46-targeting human mAb as an antibody-drug conjugate. Herein, we review CD46 and its “multiverse” of cancer interactions.
Authors
M. Kathryn Liszewski, John P. Atkinson
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)