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Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype.

Körner H, Cretney E, Wilhelm P, Kelly JM, Röllinghoff M, Sedgwick JD, Smyth MJ - J. Exp. Med. (2000)

Bottom Line: By contrast, TNF deficiency alone does not result in a striking phenotype.This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype.We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation.

View Article: PubMed Central - PubMed

Affiliation: Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany. heinrich.koerner@mikrobio.med.unierlangen.de

ABSTRACT
Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and strain-dependent systemic autoimmune disease, and succumb to premature death. It is consequently termed generalized lymphoproliferative disorder (gld). By contrast, TNF deficiency alone does not result in a striking phenotype. Thus, we sought to determine what role TNF might play in contributing to the gld phenotype by creating C57BL/6.gld.TNF(-/-) mice. Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia. To confirm these data in a strain highly permissive for the phenotype, C3H/HeJ.gld and C3H.HeJ.lpr mice were treated with a TNF-specific monoclonal antibody. This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype. We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation. Most importantly, absence of TNF protects gld mice against premature death.

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The loss of B cell follicles because of the TNF deficiency is dominant in the doubly mutant mice. This outcome does not change with age. T and B cell localization was investigated in the spleens of young (12 wk of age; A, B, D, and F) and old mice (44–48 wk of age; C, E, and G). The four genotypes were compared: (A) B6.WT; (B and C) B6.TNF−/−; (D and E) B6.gld; and (F and G) B6.gld.TNF−/−. T cell areas were stained in green (FITC), and B cell areas in red (Alexa™ 594). Original magnifications: ×200.
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Figure 3: The loss of B cell follicles because of the TNF deficiency is dominant in the doubly mutant mice. This outcome does not change with age. T and B cell localization was investigated in the spleens of young (12 wk of age; A, B, D, and F) and old mice (44–48 wk of age; C, E, and G). The four genotypes were compared: (A) B6.WT; (B and C) B6.TNF−/−; (D and E) B6.gld; and (F and G) B6.gld.TNF−/−. T cell areas were stained in green (FITC), and B cell areas in red (Alexa™ 594). Original magnifications: ×200.

Mentions: Histological analysis of the spleen demonstrated a clear difference in the microarchitectural structure between B6.WT and B6.TNF−/− mice ( Fig. 3a and Fig. b), as described previously 16 17. TNF deficiency abolished the capacity of naive B cells to form organized follicles (compare Fig. 3a and Fig. b). The compartmentalization of B and T cell areas was maintained, albeit with a relaxed demarcation between the populations ( Fig. 3 B). In 12-wk-old B6.gld mice, follicle formation was clearly identifiable ( Fig. 3 D). The B6.gld.TNF−/− strain displayed a combination of these structural phenotypes, with separated T cell compartment and small rim-like structures of naive B cells ( Fig. 3 F). The structures that were histologically visible were composed of naive, normal lymphocytes. At an older age (>40 wk), defined splenic structures in B6.gld mice diminished ( Fig. 3 E), whereas demarcated but small and rim-like B cell areas were still observed in B6.gld.TNF−/− mice ( Fig. 3 G).


Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype.

Körner H, Cretney E, Wilhelm P, Kelly JM, Röllinghoff M, Sedgwick JD, Smyth MJ - J. Exp. Med. (2000)

The loss of B cell follicles because of the TNF deficiency is dominant in the doubly mutant mice. This outcome does not change with age. T and B cell localization was investigated in the spleens of young (12 wk of age; A, B, D, and F) and old mice (44–48 wk of age; C, E, and G). The four genotypes were compared: (A) B6.WT; (B and C) B6.TNF−/−; (D and E) B6.gld; and (F and G) B6.gld.TNF−/−. T cell areas were stained in green (FITC), and B cell areas in red (Alexa™ 594). Original magnifications: ×200.
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Related In: Results  -  Collection

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Figure 3: The loss of B cell follicles because of the TNF deficiency is dominant in the doubly mutant mice. This outcome does not change with age. T and B cell localization was investigated in the spleens of young (12 wk of age; A, B, D, and F) and old mice (44–48 wk of age; C, E, and G). The four genotypes were compared: (A) B6.WT; (B and C) B6.TNF−/−; (D and E) B6.gld; and (F and G) B6.gld.TNF−/−. T cell areas were stained in green (FITC), and B cell areas in red (Alexa™ 594). Original magnifications: ×200.
Mentions: Histological analysis of the spleen demonstrated a clear difference in the microarchitectural structure between B6.WT and B6.TNF−/− mice ( Fig. 3a and Fig. b), as described previously 16 17. TNF deficiency abolished the capacity of naive B cells to form organized follicles (compare Fig. 3a and Fig. b). The compartmentalization of B and T cell areas was maintained, albeit with a relaxed demarcation between the populations ( Fig. 3 B). In 12-wk-old B6.gld mice, follicle formation was clearly identifiable ( Fig. 3 D). The B6.gld.TNF−/− strain displayed a combination of these structural phenotypes, with separated T cell compartment and small rim-like structures of naive B cells ( Fig. 3 F). The structures that were histologically visible were composed of naive, normal lymphocytes. At an older age (>40 wk), defined splenic structures in B6.gld mice diminished ( Fig. 3 E), whereas demarcated but small and rim-like B cell areas were still observed in B6.gld.TNF−/− mice ( Fig. 3 G).

Bottom Line: By contrast, TNF deficiency alone does not result in a striking phenotype.This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype.We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation.

View Article: PubMed Central - PubMed

Affiliation: Interdisziplinäres Zentrum für Klinische Forschung der Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany. heinrich.koerner@mikrobio.med.unierlangen.de

ABSTRACT
Tumor necrosis factor (TNF) and Fas ligand (FasL) play major roles in the homeostasis of the peripheral immune system. This becomes dramatically obvious in the absence of a functional FasL. Mice with such a deficiency develop a profound lymphadenopathy, splenomegaly, hypergammaglobulinemia, and strain-dependent systemic autoimmune disease, and succumb to premature death. It is consequently termed generalized lymphoproliferative disorder (gld). By contrast, TNF deficiency alone does not result in a striking phenotype. Thus, we sought to determine what role TNF might play in contributing to the gld phenotype by creating C57BL/6.gld.TNF(-/-) mice. Contrary to the expected outcome, mice deficient for both FasL and TNF had a substantially milder gld phenotype with regard to mortality, lymphoaccumulation, germinal center formation, and hypergammaglobulinemia. To confirm these data in a strain highly permissive for the phenotype, C3H/HeJ.gld and C3H.HeJ.lpr mice were treated with a TNF-specific monoclonal antibody. This transient neutralization of TNF also resulted in a significantly attenuated lymphoproliferative phenotype. We conclude that TNF is necessary for the full manifestation of the lymphoproliferative disorder, in particular playing a critical role in lymphoaccumulation. Most importantly, absence of TNF protects gld mice against premature death.

Show MeSH
Related in: MedlinePlus