Article originally published by Select Science (selectscience.net)
In recent decades, research into the complement system has witnessed remarkable advancements, particularly in understanding the intricate roles of a critical protein, C1q. C1q stands out not only as a crucial initiator of the classical complement pathway but also, as research has shown, plays diverse functions in autoimmunity, inflammation, and infectious disease progression.
In this Editorial Article, we delve into the critical role of C1q, drawing insights from Professor Dr. Leendert Trouw and Dr. Douwe Dijkstra’s research and expertise on C1q. Professor Trouw has pioneered research on the pathogenicity of anti-C1q autoantibodies, and his initial discoveries stemmed from mouse models. With the advent of new technologies, the group has now progressed to explore the role of C1q and anti-C1q in humans during Dr. Dijkstra’s PhD research.
Professor Trouw did his PhD training on Complement and Autoantibodies with Professor Daha, who was part of the initial consortium developing the Wieslab® Assays. He has investigated the role of autoantibodies in various diseases, including Rheumatoid Arthritis and Systemic Lupus Erythematosus, and recently has started to look at their role in anticancer therapy.
Dr. Douwe Dijkstra has been a PhD student in Professor Trouw’s lab for the past five years, where he has explored the role of C1q autoantibodies in different contexts, including lupus and pregnancy complications.
C1q: A Multifunctional Molecule
The complement system, a crucial part of the immune response, comprises various proteins that, when activated, help clear pathogens and damaged cells. C1q, the initial component of the classical pathway, is central to this process. However, its involvement in the context of disease seems to be a double-edged sword.
C1q plays a vital role in the clearance of apoptotic cells and immune complexes; the impairment of this process can lead to the onset of autoimmunity. In some individuals, autoantibodies that bind to C1q are present. Interestingly, these anti-C1q autoantibodies only target ‘solid-phase C1q’, meaning C1q that has bound a ligand or surface.
The presence of anti-C1q autoantibodies is strongly associated with the occurrence and severity of kidney injury (lupus nephritis) in patients with systemic lupus erythematosus (SLE). These autoantibodies promote inflammation and immune complex deposition in the kidneys, exacerbating tissue damage. Interestingly, anti-C1q autoantibodies can also be found in healthy individuals without any clinical presentation.
This indicates that their mere presence does not necessarily cause pathology, and understanding why these anti-C1q autoantibodies contribute to the severity of lupus nephritis but are not pathogenic in healthy individuals has been a major research question in the career of Prof. Trouw.
“Our research focuses on the interplay between autoantibodies and the complement system, especially the C1q interactions, where the complexity underscores the need for a deeper understanding of the mechanism to develop effective therapeutic interventions.” Prof. Trouw
C1q has been shown to be involved in infectious diseases such as tuberculosis, where increased C1q levels have been found to correlate with active tuberculosis disease and can discriminate it from latent infection and healthy individuals. However, the functional role of this increased C1q levels are still unknown and may involve enhanced opsonization of the pathogen but may also impact on the adaptive immune response as part of an immune evasion strategy.
"Considering C1q’s involvement in various diseases, it is exciting to explore how C1q can serve as a biomarker and how its molecular signature can inform the development of therapies to modulate C1q’s binding in various disease contexts.” Dr. Dijkstra
C1q’s versatility extends beyond its role in autoimmunity, encompassing significant functions in infectious diseases and anti-cancer therapy. This makes C1q a compelling diagnostic tool and target for therapeutic strategies.
"C1q has always fascinated me with its primary role in initiating the Classical pathway. However, I am now equally intrigued by the molecule’s versatility and our ability to adjust its role, either by enhancing or inhibiting binding or using it as a biomarker.” Prof. Trouw
C1q as a biomarker and potential use in personalized medicine
C1q can potentially be used as a biomarker in SLE and tuberculosis. In the case of SLE, there is a quest to find more relevant and specific markers where traditional markers for disease activity, such as C3 and C4 levels, seem insufficient.
An advantage of using C1q as a biomarker in SLE is the stricter normal range of C1q levels compared to the wider normal range for C4 with significant copy number variation resulting in varying levels of C4, making C1q a more consistent and reliable marker. So far, C1q has shown potential for use as a biomarker, compared to those traditionally used, for identifying the active phase of kidney damage. It can aid in assessing lupus nephritis activity during inactive and renal flares, as they correlate better with active renal disease.
In contrast, current diagnostic approaches for tuberculosis struggle to distinguish between active disease, latent infection, and past infection, particularly when using immunological tests. As mentioned above, C1q levels seem to effectively discriminate between active disease, latent infection, and past infection. While C1q alone may not provide a comprehensive picture of tuberculosis, it offers valuable insights that could improve diagnostic accuracy when used alongside other markers.
