Image credit: Schematic showing different autoantibodies (Y-shaped figures) attaching to the phage carrying their target protein. Different colours show which autoantibodies are specific for which phages. Image credit: Sara Vazquez (CC BY 4.0)
The immune system uses antibodies to fight microbes that cause disease. White blood cells pump antibodies into the bloodstream, and these antibodies latch onto bacteria and viruses, targeting them for destruction. But sometimes, the immune system gets it wrong. In autoimmune diseases, white blood cells mistakenly make antibodies that target the body's own tissues. Detecting these 'autoantibodies' in the blood can help doctors to diagnose autoimmune diseases. But the identities and targets of many autoantibodies remain unknown.
In one rare disease, called autoimmune polyendocrine syndrome type 1 (APS-1), a faulty gene makes the immune system much more likely to make autoantibodies. People with this disease can develop an autoimmune response against many different healthy organs. Although APS-1 is rare, some of the autoantibodies made by individuals with the disease are the same as the ones in more common autoimmune diseases, like type 1 diabetes. Therefore, investigating the other autoantibodies produced by individuals with APS-1 could reveal the autoantibodies driving other autoimmune diseases.
Autoantibodies bind to specific regions of healthy proteins, and one way to identify them is to use hundreds of thousands of tiny viruses in a technique called proteome-wide programmable phage-display, or PhIP-Seq. Each phage carries one type of protein segment. When mixed with blood serum from a patient, the autoantibodies stick to the phages that carry the target proteins for that autoantibody. These complexes can be isolated using biochemical techniques. Sequencing the genes of these phages then reveals the identity of the autoantibodies’ targets.
Using this technique, Vazquez et al successfully pulled 23 known autoantibodies from the serum of patients with APS-1. Then, experiments to search for new targets began. This revealed many new autoantibodies, targeting proteins found only in specific tissues. They included one that targets a protein found on cells in the gut, and another that targets a protein found on egg cells in the ovaries. Matching the PhIP-Seq data to patient symptoms confirmed that these new antibodies correlate with the features of specific autoimmune diseases. For example, patients with antibodies that targeted the gut protein were more likely to have gut symptoms, while patients with antibodies that targeted the egg cell protein were more likely to have problems with their ovaries.
Further investigations using PhIP-Seq could reveal the identities of even more autoantibodies. This might pave the way for new antibody tests to diagnose autoimmune diseases and identify tissues at risk of damage. This could be useful not only for people with APS-1, but also for more common autoimmune diseases that target the same organs.
