Alain Sobel

Altered C1 Inhibitor Genes in Type I Hereditary Angioedema

Hereditary angioedema is an inherited disease transmitted as an autosomal dominant trait and characterized by deficient activity of C1 inhibitor, a glycoprotein that limits intravascular activation of complement. The unavailability of markers for the C1 inhibitor locus has so far precluded access to the genetic bases of the disorder. Using a recombinant-DNA probe for the C1 inhibitor gene, we identified a cluster of four distinctive DNA restriction sites in a multigeneration family. The strict cosegregation of these markers with a low C1 inhibitor level supports the conclusion that a defective structural gene is responsible for the disease. The occurrence of distinct DNA markers in patients from unrelated kinships indicates that, like forms of the condition displaying dysfunctional C1 inhibitor variants, those characterized by protein deficiency are also genetically heterogeneous. Although multiple restriction-site changes in the C1 inhibitor gene are carried by certain patients, DNA markers for this locus are strikingly infrequent among normal persons. These findings indicate that the gene alterations responsible for hereditary angioedema arise more often from DNA rearrangements than from nucleotide substitutions. Such variations in the structure of the C1 inhibitor gene may provide the basis for early and direct identification of persons at risk.

Analysis of glomerular complement receptors in various types of glomerulonephritis

Abstract The presence of complement receptors on human glomerular cells has been confirmed. The study of the complement dose dependent binding of complement-coated sensitized erythrocytes (EAC) to glomeruli permitted a quantitative evaluation of this receptor. Application of this method to kidney biopsies of patients with various types of glomerulonephritis revealed a striking decrease in the EAC binding capacity of glomeruli having mesangial C3 and IgA deposits. In contrast, EAC binding by glomeruli with subepithelial deposits or without immune deposits was not modified. Further evidence of the mesangial localization of C3 receptors was obtained by the restoration of receptor activity after removal of immune deposits in mesangial nephritis specimens. These results suggest a role for local C3 receptors in mesangial functions.

Nephrotic syndrome associated with T-cell lymphoma

Glomerulopathies associated with non‐Hodgkins malignant lymphomas have been observed rarely. Previous reports have never determined the cell type of the lymphoproliiferative disorder. This report documents a case of nephrotic syndrome in a patient with T‐cell derived non‐Hodgkins lymphoma. The neoplastic cell was studied in terms of cell‐surface markers, cytochemical staining, and ultrastructural morphology. Nephrotic syndrome occurred shortly after the apparent onset of the lymphoma. The kidney biopsy specimen was examined by light, fluorescence, and electron microscopy. Histologic findings were consistent with the diagnosis of mild focal and segmental glomerulosclerosis. Such an association, reported here for the first time, may support the hypothesis of a pathogenetic link between acquired T‐cell abnormalities and glomerular diseases with minimal histologic injury.

Circulating immune complexes in patients with gram negative septic shock

SummaryIn order to explain complement components abnormalities observed during septic shock, circulating immune complexes (C.I.C.) were searched for in sera from 34 patients with gram negative sepsis by two different methods: polyethylene glycol precipitation test based on physical properties of C.I.C. and C1q deviation test based on the property of radiolabelled C1q to react with C.I.C. Serum immunoglobulins (IgG, IgA, IgM) and complement components (C1q, C3, C4) levels were simultaneously determined. Seventeen patients with minimal haemodynamic abnormalities had normal or increased levels (except C4 at 62% of normal) and in eleven cases both tests for C.I.C. were simultaneously positive. Seventeen patients with severe septic shock had a decrease in IgG, IgM, C1q, C3 and C4 and none had both tests for C.I.C. simultaneously positive (P<10−4). The disappearence of C.I.C. in patients with severe septic shock associated with evidence of complement activation suggests their involvement in the pathogenesis of septic shock in man.

HIV-2 cultured from blood 16 days after death

HIV-2 was cultured and verified by reverse transcriptase activity in 4 of 15 samples taken postmortem from a heterosexual West African patient who had died of AIDS. He was diagnosed with HIV-2 but not HIV-1 by several standard ELISA kits and by Western blot for HIV-2 from Pasteur Diagnostics. He died of acute myelomonocytic leukemia in the Hospital Henri Mondor Creteil France. The body was kept at 2 degrees C. Daily samples of blood from the subclavian vein by pericardial puncture were cultured with phytohemagglutinin-stimulated human lymphocytes. Supernatants were replaced twice weekly with 30% fresh medium and new lymphocytes were added weekly. The positive supernatants were found after 27-36 days of culture on samples of blood removed 10.5 11.5 and 16.5 days after death. There are other reports of HIV recovered after 15 days in an aqueous environment and 11 days after death. The long interval before detection of HIV suggests either low viral concentration or infectivity in the postmortem specimen.

Relapses of Idiopathic Diffuse Crescentic Glomerulonephritis without Immune Deposits: Report of 6 Cases

Idiopathic diffuse crescentic glomerulonephritis without immune deposits is a variant of rapidly progressive glomerulonephritis which can account for up to 40% of crescentic nephritis. The prognosis may depend on both the severity of histological injury at presentation and the efficacy of treatment. Recent advances in therapy have improved the outlook further, and prolonged stable remissions with mild renal failure can occur which contrast with the previously common evolution towards end-stage renal failure within a few weeks. However, relapses in otherwise stable remission may be seen, and we describe a series of 6 acute relapses interrupting such prolonged remissions. The relapses were defined by clinical and histological means. This modification of the natural history of some crescentic glomerulonephritis may reflect new therapeutic strategies, and the relapses may reflect a cyclical nature to the disease evolution which was previously hidden by hemodialysis. The possibility of successive flares suggests that kidney biopsies should be repeated when a rapid deterioration of renal function occurs, since treatment such as high-dose steroids and/or plasma exchange can be again effective if started early.

Lymphokine with vascular permeability enhancing action in nephrotic syndrome (NS) patients

permeability was enhanced in a synergistic manner. Using a technique in which radio-labelled microspheres (ssSr-15~ in diameter) are injected, via a carotid catheter, to measure blood flow in dermal lesions, it was also found that PGE~ was a potent inducer ofhyperemia in doses as low as 4 ng. In experiments in which the labelled microspheres and radioactive HSA were infused together, a comparison of permeability and blood flow could be made between the three chemical mediators. It was found that, whereas histamine and bradykinin could induce a strong permeability response, PGE~ was the only substance to increase blood flow to any extent. Other prostaglandins were tested and the order of potency with regard to hyperemia was PGEj > PGE 2 > PGF2a. Since it was shown that the enhancement of vascular permeabiiity, when PGE t was mixed with bradykinin, correlated well with the hyperemia it was concluded that prostaglandins may control local exudative processes by their effect on the blood flow in an inflammatory lesion.