Illustration of the complement system's role in lupus nephritis and pulmonary hypertension.

The Role of Complement Activation in Autoimmune Diseases: New Insights and Therapeutic Potential

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Nico Varela in Health & Wellness October 2026 • 4 min read.

"Exploring the Links Between Complement Pathways, Lupus Nephritis, and Pulmonary Hypertension."


Autoimmune diseases, such as systemic lupus erythematosus (SLE), are characterized by the immune system mistakenly attacking the body's own tissues and organs. A key player in this process is the complement system, a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. However, when dysregulated, the complement system can contribute to the pathology of autoimmune diseases.

One area of significant research interest is the role of the alternative complement pathway in lupus nephritis (LN), a kidney inflammation caused by SLE. Previous studies have suggested that excessive activation of this pathway, especially in the absence of factor H (a regulator of complement activity) or functional impairment, is a key factor in the development of LN. Furthermore, the connection between pulmonary hypertension (PH), a condition of high blood pressure in the arteries to the lungs, and LN has also garnered attention, with vasculopathy (disease of the blood vessels) emerging as a critical link.

Recent research has delved deeper into the clinical and pathological significance of alternative complement activation in patients with both pulmonary hypertension and lupus nephritis. By analyzing patient data, detecting complement components, and examining lung specimens, researchers aim to unravel the complex interplay between complement activation, vascular lesions, and the severity of these conditions.

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Measuring Lupus Nephritis Activity

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that predominantly affects women of childbearing age, and lupus nephritis (LN) is a relatively common, serious complication. A 2025 study set out to assess how complement levels and SLEDAI-2K relate to renal activity across different pathological types of LN. A separate 2026 ACOMPLIS project evaluated C3dg, C4d, and soluble terminal complement complex (sTCC) as markers of SLE activity and organ involvement, comparing them with conventional C3 and C4 measurements. A 2021 review notes that complement’s involvement in LN is complex and that complement levels have limitations for disease monitoring.

How Does Complement Activation Contribute to Pulmonary Hypertension in Lupus Nephritis?

Illustration of the complement system's role in lupus nephritis and pulmonary hypertension.

A study was conducted analyzing patients with and without pulmonary hypertension in the context of lupus nephritis. Plasma samples were analyzed for ANCA (anti-neutrophil cytoplasmic antibodies) and major complement components. Lung specimens from patients with both PH and LN were examined using immunofluorescence staining to detect the presence of Bb, C3d, and C5b-9, which are markers of complement activation.

The results revealed significant differences between the groups:

  • Complement Levels: Higher levels of Bb (a component of the alternative pathway) and lower levels of factor H (a complement regulator) were found in patients with pulmonary hypertension.
  • Clinical Manifestations: The pulmonary hypertension group exhibited a higher incidence of thrombocytopenia (low platelet count) and lower rates of malar rash, alopecia (hair loss), and arthritis.
  • Laboratory Findings: Patients with pulmonary hypertension and lupus nephritis had lower hemoglobin levels and higher D-Dimer levels (indicating blood clot formation). There were also higher ratios of anti-RNP and anti-cardiolipin antibodies in the lupus nephritis group.
  • Lung Pathology: The deposition of Bb in lung tissues was associated with the severity of lung injury.
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Complement Pathways and Urinary Biomarkers

The 2007 review describes complement as three pathways involving more than 30 proteins, including proteins that mediate its effects and regulatory proteins that help prevent injudicious activation on host tissue. The 2025 review’s section on noninvasive urinary biomarkers in lupus nephritis provides a contrasting focus: assessing disease through biomarkers detectable in urine. Together, these source excerpts point to two distinct analytical angles—understanding the complement system’s components and regulation, and evaluating urinary biomarkers in LN.

These findings suggest that complement activation through the alternative pathway plays a significant role in the development of pulmonary hypertension in patients with lupus nephritis. The association between Bb deposition and lung injury further highlights the involvement of complement in the pathogenesis of vascular lesions.

Implications and Future Directions

This study provides additional evidence that complement activation through the alternative pathway is a key factor in the development of pulmonary hypertension in the context of lupus nephritis. Understanding the specific mechanisms by which complement contributes to vascular lesions may pave the way for targeted therapies aimed at modulating complement activity and preventing the progression of these debilitating conditions. By targeting the alternative complement pathway, clinicians may be able to improve renal outcomes and overall prognosis for patients with pulmonary hypertension and lupus nephritis.

