Autoimmunity to the glutamate receptor in mice--a model for Rasmussen's encephalitis?

We investigated the in vivo pathogenic potential of murine autoimmunity to peptides of the glutamate/AMPA receptor subunit 3 (GluR3). Antibodies to GluR3 are found in human epilepsy, Rasmussen's encephalitis (RE). In our accompanying paper in this issue we found that murine antibodies to the GluR3B peptide (amino acids 372-395) bind neurons in culture, evoke GluR channel activity, and kill neurons in a complement-independent excitotoxic manner, mimicking the pathophysiologic effects of excess of glutamate. In the present study, we immunized four mouse strains (BALB/c, C3H/HeJ, SJL/J and C57BL/6) with the GluR3B peptide, and investigated the development of (1) anti-GluR3B antibodies; (2) anti-GluR3 T cells; (3) clinical symptoms and abnormal behaviour; (4) brain pathology. We found that BALB/c, C3H/HeJ and SJL/J mice strains developed high titres of anti-GluR3B antibodies. The low levels anti-GluR3B antibodies raised in C57BL/6 mice suggest that the genetic background of mice influences their ability to mount a humoral autoimmune response towards the GluR3B peptide. The GluR3B-immunized mice also developed anti-GluR3B T cells, and their splenocytes showed significantly biased frequencies of particular (Vbeta11, Vbeta7 and Vbeta8) TCR Vbeta families. Surprisingly, GluR3B-immunized mice also raised high anti-ssDNA humoral immunoreactivity. GluR3B-immunized mice exhibited multiple brain pathology, partially resembling that observed in RE, and subclinical behavioral abnormalities, but no epilepsy, even upon facilitating the entry of the autoreactive antibodies into the brain, by weakening the blood-brain barrier. Taken together, these results suggest that autoimmunity to the GluR3B epitope may account for the neuronal death and brain pathology seen in neurodegenerative diseases like RE, but may not be sufficient to underly epilepsy, at least not in mice.

[Nephrotic syndrome complicating treatment with interferon alpha]. / Syndrome néphrotique compliquant un traitement par interféron alpha.

UNLABELLED: We report two cases of nephrotic syndrome with minimal glomerular change complicating alpha-interferon therapy. CASE REPORTS: The first patient was a 60-year-old man with Waldenström's disease who was given 1 million units of alpha-interferon three times a week for 22 months. Acute renal failure developed when a second protocol was started. Renal biopsy revealed intraglomerular deposits and no cellular proliferation. Total remission could not be achieved with corticosteroids. The second case was a 46-year-old man given high dose alpha-interferon (15 million units 3 times a week) for lymph node metastasis of a malignant melanoma. A nephrotic syndrome without renal failure developed during the third month of treatment. Minimal glomerular involvement was seen. Symptomatic treatment led to resolution of the nephrotic syndrome. DISCUSSION: Nine other cases of nephrotic syndrome complicating alpha-interferon therapy have been reported in the literature.

Haemodialysis of pyrazinamide in uraemic patients.

The pharmacokinetics of PZA during haemodialysis were determined in 6 patients with chronic renal impairment after a single oral dose of 25.7 (1.9) mg.kg-1. The dialysis clearance of PZA and of its metabolites were: pyrazinamide 132 ml.min-1; pyrazinoic acid 121 ml.min-1; 5-hydroxy-pyrazinamide 107 ml.min-1; 5-hydroxy-pyrazinoic acid 118 ml.min-1. The average amount extracted during a dialysis session of 4.1 h was 926 mg after an oral dose of 1700 mg. The high dialysability shows that PZA can properly be administered at the end of each dialysis session in the usual dose of 25 to 30 mg.kg-1.