ANCA Autoantibodies Produced in Healthy People, Study Shows

Healthy individuals also produce a type of self-reactive antibodies — termed IgM ANCA — present in people with ANCA-associated vasculitis (AAV), a study has found.

While low, the levels in healthy people are comparable with those in AAV patients whose disease is less active. The antibodies’ role is still uncertain, but they may play roles both in health and disease.

The study, “IgM ANCA in healthy individuals and in patients with ANCA-associated vasculitis,” was published in the journal Immunologic Research.

ANCA-associated vasculitis (AAV) is a type of autoimmune disease that causes small blood vessels to swell and inflame (vasculitis). It is caused by autoantibodies called ANCAs, or anti-neutrophilic cytoplasmic autoantibodies. These are self-reactive antibodies that target and attack a certain kind of white blood cells called neutrophils.

These ANCAs set off neutrophils to attack small vessel walls, causing inflammation and swelling. Usually people with AAV make autoantibodies belonging to a class of antibodies known as immunoglobulins G, termed IgG.

However, even people without AAV can temporarily develop IgG ANCAs during chronic infections — including bacterial endocarditis, or inflammation of the heart’s inner lining — or other bacterial, viral, or fungal infections.

The clinical significance of this is uncertain, even more because low-level and low-affinity IgG ANCAs also can be made by healthy people.

In fact, not all autoantibodies are associated with disease. Self-reactive antibodies are naturally present in healthy people and play important roles for a person’s innate immunity. That’s a more immediate and nonspecific part of the body’s immune defenses. Normally, however, these natural autoantibodies belong to another class of immunoglobulins, IgMs.

Although less common, some AAV patients also may carry IgM ANCAs — and some studies have linked this type of ANCAs to pulmonary bleeds and lung infections.

Building on this, researchers set out to see if IgM ANCAs may develop in healthy people and in those with AAV who have less active disease (remission). The scientists also studied how IgM ANCAs change with age, and if bacterial infections can affect their amounts.

For that, they tested blood (sera) from 45 healthy adults and 41 patients with AAV, looking for IgM ANCAs using different methods.

Results showed that both AAV patients in remission and healthy individuals were positive for IgM ANCAs, and both had comparable levels of these antibodies, which were low in both cases.

Further experiments confirmed that antibodies found in healthy people were true ANCAs as they specifically attached to neutrophils.

Similarly to AAV patients, healthy people were either positive to perinuclear (P-ANCA), or to cytoplasmic (C-ANCA) autoantibodies. P-ANCA attach to myeloperoxidase (MPO), while C-ANCA attach to proteinase 3 (PR3), two proteins found inside neutrophils.

By comparing ANCA levels relative to participants’ age, and looking at a small group of individuals whose blood was collected over 12 years, researchers also found that levels of IgM ANCA tended to decline with age.

To determine the impact of infections, researchers compared IgM ANCA levels in healthy individuals with non-AAV patients who had bacterial infections — 10 with bacterial endocarditis and nine with Staphylococcus aureus bloodstream infection (bacteremia), both potentially life-threatening infections.

In both scenarios, IgM ANCA levels did not appear to change with infection.

“We report the presence of low-level specific IgM ANCA in the sera of healthy individuals and in patients with ANCA-associated vasculitis. Bacterial infection did not affect the level of IgM ANCA in this small study,” the researchers said.

The findings support the hypothesis that IgM ANCAs are indeed part of the body’s natural set of autoantibodies. Several scientists believe natural IgM autoantibodies are important for keeping the immune system in check, and preventing autoimmune responses that damage the body’s own tissues.

For instance, IgM ANCAs may be important to avoid binding of harmful IgG ANCAs to neutrophils.

According to some studies, however, some IgM ANCAs may be related to disease, namely to lung bleeds in people with AAV. Thus, more research is needed to determine the origin, binding affinity, and target specificity of IgM ANCA in both health and in disease.