Controlling Our Immune System — 5

Ahealthy person’s immune system is tolerant, ignoring—not attacking—one’s own antigens and cells. That’s what needs to be restored in people suffering from autoimmune disorders. Multiple initiatives underway will, one way or another, benefit those who are already being treated for autoimmune conditions as well as those at high risk. Since current treatments are lifelong, not curative, and are blunt weapons for nonspecific immunosuppression, the cumulative risk for developing resistance and opportunistic infections is high. The economic burden of current autoimmune treatments accounts for six of the top twenty drugs by worldwide sales. Despite all that pharmacology, we have not had strategies to prevent autoimmune diseases like type 1 diabetes, lupus, multiple sclerosis, and rheumatoid arthritis. With multimodal AI of genomic data, biomarkers, and electronic health records, the ability to identify the high-risk group is becoming possible, building the foundation for prevention.

That all sounds encouraging, but the challenges to restoring durable tolerance without side effects are formidable. There are two different levels of immune tolerance in our body. Central tolerance is based in the thymus, where T cells differentiate and acquire their T cell receptor expression. There are processes of selection in the thymus to weed out cells that might attack one’s own tissues, but they’re not, by any means, foolproof. Thus, the need for a backup system—peripheral tolerance—referring to all the innate and adaptive immunity mechanisms to protect against self-reactive T cells. That includes deactivating these cells or turning them into Treg cells.

While it would be nice for there to be one magical (auto-) antigen that could fully explain an autoimmune disorder, that’s not the case. For one, we don’t even know a principal antigen underlying most autoimmune conditions, and there may be many, and they vary from one person to the next. Beyond that, there’s the phenomenon of “epitope spreading,” whereby more antigens appear on the T cell surface from further activation and differentiation over time. Antigen-specific therapy—dosing people with antigens—that are known to be associated with an autoimmune condition is tricky because that could paradoxically exacerbate the autoimmune response. But clever strategies are yielding very encouraging results.