Anti-Interferon Autoantibodies Could Protect Against Diabetes

In a new study, researchers found that patients with a rare autoimmune disorder can produce antibodies that could protect against type 1 diabetes.

The study, published by Cell, included blood samples from 81 patients with autoimmune polyendocrine syndrome 1 (APECED) who have defects in the autoimmune regulator gene. This defective gene can no longer regulate the purging of autoreactive T cells that can react to the body’s proteins.

“APECED is a rare and poorly understood autoimmune disease. The defect in the autoimmune regulator gene should put APECED patients at severe risk of developing myriad autoimmune diseases, including type 1 diabetes, multiple sclerosis, lupus and rheumatoid arthritis in which an immune system that has not been purged of autoreactive cells attacks vital organs. Yet it's very unusual -- possibly unprecedented -- for APECED patients to develop multiple sclerosis or lupus, and most do not develop type 1 diabetes,” said senior author of the study Adrian Hayday, MA, PhD, F Med Sci. “So why don't they get these diseases? We wondered whether we could find out a lot more from these patients about basic human immunology and how their immune systems might be keeping these diseases at bay.”

According to the study, researchers found that greater T cell auto-reactivity in these patients increased B cell auto-reactivity. These autoreactive B cells then created autoantibodies that target proteins, such as interferons and interleukins, known to cause inflammation.

Each patient had approximately 100 different autoantibodies, and all patients together had thousands of them.

“This is very significant because antibodies make up one of the largest sectors of the pharmaceutical market, and one of the great quests in the pharmaceutical industry is to be able to routinely generate antibodies against human proteins implicated in diseases,” Dr Hayday said. “Rather than committing immense resources and expense to drug discovery, which is at best a very uncertain path, the findings suggest a route to drug recovery, in which naturally arising highly efficacious autoantibodies can be isolated from patients whose clinical information guides us as to the diseases most likely to benefit from those antibodies.”

Researchers then tested the autoantibodies in mouse models of psoriasis and found that the autoantibodies from APECED patients could stop the pathology of psoriasis.

“After establishing the antibodies could protect mice from a form of psoriasis, there came the realization that perhaps the antibodies were actively limiting disease in the APECED patients themselves,” Dr Hayday said. “Perhaps this was why the patients were arguably not so ill as they might have been expected to be.”

The researchers also discovered that these patients produce glutamic acid decarboxylase autoantibody (GAD), a biomarker for type 1 diabetes, but only 10 to 20% of patients with APECED develop diabetes, according to the study. Blood samples from 8 patients with APECED and type 1 diabetes were gathered as well as samples from 13 patients with APECED that had the GAD autoantibodies but did not have diabetes.

They discovered that patients who did not have diabetes created autoantibodies that inhibited the activity of interferon-alpha produced by immune cells and may cause inflammation, according to the study. However, these autoantibodies were not found in patients with diabetes.

The researchers believe that these autoantibodies could inhibiting interferon-alpha activity, which has been suggested to be linked to type 2 diabetes.

“Such striking correlations with type 1 diabetes were not evident for any other naturally arising anti-interleukin or anti-interferon antibodies, providing perhaps the strongest evidence yet in humans that interferon-alpha may contribute critically to the natural progression of type 1 diabetes,” Dr Hayday concluded. “This study provides correlational evidence for active anti-interferon antibodies providing protection from type 1 diabetes, but more research is needed to prove causation in humans. These findings give a firm foundation for exploring the potentials of autoantibodies from APECED patients to ameliorate type 1 diabetes and other important autoimmune diseases that are rarely, if ever, present in APECED patients.”