Unpoking the bear

The human immune system makes a powerful defender, using its arsenal of antibodies to identify and attack foreign pathogens. But such antibodies have a potential dark side: auto-antibodies can begin to attack, not invading microbes, but healthy tissues. Such attacks result in inflammation in whichever organs or body systems fall victim, and can therefore present clinically in multiple ways. A good example is coeliac disease, which is associated with a wide variety of symptoms, often leading to delays in diagnosis.

How and why does our immune system attack us? Once we can fully answer that question we will be well on our way to eradicating a large source of human misery, because the health conditions (known as autoimmune diseases) arising from such misdirected immune activity are legion. Repeated observation suggests a potential trigger for such conditions relates to microbial infection: imagining our immune system as an obedient bear, sustained infection might be the equivalent of repeatedly poking that bear with a stick. In reality, as in metaphor, this is a scenario with a range of outcomes. For example, after observing that COVID-19 infection appeared to trigger multi-system inflammatory syndromes in a rare cohort of children, recent unhappy research into post-infection autoimmunity has shown SARS-COV-2 did not discriminate by age. Other pathogens have been found to inflict similar immune system damage, as shown by the known association between lyme disease and autoimmunity and the strengthening link between multiple sclerosis and the Epstein-Barr virus.

Whatever the inciting incident might be, once the anti-pattern is in place, what can we do with an immune system fixated on the wrong targets? Traditionally, such diseases have had no cure, although lifestyle interventions, such as the avoidance of gluten in coeliac disease, can help in the management of symptoms. Sadly, many auto-immune diseases are less amenable to lifestyle intervention than coeliac disease, and certain interventions, such as exercise, may be less tractable where sufferers have restricted levels of mobility.

However, following success with immunotherapy techniques such as with the engineering of immune cells to target cancer, autoimmune diseases are now in the research spotlight. Consequently, an immune-engineering approach has recently been used successfully with Lupus (SLE), in a small trial that left five young patients with life-threatening disease in remission and medication free at the end of the treatment. All had benefited from a transfusion of chimeric antigen receptor (CAR-T) cells, engineered to attack the immune B-cells responsible for creating the auto-antibodies underpinning the disease. Studies with mice suggest a role for CAR-T in developing treatments for both multiple-sclerosis and rheumatoid arthritis. Of course, the fact CAR-T treatments to date have been manufactured bespoke to each patient has made them both expensive and slow to generate. Work is therefore ongoing to create allogenic CAR-T treatments from external donors, available in advance and at hopefully considerably lower costs. If risks around graft-to-host disease can be mitigated, this could signal a new era of treatments for immune systems gone wrong.