(6) A patient with severe disease (a virus infection) has no functional IL2 protein. DNA sequencing shows the patient has a mutant IL2 sequence. Mutant IL2 DNA:


Briefly explain why this patient does not synthesize IL2 protein, resulting in a compromised immune response to the virus:

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We have reported previously that ocular infection of different strains of mice with recombinant herpes simplex virus 1 (HSV-1) constitutively expressing interleukin-2 (IL-2) provokes central nervous system (CNS) demyelination and optic neuropathy, as determined by changes in visual evoked cortical potentials and pathological changes in the optic nerve and CNS, whereas recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 do not induce this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicits this pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic minipumps or injection of mice with recombinant IL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data, indicating that a single mutation at position T27A in IL-2 completely blocks the HSV-1-induced pathology. This study shows a novel model of autoimmunity in which viral infection and enhanced IL-2 cause CNS demyelination.

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INTRODUCTION

Several lines of evidence implicate interleukin-2 (IL-2) in the pathology of multiple sclerosis (MS) (1–4). Patients with MS have elevated levels of IL-2 in their sera and cerebrospinal fluid (CSF) (1–4). The soluble IL-2 receptor (sIL-2R) is also elevated in the sera and CSF of patients with MS (3, 5–10). These clinical findings of elevated IL-2 levels (and lower than normal IL-4 levels) in the sera of MS patients suggest a possible link between IL-2 and the onset of MS. Furthermore, supernatants harvested from T lymphocytes of MS patients cause damage to myelin and glial cells in vitro (11, 12), suggesting that the MS T lymphocytes produce demyelination factors and are activated in vivo.

In order to investigate the role of cytokines in demyelination in a viral model of MS, we had constructed a panel of recombinant herpes simplex virus 1 (HSV-1) isolates that constitutively express murine cytokines, including IL-2 (13), IL-4, gamma interferon (IFN-γ), IL-12p35, or IL-12p40 (14–16). Using these viruses, we have shown that infection of different strains of mice with a recombinant HSV-1 strain constitutively expressing IL-2 (HSV–IL-2), but not HSV–IL-4, HSV–IFN-γ, HSV–IL-12p35, or HSV–IL-12p40, results in demyelination of the optic nerves (ONs), the spinal cords (SCs), and the brains of the infected mice, as determined by histologic examination of tissues obtained at necropsy (17, 18). In addition, the HSV–IL-2-infected mice developed optic neuropathy, as determined by changes in the visual evoked cortical potentials (VECPs) (18). Using knockout mice, depletion, and transfer studies, we found that both CD8+ and CD4+ T cells contributed to HSV–IL-2-induced central nervous system (CNS) demyelination, with CD8+ T cells being the primary inducers (19). We have also found that infection of mice with a recombinant HSV-1 isolate expressing IL-12p70 or injection of mice with IL-12p70 DNA blocks the CNS demyelination induced by HSV–IL-2 (19, 20).

Since the recombinant HSV–IL-2 is not a naturally occurring virus, we used an Alzet osmotic minipump to transfer IL-2 into the brains of recipient mice prior to ocular infection with wild-type (wt) HSV-1 (rather than HSV–IL-2). We also tested the effect of administration of IL-2 DNA, IL-2 site-specific mutants, and synthetic peptide fragments prior to infection with wt HSV-1. We demonstrate that a single mutation in amino acid (aa) 27 of IL-2 abolishes CNS demyelination in mice ocularly infected with wt HSV-1. Thus, analysis of the mechanisms by which the enhanced levels of IL-2 in combination with viral infection elicit CNS demyelination suggests that full-length IL-2 is not required to induce CNS demyelination and further suggests that the region of IL-2 that is involved in CNS demyelination involves the region of IL-2 at aa 27. Collectively, these results provide evidence that this HSV-1 model represents a valid alternative to other commonly used models of MS.

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