Neuritogenic activity of peripheral nerve myelin proteins in Lewis rats

The neuritogenic activity of human peripheral nerve myelin proteins in Lewis rats was examined. Experimental allergic neuritis (EAN) was induced by human myelin fraction in all Lewis rats examined. Purified human P2 protein induced mild but definite EAN. None of purified P0 protein, total myelin lipids, gangliosides and cerebrosides induced EAN. Addition of total myelin lipids or gangliosides to the P2 protein did not enhance the neuritogenicity of the P2 protein. Bovine P2 protein, which was inactive in rabbits and guinea pigs, showed considerable neuritogenicity in Lewis rats. We postulate that induction of EAN depends both on the species of host animal and the source of antigen.     

Angled aorta ("sigmoid septum") as a cause of hypertrophic subaortic stenosis

Review of the hearts of seven patients in whom hypertrophic obstructive cardiomyopathy had been diagnosed by the usual clinical and morphologic criteria revealed diminished angles between the interventricular septa and ascending aortas in three cases. The angles in these three hearts were 90 to 110 degrees, as compared with a mean value of 145 degrees in the other four hearts with hypertrophic obstructive cardiomyopathy and 140 +/- 14 degrees in 55 control hearts. None of the patients with hypertrophic subaortic stenoses and angled aortic roots died of the heart disease, and none had either asymmetric ventricular hypertrophy or evidence of familial cardiomyopathy. It is proposed that in patients with angled aortic roots and left ventricular hypertrophy, subaortic obstruction may develop due to narrowing of the left ventricular outflow tract, resulting in clinical and morphologic findings of hypertrophic obstructive cardiomyopathy. In hearts with angled aortic roots the top of the ventricular septum is tipped toward the mitral valve, rather than tapered toward the aorta, as in normal hearts. This configuration narrows the outflow tract of the left ventricle and can result in systolic anterior motion of the mitral valve, the illusion of asymmetric septal hypertrophy when studied by M-mode echocardiography, a subaortic pressure gradient, and a subaortic endocardial plaque. This less serious form of hypertrophic subaortic stenosis should be distinguished from other forms of hypertrophic obstructive cardiomyopathy.     

The use of 2-deoxy-D-glucose to assess changes in tumor target cell membranes in vitro.

Following short-term suspension culture, cells from the Balb/C sarcoma Meth A were allowed to incorporate both [14C] leucine and 2-deoxy-D-glucose-1-[3H] (2DG). The 2DG is trapped as a small anionic marker of the cytosol. Deviation from the kinetics of spontaneous efflux of the markers is interpreted as reflecting perturbation of the target cell membrane. In the presence of guinea pig complement and a rabbit antiserum to Meth A, enhanced 2DG efflux was effected in a titer comparable to that detected with a 51Cr-release assay. With a number of alloantisera and syngeneic immune sera, 2DG efflux was enhanced while 51Cr-release was unaffected. Only in the presence of syngeneic immune sera from mice bearing a low tumor mass, syngeneic splenic leukocytes effect a retardation in the spontaneous 2DG efflux. Sera from animals with a large tumor mass were ineffective. Effux of proteins labeled with [14C] leucine was not altered. The phenomenon was not dependent on the presence of a heat-inactivatable syngeneic complement source. The method described provides a sensitive probe of target cell membrane permeability in the tumor model studied. The phenomenon detected is the capacity of serum, sampled relatively early in syngeneic oncogenesis, to direct syngeneic splenic leukocytes to interact with the target cell membrane differentially altering its permeability to the small cytosol marker.     

Nasal mucosal hyperpermeability to macromolecules in atopic rhinitis and extrinsic asthma

This study was designed to test the hypothesis that patients with atopic rhinitis and extrinsic asthma have a nasal mucous membrane defect that allows inhaled macromolecules access to immunocompetent cells. Three groups were studied: normal subjects, patients with extrinsic asthma, and patients with atopic rhinitis. Albumin ¹²⁵I(20 μc) was applied to the nasal mucosa and venous blood samples were drawn at set intervals up to 4 hours. Thirty-two minutes after administration, a significantly greater percentage of the dose was found in the plasma of patients with atopic rhinitis than in that of normal subjects (p < 0.001). Transport of intact albumin across the nasal mucosa was demonstrated by dialysis, gel filtration, and immunoprecipitation experiments in $\text{3}\text{9}$ normal subjects, $\text{1}\text{9}$ patients with asthma, and $\text{9}\text{10}$ patients with rhinitis (p < 0.02). These studies suggest that large, potentially antigenic molecules pass more readily across the nasal mucous membrane of patients with allergic rhinitis than that of normal subjects. No increase in nasal transport was seen in patients with extrinsic asthma. It has not been determined whether this defect is a cause or an effect of atopic rhinitis.     

