Protein Levels in Blood May Mark AAV Years Before Symptoms Do

Changes in immune-related protein profiles seen up to 5 years before onset

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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The blood levels of several immune-related proteins are significantly altered in people with ANCA-associated vasculitis (AAV) up to five years before they develop symptoms when compared with matched healthy people, a study showed.

Changes in these protein levels were found to be involved in inflammatory and metabolic pathways, and different protein profiles were linked to proteinase 3 (PR3)- and to myeloperoxidase (MPO)-AAV cases.

These findings support the existence of different underlying mechanisms of AAV based on the specific types of disease-causing antibodies.

“To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV,” the researchers wrote. “These findings set the stage for further research into underlying cellular and molecular mechanisms in AAV [development] and the diversification into the PR3-ANCA and MPO-ANCA [subtype-features].”

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The study, “Protein profiling in pre-symptomatic individuals separates MPO- ANCA and PR3-ANCA vasculitides,” was published in Arthritis & Rheumatology

AAV is marked by an erroneous attack by the immune system against immune cells called neutrophils, leading to inflammation and damage to small blood vessels in diverse organs and tissues.

The most common disease-causing anti-neutrophilic cytoplasmic autoantibodies, or ANCAs, target one of two proteins present at the surface of neutrophils: PR3 and MPO.

About half of people with microscopic polyangiitis (MPA), the most common AAV subtype, carry antibodies against MPO, while 75% to 90% of those with granulomatosis with polyangiitis (GPA), another disease subtype, are positive for anti-PR3 ANCAs.

The nature of these antibodies might represent a feature leading to the development of each AAV type.

To know more about the early immune mechanisms behind AAV and its most common disease-causing ANCAs, a team of researchers in Sweden analyzed the blood levels of immune-related proteins in AAV patients before symptom development — a presymptomatic phase — and in people without the disease.

They collected data from the Swedish National Patient Register that included blood samples from 85 adults who were later diagnosed with AAV — 65 with GPA, 16 with MPA, and four as eosinophilic GPA. For each patient, two age-, sex-, and sampling date-matched adults were identified within the same database, totaling 163 controls.

Out of the 73 proteins analyzed, 20 showed the most robust differences between presymptomatic AAV cases and controls. Eight of them reached statistical significance.

In addition, 18 of these 20 proteins were members of at least one of the 11 signaling pathways identified as significantly different between patients and healthy adults, including pathways involved in metabolism and inflammation. Of note, a metabolic pathway refers to the biochemical reaction to a substance that changes it to meet a need for proper bodily function, like the pathway conversion of glucose in digested food to produce cellular energy.

When the researchers took a similar approach in analyzing blood samples of other individuals — 48 presymptomatic patients and 96 controls — they found that only seven of the 20 proteins showed similar trends.

Although the individual comparison of the proteins did not entirely match, findings were replicated for all 11 pathways.

“In other words, the [disease-associated] process appeared more robust at the pathway level than at the level of individual proteins,” the researchers wrote.

“A close link between metabolism and inflammation has been described extensively for several autoimmune diseases, including both rheumatoid arthritis (RA) and AAV, making it plausible that metabolic alterations could contribute to AAV susceptibility,” they added.

Levels of 4 protein significantly higher in patients years before symptoms

In addition, the levels of four proteins were significantly higher in presymptomatic patients, compared with controls, up to five years before symptom onset.

Within the last year before the development of symptoms, nine proteins had significantly increased levels in the AAV group relative to the control samples.

Four of these proteins (CCL20, CCL23, HGF, and VEGF-A) were at increased levels at both five- and one-year time points.

Moreover, “17 of the 73 originally analyzed proteins were significantly associated with ANCA positivity,” the team wrote.

Six of these proteins (CSF-1, TNFSF14, MCP-1, urokinase, FGF-19, and CD244) were significantly linked to MPO-ANCA, while another seven (CCL25, CASP-8, TRANCE, CCL23, HGF, CSF-1, CD40) were associated with PR3-ANCA.

These findings suggest that “a panel of biomarkers involved in pathways, rather than few separate biomarkers, more preferentially identify the disease onset and the future scenario in AAV,” the researchers wrote.

In addition, “we believe that we have, at least to some extent, identified molecular fingerprints for PR3- and MPO-ANCA vasculitis,” they added.

“Because this is an exploratory analysis of pre-symptomatic markers, further studies are encouraged that target the most interesting proteins and pathway analyses identified here,” the team concluded.