The biology of the SCID mutation.
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Animals↗
Biomedical subjects
G J Bancroft
Publications and source records attributed to G J Bancroft.
Pathology of Listeria infection in murine severe combined immunodeficiency. A study by immunohistochemistry and electron microscopy.
Mice bearing the scid mutation lack functional T and B lymphocytes and partially resist infection with the intracellular pathogen Listeria monocytogenes. In this study, we describe the histopathologic features of the infection in scid mice. Infected scid showed hyperplasia of mononuclear cells in lymphoid organs without any evidence of granulomas nor of lymphoid cell development. Mononuclear phagocytes in various tissues of infected scid mice had markedly enhanced expression of class II histocompatibility molecules (or Ia molecules). Furthermore, Ia expression was also found in endothelial and epithelial cells of many organs in the later stages of infection. These results confirm that scid mice have a mechanism for activation of Ia antigen expression, which is independent of lymphocyte function.
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A T cell-independent mechanism of macrophage activation by interferon-gamma.
A primary interest in immunity to intracellular pathogenic microorganisms and tumors is to understand the mechanisms by which macrophages are activated for various functions. Two parameters of macrophage activation are the expression of the class II histocompatibility proteins or Ia molecules (1), and cytotoxic activity. The ability of T cells to induce these responses has been extensively documented and occurs via their secretion of interferon-gamma (IFN-gamma) after interaction with antigen (2-6). However, in a recent study using mice with the severe combined immunodeficiency (scid) mutation (7) which have no detectable T or B cell functions (7-9), we were surprised to find the induction of Ia expression on macrophages and the partial inhibition of bacterial growth after infection with Listeria monocytogenes (10). We have now utilized neutralizing monoclonal antibodies specific for murine IFN-gamma to investigate the mechanism of macrophage activation in scid mice. We show here that IFN-gamma can be produced by scid mice in the absence of lymphocyte-mediated immunity, and this IFN-gamma is important for macrophage activation during infection with Listeria. These results indicate the presence of an important T lymphocyte-independent mechanism of macrophage activation and IFN-gamma production in response to infection.
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Regulation of macrophage Ia expression in mice with severe combined immunodeficiency: induction of Ia expression by a T cell-independent mechanism.
We have studied the expression of Ia molecules by macrophages from mice with severe combined immunodeficiency (CB-17 scid) that lack demonstrable T cell and B cell functions. CB-17 scid mice had approximately normal numbers of Ia-bearing macrophages in the peritoneal cavity, spleen, and liver. Peritoneal macrophages responded in culture to T cell-derived lymphokines with enhanced expression of Ia molecules. However, unlike immunocompetent controls, SCID mice could not enhance Ia expression in an antigen-specific T cell-dependent manner after secondary challenge in vivo with a conventional protein antigen such as hemocyanin. Further demonstration of their T cell deficiency was the failure of CB-17 scid spleen cells to proliferate and produce IL 2 in response to the T cell mitogen, concanavalin A. Upon infection with Listeria monocytogenes, CB-17 scid mice developed chronically high loads of bacteria, whereas CB-17 control mice eliminated all viable bacteria and became resistant to secondary infection. However, Listeria-infected CB-17 scid mice did show, in parallel with the CB-17 controls, an unexpected and striking increase of Ia-positive macrophages. These data indicate that induction of Ia expression in macrophages can occur via a mechanism that is independent of mature T cells.
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Suppression of immune response to Listeria monocytogenes: mechanism(s) of immune complex suppression.
We have investigated possible mechanisms underlying immune complex suppression of resistance to Listeria monocytogenes. Inhibition of resistance was found when immune complexes were formed in vivo in immune mice or in nonimmune mice adoptively transferred with specific antibody. Suppression was also found when nonimmune mice were injected with immune complexes preformed in vitro. We investigated the role of complement by decomplementing mice with cobra venom factor purified by high-pressure liquid chromatography. Complete depletion of serum C3 did not eliminate immune complex suppression of resistance to L. monocytogenes, suggesting that complement activation is not required for immune complex suppression. Infection-induced changes in the surface phenotype and functional properties of macrophages from normal and immune complex-suppressed mice were also investigated. Macrophage expression of both H-2K and Ia molecules increased during the response of normal mice to L. monocytogenes. However, these changes were not found in immune complex-suppressed mice. In contrast, membrane interleukin 1 expression was increased in macrophages from suppressed mice compared with macrophages from normal mice. Macrophages from L. monocytogenes-infected normal and immune complex-suppressed mice expressed cytotoxicity against tumor cells in vitro. We conclude that immune complexes do not inhibit resistance to L. monocytogenes by activation of complement or decreasing macrophage cytotoxic activity. Rather, defects in Ia expression by macrophages from suppressed mice might be one component responsible for immune complex suppression of resistance to L. monocytogenes.