Effect of histamine and methacholine on nasal airway resistance in atopic and nonatopic subjects: Comparison with bronchial challenge and skin test responses

Serial nasal, intracutaneous, or bronchial challenges were carried out with solutions containing 2- or 3-fold increments in histamine (H) or methacholine (Meth) concentration until nasal airway resistance (NAR) increased by more than 100%, a large intracutaneous reaction was elicited, or FEV₁ decreased by 20% or more. Thirty nonatopic and 48 asymptomatic atopic subjects were studied, the latter group divided into rhinitic patients with and without asthma. Several types of data analysis demonstrated there was no significant difference in the nasal or cutaneous effects of H or Meth between the atopic and nonatopic groups. Comparable results were obtained in a subgroup of 39 subjects (13 normal, 13 atopic, and 13 atopic with asthma) who underwent all six test sequences (i.e., nasal, cutaneous, and bronchial with both drugs). As expected, the asthmatics showed significantly increased bronchial reactivity to both agents. In comparison with Meth, H had a much greater effect on the nasal mucosa and skin than on the bronchi. It is concluded that, contrary to bronchial responses, but in accord with cutaneous reactivity, the nasal responses of nonatopic subjects, atopic persons with allergic rhinitis alone, and subjects with both allergic rhinitis and asthma show no intergroup differences on testing with H or Meth.     

Relationship between numbers of beta adrenergic receptors in lymphocytes and disease severity in asthma

In order to assess the status of beta adrenergic receptors in bronchial asthma, binding studies using (−) [³H] dihydroalprenolol (DHA) were performed on lymphocytes of 10 control subjects and 11 stable asthmatic patients. Specific DHA binding was generally lower at all DHA concentrations in asthmatics. At 12 nM DHA concentration, specific DHA binding was 391 ± 40 fM/mg protein in controls and 263 ± 35 fM/mg protein for asthmatic subjects (p < 0.05). A highly statistically significant positive correlation between specific DHA binding (at 12 nM DHA) and FEV₁/FVC% was observed (r = 0.93, p < 0.01), with those asthmatic subjects with the more severe airway obstruction and disease severity showing lower DHA binding. The results of the study suggest that a lymphocyte beta adrenergic receptor defect may be present among some patients with asthma. The magnitude of the receptor abnormality appears to be related to disease severity and degree of airway obstruction as measured by FEV₁/FVC%. Documentation of drug consumption was made, and restriction of beta adrenergic agonists was attempted; theophylline and corticosteroids were the predominant drugs used in the study. Even with these precautions, it is possible that the differences in DHA binding observed among subjects are the results of greater drug (e.g., theophylline and corticosteroids) consumption by the clinically more severe patients. On the other hand, the lymphocyte receptor alteration noted may reflect a more general beta adrenergic receptor abnormality in bronchial asthma.     

M protein instability and lack of H protein processing associated with nonproductive persistent infection of HeLa cells by measles virus

Persistent infections such as subacute sclerosing panencephalitis (SSPE) which do not produce infectious virus particles (nonproductive persistence) are often accompanied by a reduced steady-state amount of the viral matrix (M) protein and/or reduced hemadsorption activity. The possible causes of these aberrations associated with nonproductive persistence were investigated by following changes in the viral proteins with time in pulse-chase experiments. Three HeLa cell lines persistently infected with measles virus; K11, K11A, and HG111; were compared to each other and to acutely infected HeLa cells. K11 produces infectious virions at a low level (productive persistence). K11A and HG111 are both nonproductive persistently infected cell lines derived from K11. K11A cells have a reduced steady-state amount of viral M protein and reduced hemadsorption activity. HG111 cells have reduced hemadsorption but a normal level of viral M protein. As such, these cell lines serve as good model systems for the study of nonproductive persistent infection associated with SSPE. The reduced amount of M protein in K11A was found to result from rapid degradation of the protein. Degradation of the protein resulted from changes in the protein itself rather than from cellular changes. The hemagglutination (H) protein was found to be present at a low level in K11A cells. In addition, in both K11A and HG111 cells, conversion of the sugar moiety of the H glycoprotein from the high mannose form to the complex sugar form did not take place. Such modification usually occurs concomitant with transport of glycoproteins onto the cell surface. As such, lack of processing could preclude the appearance of functional H proteins on the cell surface. This could account for the reduced hemadsorption activity in these cells. The roles that these changes may play in the generation of nonproductive persistence are discussed.     

