Isolated pituitary granuloma by atypical Mycobacterium in a nonimmunosuppressed woman.

A 32-year-old woman presented with a 10-day history of fever (38.0 degrees C), headaches, nausea, vomiting and a 6-month history of diabetes insipidus and amenorrhoea. Two months previously she had undergone a surgical drilling of the right mastoid area because of mastoiditis. Endocrine investigation showed elevated serum prolactin levels, secondary adrenal and gonadal failure and a normal thyroid function. Cranial MRI scan revealed a contrast enhancing intrasellar mass (approximately 2 cm) of heterogeneous appearance with suprasellar extension and thickening of the pituitary stalk. Lumbar puncture was suggestive of aseptic meningitis. The Ziehl-Neelsen stain of cerebrospinal fluid (CSF) and the tuberculin skin test were both negative. The pituitary mass was removed with a transsphenoidal approach. Histological examination demonstrated destruction of the adenohypophysis by epithelioid granulomas with partial caseous necrosis and microabscess formation, suggestive of a mycobacterial infection. A polymerase chain reaction analysis performed on paraffin-embedded tissue was positive for mycobacterial DNA. According to the individual 16S sequence, it was identified as Mycobacterium malmoense, an atypical nontuberculous mycobacterium (NTM). In conclusion, this is the first case of an isolated pituitary granuloma caused by an NTM infection in a nonimmunosuppressed patient.

Transformation of Golgi membrane into the envelope of herpes simplex virus in rat anterior pituitary cells.

Envelopment of herpes simplex virus type-1 (HSV-1) was investigated in relation to membrane differentiation in dissociated anterior pituitary cells. The number of cells stained positively with anti-HSV-1 serum was increased from 16 h to 31 h post infection. During this period, electron microscopy revealed that a number of nucleocapsids (unenveloped particles) were accumulated in the Golgi area, where they frequently became surrounded by a double membrane of short Golgi cisternae or by one with a Golgi associated endoplasmic reticulum lysosome (GERL)-like structure. The inner membrane of the cisterna surrounding the nucleocapsids showed regional specialization which was characterized by increased thickness and electron opacity. Acid phosphatase activity, a marker for GERL or trans Golgi cisternae, appeared in the cytoplasmic short cisternae surrounding the nucleocapsids, whereas glucose-6-phosphatase activity, a marker for the nuclear envelope or for endoplasmic reticulum, was not demonstrated in such cisternae. Monoclonal antibody against glycoprotein gD revealed that gD was localized in the trans Golgi membrane as well as in the envelope of the virion. The antibody-binding sites were highly concentrated in the area where Golgi membranes showed increased opacity. Furthermore, nucleocapsids were surrounded exclusively by gD-positive cisternal (Golgi or Golgi-derived) membranes. Thus, our results indicate that the envelope of HSV is derived from trans Golgi cisterna (GERL), and that some viral components, including gD, destined for the envelope may be assembled initially in the Golgi membrane, which is thereby transformed into the envelope of the virus.

Perturbation of differentiated functions in vivo during persistent viral infection. III. Decreased growth hormone mRNA.

Lymphocytic choriomeningitis virus (LCMV) persistent infection that results from the inoculation of C3H/St newborn mice causes growth hormone (GH) deficiency and associated disease characterized by both reduced weight and serum glucose levels. Molecular analysis of pituitary nucleic acids shows GH deficient mice have, on average, fivefold reduced levels of GH mRNA although the histopathology of such GH producing cells is normal. Northern blots indicate that the length of GH mRNA is comparable in the GH deficient, virus infected mice and the GH normal, uninfected age-matched controls. Hence, truncated GH mRNA cannot account for hormonal defect. Mice infected congenitally through mating of persistently infected parents have normal growth and blood glucose levels. GH mRNA levels in pituitaries of these mice are equivalent to those of uninfected age-matched controls but significantly greater than those seen in neonatally infected GH deficient mice. Although infectious virus titers in the sera are equivalent in congenitally and neonatally infected age- and sex-matched mice, virus titers are significantly lower in pituitaries and brains of the congenitally infected mice when compared to neonatally inoculated mice. Additionally, the number of GH-producing pituitary cells expressing viral proteins is less in congenitally infected mice relative to those in neonatally inoculated mice. Hence there is a direct association between viral replication in GH-producing cells, lowered GH mRNA, and GH deficiency.