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Interaction of African trypanosomes with the immune system.
African trypanosomes cause disease in man and domestic animals. The parasites have the ability to escape immune control by two means: by antigenic variation of the surface glycoprotein coat so that waves of variant parasites arise and by inducing a general immunosuppression affecting immune responses to the parasite as well as to parasite-unrelated antigens. The cellular basis of the immune dysfunction will be discussed in relation to a mouse model system - it is the result of proliferative stimuli to T- or B-cells which then become refractory to selection by antigen and normal control signals. Recent experiments have focused on macrophages as important direct target cells for parasite action. We have obtained no evidence for a parasite derived mitogen acting directly on B- or T-cells. In vitro cell proliferation is associated with accessory cells and relates only to T-cells. During infection, macrophages become activated with changes in receptor expression and mediator release, so that there is, for example, spontaneous IL-1 release (with a role in T- and possibly in B-cell proliferation) and several-fold increases in PGE2 secretion, with its immunosuppressive activities. We also find parasitaemia-associated release of alpha-beta and gamma interferon by various cells which in turn influences immune function. The active parasite component is associated with parasite membranes, but its nature has not been further defined. We proposed that the macrophage changes provide a general pathway causing immune dysfunction associated with many infections, be they parasitic or caused by other invading organisms.
Adjuvants, Immunologic↗
Production of interferons during experimental African trypanosomiasis.
African trypanosomiasis is associated with profound changes in the function of the immune system. In this study we find that alpha/beta and gamma interferon (IFN) are released into the serum of mice infected with Trypanosoma brucei. The parasite-induced rise in serum IFNs is associated with a detectable parasitaemia, but the serum IFN peak precedes the peak parasitaemia in some cases. Unlike other protozoan interferon inducers, no parasite-dependent IFN production was observed in the pre-patent period of infection; while the most virulent clone induced very high IFN levels, no clear difference in stimulation was noted in the first waves of semi-acute and chronic T. brucei clones. However, subsequent IFN augmentation more closely reflected the host parasite load and virulence of infection. The nature of the stimulatory parasite component is as yet unknown, and the parasite surface glycoprotein had no effect on serum IFN. Injection of large quantities of lethally irradiated, but intact organisms did not stimulate IFN production; however this treatment significantly impaired antibody responses to the heterologous antigen SRBC. This suggests that the more severe effects of an actual trypanosome infection are required for induction of IFN synthesis, and that the presence of measurable serum IFN is not a prerequisite for parasite-induced suppression of host antibody responses.
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Increased susceptibility to cytomegalovirus infection in beige mutant mice.
Mice homozygous for the beige gene (bg/bg) are a homologue of the Chédiak-Higashi syndrome of man and are known to be selectively defective in natural killer (NK) cells. We have compared the susceptibility of bg/bg and bg/+ C57BL/6J mice to infection with murine cytomegalovirus (MCMV). Beige mice are more susceptible to lethal infection and develop 33- to 43-fold higher virus titers in the liver, spleen, and kidney than do bg/+ mice after a sublethal infection, although virus replication is the same in vitro in cultured fibroblasts or epithelial cells from these mice. Inoculation with a sublethal dose of virus stimulates a NK cell response, although this is lower in bg/bg mice despite higher titers of interferon type 1 than in bg/+. A dose of MCMV that is lethal only to bg/bg augments cytotoxicity within 12 hr in bg/+ mice, whereas cytotoxicity in bg/bg remains very low. In bone marrow chimeras, recipients of bg/bg marrow were more susceptible to MCMV and had lower NK cell responses after virus inoculation than did recipients of marrow from bg/+ donors. The greater susceptibility of beige mice to the virus suggests that NK cells may contribute to resistance early in McMV infection.
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Genetic influences on the augmentation of natural killer (NK) cells during murine cytomegalovirus infection: correlation with patterns of resistance.
Cytotoxic activity attributable to natural killer (NK) cells was augmented in the spleens of mice infected with murine cytomegalovirus (MCMV). Stimulation was observed as early as 10 hr after virus administration but was dependent upon the dose used, and in particular, the host genotype. Effector cells were capable of killing a range of tumor cell targets as well as normal syngeneic thymocytes, and were induced in nude (nu/nu) and heterozygous (nu/+) mice. A significant correlation existed between resistance to the lethal effects of MCMV infection and the degree of NK cell augmentation by this virus in 10 of 11 strains examined. Non-H-2 related differences in activity were observed, but a clear association between high NK cell responses and the possession of a particular H-2 haplotype was not apparent. Beige mutant C57BL/6J mice, previously reported as defective in NK cell function were susceptible to MCMV and expressed low levels of cytotoxicity during infection. Thus, the genetically controlled stimulation of NK cells in the early stages of infection with MCMV may contribute to the genotype related patterns of resistance seen with this virus.
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