Bronchial hyperreactivity to histamine and methacholine in asthmatic children after inhalation of SCH 1000 and chlorpheniramine maleate.

Nine asthmatic patients with a mean age of 14 yr received bronchial challenges with histamine and methacholine. The challenges were repeated after inhalation of 80 microgram of SCH 1000 (ipratropium bromide) and 5 mg of chlorpheniramine maleate. The provocation doses which produced a 20% fall in forced expiratory volume in 1 sec (FEV1) and the slopes of the dose-response curves were analyzed. SCH 1000 prevented methacholine-induced bronchoconstriction and chlorpheniramine prevented methacholine-induced bronchoconstriction. There was no significant change in the dose-response curve of histamine after SCH 1000 or in the dose-response curve of methacholine after chlorpheniramine. The findings indicate that the mechanisms and receptor sites involved in bronchial provocation by histamine and methacholine are distinctly different. The histamine response is unlikely to be vagally mediated because histamine-induced bronchoconstriction was not prevented by SCH 1000. Both SCH 1000 and chlorpheniramine caused significant bronchodilatation, suggesting the presence of both histamine- and vagal-dependent bronchomotor tone.     

Elevated serum immunoglobulin E in T cell-deficient infants fed cow's milk

Serum IgE levels at various ages during infancy were related to the number of T cells assessed at the age of 1 mo and type of feeding. Cow's milk-fed babies with low T cell counts had higher IgE at the ages of 3 and 6 mo than breast-fed babies with low T cell counts. Of the babies fed cow's milk, those with low T cell counts had higher IgE levels than those with normal T cell counts. Onset of cow's milk feeding before the age of 3 mo in babies with low T cell counts was associated with continuously elevated IgE during the first year of life, as compared with babies with normal T cell counts. However, when cow's milk feeding was instituted after the age of 3 mo such a difference was not noted. It is concluded that in T cell-deficient infants there might exist a critical period during which onset of cow's milk feeding is associated with subsequently increased IgE synthesis.     

Lymphocyte subpopulations in the skin of patients with chronic urticaria

In order to characterize the nature of the mononuclear cells in the perivascular infiltrates in the skin of 11 patients with CU, skin biopsy specimens were analyzed in situ by an avidin-biotin immunoperoxidase technique. Serial frozen sections were stained for total T cells, helper-inducer T cells, suppressor-cytotoxic T cells, B cells, monocytes/macrophages, and HLA-DR antigen. The infiltrates were found to consist mainly of T cells, whereas B cells and macrophages were rarely seen. Most of the T cells possessed the T4+ helper phenotypes, whereas smaller numbers of infiltrating cells were defined as suppressor-cytotoxic cells. Most of the helper-inducer T cells coexpressed the Ia (HLA-DR) antigen. Several potential pathogenic mechanisms could be implicated in CU based on these observations.     

Cutaneous immediate hypersensitivity in man: effects of systemically administered adrenergic drugs.

In in vitro models of hypersensitivity, beta adrenergic drugs inhibit the antigen-induced release of histamine and other mediators from mast cells and basophils. Epinephrine, an agent with both beta and alpha adrenergic properties, is clinically useful for treating immediate hypersensitivity reactions. We examined the effects of intravenously administered adrenergic drugs on cutaneous wheal-and-flare reactions to antigens and histamine in 7 normal men. Both epinephrine and isoproterenol, a beta agonist, inhibited skin reactions produced by antigen or histamine. Phenylephrine, an alpha adrenergic agonist, produced no effect. These results suggest that epinephrine's inhibition of cutaneous immediate hypersensitivity in vivo is mediated by beta, rather than alpha, receptors. This inhibitory effect in vivo is probably not mediated solely in preventing allergic release of inflammatory mediators since the skin reactions to histamine were inhibited as well.     

