Could influenza trigger a transient stiff-person syndrome mimic? Exploring molecular mimicry between hemagglutinin and GAD65

To the Editor, Stiff person syndrome (SPS) is a rare autoimmune neurological disorder that often presents with progressive, painful muscle spasms, stiffness in the limbs and axial skeleton, and loss of balance due to autoantibodies against a key enzyme, glutamic acid decarboxylase-65 (GAD65), which is used in the synthesis of gamma-aminobutyric acid, the principal inhibitory neurotransmitter responsible for muscle relaxation. The estimated occurrence of SPS is 1–2 cases per million people1. Recently, the increasing recognition of post-viral autoimmune disorders has brought solid distinctions between a temporary autoimmune condition and a permanent autoimmune disease. Additionally, it has been documented that SPS symptoms can mimic those secondary to hypothyroidism2. We hypothesize that it is possible SPS symptoms can also mimic those in patients with the influenza virus. Molecular mimicry is a well-understood mechanism in post-infectious autoimmune response, in which structural resemblance between pathogenic antigens and self-proteins induces immune cross-reactivity. Anti-GAD65 is a known autoantigen not only found in patients with SPS but also in type 1 diabetes mellitus, suggesting that immune tolerance to this protein is particularly susceptible to disruption3. Hemagglutinin (HA) is a surface glycoprotein present on the outer envelope of the influenza virus. Influenza virus strains, indicating frequent antigenic divergence from prior seasonal strains, produce new HA forms, suggesting that it is the most variable part of the influenza virus4. Recent literature also suggests that human influenza viruses are interchangeable with the help of HA based on the organism they are in5. This mechanism raises the possibility that new HA variants could share linear or structural epitopes with regions of GAD65. Failure to recognize a transient SPS-mimic carries significant drawbacks, and patients can be subjected to prolonged immunosuppression. Current evidence demonstrates that using long-term immunosuppressants in patients with SPS-related stiffness is not beneficial. Although persistent GAD65 autoimmunity, high-dose intravenous immunoglobulins enhanced sensitivity scores and reduced stiffness distribution (P = 0.01 and P = 0.03, respectively) in a pivotal randomized, double-blinded crossover trial of 16 SPS patients, 11 patients reported better clinical outcomes; however, these clinical benefits wore off within 6–12 weeks, and symptoms reemerged during the placebo period6. In a larger cohort of 56 patients with anti-GAD65 neurological syndromes, immunotherapy showed clinical benefits in 75% of the treated cases; still, no case reached total remission, and relapses were common during tapering, showing the inadequate efficacy and chronic burden of current SPS therapies7. However, various clinical and methodological weaknesses must be overcome before the suggested post-influenza SPS-mimic can be confidently identified and managed in clinics. SPS spectrum illnesses are often incorrectly diagnosed as functional, orthopedic, or major psychiatric illnesses, which hinders the diagnosis for several years, making it challenging to recognize and investigate an early post-viral SPS mimic8. At the molecular level, in silico homology between influenza HA and GAD65 is hindered by ongoing challenges of conformational B-cell epitope prediction; existing computational models do not perform better than random chance, and even consensus methods provide only minor improvements in accuracy9. Furthermore, the lack of any biomarkers that distinguish SPS from temporary post-viral SPS mimics at initial presentation complicates early therapy decisions10. To summarize, a transient post-influenza SPS mimic, different from typical progressive SPS, could significantly improve how early SPS-like symptoms are managed. Mixing post-viral SPS-like disease and lifelong SPS may result in years of unwanted immunosuppression with minimal effects. Establishing multicenter cohorts with viral sequencing, epitope mapping, and follow-up is mandatory for identifying individuals with self-limited SPS mimics. Developing specific biomarkers that can differentiate between SPS mimics and persistent SPS could enable physicians to use targeted immunotherapy in post-viral SPS mimics.