Aberrant Humoral Immune Responses in Neurosyphilis: CXCL13/CXCR5 Play a Pivotal Role for B-Cell Recruitment to the Cerebrospinal Fluid.

Background: Previous studies documented that humoral immune responses participated in neurological damage in neurosyphilis patients. However, the mechanisms that trigger and maintain humoral immunity involved in neurosyphilis remain unknown. Methods: Using flow cytometry, expression of B cells was measured in neurosyphilis and non-neurosyphilis. Expression of immunoglobulin indices and chemokine ligand CXCL13 was detected by enzyme-linked immunosorbent assay. The migration and inhibition assays were evaluated by modified chamber assays. The presence of CXCL13+ cells, cluster of differentiation (CD)20+ B cells, CD3+ T cells, CD138+ plasma cells and CD35+ follicular dendritic cells was studied by immunohistochemistry. Results: Enrichment of B cells was observed and activated in the cerebrospinal fluid (CSF) of neurosyphilis patients. Immunoglobulin indices were increased and associated with the progress to neurosyphilis. High expression of CSF CXCL13 mediated B cell migration both in vitro and in vivo. There was a positive correlation among the CSF B cells, immunoglobulin indices, and CSF CXCL13 levels. Ectopic germinal centers (EGCs), important structures for humoral immunity, were observed in the intracranial syphilitic gumma. Conclusions: CXCL13/CXCR5 mediated the aggregation of B cells, that directed the aberrant humoral immune responses via the formation of EGCs, which suggests a molecular mechanism of neurological damage in neurosyphilis.

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

BACKGROUND: Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. METHODOLOGY/PRINCIPAL FINDINGS: Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. CONCLUSIONS/SIGNIFICANCE: Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin.