MS Feedback Loops and Heterogeneity: Why Disease Course Varies

In "MS Feedback Loops and Heterogeneity: Why Disease Course Varies," our experts turn to why the same disease behaves so differently from one patient to the next.

Dr. Greenberg asks whether an immune network model explains how disease activity and progression coexist in one patient. Dr. Krieger says he has argued for a continuum for a long time. His topographical model of MS, the "leaky pool," holds that lesions in certain locations are more likely to cross the clinical threshold without compensation. Spinal cord lesions and atrophy represent the shallow end of the pool of reserve. He argues the field has focused on brain imaging and neglected the cord, because clinicians see only what they look at.

Dr. Krieger now views the immune processes that form lesions and erode reserve as potentiating each other in a feedback loop. Immune cells enter, activate microglia, and the inflammatory process feeds itself within the central nervous system. Interrupting that crosstalk, perhaps with co-stimulatory molecules, matters because progression cannot be stopped by targeting lesions alone and nothing yet rebuilds a damaged nervous system. He points to the interfaces at the leptomeninges, the periventricular regions, and the borders of lesions.

Dr. Greenberg then turns to variability, noting that the old notion of benign MS has largely fallen out of favor. Dr. Rosenthal says a network with so many players allows endless possibilities for dysfunction, compounded by genetic variation and environmental risk factors. One patient may lose the signals that support repair, another may show increased effector cell activity, and another may have predominantly B-cell activity. Such differences may shape trajectory, incomplete recovery from acute inflammation, and treatment response.

She links this heterogeneity to precision medicine. Dr. Greenberg adds that published work on sex, race, ethnicity, comorbid conditions, and genetics layers on further complexity, making the combinatorial math difficult. Even so, he says, a conceptual model still gives clinicians something to intervene on.

Up next, in "PIRA in MS: Recognizing Progression Independent of Relapse Activity," Dr. Singer defines a concept that has taken center stage in clinical trials.