Increased Cell-Mediated Immune Responses in Patients with Recurrent Herpes Simplex Virus Type 2 Meningitis

Abstract

The clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV-seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV-2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis.

Frequent Recurrences of Genital Herpes Are Associated with Enhanced Systemic HSV-Specific T Cell Response

“…Only scarce data are available on systemic HSV-specific T cell-mediated responses in the blood of patients with recurrent GH. A study of CD4+ T cell-mediated responses after ex vivo stimulation with HSV antigens did not demonstrate significant differences among patients with recurrent GH-and HSV-seropositive healthy controls [6]. In this study, the only significant difference in HSV-specific peripheral CD4+ T cell response was found between recurrent GH and HSV meningitis.…”

Herpes simplex virus specific T cell response in a cohort with primary genital infection correlates inversely with frequency of subsequent recurrences

“…In agreement with this, our earlier studies of the immune responses in patients with recurrent genital HSV-2 infection and HSV-2 meningitis clearly showed a strong HSV-specific T cell reactivity and a higher innate function compared with healthy controls. The cytokines IL-12, TNF-α and IL-10 were particularly elevated in the patients with meningitis, suggesting that repeated exposures of HSV to the adaptive immune system provide a response with a Th1 profile 26. It would be interesting to combine a study like ours with monitoring HSV shedding to further illuminate the nature of the specific T cell responses and its significance for controlling HSV reactivation and viral shedding as well as the development of HSV-induced lesions.…”

Recurrent Herpes Simplex Virus 2 Lymphocytic Meningitis in Patient with IgG Subclass 2 Deficiency

“…Franzen-Röhl et al (6) showed that, contrary to their hypothesis, patients with recurrent HSV-2 meningitis have a stronger HSV-specific cell-mediated immune response compared with patients with recurrent genital HSV-2 infections and healthy seropositive persons. RBLM patients were found to have increased expression of Toll-like receptors (TLRs) and increased interferon (IFN)-α and specific T cell responses, suggesting that the proinflammatory state leads to a more severe clinical disease because of destruction of the blood-brain barrier, tissue remodeling, and vascular leakage (6). IgG1 and IgG3, which largely act against protein components such as tetanus and diphtheria toxin, mediate antibody-dependent cellular cytotoxicity important for clearance of bacterial and viral infections.…”