Vaccination against tuberculosis and leprosy.
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Antigens, Bacterial↗
Biomedical subjects
D B Young
Publications and source records attributed to D B Young.
Heat-shock proteins: immunity and autoimmunity.
Antigens from a wide variety of pathogens have been identified as members of conserved heat-shock protein families, sharing upwards of 50% amino acid identity with corresponding host-cell proteins. Analysis of the responses to these conserved antigens may provide insights into regulation of the immune system during infection and autoimmunity.
Animals↗
Potassium and catecholamine concentrations in the immediate post exercise period.
The minutes immediately after cessation of strenuous exercise have been termed the "vulnerable period" regarding the occurrence of lethal cardiac arrhythmias. In the present study, we analyzed the rates of change with a high degree of temporal resolution of factors known to be associated with induction of arrhythmic activity. Thirteen subjects walked and ran on a treadmill to the point of exhaustion after a modified Bruce protocol. Samples were drawn from the antecubital vein immediately before exercise, at the moment exercise stopped, and at 1, 2, 3, 5, and 10 minutes of recovery. Plasma potassium concentration rose during exercise from 3.98 +/- .05 to 5.09 +/- .09 mEq/L. After the exercise period, plasma potassium fell rapidly. The mean maximum rate of change was -0.54 +/- .04 mEq/L/min, and -0.88 +/- .08 mEq/L/2 min. Plasma epinephrine concentration increased from 63 +/- 14 to 497 +/- 41 pg/ml and norepinephrine increased from 503 +/- 57 to 2800 +/- 519 pg/ml during exercise. During the first minute after cessation of exercise, the concentrations of both catecholamines increased still further. We propose that the rapid decline of potassium concentration while catecholamine levels are elevated to near maximal levels may contribute to the vulnerability of some individuals to post exercise arrhythmias.
Adult↗
Mycobacterial protein antigens: a compilation.
In response to recommendations from the Steering Committees responsible for co-ordination of World Health Organization programmes for research on the immunology of leprosy (IMMLEP) and tuberculosis (IMMTUB), a list was prepared summarizing the properties of mycobacterial proteins currently under investigation with respect to their immunological activities. After consultation with more than 40 laboratories world-wide this list was extended to form the compilation shown below and is intended to provide a comprehensive and convenient reference for future studies in this field.
Amino Acid Sequence↗
Migraine with aura: a vicious cycle perpetuated by potassium-induced vasoconstriction.
Two hypotheses have dominated attempts to understand the etiology of migraine with aura or classic migraine; the vascular spasm model proposed by Wolff and colleagues, and the spreading cortical depression hypothesis. Neither can provide a fully satisfactory explanation for the syndrome, however. We propose that classic migraine is both spreading cortical depression and localized ischemia linked in a vicious cycle by potassium induced vasoconstriction. The cycle can be initiated by any event which raises the local cortical ECF potassium concentration to approximately 20 mM. Such an event could be a localized burst of activity of a group of cells, localized metabolic impairment, or a transient reduction in blood flow to a region of the cortex. Once this level of potassium concentration is reached, it may result in localized depolarization of neurons, releasing more potassium into the ECF. Glial siphoning can distribute the potassium preferentially toward the blood vessels in the area, leading to an elevation in potassium concentration in the ECF surrounding the vascular smooth muscle of the arterioles. Above approximately 15 mM, vascular smooth muscle increases its tension in response to elevations in potassium. Therefore, as cortical ECF potassium concentration rises above 15 to 20 mM, localized vasoconstriction occurs, thereby reducing both the supply of oxygen for aerobic metabolism and the removal of potassium in the blood. Under these conditions, the effectiveness of the mechanisms which control potassium concentration is impaired and unable to prevent additional elevations in potassium. As the concentration continues to rise, vasoconstriction becomes more intense, perpetuating the cycle that results in localized depression of cortical neuronal activity and ischemia. The condition is propagated to adjacent regions of the cortex by diffusion and glial-mediated spread of potassium. In many respects, the hypothesis unites the vascular spasm and spreading depression models. If verified, it may provide insight into the causes of classic migraine as well as give direction toward development of effective therapies.
Humans↗
hsp70 synthesis in Schwann cells in response to heat shock and infection with Mycobacterium leprae.
Induction of heat shock protein synthesis was monitored in murine and monkey Schwann cells exposed to elevated temperatures. Synthesis of the stress-inducible 70-kDa heat shock protein (hsp70) was detected in both murine and primate Schwann cells by metabolic labelling and by immunoblotting with a specific monoclonal antibody. hsp70 synthesis was also induced in Schwann cells after infection with Mycobacterium leprae and was detected from 24 h to 1 week postinfection. These results are discussed with respect to the possible role of heat shock proteins in immunopathological events associated with the clinical manifestations of leprosy.
Animals↗
The 14,000-molecular-weight antigen of Mycobacterium tuberculosis is related to the alpha-crystallin family of low-molecular-weight heat shock proteins.
