When Immunity Misfires - What Autoimmunity Can Teach Us About Better Therapies

Autoimmune responses are often seen as rare anomalies. An unfortunate failure of immune tolerance. But new data suggests that’s only part of the story. In a recent CDI Labs webinar, Chief Scientific Officer Dr. Tyler Hulett challenged the traditional narrative, suggesting that autoantibodies are not only common, but can provide insights into immune health, facilitate new diagnostic approaches, and drive next-generation therapies. 

Drawing from decades of high-density protein microarray data and phage display libraries, Dr. Hulett showed that nearly everyone harbours extensive, stable, and unique autoantibody signatures. Using CDI Labs’ HuProt^TM array, profiling tens of thousands of samples, the data is clear: almost every individual exhibits 100–400 autoantibody responses, many of which remain stable for years, even decades. Most of these so-called “natural autoantibodies” likely play benign or even beneficial roles. But, as Dr. Hulett pointed out, certain autoantibodies that bind to extracellular or signalling proteins can contribute to conditions that would not typically be regarded as autoimmune mediated.

The Impact of Immune Misfires

These “immune misfires” can underlie previously mysterious conditions. For instance, recent research found that an autoantibody targeting the vitamin B12 receptor (transcobalamin/CD320) can block B12 import into cells, resulting in CNS symptoms similar to classic B12 deficiency, despite normal serum levels. Nearly 5% of the U.S. population could show elements of this response. Other case studies link autoantibody signatures to post-infectious syndromes like long COVID or neurological impairment, illuminating over-arching mechanisms for chronic disease that have long evaded standard clinical diagnostics.

Why does this happen?  It’s unfortunately not purely a series of accidents. The immune system is continually recalibrating what it recognizes as self, especially as cells age, mutate, and undergo environmental stress. Molecular mimicry, where infectious agents mimic self-proteins, further complicates matters, potentially triggering or expanding autoantibody repertoires. Just finding an autoantibody is only the first step. As Dr. Hulett emphasized, understanding function is key for translating insights into drug development. Platforms like whole-proteome phage display immunoprecipitation sequencing (PhIP-Seq), allow for high-resolution mapping of these interactions and rapid screening for elite responder antibodies that behave like naturally evolved drugs.

The Future of Immunotherapies

Our own bodies may therefore be the source of next-generation immunotherapies, provided we have the tools to identify and interrogate these responses. Paul Ehrlich’s “horror autotoxicus” once proclaimed that true autoimmunity was impossibly rare. Today, the science has evolved. Autoantibody signatures are as individual as fingerprints, and some immune misfires may point the way to new diagnostics, a deeper understanding of chronic disease, and groundbreaking therapies.

Explore how CDI Labs is helping redefining autoimmunity. Watch the full webinar here

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