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PubMed1963

MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS. I. SPECIFICITY OF PYROGENIC TOLERANCE AND THE ROLE OF HYPERSENSITIVITY IN PYROGENICITY, LETHALITY, AND SKIN REACTIVITY.

Evidence is presented suggesting that the apparent non-specificity of pyrogenic tolerance observed with Gram-negative bacterial endotoxins is due to related antigenic determinants associated with the macromolecular toxins. This is based on results obtained in rabbits from pyrogenic cross-tolerance tests with selected endotoxins. In these tests, purified endotoxins from Escherichia coli (COO8) and Chromobacterium violaceum (CV) gave results one might expect with non-reciprocal cross-reacting antigens in classical immune systems. Additional evidence for an immune mechanism in tolerance is suggested by the highly significant anamnestic response observed. Lipid A, a toxic derivative of the purified COO8 endotoxin, failed to induce pyrogenic tolerance against the parent toxin. These results are explained by assuming that endotoxins have two interdependent activities associated with different portions of the macromolecule; one is assumed to be responsible for the primary toxicity, and the other is involved in secondary toxicity. The latter is dependent on the hypersensitive state of the host. Additional evidence for the role of hypersensitivity in secondary toxicity is based on the observation that adult rabbits are highly sensitive to the pyrogenic, lethal, and skin-reacting activities of endotoxin in contrast to young animals which are more resistant to all of these attributes of toxicity. In adults, the host responses to pyrogenicity, lethality, and skin reactivity could be partially inhibited by the early exposure of the animals to massive doses of endotoxin equivalent to a LD(50). The pyrogenic tolerance shown in these animals was specific indicating that the inhibition of the hypersusceptibility to endotoxin involved an immunological mechanism. A mechanism of endotoxin tolerance is proposed and discussed based on the induction of specific antibodies capable of assisting the RES in the clearance and destruction of endotoxin. It is suggested that the present inconsistencies relative to the chemical nature and biological activities of endotoxins might be explained on the basis of these two activities and the failure to recognize the importance of the immunological state of the host in which the toxins are tested.

Animals↗
PubMed1963

ASSOCIATION OF "NATURAL" ANTIBODIES TO GRAM-NEGATIVE BACTERIA WITH THE GAMMA-1-MACROGLOBULINS.

"Natural" antibodies to representative species of Enterobacteriaceae were found to be principally associated with the gamma(1)-macroglobulin prepared from Cohn fraction III-I of pooled human plasma. The amount of antibodies present was estimated by measuring the bactericidal, hemagglutinating, mouse-protective, and opsonophagocytic activities of this fraction. Comparison with the antibody activity of gamma(2)-globulin of Cohn fraction II showed that up to 100 times more antibody activity on a weight basis was present in the macroglobulin fraction. These findings suggest that differences between natural and immune antibody result from the physicochemical properties of 2 different classes of immune globulin.

Animals↗
PubMed1964

EVOLUTION OF THE IMMUNE RESPONSE. I. THE PHYLOGENETIC DEVELOPMENT OF ADAPTIVE IMMUNOLOGIC RESPONSIVENESS IN VERTEBRATES.

1. The California hagfish, Eptatretus stoutii, seems to be completely lacking in adaptive immunity: it forms no detectable circulating antibody despite intensive stimulation with a range of antigens; it does not show reactivity to old tuberculin following sensitization with BCG; and gives no evidence of homograft immunity. 2. Studies on the sea lamprey, Petromyzon marinus, have been limited to the response to bacteriophage T(2) and hemocyanin in small groups of spawning animals. They suggest that the lamprey may have a low degree of immunologic reactivity. 3. One holostean, the bowfin (Amia calva) and the guitarfish (Rhinobatos productus), an elasmobranch, showed a low level of primary response to phage and hemocyanin. The response is slow and antibody levels low. Both the bowfin and the guitarfish showed a vigorous secondary response to phage, but neither showed much enhancement of reactivity to hemocyanin in the secondary response. The bowfin formed precipitating antibody to hemocyanin, but the guitarfish did not. Both hemagglutinating and precipitating antibody to hemocyanin were also observed in the primary response of the black bass. 4. The bowfin was successfully sensitized to Ascaris antigen, and lesions of the delayed type developed after challenge at varying intervals following sensitization. 5. The horned shark (Heterodontus franciscii) regularly cleared hemocyanin from the circulation after both primary and secondary antigenic stimulation, and regularly formed hemagglutinating antibody, but not precipitating antibody, after both primary and secondary stimulation with this antigen. These animals regularly cleared bacteriophage from the circulation after both the primary and secondary stimulation with bacteriophage T(2). Significant but small amounts of antibody were produced in a few animals in the primary response, and larger amounts in the responding animals after secondary antigenic stimulation. 6. Studies by starch gel and immunoelectrophoresis show that the hagfish has no bands with mobilities of mammalian gamma globulins; that the lamprey has a single, relatively faint band of this type; and that multiple gamma bands are characteristic of the holostean, elasmobranchs, and teleosts studied. By this method of study, the bowfin appeared to have substantial amounts of gamma(2) globulin. 7. We conclude that adaptive immunity and its cellular and humoral correlates developed in the lowest vertebrates, and that a rising level of immunologic reactivity and an increasingly differentiated and complex immunologic mechanism are observed going up the phylogenetic scale from the hagfish, to the lamprey, to the elasmobranchs, to the holosteans, and finally the teleosts.

Adaptation, Physiological↗
PubMed1964

STUDIES RELATING TO THE SERUM RESISTANCE OF CERTAIN GRAM-NEGATIVE BACTERIA.

Paracolobactrum ballerup, an organism considered completely insusceptible to the bactericidal action of the antibody-complement system, became extremely sensitive to immune serum and even to normal serum, in conjunction with complement, when cultivated at temperatures above 37 degrees C. This conversion to serum sensitivity was associated with the loss of the organism's Vi antigen and its tendency to assume a rough state. It did not result in a genetic change in the organism, however, since reincubation of serum-sensitive P. ballerup at 37 degrees C resulted in a restoration of its resistance. The loss of serum resistance as a result of cultivation temperatures above 37 degrees C may be of significance as an example of the enhancement of host defense mechanisms induced by fever. Special conditions of testing indicated that P. ballerup cultured at 37 degrees C and S. paratyphosa C, organisms considered insusceptible to serum bactericidal action, were not entirely refractory to serum. These conditions included simply a relatively low ratio of the number of test organisms to serum volume and an extended incubation period of the organisms with serum bactericidal substances, or even without these substances, prior to the initiation of bactericidal action. It is likely, therefore, that an absolute distinction between serum-sensitive and serum-resistant Gram-negative organisms does not exist, but rather that there is a very broad distribution of serum sensitivity among these organisms.

Animals↗