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Complement’s Dual Role in Kidney Disease

Complement has a dual relationship with renal disease: both genetic deficiency of complement components and excessive complement activation are implicated in primary and secondary renal diseases, including lupus nephritis. A 2021 review emphasizes that the kidney can bear the consequences of uncontrolled complement activation, particularly in autoimmune disease, and examines the relevance of this relationship to LN treatment. These perspectives frame complement as both a contributor to disease processes and a potential therapeutic consideration.

Treatment Evidence and Global Perspectives

A 2026 review of lupus nephritis treatment summarizes 34 high-quality studies published from 2021 through 2025, offering an overview of current treatments. Its source description notes that LN is a serious kidney complication of lupus and can lead to kidney failure if it is not treated effectively. A separate 2026 review takes a global-perspectives approach and describes LN as the most common and severe renal complication associated with SLE, which is characterized by widespread inflammation and tissue damage.

Complement and SLE Tissue Injury

Complement activation is described as a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus. This places complement within the broader disease process, linking its activation to inflammatory tissue damage in SLE. The available source excerpt does not quantify this contribution or specify how it varies among organs.

A Phase 1b Study in Active Lupus Nephritis

A poster dated October 25, 2023 reports results from a single-arm Phase 1b study of ANX009, an anti-C1q treatment, in patients with active lupus nephritis. The poster’s title states that the results show the classical pathway is a key driver of complement activation and consumption in these patients. The supplied source description does not provide patient experiences, outcome figures, or additional details about the study results.

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

Everything You Need To Know

1

What is the complement system, and why is it important in the context of autoimmune diseases?

The complement system is a crucial part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promote inflammation, and attack pathogens. However, in autoimmune diseases like systemic lupus erythematosus (SLE), it can become dysregulated, mistakenly attacking the body's own tissues and organs. Its significance lies in its role in the pathology of autoimmune diseases, specifically in lupus nephritis and pulmonary hypertension. Implications include potential vascular lesions and the need for targeted therapies.

2

What is the relationship between lupus nephritis, pulmonary hypertension, and vascular issues?

Lupus nephritis (LN) is kidney inflammation caused by systemic lupus erythematosus (SLE), while pulmonary hypertension (PH) is high blood pressure in the arteries to the lungs. The key connection is vasculopathy, or disease of the blood vessels. Studies analyze patient data, detect complement components, and examine lung specimens to understand the interplay between complement activation, vascular lesions, and the severity of these conditions. The link is critical because dysregulation of the complement system, particularly the alternative pathway, significantly contributes to the development of both conditions, leading to vascular damage.

3

What is the significance of the alternative complement pathway in this context?

The alternative complement pathway is a specific part of the complement system. It is particularly relevant in lupus nephritis and pulmonary hypertension. Excessive activation of this pathway, especially in the absence of factor H (a regulator), is a key factor in the development of lupus nephritis. The study found higher levels of Bb (a component of the alternative pathway) in patients with pulmonary hypertension and lupus nephritis. This suggests the pathway's direct involvement in the development of vascular lesions in the lungs. Its implications point to the need to target this pathway in therapies.

4

What specific findings from the study support the role of the complement system in pulmonary hypertension and lupus nephritis?

The study's findings show that patients with pulmonary hypertension in the context of lupus nephritis exhibit higher levels of Bb (a component of the alternative pathway) and lower levels of factor H (a complement regulator). These patients also had lower hemoglobin levels, higher D-Dimer levels (indicating blood clot formation), and higher ratios of certain antibodies. Moreover, the deposition of Bb in lung tissues was associated with the severity of lung injury. These observations highlight that complement activation through the alternative pathway plays a significant role in the development of pulmonary hypertension and the associated vascular lesions in the context of lupus nephritis, further underscoring the importance of the complement system in the pathogenesis of these conditions.

5

What are the potential implications of these findings for the treatment of pulmonary hypertension and lupus nephritis?

Targeting the alternative complement pathway is a potential therapeutic strategy for pulmonary hypertension and lupus nephritis. The study's findings emphasize that understanding the specific mechanisms by which the complement system contributes to vascular lesions may lead to therapies aimed at modulating complement activity. By targeting the alternative complement pathway, clinicians may improve renal outcomes and overall prognosis for patients with pulmonary hypertension and lupus nephritis. This strategy’s significance lies in its potential to prevent the progression of these debilitating conditions by addressing the underlying immunological dysregulation.

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