Immune responses in the post-polio syndrome.
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Biomedical subjects
Publications and source records attributed to L T Rosenberg.
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Each of the two mutants isolated from a fliC (= hag, flagellin-deficient) Escherichia coli strain made motile by a plasmid carrying the fliC gene of Salmonella muenchen by selection for motility in the presence of anti-d (Salmonella flagellar antigen) serum had both lost and gained one or more subfactors of the wild-type antigen. In one mutant codon 246 was GAC (alanine) instead of GCC (asparagine); the other had a deletion of 105 base pairs, explicable by a 10bp direct repeat, starting at bases 782 and 887. The in vitro removal of a 48bp EcoRV(631)/EcoRV(679) fragment produced plasmid pLS408, which was found to lack a subfactor of wild-type antigen d but able to confer motility on flagellin-negative Salmonella sp. (and used for insertion of epitope-specifying oligonucleotides at its EcoRV site). Immunoblotting with absorbed and unabsorbed sera from rabbits immunized with E. coli with wild-type or mutated antigen d showed that the fusion proteins specified by lambda gt11 with the N-terminal part of gene lacZ joined to a restriction fragment coding for residues 145-391 of flagellin gave the same pattern of parent-specific and mutant-specific reactions as the flagellate bacteria. Four out of five similarly selected mutants had the same 105 bp deletion as the first-isolated mutant; the fifth had a 72 bp deletion made possible by a 7-base pair direct repeat, starting at positions 649 and 721. All these changes in serological character without loss of function affected segment IV, specifying residues 182 to 308 of the total of 505, where there is little homology between different flagellar-antigen alleles.
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The following research assessed the influence of developmental, hormonal, and psychological factors on immunoglobulin and complement protein levels in the squirrel monkey. A cross-sectional life span study established that the developmental pattern of immunoglobulins and complement proteins was similar to that observed in humans. IgG and IgM levels rose progressively with age, while the complement system was mature at birth. In contrast to humans, this species showed a significant sex difference in IgG levels, with higher levels in males during both infancy and adulthood. Males also showed a greater antibody response to viral challenge than did females, and evaluation of gonadectomized subjects suggested that the sex difference in antibody production was testosterone-dependent. The effect of acute and sustained psychological disturbance on IgG levels was also evaluated in infant monkeys. Repeated, brief separations from the mother did not alter IgG levels, but IgG levels were suppressed after a 7-day removal from the mother. Therefore, despite the general view that immunoglobulin levels are relatively stable, these studies have established that immunoglobulin levels can be strongly influenced by hormonal and experiential factors in the squirrel monkey.
The following study assessed changes in macrophage responsiveness after a 24-h period of psychological disturbance in mother and infant squirrel monkeys. Utilizing a luminol-dependent assay, an 80-min chemiluminescent burst was measured in blood monocytes in response to zymosan stimulation. Cells obtained from stressed mothers and infants showed significant increases in chemiluminescence (CL) as compared to baseline levels. Moreover, the elevated pattern of response persisted for at least 2 weeks after the mothers and infants were reunited. The initial change in CL was associated with increased pituitary-adrenal activity and leukocyte redistribution, but these measures returned to normal levels following reunion. Thus, this study has demonstrated a prolonged change in an immune parameter following a transient alteration in the psycho-endocrine status of the host.
Hemolytic complement activity and complement protein levels were evaluated before and after psychological disturbance in the squirrel monkey. Significant increases in hemolytic complement activity were observed following separation of 6-month-old infants from their mothers. Complement protein levels were generally correlated with hemolytic activity, but did not show the same pattern of change. C3 levels did not change consistently after maternal separation, while C4 decreased significantly on Day 7, and then began to return toward basal levels by Day 14. The alterations in complement activity were associated with elevated adrenal hormone secretion, but were not directly correlated with plasma cortisol levels. A second experiment showed that increased hemolytic complement activity also occurred in juvenile squirrel monkeys following 4-hour to 7-day removals from a peer group. The effect of maternal separation on antibody responses to viral challenge was evaluated in a third experiment. Separated infant squirrel monkeys mounted a smaller antibody response than did control infants that remained with their mothers. A similar decline in antibody responses was observed in separated rhesus macaque infants, but the effect was less marked in this species. Thus, the strong effect of psychological disturbance on immunity in the squirrel monkey is probably related to its prolonged endocrine responses.
The capacity of infant squirrel monkeys to mount an antibody response to viral challenge was evaluated after removal from their mothers in several social and physical environments. Control and separated infants were injected with a benign virus, the bacteriophage X174, and levels of neutralizing antibody were assessed for 3 weeks. Infants separated alone in an unfamiliar environment showed a significant reduction in antibody levels as compared to control infants. Allowing infants to remain in the home environment, either alone or with peers, prevented this inhibition of antibody responses from occurring. Similarly, providing familiar peers in the novel environment facilitated the normal expression of antibody responses. These results indicate that the trauma of maternal separation is significantly reduced when infants are familiar with the separation environment or familiar social companions are available. The reduced antibody response was associated with the highest level of adrenal activation induced by the unfamiliar separation condition, but antibody titers and plasma cortisol levels could not be specifically correlated in individual infants.