Viral perturbation of endocrine function: disordered cell function leads to disturbed homeostasis and disease.

Virus-induced disease occurs both through direct destruction of cells by viruses and/or secondarily through lysis of infected cells by immunological assault. We asked whether viruses could also cause injury and disease by altering the cell's normal or expected functions without destroying the cells. Here we show that a relatively noncytopathic virus can perturb endocrine functions by disordering the synthesis of a hormone needed for growth and glucose regulation, while replicating in a specialized cell making that hormone. Yet, despite viral replication and alteration in synthesis of the specialized cell's homeostatic product, the infected cell remains free from structural injury.

Pituitary dwarfism in mice persistently infected with lymphocytic choriomeningitis virus.

Most strains of mice injected intracerebrally with lymphocytic choriomeningitis virus grow to adulthood maintaining a persistent virus infection associated with chronic virus-induced immune complex disease. However, mice on a k background are highly susceptible to neonatal infection and develop the clinical syndrome of pituitary dwarfism and hypoglycemia. Examination of pituitary tissue fails to reveal morphologic alteration by light and electron microscopy. Within the pituitary, viral antigens are exclusively distributed within the cells of the adenohypophysis. Using ultrastructural colloidal gold-labeling techniques, we demonstrate the presence of mature virus particles budding from the surface of growth hormone containing cells from the pituitary. This study indicates that persistent lymphocytic choriomeningitis virus infection of the growth hormone cells in susceptible mice is associated with pituitary dwarfism without producing visible structural damage.

Virus-induced alterations in homeostasis: alteration in differentiated functions of infected cells in vivo.

The noncytopathic lymphocytic choriomeningitis virus displays a tropism for the anterior lobe of the murine pituitary gland. Virus replicates in cells that make growth hormone. This results in a diminished synthesis of growth hormone with a concomitant clinical picture of retarded growth and hypoglycemia. However, there is no morphologic evidence of either cell necrosis or inflammation in the anterior lobe of the pituitary. Hence, during infection in vivo, a noncytopathic virus may turn off the "differentiation" or "luxury" function of a cell while not killing that cell (loss of vital function). This is turn can disrupt homeostasis and cause disease. This model illustrates a novel way whereby viruses may cause disease.

Acute membrane responses to viral action.

The effects of Sendai, a paramyxovirus, on the functional activity of 3 cell types, have been studied in vitro to establish whether a virus alone can cause pathophysiological changes. Neuronal cells are depolarized and suffer a loss of excitability which was attributed to an increase in membrane conductance. Spontaneously beating cardiac cells initially stop beating and then beat more rapidly and asynchronously. Anterior pituitary cells release hormones. In all 3 cases the effects are transient and the cells recover completely.

Virus-induced diabetes mellitus. XX. Polyendocrinopathy and autoimmunity.

Mice infected with reovirus type 1 developed transient diabetes and a runting syndrome. The diabetes was characterized by hyperglycemia, abnormal glucose tolerance tests, and hypoinsulinemia. Inflammatory cells and viral antigens were found in the islets of Langerhans, and virus particles were seen in alpha, beta, and delta cells. The runting syndrome consisted of retarded growth, oily hair, alopecia, and steatorrhea. Inflammatory cells and viral antigens were found in the anterior, but not posterior pituitary. Electron microscopy revealed virus particles in growth hormone (GH)-producing cells and radioimmunoassay showed that the concentration of GH in the blood was decreased. Examination of sera from infected mice revealed autoantibodies that, by immunofluorescence, reacted with cytoplasmic antigens in the islets of Langerhans, anterior pituitary, and gastric mucosa of uninfected mice. Absorption studies and enzyme-linked immunosorbent assays designed to identify the reactive antigens showed that some of the autoantibodies were directed against insulin and others against GH. Reovirus type 3, in contrast to reovirus type 1, did not induce autoantibodies to GH. By use of recombinant viruses, the segment of the reovirus genome responsible for the induction of autoantibodies to GH was identified. Virus containing the S1 gene segment from reovirus type 1, which codes for the sigma 1 polypeptide (i.e., hemagglutinin), infected cells in the anterior pituitary and induced autoantibodies to GH, whereas virus containing the S1 gene segment from reovirus type 3 failed to infect cells in the anterior pituitary and did not induce autoantibodies to GH. We conclude that reovirus type 1 infection can lead to polyendocrinopathy and autoimmunity and that the S1 gene segment is required for the induction of autoantibodies to GH.