Eight monoclonal antibodies (MAbs) directed against the 14,000-molecular-weight (14K) antigen of Mycobacterium tuberculosis reacted specifically with mycobacteria of the M. tuberculosis complex. The nucleotide sequence of the gene encoding the 14K antigen was determined by using recombinant DNA clones isolated from lambda gt11 and cosmid libraries of the M. tuberculosis genome. The DNA sequence of the 14K protein gene coded for a polypeptide of 144 amino acids with a calculated molecular mass of 16,277 Da. The 14K antigen has a marked homology with proteins belonging to the alpha-crystallin family of low-molecular-weight heat shock proteins, which includes the 18K antigen of M. leprae. The eight MAbs recognized at least four distinct epitopes localized within the following three regions of the 14K protein: amino acids 10 to 92 (MAbs F67-8 and F67-16), amino acids 41 to 92 (F159-1 and F159-11), and amino acids 41 to 144 (F23-41, F24-2, F23-49, and TB68).
Amino Acid Sequence↗
Evidence of a K(+)-H(+)-ATPase in vascular smooth muscle cells.
In earlier studies Na(+)-K(+)-adenosinetriphosphatase (ATPase) and Na(+)-K(+)-2Cl- cotransport partially accounted for vascular smooth muscle cell (VSMC) K+ (Rb+) uptake. In other cells Rb+ is taken up by a K(+)-H(+)-ATPase that is sensitive to NC-1300-B, SCH28080, omeprazole, and N-ethylmaleimide (NEM). This study examines the effects of K(+)-H(+)-ATPase inhibitors on VSMC. Rubidium uptake by primary cultures of canine coronary artery (CCA) VSMC or cultured rat aortic (CRA) VSMC line A7r5 was reduced 19-37% by NC-1300-B, SCH28080, or omeprazole. N-ethylmaleimide reduced CCA VSMC K+ content from 1.55 +/- 0.02 to 1.24 +/- 0.06 mu eq/mg protein. The NC-1300-B-sensitive portion of CRA VSMC Rb+ uptake was not blocked by ouabain (0.1 mM) or bumetanide (0.1 mM), but was reduced by alkalinization with 7.5 mM NH4Cl, and increased by acidification with 7.5 mM Na-acetate. Intracellular pH (pHi) of CRA VSMC was reduced 0.14 +/- 0.03 U by NC-1300-B and 0.22 +/- 0.03 U by NEM. pHi of CCA VSMC was reduced 0.20 +/- 0.03 U by omeprazole (1 mM) and 0.20 +/- 0.03 U or 0.20 +/- 0.05 U by amiloride in the absence or presence of omeprazole, respectively. Fluorescence of 2',7'-bis(carboxyethyl)-5-(6')- carboxyethyl)-5-(6')-carboxyfluorescein due to excitation at 500:441 nm in rat aortic strips was reduced by 0.21 +/- 0.02 U by omeprazole and 0.22 +/- 0.03 U by K+ removal and increased by 0.21 +/- 0.06 U by K+ repletion. We conclude that VSMC possess a previously unknown Rb+ uptake mechanism. This newly discovered mechanism helps to maintain K+ gradient and pHi by extruding H+ in exchange for K+, and is presumably a K(+)-H(+)-ATPase similar to those described in other tissues.
Adenosine Triphosphatases↗
Heat shock proteins as virulence factors of pathogens.
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Animals↗
Autoimmunity, microbial immunity and the immunological homunculus.
Clonal deletion and anergy are believed by many immunologists to be the fundamental mechanisms responsible for self tolerance. Nevertheless, as Irun Cohen and Douglas Young point out, such notions of nonreactivity cannot explain certain key features of immune behaviour: the immunological dominance of microbial antigens that mimic self, the uniformity of autoimmune diseases and the prevalence of natural autoimmunity among the healthy. The theory of the immunological homunculus is presented here as a unifying principle.
Animals↗
Chronic hypokalemia and the left ventricular responses to epinephrine and preload.
The effects of moderate, chronic (5 days) potassium depletion on cardiac function were assessed in 14 normokalemic and 13 hypokalemic open chest, anesthetized dogs. Cardiac responses to intravenous bolus injection of 2.5 micrograms/kg body weight epinephrine (10 normokalemic and 11 hypokalemic dogs) and to rapidly increased preload (8 dogs in each group) were evaluated. Hypokalemic dogs received a low potassium diet plus chlorthalidone. Plasma potassium levels were lower (p less than 0.001) in the hypokalemic dogs (3.2 +/- 0.1 mEq/liter [mean +/- SEM]) than in the normokalemic dogs (4.1 +/- 0.1). The inotropic response to epinephrine was lower in hypokalemic than in normokalemic dogs, the response of the maximal rate of rise of left ventricular pressure was 20% greater (p less than 0.03) and the response of the peak rate of change of ejection power was 60% greater in the normokalemic dogs. The relaxation response to epinephrine (the maximal rate of fall of left ventricular pressure) was 33% lower (p less than 0.02) in hypokalemic dogs. Responses to rapid volume expansion were impaired by hypokalemia; maximal stroke volume index was 31% lower (p less than 0.01), maximal cardiac index was 26% lower (p less than 0.01) and the peak response to the maximal rate of filling was 51% lower (p less than 0.01). There were no differences in basal cardiac function. Therefore, modest potassium depletion within the clinical range impaired the contractile and relaxation responses to epinephrine and preload and impaired rapid filling.