Harnessing C1q for therapeutic development
Modulation of C1q’s ability to bind antigen-antibody complexes has been proposed as a strategy in therapeutic development by Prof. Trouw and others. This approach offers a way to modulate its binding—a strategy currently being explored to inhibit its role in causing tissue damage in autoimmune diseases or to enhance the immune system’s ability to kill tumor cells via ComplementDependent Cytotoxicity (CDC).
Blocking C1q with antibodies or small molecules could be an effective treatment for diseases with a clear contribution of the classical pathway of complement. However, because of the complexity of the roles played by C1q in the body it will be important to monitor carefully what happens to individuals treated with such interventions.
“In particular, C1q’s role in systemic lupus erythematosus has been a major area of interest. Beyond lupus, we are exploring its involvement in other autoimmune conditions, tuberculosis, and its potential in cancer therapy.” Prof. Trouw
An exciting area is using C1q as a therapeutic target in cancer. Using antibody engineering, the team is looking into recruiting and capturing C1q in places where it might not usually be activated, harnessing classical pathway activation on tumor cells or other targets that would not typically activate complement. This approach is especially relevant for tumor types that evade the complement system.
Circumventing undesired effects - moving into
local inhibition
Given C1q’s central role in the complement cascade, completely inhibiting this molecule or the classical pathway could elevate the risk of infections. Therefore, local inhibition has emerged as a promising strategy. Prof. Trouw highlights the importance of targeted, transient inhibition, which specifically blocks the classical pathway without a broader impact on the immune system. Selecting the specific level of the cascade to inhibit depends on identifying the most pathogenic activation paths in particular diseases, guiding the focus of targeting efforts.
“With my team, we work on both sides of the coin – enhancing activation in some diseases and inhibiting activation in others, but always aiming to modulate locally.” Prof. Trouw
As part of his PhD studies, Dr. Dijkstra isolated and recombinantly reproduced anti-C1q antibodies with properties that enable specific binding to C1q in solid phase, which is C1q that is bound to one of its ligands. A conformational change in C1q upon binding to its target or surface reveals an epitope to which these autoantibodies can bind. These antibodies hold potential for targeted therapy in conditions where C1q’s binding plays a critical role, such as lupus nephritis.
“Since C1q levels cannot be depleted from the circulation by antibodies specific for only ‘solid-phase’ C1q, these antibodies are a great tool with great potential and specific effects.” Dr. Dijkstra
These insights open potential therapeutic applications and contribute to a broader understanding of how antibody interactions with C1q can be leveraged in therapeutic contexts Through sophisticated bioengineering, these antibodies could specifically modulate immune responses in targeted locations, representing a significant advance in the therapeutic modulation of C1q. These antibodies could recruit a specific regulator or attach some other modality to have a specific effect in that location. This represents a very sophisticated on-and-off switch allowing for local control of immune responses.
“C1q and Factor H are known to be quite stable proteins; however, when measuring activation fragments of certain complement proteins, you have to be very careful with the temperature and how the samples are handled.” Dr. Dijkstra
Challenges in complement assessment:
Tips from the experts
Studying the complement system in different assays requires meticulous handling to preserve activation. From the moment the serum is harvested to the assay’s execution, maintaining the integrity of the samples is crucial. This thorough approach ensures that the dynamic nature of complement activation is accurately captured in experimental settings. An equally critical consideration is the stability of the biomarkers under analysis.
This underscores the importance of precise temperature control and careful handling protocols throughout the experimental process. In complement system research, ensuring the preservation of activation states is essential for obtaining reliable results. Therefore, maintaining consistency in handling procedures is crucial to prevent unintended alterations in complement activity profiles during experimentation.
In summary, meticulous attention to detail, from sample collection to assay execution, is paramount in complement assessment. By adhering to rigorous protocols and maintaining optimal conditions, accurate and reliable results can be secured, as well as their implications in various physiological and pathological contexts.
C1q offers strategic avenues for local modulation of the Complement System
C1q emerges as a multifaceted molecule with a pivotal role across different areas. It underlines various biomedical domains and encompasses its utility as both a biomarker and therapeutic target.
C1q as a biomarker presents significant advantages, particularly in systemic lupus and tuberculosis. Therapeutically targeting C1q offers strategic avenues by selectively modulating this classical pathway initiator; the roles in autoimmunity can potentially be mitigated and immune-mediated tumor cell destruction enhanced. Drifting away from systemic inhibition towards localized approaches could minimize adverse effects while maximizing therapeutic efficacy, a sentiment echoed by ongoing research efforts.
“The shift towards local inhibition is crucial in targeting specific disease processes while minimizing systemic side effects. This strategic approach aims to maximize therapeutic benefits while reducing risks associated with broad immune suppression.” Prof. Trouw
The role of complement activation in disease contexts is very complex. It’s crucial to discern between its physiological and pathological roles, recognizing its dual potential in promoting tissue repair or exacerbating damage. The physiological and pathological roles of C1q-mediated complement activation underscore the importance of context-specific interventions tailored to the precise dynamics of complement activation.
