Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease

Hemant Agrawal, Noam Jacob, Esther Carreras, Sandra Bajana, Chaim Putterman, Sean Turner, Barbara Neas, Alexis Mathian, Michael N. Koss, William Stohl, Susan Kovats, Chaim O. Jacob

Research output: Contribution to journalArticle

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Abstract

Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR-/- mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZMIFNAR -/- mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR-/- spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR-/- DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR-/- DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR-/- DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.

Original languageEnglish (US)
Pages (from-to)6021-6029
Number of pages9
JournalJournal of Immunology
Volume183
Issue number9
DOIs
StatePublished - Nov 1 2009

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New Zealand
Dendritic Cells
Cell Count
Spleen
Lymph Nodes
Interleukin-12 Subunit p40
Kidney
Lupus Nephritis
Adaptive Immunity
Innate Immunity
Systemic Lupus Erythematosus
Mental Competency
B-Lymphocytes
Ligands
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology

Cite this

Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. / Agrawal, Hemant; Jacob, Noam; Carreras, Esther; Bajana, Sandra; Putterman, Chaim; Turner, Sean; Neas, Barbara; Mathian, Alexis; Koss, Michael N.; Stohl, William; Kovats, Susan; Jacob, Chaim O.

In: Journal of Immunology, Vol. 183, No. 9, 01.11.2009, p. 6021-6029.

Research output: Contribution to journalArticle

Agrawal, H, Jacob, N, Carreras, E, Bajana, S, Putterman, C, Turner, S, Neas, B, Mathian, A, Koss, MN, Stohl, W, Kovats, S & Jacob, CO 2009, 'Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease', Journal of Immunology, vol. 183, no. 9, pp. 6021-6029. https://doi.org/10.4049/jimmunol.0803872
Agrawal, Hemant ; Jacob, Noam ; Carreras, Esther ; Bajana, Sandra ; Putterman, Chaim ; Turner, Sean ; Neas, Barbara ; Mathian, Alexis ; Koss, Michael N. ; Stohl, William ; Kovats, Susan ; Jacob, Chaim O. / Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. In: Journal of Immunology. 2009 ; Vol. 183, No. 9. pp. 6021-6029.
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abstract = "Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR-/- mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZMIFNAR -/- mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR-/- spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR-/- DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR-/- DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR-/- DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.",
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AU - Putterman, Chaim

AU - Turner, Sean

AU - Neas, Barbara

AU - Mathian, Alexis

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N2 - Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR-/- mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZMIFNAR -/- mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR-/- spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR-/- DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR-/- DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR-/- DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.

AB - Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR-/- mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZMIFNAR -/- mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR-/- spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR-/- DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR-/- DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR-/- DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.

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