Andrew A. Lackner

Increased Cerebrospinal Fluid Quinolinic Acid, Kynurenic Acid, and L-Kynurenine in Acute Septicemia

Abstract: Increases in brain quinolinic acid have been implicated in neurodegeneration and convulsions that may accompany infectious diseases. In three rhesus macaques (Macaca mulatta) with septicemia, both CSF and serum quinolinic acid concentrations were markedly elevated and were accompanied by increases in CSF kynurenic acid levels that were of a smaller magnitude. Elevated serum and CSF L‐kynurenine concentrations also occurred and are consistent with activation of indoleamine‐2,3‐dioxygenase and increased substrate flux through the kynurenine pathway. Although it is probable that the marked increases in CSF quinolinic acid and kynurenic acid concentrations are reflected in the extracellular fluid space of brain, it remains to be determined whether the magnitude of such increases influences the activity of excitatory amino acid receptors in brain to produce excitotoxic pathology or noncytolytic disruption of functions mediated by excitatory amino acid receptors.

Cerebral cortex and lung indoleamine-2,3-dioxygenase activity is increased in type-D retrovirus infected macaques

Increased concentrations of the neuroactive kynurenine pathway metabolites, quinolinic acid (QUIN) and kynurenic acid (KYNA), occur in the CSF of humans infected with the human immunodeficiency virus and macaques infected with retroviruses, including the D/1/California serotype. In the present study, increased activity of indoleamine-2,3-dioxygenase (IDO), the first enzyme of the kynurenine pathway, occurred in cerebral cortex and lung of macaques with clinical SAIDS. Such increases provide a mechanism to accelerate the formation of kynurenine pathway metabolites in both systemic tissues and the central nervous system.

Asymptomatic Infection of the Central Nervous System by the Macaque Immunosuppressive Type D Retrovirus, SRV-1

The aetiological agent of spontaneously occurring simian acquired immune deficiency syndrome (SAIDS) in rhesus monkeys (Macaca mulatta) at the California Primate Research Center is a type D retrovirus designated SAIDS retrovirus serotype 1 (SRV-1). SRV-1 DNA and RNA have previously been detected in the brains of rhesus monkeys with SAIDS in the absence of viral antigen or neuropathological lesions. In this study we further define the relationship between SRV-1 and the central nervous system (CNS) in rhesus monkeys by examining the CNS for infectious SRV-1, viral antigen and anti-SRV-1 antibodies. In addition, cerebrospinal fluid (CSF) was assayed for alterations in IgG and albumin levels, IgG/albumin ratios and cell count in comparison to uninfected control animals. No differences in CSF parameters were detected between infected and uninfected animals except for the presence of infectious SRV-1 which was isolated from the CSF from 13 out of 19 (68%) viraemic rhesus monkeys. The probable source of this virus was the choroid plexus, where approximately 1 in 1000 surface epithelial cells were found to contain viral antigen by immunohistochemistry. Antibodies against SRV-1 were not detected in the CSF even when present in the serum. Neither infectious virus nor viral antigen were found in the brain parenchyma of any animal examined. Thus infection of the CNS by SRV-1 appears to be subclinical without an intrathecal immune response. This may be related to the apparent restriction of productive infection in the CNS to cells of the choroid plexus.

Oral lesions in rhesus monkeys associated with infection by simian AIDS retrovirus, serotype-I (SRV-1)

Simian acquired immunodeficiency syndrome (SAIDS) is a retrovirus-induced immunodeficiency disease that affects certain nonhuman primates and has many parallels to human AIDS. We examined 72 rhesus monkeys (Macaca mulatta) exposed to SAIDS retrovirus serotype-1 (SRV-1) and 81 healthy control monkeys at the California Primate Research Center to determine the prevalence of oral lesions. At the time of examination, 69 of the 72 monkeys exposed to SRV-1 had serologic and/or virologic evidence of SRV-1 infection. None of the 81 control monkeys had any evidence of infection with SRV-1. Acute necrotizing ulcerative gingivitis (ANUG), oral yeast infections, and noma occurred in 10% (p less than 0.01), 4%, and 1%, respectively, of the study group of 72 animals but were found in none of the control animals. Thus, ANUG occurs rather frequently in rhesus monkeys with evidence of SRV-1 infection. The reproducible immunodeficiency that follows inoculation of SRV-1 in rhesus monkeys promises to be a useful model for studying the pathogenesis of ANUG associated with immunodeficiency.

Langerhans cells in oral mucosa of rhesus monkeys before and after infection by simian retrovirus-1 and simian immunodeficiency virus☆

To study the influence of experimental infection with simian retrovirus-1 and simian immunodeficiency virus on the number and distribution of Langerhans cells in oral mucosa of rhesus monkeys, 10 monkeys were intravenously inoculated with simian retrovirus-1, 7 with simian immunodeficiency virus, and 2 were mock-inoculated. Biopsies were taken from gingiva and cheek pouch before infection and at 1 (simian immunodeficiency virus group only), 4, and 7 months after infection. Langerhans cells were detected in frozen sections by immunohistochemistry with monoclonal antibodies Leu-6 and HLA-DR. The mean number of Langerhans cells per surface millimeter and square millimeter of epithelium was calculated under blind conditions. The results showed no statistically significant differences in the number or distribution of Langerhans cells in the three groups at the various time points of examination. Similarly, no differences were detected within any group over the observation period. Thus systemic infection of rhesus monkeys with either simian retrovirus-1 or simian immunodeficiency virus does not lead to a significant change in the number of Langerhans cells in oral mucosal epithelium.

Gingival Fibromatosis, Macaca mulatta

Gingival fibromatosis is characterized by a firm enlargement of the marginal and alveolar gingiva, including the interdental papillae. The color of the enlarged gingiva is normal pink and the surface exhibits normal stippling (Fig. 34). The gingival enlargement is particularly pronounced in the anterior maxillary region, but any region may become affected. The moderate forms of gingival fibromatosis are associated with formation of pseudo-pockets between the teeth and the enlarged tissue, whereas the most extensive forms can result in submersion of the teeth.

Noma, Macaca mulatta

Noma is a rapidly progressive gangrenous process that affects the oral cavity, particularly the gingiva, cheeks, and lips, causing bone denudation and extensive facial disfigurement (Fig. 72). The disease process may be unilateral or bilateral and may affect both upper and lower jaws. In the earliest stages the lesions may be limited to a small area of oral mucosal ulceration and edema.

Gingivitis, Necrotizing Ulcerative, Macaca mulatta

Necrotizing ulcerative gingivitis is a severe, rapidly developing, gingival infection that initially affects the gingival tissues between the teeth. The interproximal gingiva becomes markedly erythematous and ulcerated. Eroded crateriform depressions with a “punched-out” appearance develop at affected sites (Fig. 30). Spontaneous gingival bleeding is commonly observed. The disease can develop around any teeth (i.e., deciduous/permanent, upper/lower, anterior/posterior). It is usually localized to fewer than six teeth, but can gradually spread to adjacent gingival tissues if left untreated. In long-standing cases, deep interproximal craters with destruction of alveolar bone can occur (Fig. 31).