The ability of the microbial siderophores deferriferrichrome, deferriferrichrome A, and enterobactin to remove iron from ferritin has been investigated. In contrast to previously published data with other chelators, all three siderophores rapidly released iron from the mammalian storage protein. Enterobactin was found most efficient at removing ferritin-bound iron. Using this siderophore, the mechanism by which ferritin sequesters iron was studied. The relative iron saturation level of ferritin influenced the rate of chelation by the microbial siderophores.
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Male and female guinea pigs receiving, respectively, 100 and 280 mg/day Vitamin C throughout the duration of immunization showed enhanced humoral antibody production to bovine serum albumin (BSA) and, in castrated females, to penicilloyl-coupled guinea pig gamma-globulin. A significant degree of protection was afforded against fatal anaphylactic shock in passively sensitized males. Under appropriate conditions of sensitization with rabbit anti-HGG and challenge with human gamma-globulin, 8 of 20 unsupplemented animals died of shock, whereas in the group receiving 280 mg Na ascorbate/day for 4 days preceding passive transfer and again 60' before challenge, only 2 of 18 died. The rate of dose-dependent mortality observed when groups of passively sensitized animals were challenged with increasing doses of antigen was reduced in animals supplemented as above. Actively immunized guinea pigs were not protected by 5 daily doses of 280 mg Na ascorbate given prior to challenge. There were no significant differences in the total hemolytic activity of the serum nor in the C3 and C4 components of complement in immunized animals. There was no change in the concentration of Cl esterase in non-immunized controls, but immunization with BSA was followed by a rapid decline in Cl concentration, the decrease being greater in the ascorbate-treated group than in the unsupplemented controls, possibly reflecting a higher level of circulating immune complexes in the former case.
The genetic polymorphism in early, immunoglobulin M, responsiveness to the Klebsiella pneumoniae type 47 polysaccharide (K47-PS) is determinant specific, and L-rhamnose is probably the determinant against which differential responsiveness is expressed. This is inferred from tests of the response to the cross-reacting Streptococcus pneumoniae type 23 and non-cross-reacting pneumococcal polysaccharides of known chemical construction. B10.2/Sn new-line mice are high responders and BALB/c mice are low responders to K47-PS. Upon immunization with killed S. pneumoniae type 23, these strains produce cross-reacting antibody to K47-PS. The cross-reacting antibody responses of these strains are congruent with their responses to K47-PS.
Acute infection with lactic dehydrogenase virus (LDV) causes a systemic alteration in lymphocyte circulatory patterns. Peripheral lymph nodes (LN) and spleens in acutely, but not chronically, infected mice retain a significantly greater proportion of injected 51Cr-labeled lymphocytes than the respective tissues in noninfected controls. This increase in lymphocyte localization in LN and spleen is dependent upon the dose of LDV injected and the timing of the infection. A relatively large dose of LDV (10(8) infectious units) causes an early but very transient increase in splenic lymphocyte localization accompanied by an early but prolonged increase in lymphocyte recovery in LN. Smaller doses of LDV cause more prolonged effects on splenic lymphocyte recovery and retarded effects on lymphocyte localization in LN. Increases in splenic recovery were always accompanied by decreases in hepatic recovery of lymphocytes. LDV-induced alteration in lymphocyte circulation may be responsible for many previously observed modifications of immune responses in LDV-infected mice.
Cell-free fluid from several ascites promoting tumors inhibits lymphocyte trapping. Lactic dehydrogenase virus (LDV), a common passenger virus in many mouse tumors, was found to be a trapping inhibitor component in these fluids. Procedures used to eliminate infective LDV, such as dilution, passage of the tumor through irradiated rats, ether fractionation, and ultraviolet (UV) irradiation abolished the trapping inhibitory capacity of the fluids. LDV, dissociated from tumors, was inhibitory. Lymph nodes in mice with acute, but not chronic, LDV infections were inhibited from trapping. LDV does not appear to inhibit the capacity of circulating cells to be trapped, and as measured by mitogen responsiveness, the virus does not directly interfere with T-cell function. LDV may inhibit trapping by indirectly affecting the T cell or directly affecting the macrophage in which it replicates. The known characteristics of LDV infection may explain a number of reported immunosuppressive attributes of tumor-associated ascitic fluids.
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Experiments performed to determine the influence of the C5 component of complement in experimental Toxoplasma infection revealed that mice deficient in C5 had reduced mortality due to acute toxoplasmosis. Similar results were noted when inbred congenic mice of known complement type, as well as random-bred mice selected for complement type, were used. In both, mice with high complement activity were less resistant to Toxoplasma than were mice deficient in C5. However, many factors must interact in susceptibility to infection with T. gondii. Thus, lower resistance to Toxoplasma was noted in C5-deficient DBA/2J mice, whereas a high degree of resistance was noted in DBA/1J mice, which are not related to DBA/2J mice and which possess a normal sequence of complement. This accentuates the importance of using both random-bred and where possible cogenic lines in assessing the importance of individual factors in infectious immunity.