Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin.

Interleukin 18 induces both T helper 1 and T helper 2 cytokines, proinflammatory cytokines, chemokines, and IgE and IgG1 production. A role of interleukin 18 in inflammatory cutaneous reactions is still unclear, however. Here we generated keratin 5/interleukin 18 transgenic mice overexpressing mature murine interleukin 18 in the skin using a human keratin 5 promoter. In the contact hypersensitivity model, trinitrochlorobenzene elicited a stronger ear swelling in keratin 5/interleukin 18 transgenic mice compared with control littermate wild-type or immunoglobulin/interleukin 18 transgenic mice in which mature interleukin 18 was expressed by B and T cells under the control of the immunoglobulin promoter. Application of an irritant, croton oil, induced stronger and more sustained ear swelling in keratin 5/interleukin 18 transgenic mice than in immunoglobulin/interleukin 18 transgenic or wild-type mice. Repetitive topical application (weekly for six consecutive weeks) of trinitrochlorobenzene to their ears also elicited a stronger cutaneous inflammation in keratin 5/interleukin 18 transgenic mice than seen in immunoglobulin/interleukin 18 transgenic or wild-type mice. After these six trinitrochlorobenzene applications, the expression of interferon-gamma, interleukin-4, and CCL20 mRNA in the ear tissue was increased and dermal changes, such as acanthosis and eosinophilic, neutrophilic, and mast cell infiltration, were greater in keratin 5/interleukin 18 transgenic mice than in wild-type mice. Furthermore, the repetitive application elicited a significant increase in serum IgE levels and the number of B cells in the draining lymph node in keratin 5/interleukin 18 transgenic mice. These results suggest that overexpression of interleukin 18 in the skin aggravates allergic and nonallergic cutaneous inflammation, which is accompanied by high expression of T helper 1 and T helper 2 cytokines and chemokines in the skin.

A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation.

Heterozygous point mutations in the coding region of the human glial fibrillary acidic protein (GFAP) gene have been reported in patients with various forms of Alexander disease (AD). We report a case of genetically confirmed adult-onset AD with palatal myoclonus, pyramidal tract signs, cerebellar signs, and marked atrophy of the medulla oblongata and spinal cord, autonomic dysfunction and heterozygous R416W GFAP mutation. Interestingly, this R416W mutation has also been reported in both infantile and juvenile forms of Alexander disease. The fact that a R416W mutation causes various types of AD suggests that clinical severities of AD are due not only to the different sites and nature of mutations in GFAP, but also to other modifying factor(s).

Herpesvirus infections of the central nervous system.

In recent years, advances in the diagnosis and treatment of herpes simplex encephalitis (HSE) have been achieved due to the prevalence of antiviral drugs and the introduction of the polymerase chain reaction (PCR) to test the cerebrospinal fluid. The several clinical forms of herpes simplex virus type 1 (HSV-1) infections of the central nervous system (CNS), including acute disseminated encephalomyelitis and brainstem encephalitis, have been clarified. However, fatal, prolonged, or relapsed cases are still observed, and early detection and appropriate treatment is necessary to lead to a good prognosis for these intractable HSE cases. In adult HSV-2 infections, meningitis and myelitis associated with genital herpes are common. In the past, HSV-2 myelitis has been reported as a form of fatal necrotizing myelopathy; however, using PCR and magnetic resonance imaging studies, mild surviving cases are increasingly likely to be identified. Meanwhile, various CNS syndromes resulting from the herpes group viruses, including varicella-zoster virus and Epstein-Barr virus have also been reported. These herpesviruses have several characteristics in common, e.g., they exist in the latent state and they occur in both mucocutaneous and CNS infections. Adult HSV-1 and -2 infections of the CNS are discussed together with other herpes group virus infections of the CNS.

Epstein-Barr virus infections of the central nervous system.

OBJECTIVE: Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. PATIENTS AND METHODS: For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. RESULTS: Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. CONCLUSION: Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.

Adult meningism and viral meningitis, 1997-2004: clinical data and cerebrospinal fluid cytokines.

OBJECTIVE: Although meningism manifesting acute headache has been observed to be associated with common viral and bacterial infections, its definition and pathogenesis have not been clarified. Clinical findings and cerebrospinal fluid (CSF) cytokines in adult patients with meningism were investigated and compared with those in viral meningitis. PATIENTS AND METHODS: Among the adult inpatients in our hospital from 1997 to 2004, 5 with meningism and 17 with viral meningitis were identified according to the criteria described in this study, and their clinical data were analyzed. In the CSF samples of the 5 patients with meningism and the 17 with viral meningitis, the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-10 were determined using a cytometric bead array. RESULTS: The five patients with meningism all showed fever and meningeal signs such as severe headache and nuchal stiffness without CSF pleocytosis (<5 cells/mm3). Four patients were associated with herpetic Kaposi's eczema, herpes simplex, or herpes zoster, and all five patients had favorable outcomes. The levels of all CSF cytokines in patients with meningism were below normal values, whereas IFN-gamma and IL-6 in patients with viral meningitis were moderately elevated. CONCLUSION: The normal cytokine levels in meningism may possibly reflect the lack of direct viral infection and may be helpful in differentiating both meningism and viral meningitis at an early stage.

Probable chronic viral encephalitis with microglial nodules in the entire brain: a case report with necropsy.

BACKGROUND: Chronic encephalitis has rarely been seen, probably due to its viral origins, which may produce the disease in healthy or immunocompromised hosts. The etiology and pathophysiology of these types of encephalitis have not yet been clarified. CASE REPORT: A 63-year-old Japanese woman with underlying multiple myeloma developed chronic encephalitis with fever and progressive dementia, bilateral mild thalamic lesions on magnetic resonance imaging, and a prolonged pleocytosis, normal glucose value, and elevated interleukin-6 and interferon-gamma in the cerebrospinal fluid (CSF). The patient died of pneumonia 6 months after the onset of illness, and diffuse microglial nodules were found in the entire brain. No causative viral agents were identified by polymerase chain reaction and serological tests. CONCLUSIONS: The patient was presumed to have suffered from chronic viral encephalitis, based on clinical findings, including CSF and cytokine changes. Microglial nodules are observed in flavivirus group encephalitides, Rickettsia infections, and cytomegalovirus encephalitis in immunocompromised hosts. The possible pathogenesis of this rare encephalitis is discussed.