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Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema
VOLUME 74 NUMBER 6
developed immune complexes (IgE and IgG), the appearance of which corresponded to the onset of symptoms; pretreatment with SCG was protective. Ten of 14 patients had a positive RAST to one or more foods, and in nine subjects, a good correlation was observed between RAST and clinical challenge responses. The RAST-specific IgE antibodies to the relevant food was positive in most patients before challenge and increased in some after challenge with the specific antigen. Total IgE measurements before and after challenge demonstrated a similar pattern. Within 1 hour of challenge, all 10 subjects had a fall in serum levels of monomeric IgE antibody and increased formation of complexed IgE (peak at 24 hours), which was still evident 72 hours after a single challenge. This pattern was prevented by pretreatment with SCG. Control subjects had no IgE immune complexes before or after challenge. Serum ovalbumin levels were measured in each pre- and postchallenge serum sample, and in the responder patients, postchallenge values increased to 30 ng/mL at 3 hours and decreased to an elevated plateau of 12 ng/mL at 24 hours. Pretreatment with SCG was associated with significantly lower antigen levels in both responder and nonresponder subjects. Although patients challenged without pretreatment SCG had both specific IgE as well as nonspecific in their 24-hour EDTA eluates, those with pretreatment had neither. Control patients had no IgE in their EDTA eluates. The authors postulate that an IgE-mediated mechanism alters intestinal mucosal permeability and permits the egress of antigen and formation of immune complexes, which may then induce delayed onset of symptoms and affect few or many target organs. Such responses may be viewed as a form of serum sickness. S.B.
Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema Cicardi M, Igarashi J, Rosen FS, Davis AE III. J Clin Invest 1987;79:698. In vitro synthesis of C-I esterase inhibitor (CI INH) was examined in peripheral blood monocytes from patients with type I hereditary angioneurotic edema (HAE) with immunoprecipitation and gel electrophoresis. Deficient quantities of immunoprecipitable proteins corresponding to the molecular weights of glycosylated CI INH were found in both cell lysates and cell supernatant. Kinetic studies demonstrated a normal time course of CI INH synthesis with the protein being detectable after only 90 minutes in culture. With electroblotting and hybridization with CI INH-specific DNA probes, CI INH mRNA levels were demonstrated to be reduced in the monocytes of patients with HAE. Southern blot assessment of total DNA for the CI INH gene was quantitatively similar to that of normal subjects. The magnitude of CI INH secretion reductions was greater than the
Abstracts 23
reduction of serum CI INH in the same patients. These studies demonstrate a pretranslational defect in type I HAE. R. Y. L.
Stage V (fibrotic) allergic bronchopulmonary aspergillosis: A review of 17 cases foNowed from diagnosis Lee TM, Greenberger PA, Patterson R, Roberts M, Liotta JL. Arch Intern Med 1987;147:319. Seventeen patients (mean age 42 years) suffering from stage V (fibrotic) allergic bronchopulmonary aspergillosis (ABPA) were observed for approximately 5 years from the time of their diagnosis. During this period, six patients died, five from respiratory failure and one because of pulmonary adenocarcinoma. R»ur of the 11 survivors were found to have severe respiratory impairment, but the other seven patients had only moderate respiratory dysfunction, demonstrating little clinical deterioration during the 5-year study. All 17 patients had documented central bronchiectasis. Lung biopsy specimens obtained from five patients with unexplained pulmonary infiltrates or infections proved to be of little diagnostic value. All patients had (1) immediate wheal and erythema response on prick or intracutaneous testing with Aspergillus antigen, (2) asthma as defined by the criteria of the American Thoracic Society, (3) recurrent pulmonary infiltrates with peripheral blood eosinophilia, (4) elevated IgE and/or IgG level specific for Aspergillus fumigatus with 15 of the group having an elevated serum total IgE level as well, and (5) positive precipitins to Aspergillus antigens (found in 11 of the 17 patients). Treatment included bronchodilators for control of asthma, as well as long-term oral steroids, since inhaled, nebulized steroids proved to be unsuccessfiil. Antibiotics were prescribed when the ABPA was complicated by purulent bronchitis or bacterial pneumonia. Several patients experienced asymptomatic pulmonary infiltrates associated with increased total serum IgE. For this reason it was believed that IgE titers should be monitored serially and that chest x-ray should be taken if the IgE titer demonstrated an increase of twofold or more over baseline. Although determination of the total IgE level during stage V (fibrotic) ABPA was helpful in detecting asymptomatic pulmonary infiltrates, the IgE titer was not helpful in adjusting maintenance corticosteroid therapy. Those subjects treated with long-term high-dose prednisone therapy who could not raise their FEV, above 0.8 L proved to have a poor prognosis. In contrast, patients who demonstrated moderate lung damage (FEV, above 0.8 L) at the time of diagnosis remained stable despite fibrotic disease. It was thus evident that those patients with ABPA who could be diagnosed early enough have a more favorable prognosis. B. K.
