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Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression.

Giese NA, Gabriele L, Doherty TM, Klinman DM, Tadesse-Heath L, Contursi C, Epstein SL, Morse HC - J. Exp. Med. (1997)

Bottom Line: In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response.Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide.This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0760, USA. ngiese@atlas.niaid.nih.gov

ABSTRACT
Mice with a mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a chronic myelogenous leukemia-like syndrome and mount impaired responses to certain viral and bacterial infections. To gain a mechanistic understanding of the contributions of ICSBP to humoral and cellular immunity, we characterized the responses of control and ICSBP-/- mice to infection with influenza A (flu) and Leishmania major (L. major). Mice of both genotypes survived infections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response. In sera of ICSBP-/- mice, however, IgG1 antibodies dominated over IgG2a antibodies, a pattern indicative of a Th2-driven response. The dominance of IgG1 and IgE over IgG2a was detected in the sera of uninfected mice as well. A seeming Th2 bias of ICSBP-deficient mice was also uncovered in their inability to control infection with L. major, where resistance is known to be dependent on IL-12 and IFN-gamma as components of a Th1 response. Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide. Compromised Th1 differentiation in ICSBP-/- mice could not be attributed to hyporesponsiveness of CD4(+) T cells to interleukin (IL)-12; however, the ability of uninfected and infected ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

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Microscopic examination of tissues from ICSBP mutant mice. (A) Histopathology of infected footpads, liver, spleen, and DLNs of ICSBP−/−  (KO) or ICSBP+/+ (WT) mice injected with L. major on day 49 after infection. Sections were stained with hematoxylin and eosin. The original magnification was 4 for liver, spleen, and left DLN panel; 40 for footpads and right DLN panel. Detailed description is given in the text. (B) Photomicrograph of  cytospin preparations of thioglycollate-induced peritoneal washout cells obtained from uninfected ICSBP−/− (KO) and ICSBP+/+ (WT) mice (Wright's-Giemsa stain; original magnification: 100).
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Figure 4: Microscopic examination of tissues from ICSBP mutant mice. (A) Histopathology of infected footpads, liver, spleen, and DLNs of ICSBP−/− (KO) or ICSBP+/+ (WT) mice injected with L. major on day 49 after infection. Sections were stained with hematoxylin and eosin. The original magnification was 4 for liver, spleen, and left DLN panel; 40 for footpads and right DLN panel. Detailed description is given in the text. (B) Photomicrograph of cytospin preparations of thioglycollate-induced peritoneal washout cells obtained from uninfected ICSBP−/− (KO) and ICSBP+/+ (WT) mice (Wright's-Giemsa stain; original magnification: 100).

Mentions: Histologic studies of infected wild-type mice showed that the inflamed footpads gradually healed and that there were no lesions in the spleens or livers (Fig. 4 A). In contrast, the footpads of ICSBP−/− mice exhibited marked swelling with both superficial and deep ulceration, necrosis, and striking accumulation of extremely heavily parasitized macrophages (≫100 parasites/cell). Of interest, the lesions contained few neutrophils or lymphocytes, and signs of chronic inflammation or formation of granulation tissue were not observed. Excessive parasite burdens were also detected in the DLNs (Fig. 4 A), in which isolated foci of lymphocytes were shouldered to the periphery by sheets of ballooned, infested macrophages. The DLNs of infected ICSBP−/− mice were also significantly enlarged over those of wild-type animals, with weights of 98 ± 19 versus 17 ± 3 mg, respectively, at 53 d after infection. The cellularity of nodes from the knockout mice was increased only 1.5-fold over that of their wild-type counterparts, however, reflecting the differential contributions of parasitized macrophages versus responsive lymphocytes to nodal structure.


Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression.

Giese NA, Gabriele L, Doherty TM, Klinman DM, Tadesse-Heath L, Contursi C, Epstein SL, Morse HC - J. Exp. Med. (1997)

Microscopic examination of tissues from ICSBP mutant mice. (A) Histopathology of infected footpads, liver, spleen, and DLNs of ICSBP−/−  (KO) or ICSBP+/+ (WT) mice injected with L. major on day 49 after infection. Sections were stained with hematoxylin and eosin. The original magnification was 4 for liver, spleen, and left DLN panel; 40 for footpads and right DLN panel. Detailed description is given in the text. (B) Photomicrograph of  cytospin preparations of thioglycollate-induced peritoneal washout cells obtained from uninfected ICSBP−/− (KO) and ICSBP+/+ (WT) mice (Wright's-Giemsa stain; original magnification: 100).
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Related In: Results  -  Collection

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Figure 4: Microscopic examination of tissues from ICSBP mutant mice. (A) Histopathology of infected footpads, liver, spleen, and DLNs of ICSBP−/− (KO) or ICSBP+/+ (WT) mice injected with L. major on day 49 after infection. Sections were stained with hematoxylin and eosin. The original magnification was 4 for liver, spleen, and left DLN panel; 40 for footpads and right DLN panel. Detailed description is given in the text. (B) Photomicrograph of cytospin preparations of thioglycollate-induced peritoneal washout cells obtained from uninfected ICSBP−/− (KO) and ICSBP+/+ (WT) mice (Wright's-Giemsa stain; original magnification: 100).
Mentions: Histologic studies of infected wild-type mice showed that the inflamed footpads gradually healed and that there were no lesions in the spleens or livers (Fig. 4 A). In contrast, the footpads of ICSBP−/− mice exhibited marked swelling with both superficial and deep ulceration, necrosis, and striking accumulation of extremely heavily parasitized macrophages (≫100 parasites/cell). Of interest, the lesions contained few neutrophils or lymphocytes, and signs of chronic inflammation or formation of granulation tissue were not observed. Excessive parasite burdens were also detected in the DLNs (Fig. 4 A), in which isolated foci of lymphocytes were shouldered to the periphery by sheets of ballooned, infested macrophages. The DLNs of infected ICSBP−/− mice were also significantly enlarged over those of wild-type animals, with weights of 98 ± 19 versus 17 ± 3 mg, respectively, at 53 d after infection. The cellularity of nodes from the knockout mice was increased only 1.5-fold over that of their wild-type counterparts, however, reflecting the differential contributions of parasitized macrophages versus responsive lymphocytes to nodal structure.

Bottom Line: In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response.Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide.This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0760, USA. ngiese@atlas.niaid.nih.gov

ABSTRACT
Mice with a mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a chronic myelogenous leukemia-like syndrome and mount impaired responses to certain viral and bacterial infections. To gain a mechanistic understanding of the contributions of ICSBP to humoral and cellular immunity, we characterized the responses of control and ICSBP-/- mice to infection with influenza A (flu) and Leishmania major (L. major). Mice of both genotypes survived infections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response. In sera of ICSBP-/- mice, however, IgG1 antibodies dominated over IgG2a antibodies, a pattern indicative of a Th2-driven response. The dominance of IgG1 and IgE over IgG2a was detected in the sera of uninfected mice as well. A seeming Th2 bias of ICSBP-deficient mice was also uncovered in their inability to control infection with L. major, where resistance is known to be dependent on IL-12 and IFN-gamma as components of a Th1 response. Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-gamma and macrophages of producing nitric oxide. Compromised Th1 differentiation in ICSBP-/- mice could not be attributed to hyporesponsiveness of CD4(+) T cells to interleukin (IL)-12; however, the ability of uninfected and infected ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

Show MeSH
Related in: MedlinePlus