Variants in alternative complement genes linked to AAV, kidney damage

Components of alternative pathway may be therapeutic target in AAV: Study

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Common variants in genes that encode proteins of the alternative complement pathway, a part of the immune system, may raise the risk of ANCA-associated vasculitis (AAV) and severe disease-related kidney damage, a study shows.

Researchers also found a link between worse disease outcomes and AAV patients who had a more active alternative complement pathway at diagnosis. A protein called FHR1, which activates this pathway, was associated with more severe kidney involvement, suggesting this protein may be a therapeutic target in AAV.

“The clear involvement of complement in AAV pathogenesis [disease mechanisms] makes targeting complement components an attractive therapeutic approach,” researchers wrote.

The study, “Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis,” was published in Kidney International.

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In AAV, the production of self-reactive antibodies called ANCAs results in inflammation and damage to small blood vessels. While this can happen anywhere in the body, causing a wide range of symptoms, the kidneys are often affected.

The immune complement system is a network of proteins that must be tightly regulated so they target only foreign or potentially damaging material and do not damage the body’s healthy cells.

Excessive activation of complement cascade thought to contribute to AAV

Excessive activation of the complement cascade, and particularly its alternative pathway, is thought to contribute to AAV. Unlike the other two complement pathways, the alternative pathway “is always in ‘ready to fire’ status; therefore, regulatory mechanisms are crucial to prevent uncontrolled complement activation,” the researchers wrote.

“Although the involvement of complement in AAV pathogenesis is unquestionable, the exact molecular mechanisms leading to dysregulation of the AP [alternative pathway] are unclear,” the researchers added.

Now, a team of researchers in Spain looked for common genetic variants known to influence alternative pathway activity and measured the blood levels of complement proteins in adults with a diagnosis of AAV and kidney involvement.

Genetic testing was first performed in a group of 102 patients (60 men and 42 women) — 54 of whom had active disease and 48 were in remission — and a matched control group of 389 people who did not have AAV.

Results showed AAV patients had a 41% lower chance of carrying CFB32Q/W, a variant of the gene encoding complement factor B (CFB), which is part of the alternative pathway activation cascade, relative to the controls.

This finding was confirmed in 100 additional AAV adult patients with kidney involvement (validation group), suggesting the CFB32Q/W variant may be “a protective factor for the development of AAV,” the researchers wrote.

No significant differences between patients and controls were observed for variants in other evaluated genes, including CFH, C3, and MPC.

The clear involvement of complement in AAV pathogenesis [disease mechanisms] makes targeting complement components an attractive therapeutic approach.

CFH-H1 variant linked to more severe kidney disease

When focusing in AAV patients alone, the team found a variant within the CFH gene cluster, called CFH-H1, was linked to more severe kidney disease. CFH encodes for complement factor H (CFH), a protein that prevents the alternative pathway from being activated when it’s not needed.

In turn, the CFH-H2 variant and a deletion in CFHR3/CFHR1, two genes coding for proteins of the CFH family, were associated with milder forms of kidney disease in AAV patients.

“We show, for the first time, to our knowledge, that genetic variants in complement components of the AP associate with protection to develop AAV (CFB32Q/W) and with severe forms of the disease (CFH-H1CFH-H2, and [CFHR3/1 deletion]),” the researchers wrote.

In the blood, the median levels of CFH, CFB, and two proteins involved in alternative pathway activation, called C3 and properdin, were significantly lower in patients with active disease than in those in remission or in healthy controls.

Lower levels of pathway activators may indicate their exhaustion due to their use for alternative pathway activation.

Blood levels of soluble C5b-9, a marker of complement activation, were significantly higher in patients with active disease.

In the urine, high levels of soluble C5b-9 were linked to signs of more severe kidney disease in active AAV patients, suggesting it may be a marker of kidney complement overactivation and damage, and a better one than soluble C5b-9 levels in blood.

Blood CFH, C3, and properdin levels were also significantly reduced with increased kidney disease severity, “suggesting that there is more complement activation in the severe forms of the disease,” the researchers wrote.

FHR1, a protein similar in structure to CFH but works to activate the complement system, was also found at significantly higher levels in the blood of patients with active disease relative to those in remission and the controls.

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FHR1 levels significantly higher in patients with more severe kidney disease

Levels of FHR1 were significantly higher in patients with more severe kidney disease than in those with less severe kidney disease.

“Altogether, these data provide evidence of complement system activation through the AP” in AAV, the team wrote, adding “the balance between the AP regulator [CFH] and the FHRs may be compromised during the acute phase of the disease.”

Further analyses showed FHR1 levels were mostly determined by the presence of the CFHR3/CFHR1 deletion, being null in patients with two copies of the deletion, intermediate in those with one copy, and high in those without the deletion (0 vs. 130 vs. 250 micrograms/mL).

Blood CFH levels were also influenced by the CFHR3/CFHR1 deletion, being significantly higher in patients with two copies of the deletion compared with those with only one copy and those without it (261 vs. 216 vs. 199 micrograms/mL).

Patients who did not achieve disease remission over one year of follow-up had significantly lower levels of CFH, CFB, and properdin at diagnosis than those achieving remission. This suggests that “a higher degree of AP activation at disease onset associates with a worse disease outcome,” the team wrote.

“In addition, C3, [soluble C5b-9], and FHR-1 were useful markers of disease activity as their levels normalized over time in patients achieving remission,” the researchers added.

These findings highlight that suppressing components of the alternative pathway, such as CFB and FHR-1, may be a potential therapeutic approach in AAV, the researchers wrote. They noted several AP-targeting medications are already approved or in development for other conditions associated with complement overactivation.