Lessons from TNF-α Inhibitor-Induced Alopecia Areata: Does TNF-α Operate as a Hair Follicle Immune Privilege Guardian under Inflammatory Conditions?

The inhibition of tumor necrosis factor-α (TNF-α) signaling with inhibitors (TNFi) like infliximab, adalimumab, or etanercept has become a staple of dermatological and rheumatological therapy. Intriguingly, a sizeable minority of patients under TNFi therapy develop alopecia areata (AA), the most common inflammatory hair loss disease, at a higher prevalence than the general population. This appears paradoxical, since the pro-inflammatory Th1 cytokine TNF-α, inhibits hair follicle (HF) growth, but encourages one to reconsider the as yet under-investigated roles of TNF-α in human HF physiology. Because AA only affects HFs whose immune privilege (IP) has collapsed, the occurrence of AA under TNFi therapy raises the question if inhibiting TNF-a signaling could be detrimental to the maintenance of HF IP. Here, we probe this question by exploring lesser-known aspects of TNF-α biology, notably within the context of skin inflammation. We hypothesize that, under inflammatory conditions, TNF-α exerts underappreciated functions as a HF IP guardian, e.g., by stimulating perifollicular immunoinhibitory cells and suppressing IFN-α secretion. Thus, TNFi may weaken HF IP and facilitate the onset of AA. We delineate how this provocative hypothesis can be tested experimentally, and why it is both biologically and clinically important to do so.