Complement System Activated Years Before Symptoms in 2 AAV Subtypes

Somi Igbene, PhD avatar

by Somi Igbene, PhD |

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The body’s complement system — comprised of blood proteins that fight infection — is specifically activated in individuals with microscopic polyangiitis and ANCA-associated vasculitis (AAV) with myeloperoxidase (MPO) antibodies years before a patient’s symptoms begin, new research shows.

“These findings support differential pathogenic [disease-causing] mechanisms behind” these two AAV subtypes, the researchers noted.

The study, “Complement activation prior to symptom onset in myeloperoxidase ANCA-associated vasculitis but not proteinase 3 ANCA associated vasculitis – A Swedish biobank study,” was published in the Scandinavian Journal of Rheumatology.

The complement system consists of a group of proteins in the blood that interacts in a coordinated manner to fight infection. The proteins are usually inactive but become activated by foreign organisms or antibodies carrying them.

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In AAV, anti-neutrophil cytoplasmic antibodies, known as ANCAs, target one of two proteins: proteinase-3, called PR3, or myeloperoxidase — MPO. These proteins, in turn, activate immune cells that can trigger the complement system. Studies previously have found complement proteins, including C3c and C4d, in AAV patients’ kidneys, and high blood levels of activated complement proteins such as C5a and C3a in patients with PR3- and MPO-positive AAV.

While these studies show that the complement system is active and plays a role in AAV development, when the complement system becomes activated is unknown. Now, a team of Swedish scientists investigated whether the complement system is activated before patients begin experiencing symptoms.

To identify suitable participants, the team analyzed medical data of patients enrolled in the Swedish National Patient Register and the Cause of Death register. Eligible participants were adults who had provided blood samples between one month and 10 years before their AAV symptoms began and were later diagnosed with AAV.

Using the blood samples provided before symptoms started, the scientists extracted the serum, which is the fluid component of the blood that does not contain clotting elements. They then measured the levels of four complement proteins, specifically C2, C5, C4b, and C5a. C2 and C5 proteins generally increase with any inflammation, whereas C4b and C5a only increase when the complement system is specifically activated.

The study involved a total of 64 patients and 122 healthy people matched by age, sex, and blood sampling, who served as controls. The mean age of the participants was 52 years and, on average, symptoms began 4.4 years before the AAV diagnosis.

The levels of all complement proteins measured were similar in the presymptomatic individuals with AAV and the control group. However, C5 and C5a levels in patients significantly increased before symptoms began, compared with the control group. Notably, C5 levels increased up to 6.5 years before symptoms started, and C5a, up to five years before symptoms began.

“In this study, using serum samples from individuals who subsequently developed AAV, we found increased levels of C5 collected up to 6.5 years before symptom onset and a gradual increase in C5a towards symptom onset. We have previously reported that the presence of both MPO- and PR3- ANCAs pre-date the onset of symptoms of AAV by up to nine years,” the researchers wrote.

“The present study further supports the hypothesis of an inflammatory pathogenic process starting years before symptom onset in AAV and suggests that activation of the complement system is an early event in AAV pathogenesis,” they wrote.

Comparing complement protein levels by ANCA subtype showed that patients who were later diagnosed with MPO-positive ANCA had significantly higher C2, C5a, and C4b in their serum than those with MPO-negative ANCA, irrespective of when their symptoms started. However, the levels of complement proteins were similar in individuals with PR3 positive and PR3 negative ANCA. The levels of C2, C5a, and C4b also were significantly higher in patients with MPO-positive ANCA than in those with PR3-positive ANCA.

“In our study, specifically MPO-ANCA+ presymptomatic individuals showed increased levels in three complement biomarkers compared with MPO-ANCA- individuals. These results … suggest that the contribution of complement activation to the inflammatory cascade in presymptomatic individuals is larger in MPO-ANCA+ vasculitis than in PR3-ANCA+ vasculitis,” they wrote.

C5 and C5a serum levels were significantly higher in individuals later diagnosed with microscopic polyangiitis than controls. But the levels of all complement proteins investigated (C2, C5, C5a, and 4b) were similar in patients later diagnosed with granulomatosis polyangiitis than those in the control group.

Interestingly, while the levels of complement proteins were similar between the control group and patients whose first symptoms occurred in the lungs, kidneys, nerves, ear, nose, and throat, individuals who had kidney symptoms first had higher levels of C5 proteins.

Despite including just 64 participants, the researchers note that the study is the largest so far to measure complement levels before the start of symptoms in AAV. The study supports existing evidence that complement activation plays a role in AAV and sheds more light on how early it is activated.

“Activation of the complement system is an early event in the pathogenesis of AAV and is mainly associated with MPO-ANCA+ AAV and with microscopic polyangiitis,” the researchers concluded.