developed immune complexes (IgE and IgG), the appearance of which corresponded to the onset of symptoms; pretreatment with SCG was protective. Ten of 14 patients had a positive RAST to one or more foods, and in nine subjects, a good correlation was observed between RAST and clinical challenge responses. The RAST-specific IgE antibodies to the relevant food was positive in most patients before challenge and increased in some after challenge with the specific antigen. Total IgE measurements before and after challenge demonstrated a similar pattern. Within 1 hour of challenge, all 10 subjects had a fall in serum levels of monomeric IgE antibody and increased formation of complexed IgE (peak at 24 hours), which was still evident 72 hours after a single challenge. This pattern was prevented by pretreatment with SCG. Control subjects had no IgE immune complexes before or after challenge. Serum ovalbumin levels were measured in each pre- and postchallenge serum sample, and in the responder patients, postchallenge values increased to 30 ng/mL at 3 hours and decreased to an elevated plateau of 12 ng/mL at 24 hours. Pretreatment with SCG was associated with significantly lower antigen levels in both responder and nonresponder subjects. Although patients challenged without pretreatment SCG had both specific IgE as well as nonspecific in their 24-hour EDTA eluates, those with pretreatment had neither. Control patients had no IgE in their EDTA eluates. The authors postulate that an IgE-mediated mechanism alters intestinal mucosal permeability and permits the egress of antigen and formation of immune complexes, which may then induce delayed onset of symptoms and affect few or many target organs. Such responses may be viewed as a form of serum sickness. S.B.
Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema Cicardi M, Igarashi J, Rosen FS, Davis AE III. J Clin Invest 1987;79:698. In vitro synthesis of C-I esterase inhibitor (CI INH) was examined in peripheral blood monocytes from patients with type I hereditary angioneurotic edema (HAE) with immunoprecipitation and gel electrophoresis. Deficient quantities of immunoprecipitable proteins corresponding to the molecular weights of glycosylated CI INH were found in both cell lysates and cell supernatant. Kinetic studies demonstrated a normal time course of CI INH synthesis with the protein being detectable after only 90 minutes in culture. With electroblotting and hybridization with CI INH-specific DNA probes, CI INH mRNA levels were demonstrated to be reduced in the monocytes of patients with HAE. Southern blot assessment of total DNA for the CI INH gene was quantitatively similar to that of normal subjects. The magnitude of CI INH secretion reductions was greater than the
Abstracts 23
reduction of serum CI INH in the same patients. These studies demonstrate a pretranslational defect in type I HAE. R. Y. L.
Stage V (fibrotic) allergic bronchopulmonary aspergillosis: A review of 17 cases foNowed from diagnosis Lee TM, Greenberger PA, Patterson R, Roberts M, Liotta JL. Arch Intern Med 1987;147:319. Seventeen patients (mean age 42 years) suffering from stage V (fibrotic) allergic bronchopulmonary aspergillosis (ABPA) were observed for approximately 5 years from the time of their diagnosis. During this period, six patients died, five from respiratory failure and one because of pulmonary adenocarcinoma. R»ur of the 11 survivors were found to have severe respiratory impairment, but the other seven patients had only moderate respiratory dysfunction, demonstrating little clinical deterioration during the 5-year study. All 17 patients had documented central bronchiectasis. Lung biopsy specimens obtained from five patients with unexplained pulmonary infiltrates or infections proved to be of little diagnostic value. All patients had (1) immediate wheal and erythema response on prick or intracutaneous testing with Aspergillus antigen, (2) asthma as defined by the criteria of the American Thoracic Society, (3) recurrent pulmonary infiltrates with peripheral blood eosinophilia, (4) elevated IgE and/or IgG level specific for Aspergillus fumigatus with 15 of the group having an elevated serum total IgE level as well, and (5) positive precipitins to Aspergillus antigens (found in 11 of the 17 patients). Treatment included bronchodilators for control of asthma, as well as long-term oral steroids, since inhaled, nebulized steroids proved to be unsuccessfiil. Antibiotics were prescribed when the ABPA was complicated by purulent bronchitis or bacterial pneumonia. Several patients experienced asymptomatic pulmonary infiltrates associated with increased total serum IgE. For this reason it was believed that IgE titers should be monitored serially and that chest x-ray should be taken if the IgE titer demonstrated an increase of twofold or more over baseline. Although determination of the total IgE level during stage V (fibrotic) ABPA was helpful in detecting asymptomatic pulmonary infiltrates, the IgE titer was not helpful in adjusting maintenance corticosteroid therapy. Those subjects treated with long-term high-dose prednisone therapy who could not raise their FEV, above 0.8 L proved to have a poor prognosis. In contrast, patients who demonstrated moderate lung damage (FEV, above 0.8 L) at the time of diagnosis remained stable despite fibrotic disease. It was thus evident that those patients with ABPA who could be diagnosed early enough have a more favorable prognosis. B. K.