Cutting Edge: Biasing Immune Responses by Directing Antigen to Macrophage Fcγ Receptors

Anderson, Charles; Mosser, David M.

doi:10.4049/jimmunol.168.8.3697

Cited by 174 publications

(178 citation statements)

References 23 publications

(24 reference statements)

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“…Fc␥R engagement induces IL-12 production, and has also been shown to effectively prime CTL responses in vivo (30), suggesting that DC activation by ICs would result in Th1 polarization. In contrast, macrophages were recently reported to reverse a Th1-like response toward a Th2-like phenotype when Ag was targeted on Fc␥R (31). The signaling pathways activated during DC maturation leading to the secretion of different cytokines are still unclear.…”

Section: Discussionmentioning

confidence: 98%

A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

Sedlik

Orbach

Véron

et al. 2003

The Journal of Immunology

127

126

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Dendritic cells (DCs) are the only APCs capable of initiating adaptive immune responses. The initiation of immune responses requires that DCs 1) internalize and present Ags; and 2) undergo a differentiation process, called “maturation”, which transforms DCs into efficient APCs. DC maturation may be initiated by the engagement of different surface receptors, including certain cytokine receptors (such as TNFR), Toll-like receptors, CD40, and FcRs. The early activation events that link receptor engagement and DC maturation are not well characterized. We found that FcR engagement by immune complexes induced the phosphorylation of Syk, a protein tyrosine kinase acting immediately downstream of FcRs. Syk was dispensable for DC differentiation in vitro and in vivo, but was strictly required for immune complexes internalization and subsequent Ag presentation to T lymphocytes. Importantly, Syk was also required for the induction of DC maturation and IL-12 production after FcR engagement, but not after engagement of other surface receptors, such as TNFR or Toll-like receptors. Therefore, protein tyrosine phosphorylation by Syk represents a novel pathway for the induction of DC maturation.

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Section: Discussionmentioning

confidence: 98%

A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

Sedlik

Orbach

Véron

et al. 2003

The Journal of Immunology

127

126

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“…Accordingly, complement involvement in plaque clearance may be more pronounced at higher doses of antibody, where there would be an increased density of antibody bound to plaques. Interestingly, in contrast to other macrophage-activation paradigms, it has been shown that activation of phagocytic cells through Fc receptors results in production of the antiinflammatory cytokine IL-10 and inhibition of proinflammatory IL-12 (22). Thus, antibodies against A␤ may allow resolution of an otherwise chronic, unresolving inflammatory response associated with plaques in AD by both clearing A␤ and altering the inflammatory environment.…”

Section: Resultsmentioning

confidence: 99%

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

Bard

Barbour

Cannon

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

375

310

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Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing ␤-amyloid peptide (A␤) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the A␤ peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against A␤. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different A␤ epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of A␤ were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble A␤ was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for A␤ itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.I mmunization of the transgenic PDAPP mice with ␤-amyloid peptide (A␤)-derived immunogens results in an antibody response that facilitates the clearance of plaques within the central nervous system (CNS) (1-4). Although a number of mechanisms are likely to operate in this clearance response (5, 6), our previous findings strongly indicate that antibodymediated, Fc-dependent phagocytosis by microglial cells and͞or macrophages is important to the process (7). Importantly, a T cell response was not required for amyloid plaque clearance. When peripherally administered, antibodies against A␤ entered the CNS of PDAPP transgenic mice, decorated amyloid plaques, and induced plaque clearance. Comparing different antibodies in an ex vivo assay with sections of PDAPP or Alzheimer's disease (AD) brain, there was a strong correlation between those that produced ex vivo efficacy and those that were efficacious in vivo. Fc receptors on microglial cells were found to be key for the clearance response in this assay. However, it has been reported that antibody efficacy can also be obtained in vivo by mechanisms that are independent of Fc interactions (8). Studies have indicated that an antibody directed against the midportion of A␤, which cannot recognize amyloid plaques, appears to bind to soluble A␤ and reduce plaque deposition (6). In addition, it has been reported recently that short-term...

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“…Distinction between immunosuppressive alternatively activated macrophages, activated by IL-4 or glucocorticoids, and anti-inflammatory type 2 macrophages, which promote Th2 cell responses [57] and are elicited by TLR or Fcc receptor ligation [58], has been suggested. Verreck and coworkers recently described that human macrophages, polarized by M-CSF rather than GM-CSF (Mf-2), subvert T cell responses to mycobacteria by down-regulating antigen-presenting activities and producing IL-10 rather than IL-12 or IL-23 [59].…”

Section: Discussionmentioning

confidence: 99%

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

et al. 2006

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A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after co-infection with Mycobacterium tuberculosis and Th2-eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow-derived macrophages alternatively activated by IL-4 in response to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4-and IFN-c-activated macrophages revealed delayed and partially diminished responses to intracellular bacteria in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix-remodeling enzyme matrix metalloproteinase (MMP)-12 was induced in alternatively activated macrophages in vitro, and MMP-12-expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms that limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis.

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Cutting Edge: Biasing Immune Responses by Directing Antigen to Macrophage Fcγ Receptors

Cited by 174 publications

References 23 publications

A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

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