Animals↗
Lipoprotein antigens of Mycobacterium tuberculosis.
Detergent phase separation and metabolic labelling have been used to screen for the presence of lipoproteins amongst the antigens of Mycobacterium tuberculosis. Both techniques indicated that four antigens, with subunit molecular weights of 19, 26, 27 and 38 kilodaltons (kDa), are lipoproteins. This finding is consistent with the presence of conserved cysteine residues characteristic of other bacterial lipoproteins within the amino terminal sequences of the 38 kDa and 19 kDa proteins. It is proposed that lipoproteins are involved in the induction of humoral and cellular immune responses to mycobacteria and have a functional role in the transport of nutrients through the mycobacterial cell wall.
Antigens, Bacterial↗
Prolongation of xylazine/ketamine induced recumbency time with temazepam in horses.
Short term anaesthesia induced with xylazine and ketamine was compared to a combination of xylazine, ketamine and temazepam (a benzodiazepine) in six adult horses. Duration of recumbency was significantly prolonged when temazepam was administered with xylazine and ketamine. No significant differences in heart rate, respiratory rate, blood pressure or arterial pH, pCO2 and pO2 were seen between the xylazine and ketamine combination plus temazepam, and xylazine and ketamine combination only treated horses.
Anesthesia↗
Genetic and immunological analysis of Mycobacterium tuberculosis fibronectin-binding proteins.
Recombinant phage clones, TB1 and TB2, were selected from a Mycobacterium tuberculosis lambda gt11 DNA expression library by screening with a polyclonal antiserum raised against the antigen 85 complex of Mycobacterium bovis BCG. Analysis of recombinant DNA inserts and expressed fusion proteins showed that two new genes had been isolated. The product of clone TB2 was identified as a member of the 30/31-kDa antigen 85 complex. Restriction enzyme analysis showed that this gene differs from previously cloned members of this antigen complex, with detailed serological analysis indicating that it may encode the 85C component. Antisera raised against the expressed product of clone TB1 recognized a 55-kDa protein in M. tuberculosis extracts. The 55-kDa protein also has fibronectin-binding activity and, like the 30/31-kDa family, is a prominent target of the antibody response in patients with mycobacterial disease. Although the clones were selected by using the same antiserum, detailed analysis by serology and by DNA hybridization showed that they represent two quite distinct types of fibronectin-binding activities expressed by M. tuberculosis. Further analysis of the fibronectin-binding antigens of M. tuberculosis may provide important insights into their role in mediating the interaction with the host immune system.
Antibodies, Monoclonal↗
Heat shock proteins and antigens of Mycobacterium tuberculosis.
The heat shock response of Mycobacterium tuberculosis has been characterized in detail by one- and two-dimensional polyacrylamide gel electrophoresis after metabolic labeling with [35S]methionine and 14C-amino acids. A temperature increase from 37 to 42 degrees C induced elevated synthesis of three major proteins corresponding to the DnaK, GroEL, and GroES proteins of M. tuberculosis previously identified as prominent antigens. At higher temperatures (45 to 48 degrees C), synthesis of GroEL decreased and novel heat shock proteins with molecular masses of 90, 28, 20, and 15 kDa were observed. These new proteins did not comigrate with known antigens during two-dimensional gel electrophoresis. The heat shock response is discussed with regard to the possible importance of transcriptional regulation of mycobacterial genes in vivo.
Animals↗
Stimulation of renin release by hyperkalemia in the nonfiltering kidney.
This study was designed to analyze the acute effects of hyperkalemia on renin release in the normal filtering kidney and the nonfiltering kidney. Plasma K was increased by acute intravenous KCl infusion. In the normal filtering kidney experiment plasma K was 5.7 vs. 3.5 meq/l. Hyperkalemia resulted in a 45% increase in renal blood flow (RBF) and a 35% increase in glomerular filtration rate (GFR) at the 120-mmHg pressure level. Renin release was significantly greater in the hyperkalemic group than in the control group (P less than 0.01) with the greatest effect over the lower pressure range. In the nonfiltering kidney experiment plasma K was 6.09 vs. 3.5 meq/l. RBF was 33% greater in the hyperkalemic than in the normokalemic group at the 130-mmHg pressure level. Renin release was also greater in the hyperkalemic group than in the normokalemic group (P less than 0.01). However, unlike the normal filtering kidney experiments, in the nonfiltering kidneys the difference in renin release was most prominent at the highest level of renal perfusion pressure. These experiments demonstrate that acute hyperkalemia can cause renal vasodilation and stimulate renin release in both filtering and nonfiltering kidney preparations and that potassium may affect renin release both through a direct effect on the juxtaglomerular cells and indirectly by affecting delivery of fluid and/or NaCl to the macula densa.
Animals↗
Stress proteins and the immune response.
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Animals↗