Autoimmune Heterogeneity

Recent advances in genetics have deepened our understanding of the pathogenic mechanisms behind autoimmune and immune-mediated diseases. This has revealed both shared pathways and a considerable degree of heterogeneity between diseases.

If both Secukinumab (anti-IL17A) and Ustekinumab (anti-IL12/23) act on Th17 cells, albeit the former downstream while the latter upstream, why does the former possibly worsen Crohn’s while the latter succeed?

Various theories have been put forth:
1) Anti-IL17A is too narrow a downstream target, or the maintenance dose is inadequate to sufficiently suppress the Th17 axis. Blocking IL17F and IL22 in addition to IL17A may be more effective;
2) Excessive IL17A suppression leads to gut fungal overgrowth, which in turn triggers an inappropriate immune response resulting in Crohn’s. The Anti-Saccharomyces Cerevisiae Antibody (ASCA), strongly associated with Crohn’s, is after all, directed at a type of yeast;
3) Crohn’s is partly/mainly Th1 mediated, evidenced by granulomas formation; so IL12 inhibition helps. Anti-TNFs remain the mainstay of treatment.

This article explores the heterogeneity and complexity of immune-mediated diseases. As we increasingly adopt a more targeted approach to therapeutics (in contrast to the blunderbuss efficacy of corticosteroids), our as yet infantile understanding of pathogenic mechanisms becomes our major handicap.