Allergen-induced depression of neutrophil chemotaxis in allergic individuals

In previous studies we have shown that neutrophil (PMN) chemotaxis is depressed in patients with allergic disease, hyperimmunoglobulinemia E, and recurrent infections. Although a number of these patients have now been described, little is known about the mechanism of defective PMN function in such individuals. The present studies were carried out to define the relationship between defective PMN chemotaxis and allergic hypersensitivity. Neutrophil chemotaxis was assessed in individuals with sensitivity to ragweed pollen as documented by intradermal skin testing. In each patient, chemotaxis was measured before and after in vitro exposure of their leukocytes to ragweed. A total of 21 individuals in 3 groups have been studied. These include 7 patients with allergic symptomatology and recurrent infections who were ragweed sensitive, 6 patients with a prior history of ragweed sensitivity who had undergone successful desensitization, and 8 nonatopic control subjects. Following in vitro exposure of the leukocytes of the 7 symptomatic patients to ragweed, a profound depression (54% ± 16%) in chemotatic activity was noted. In contrast the control subjects and 6 desensitized patients showed no depression of PMN chemotaxis. Further studies were carried out which demonstrate the antigen-specific nature of the phenomenon and the ability to transfer the depression to normal cells suspended in allergic serum. These data suggest that defective PMN chemotaxis in allergic patients results from an interaction, either directly or indirectly, of antigen with sensitized leukocytes. Specific immunotherapy may have an effect to prevent the chemotactic abnormality in these patients.     

The relationship of respiratory allergy, skin test reactivity, and serum IgE in a community population sample.

The relationship between prick and intradermal skin test reactivity and serum levels of total and specific IgE was evaluated in 311 subjects selected from a general population. Test results were related to the historical allergy status of the subjects. Prick test reactivity to 14 common local allergens correlated with the presence of allergy symptoms. Similarly, mean total serum IgE (PRIST) levels were significantly higher (p < 0.02) in allergic (187.9 IU) than in nonallergic subjects (107 IU) and were found to be positively correlated with the degree of prick test reactivity. Conversely, intradermal reactions following a negative prick test for that allergen showed no correlation with either the clinical allergy status or the level of total serum IgE. Bermuda-specific IgE was found to correlate closely with prick reactivity to that allergen as an overall agreement of 89.2% was observed. In contrast, only 2 of 12 positive Bermuda intradermal tests ≥5 mm and none of 38 smaller reactions following a negative prick response were associated with positive RASTs. The results strongly suggest that prick test reactivity correlates with both total and specific IgE and allergic symptomatology, but intradermal reactions in the absence of prick reactivity do not correlate with either clinical or immunologic evidence of allergy.     

T lymphocytes and blood eosinophils in early infancy in relation to heredity for allergy and type of feeding.

T lymphocytes in 50 one-month-old infants were determined and correlated to heredity for allergy, blood eosinophil counts, and type of feeding. It was found that infants with heredity for atopy had significantly lower relative numbers of T lymphocytes than infants without heredity (p less than 0.05). This difference was particularly obvious in heredity for asthma on the paternal side (p equals 0.001). There was an inverse correlation between T lymphocyte counts and blood eosinophil counts in infants who were cow's milk-fed; i.e., low T lymphocyte counts were associated with high blood eosinophil counts (r = -0.59, p less than 0.01). T lymphocyte counts were not correlated to the type of feeding, whereas blood eosinophils were significantly higher in the cow's milk-fed than in the breast-fed group (p less than 0.01). The results suggest that atopic allergy may be associated with a genetically determined lymphocyte defect.     

Distribution of IgE in a community population sample: correlations with age,sex, and allergen skin test reactivity

The distribution of total serum IgE determined by the paper radioimmunosorbent test (PRIST) is examined in a large random stratified community population. Prior to logarithmic conversion the distribution of this immunoglobulin is not normal, with almost 40% of values below 20 lU/ml. A normal distribution occurs following such conversion, with a geometric mean value of 32.1 lU/ml. Both age and sex, in addition to atopic status, relate to IgE level. In both sexes highest levels occur among 6- to 14-year-olds, and males have higher levels than females at any given age. Women over age 75 yr have the lowest levels (geometric mean 9.2 lU/ml). Subjects with positive skin test results have several times the concentration of IgE as their nonatopic counterparts.