Decoding complement: Novel disease insights and therapeutic horizons

Abstract

We are delighted to present this special issue of the European Journal of Immunology, dedicated to the 19th European Meeting on Complement in Human Diseases (EMCHD 2024) in Lübeck. This issue served as a prelude to the main topics that were discussed at the meeting, providing novel insights into disease mechanisms, therapeutic targeting strategies, and future directions in the complement field. The nine selected reviews written by international leaders in the field highlight recent advances in understanding the multifaceted roles of the complement system in immunity and disease pathogenesis, as well as innovative approaches to diagnostics and therapeutic intervention. By exploring these cutting-edge developments, we aim to provide a timely overview that will enrich the discussions and stimulate new ideas, setting the stage for future breakthroughs in complementary research. On behalf of the Board of the European Complement Network and the Local Organizing Committee of EMCHD 2024, we would like to thank all authors for their excellent contributions.

The opening review focuses on alternative pathway (AP) activation as an important mechanism underlying complement-mediated human diseases. Mohammadyari et al. [1] discuss the role of Factor D (FD) and MASP3 in AP activation in the context of disease. They also provide new insights into how FD, the rate-limiting enzyme in the AP, and its regulation by MASP3, which converts FD to its active form, may serve as therapeutic targets. The review details findings from mouse models that highlight the efficacy and challenges of targeting these proteins in several diseases, including arthritis, aHUS, and C3G. The findings underscore the complexity of translating these findings to human therapies and suggest potential strategies for clinical application.

The complement system has evolved as an important part of innate immunity to sense infection and cell damage [2]. Bosmann et al. [3] examine the dual role of the complement system during infection, highlighting its protective functions in pathogen defense and its potential to cause excessive inflammation and tissue damage. They discuss complement evasion strategies by pathogens, the impact of genetic deficiencies on infection susceptibility, and the complications of complement hyperactivation. The authors also explore therapeutic strategies to regulate complement activity to enhance pathogen clearance while minimizing harmful inflammation, emphasizing the importance of precise timing and targeted approaches in treatment to balance the benefits and risks of complement modulation during infection.

In their review article, Mannes et al. [4] discuss the dual role of the complement system in trauma resulting in massive tissue damage. While excessive complement activation in response to sensing tissue damage can lead to systemic inflammation and organ dysfunction, localized and regulated activation can aid in healing by removing debris and promoting tissue regeneration. The authors emphasize the need for targeted complement inhibition strategies that take into account the timing and location of trauma. They also review the beneficial roles of complement in immune responses, suggesting potential therapeutic applications while highlighting the complexity of the role of complement in injury and recovery.

Another example of the complex role of complement in disease pathogenesis is systemic lupus erythematosus (SLE). Pickering and Botto [5] explore the dual role of the complement system, particularly C1q, in SLE. They describe how complement components can both promote inflammation and protect against tissue damage. Noncanonical functions of C1q in immune regulation and their implications for complement-targeted therapies are discussed. Further, the relationship between complement deficiencies and SLE, the role of C1q in immune complex clearance, and its regulation of CD8⁺ T cells are examined. Clinical implications include the monitoring of complement levels and the potential of complement inhibitors in the treatment of lupus nephritis.

The review by Schmidt et al. [6] discuss the concepts of complement activation and inhibition in paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder characterized by complement-mediated intravascular hemolysis due to a somatic mutation of the PIGA gene affecting the GPI-anchored complement regulators CD55 and CD59 [7]. First, they trace the development of complement-targeted therapies for PNH, starting with C5-targeting by eculizumab in 2007. While this approach significantly reduced hemolysis and thrombotic events, more recent mechanistic analyses revealed suboptimal clinical responses: intravascular breakthrough hemolysis, persistent low-level residual intravascular hemolysis, and extravascular hemolysis. The authors discuss novel complement therapeutics targeting proximal complement proteins that address these remaining challenges, including the Factor D inhibitor danicopan, which has been approved as an add-on therapy to C5 inhibition. This group of authors also reviews the recently approved C3 inhibitor pegcetacoplan and the Factor B inhibitor iptacopan, which promise better control of intravascular and extravascular hemolysis. Taken together, this review highlights the role of PNH in driving complement research and targeted therapy development and details current and future directions in PNH management.

