Neurosyphilis: from infection to autoinflammation?

Dear Editor,

The interesting paper of Hu et al. ¹ on the role of CXCL13 in the diagnosis of neurosyphilis prompted us to make some considerations about its pathogenesis.

Penicillin, although effective in clearing the early manifestations of syphilis, may be unable to prevent long-term complications such as neurosyphilis, even if initiated promptly and independent of the dosage. ² Explanations may be that benzathine penicillin fails to provide treponemicidal levels in the central nervous system (CNS) and/or that neurosyphilis results from particularly neuroinvasive Treponema pallidum strains.

Indeed, sophisticated strategies may be used by treponemes to evade immune clearance and persist in the host: neuraminidase activity, hiding themselves from sialic acid of the host, the formation of a biofilm, the induction of σ-factors that, transcribing specific groups of response genes, can help to respond to harmful stimuli in the host environment, antigenic variations of membrane proteins, impaired antibody-mediated opsonization and adaptive phase variation acquired during human infection.^3,4 Furthermore, following antibiotic treatment, replicating treponemes might descend to a state where only proteins of the bacteria that remain detectable in the host tissue ⁵ are no longer affected by the antibiotic and can again replicate and revert to normal bacteria when antibiotics are withdrawn. ⁵ Other hypotheses, however, that involve autoimmune or autoinflammatory mechanism, can be made for explaining the neurological damage. Indeed, a strong specific immune response of the host, though not capable of eliminating all treponemes and eradicating the infection, plays a role in the resolution of primary lesions and in limiting the spreading of spirochetes in the organism. Most of the symptoms and tissue damage related to primary and secondary syphilis are due to activation of the host inflammatory and immune response against several T. pallidum lipoproteins. Likewise, such a mechanism may act in the CNS lesions. Furthermore, treponemal antigens, remnants of infection, may promote chronic inflammation in CNS through persistent T-cell stimulation, independent of the infection. Increased CSF levels of interferon-γ and interleukin-17A confirm the role of adaptive immunity in the inflammatory response associated with neurosyphilis. ⁶ Recently, evidence suggest a role of regulatory T cells (Tregs). Neurosyphilis patients have higher Treg numbers in peripheral blood compared to syphilis patients without neurological involvement, but had reduced numbers in CSF. ⁷ Given the crucial role of Tregs and their immunosuppressive cytokines, namely transforming growth factor β and interleukin-10, in modulating immune-mediated response and tissue damage, this finding suggests that in neurosyphilis patients the down regulation of the systemic immune response may promote disease progression towards neurological involvement and, conversely, the CNS damage may be due to an uncontrolled local host immune response. The elevation of CXCL13, a B-cell-attracting chemokine, in CSF of patients with neurosyphilis suggests an intrathecal synthesis of antibodies against persistent antigens. ⁸ Thus, B and T cells may cooperate and contribute in sustaining a CNS chronic inflammation. Therefore, an uncontrolled local production of antibodies by persistent antigenic stimulation due to survival of spirochetes or, most likely, from residues of bacteria in the form of protein, may contribute to the development of neuroinflammation.

In conclusion, T. pallidum may initiate and maintain chronic inflammation and tissue damage in neurosyphilis, independent of active infection.