Splenic Marginal Metallophilic Macrophages and Marginal Zone Macrophages are the Major Interferon‐α/β Producers in Mice upon Intravenous Challenge with Herpes Simplex Virus

Eloranta, M-L; Alm, G.

doi:10.1046/j.1365-3083.1999.00514.x

Cited by 90 publications

(74 citation statements)

References 20 publications

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“…Both pDC and myDC could be detected early (6 h) and localized to the MZ. Here, B cells, DC, and also NK cells (30, 31) encounter blood-borne Ags, along with different subtypes of macrophages (15). By 24 h post-HSV infection, many pDCs and lyDCs had accumulated.…”

Section: Discussionmentioning

confidence: 99%

“…However, it now appears unlikely that the major burst of viral-induced IFN-␣ derives from macrophages, although it is possible that these may contribute (15).…”

Section: Discussionmentioning

confidence: 99%

“…Myeloid DC (myDC) and lymphoid-related DCs (lyDC) have also been found in different locations in steady state (14). However, after in vivo viral challenge, cells producing IFN-␣ can be detected in the marginal zone (MZ) of the spleen (15). In this early study, the cells were suggested to be macrophages because they expressed little MHC class II Ags and CD11c but it is possible that these cells and the pDC are the same (16,17).…”

mentioning

confidence: 99%

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Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-α after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity

Björck

2004

The Journal of Immunology

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Plasmacytoid dendritic cells (DC) are known to produce large amounts of IFN-α when stimulated with virus in vivo and in vitro. Immunohistological staining of spleens from mice taken at different times after HSV infection revealed an early infiltration of plasmacytoid DC whereas both the myeloid DC and lymphoid-related DC had different kinetics. Upon rechallenge with virus in vitro, total splenic DCs from viral-infected mice were unable to produce IFN-α when compared with DC from mice that received an initial in vivo injection with PBS. Furthermore, DC from mice that were infected with increasing doses of HSV expressed high levels of accessory and activation molecules compared with control mice. However, when cultured in vitro together with allogeneic T cells, DC from mice that had been exposed to the highest viral titers in vivo induced the lowest levels of T cell proliferation. DC exposed to PBS in vivo promoted a Th1 response upon coculture with CD4+ T cells whereas T cells cultured with DC exposed to increasing viral titers in vivo resulted in a gradually decreased Th1 response. The data suggest HSV induces DC maturation and at higher titers, exhaustion, diminishing T cell proliferation, and IFN-γ secretion.

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Section: Discussionmentioning

confidence: 99%

“…However, it now appears unlikely that the major burst of viral-induced IFN-␣ derives from macrophages, although it is possible that these may contribute (15).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-α after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity

Björck

2004

The Journal of Immunology

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“…Earlier reports have shown that UV-inactivated HSV is able to induce IFN-␣␤ (25,44,45), indicating that viral transcription and replication are not involved in the induction pathway. Because our results in Fig.…”

Section: Viral Glycoproteins Are Not Responsible For Ifn-␣␤ Inductionmentioning

confidence: 98%

Viral Activation of Macrophages through TLR-Dependent and -Independent Pathways

Malmgaard

Melchjorsen

Bowie

et al. 2004

The Journal of Immunology

113

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Induction of cytokine production is important for activation of an efficient host defense response. Macrophages constitute an important source of cytokines. In this study we have investigated the virus-cell interactions triggering induction of cytokine expression in macrophages during viral infections. We found that viral entry and viral gene products produced inside the cell are responsible for activation of induction pathways leading to IFN-αβ expression, indicating that virus-cell interactions on the cell surface are not enough. Moreover, by the use of cell lines expressing dominant negative versions of TLR-associated adaptor proteins we demonstrate that Toll/IL-1 receptor domain-containing adaptor inducing IFN-β is dispensable for all virus-induced cytokine expression examined. However, a cell line expressing dominant negative MyD88 revealed the existence of distinct induction pathways because virus-induced expression of RANTES and TNF-α was totally blocked in this cell line whereas IFN-αβ expression was much less affected in the absence of signaling via MyD88. In support of this, we also found that inhibitory CpG motifs, which block TLR9 signaling inhibited early HSV-2-induced TNF-α and RANTES expression dramatically whereas IFN-αβ induction was only slightly affected. This suggests that virus activates macrophages through distinct pathways, of which some are dependent on TLRs signaling through MyD88, whereas others seem to be independent of TLR signaling. Finally we demonstrate that IFN-αβ induction in HSV-2-infected macrophages requires a functional dsRNA-activated protein kinase molecule because cells expressing a dsRNA-dependent protein kinase version unable to bind dsRNA do not express IFN-αβ on infection.

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“…This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which in turn would support humoral immune responses against deposited MZ self-antigens.…”

Section: Introductionmentioning

confidence: 97%

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

et al. 2007

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Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...

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Splenic Marginal Metallophilic Macrophages and Marginal Zone Macrophages are the Major Interferon‐α/β Producers in Mice upon Intravenous Challenge with Herpes Simplex Virus

Cited by 90 publications

References 20 publications

Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-α after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity

Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-α after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity

Viral Activation of Macrophages through TLR-Dependent and -Independent Pathways

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

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