The complex role of the complement system in cancer is the topic of the review by Merle et al. [8], who highlight the dual nature of complement in cancer progression, emphasizing its context-dependent effects. The authors explore antitumor properties through opsonophagocytosis and cytotoxicity and tumor-promoting effects through chronic inflammation mediated by the C5a/C5aR1 axis. Further, they discuss recent findings on complement gene co-expression patterns in different cancer types and their correlation with prognosis. In particular, the authors highlight the significant intrapatient heterogeneity and the complexity added by locally produced and intracellular complement proteins in the tumor microenvironment. They also highlight ongoing clinical trials of complement targeting in cancer and emphasize the need for tailored approaches. This review provides valuable insights for researchers and clinicians in the fields of immunology and oncology, highlighting the potential of complement-targeted therapies in cancer treatment, while emphasizing the importance of patient-specific approaches.

Neurodegenerative diseases including Alzheimer's disease (AD) are increasing at an alarming rate [9]. In their review, Gedam and Zheng [10] give an update on the pathogenesis of AD, with a particular focus on the role of the C3a receptor (C3aR). The authors show that C3aR signaling plays a critical role in the progression of AD by influencing numerous pathological processes. This receptor promotes neuroinflammation by stimulating microglia and astrocytes, contributes to tau hyperphosphorylation and aggregation, impairs microglial phagocytosis of amyloid-β, leads to synaptic loss and impaired synaptic plasticity, contributes to cognitive decline, promotes metabolic dysfunction in microglia, and compromises the blood-brain barrier integrity. Given these multiple effects, the authors suggest that inhibition of C3aR or its downstream pathways may represent a multifaceted approach to slowing down the progression of AD.

Traditionally, the complement has been viewed as a guardian of the extracellular space [11]. In their review, King and Blom [12] discuss the role of complement proteins beyond their traditional extracellular functions, emphasizing their intracellular activities. They describe, how intracellular complement activation influences T-cell metabolism and immune responses, highlighting mechanisms such as the cleavage of C3 and C5 by enzymes such as cathepsin L and D. The review also considers the potential therapeutic implications of targeting intracellular complement pathways, noting challenges like the abundance of extracellular complement factors or cleavage fragments, which requires the need for specific targeting strategies to inhibit intracellular complement-dependent processes.

Finally, Ricklin discusses the significant advances in complement-targeted therapeutics over the past two decades. The author highlights the transformation of the field from initial skepticism about the feasibility of such drugs to the development of a market with multiple approved therapies. The review provides a historical overview, current status, and future potential of these treatments, focusing on several diseases affected by complement dysregulation, such as PNH and aHUS. It emphasizes the importance of clinical data, careful selection of intervention points, and combination therapies. The review also addresses ongoing challenges, potential new indications, and the need for continued research and development in the field.

In conclusion, this special issue offers substantial novel insights into the complement system's role in various diseases, with a particular focus on alternative pathway activation, infection, trauma, cancer, SLE, PNH, AD, and intracellular complement functions. It elucidates the dual roles of the complement system in promoting inflammation and protecting against tissue damage while underscoring the potential clinical applications of therapeutic developments such as novel or improved complement inhibitors. The reviews highlight the difficulties in translating findings from animal models to human therapies, emphasizing the complexity of complement regulation in different disease contexts and the necessity for tailored and precise therapeutic strategies. Future research should concentrate on the refinement of complement-targeted therapies, addressing the challenges of specificity, timing, and individual patient variability. A more comprehensive grasp of the complement's dual roles in diverse pathologies, particularly its intracellular functions, could unlock new therapeutic avenues. Investigating the role of complement modulation in personalized medicine, combination therapies, and gene editing technologies could assist in optimizing treatment outcomes. Moreover, translational studies should prioritize the bridging of gaps between animal models and human applications, leveraging advances in biotechnology to design safer and more effective complement inhibitors.