title: Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease.
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 CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) 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-alpha 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.
authors.affiliation: Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Hemant
authors.initials: H
authors.lastname: Agrawal
authors.forename: Noam
authors.initials: N
authors.lastname: Jacob
authors.forename: Esther
authors.initials: E
authors.lastname: Carreras
authors.forename: Sandra
authors.initials: S
authors.lastname: Bajana
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
authors.forename: Sean
authors.initials: S
authors.lastname: Turner
authors.forename: Barbara
authors.initials: B
authors.lastname: Neas
authors.forename: Alexis
authors.initials: A
authors.lastname: Mathian
authors.forename: Michael N
authors.initials: MN
authors.lastname: Koss
authors.forename: William
authors.initials: W
authors.lastname: Stohl
authors.forename: Susan
authors.initials: S
authors.lastname: Kovats
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis; D002452:Cell Count; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D016898:Interferon-alpha / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D001323:Autoantibodies; C508032:Ifnar1 protein, mouse; D018836:Inflammation Mediators; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta