Anti-cytokine autoantibodies linked to susceptibility, bacterial load, and outcome in pneumococcal meningitis: prospective cohort studies in CNS infections, Alzheimer's disease, and Parkinson's disease

Background: Streptococcus pneumoniae is a nasopharyngeal coloniser but can also cause life-threatening invasive disease such as meningitis. The role of anti-cytokine autoantibodies as mechanism of acquired immunomodulation and immunodeficiency has recently been recognised. Methods: This study investigates the presence and potential role of anti-cytokine autoantibodies in central nervous system infections by analysing 14 anti-cytokine autoantibodies in the cerebrospinal fluid of 623 patients with pneumococcal meningitis, 86 with meningococcal meningitis, 56 with viral meningoencephalitis, 206 with Alzheimer's disease, 61 with Parkinson's disease, and 264 healthy controls from prospective cohort studies. Findings: Anti-cytokine autoantibodies were detected at significantly higher frequencies in patients with pneumococcal meningitis than in uninfected controls, particularly against IFN-γ (11% vs. 1%) and IFN-ω (11% vs. 0%), IL-1α (5% vs. 0%), IL-6 (12% vs. 1%), and IL-17A (9% vs. 1%) and IL-17F (10% vs. 0%), suggesting a role in disease susceptibility. In meningococcal meningitis, antibodies targeting IFN-γ (10%), IL-1α (7%), and IL-17F (7%) were associated with infection, while antibodies against IFN-γ were more prevalent in viral meningoencephalitis (12%). In Alzheimer's and Parkinson's disease, prevalence of autoantibodies was similar to controls. In pneumococcal meningitis, anti-IL-17A antibodies correlated with bacterial loads, and antibodies against IL-17A and IFN-ω were independently associated with death (adjusted odds ratios 3.06 [95% CI 1.35–6.92; p = 0.007]; 2.15 [95% CI 1.06–4.34; p = 0.033]). Only one of the autoantibodies against IFN-ω and none of the autoantibodies against IL-17A were shown to be neutralising. Interpretation: Anti-cytokine autoantibodies are present in the CSF of patients with central nervous system infections, particularly in pneumococcal meningitis. The observed correlation between these autoantibodies and death, as well as elevated bacterial loads in CSF, suggest that they might actively shape disease progression; however, further research is needed to establish a causal role. Funding: Nederlandse organisatie voor Wetenschappelijk Onderzoek, ItsME Foundation, European Research Council, Dutch Parkinson Foundation, Neuroscience Campus Amsterdam, ZonMW, Van Alkemade fonds, Stichting Woelse Waard, Hersenstichting and AbbVie.