Article

Inhibition of Experimental Autoimmune Encephalomyelitis in Human C-Reactive Protein Transgenic Mice Is FcγRIIB Dependent

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 1825 University Boulevard, SHEL 214, Birmingham, AL 35294-2182, USA.
Autoimmune diseases 01/2011; 2011:484936. DOI: 10.4061/2011/484936
Source: PubMed

ABSTRACT We showed earlier that experimental autoimmune encephalomyelitis (EAE) in human C-reactive protein (CRP) transgenic mice (CRPtg) has delayed onset and reduced severity compared to wild-type mice. Since human CRP is known to engage Fc receptors and Fc receptors are known to play a role in EAE in the mouse, we sought to determine if FcγRI, FcγRIIb, or FcγRIII was needed to manifest human CRP-mediated protection of CRPtg. We report here that in CRPtg lacking either of the two activating receptors, FcγRI and FcγRIII, the beneficial effects of human CRP are still observed. In contrast, if CRPtg lack expression of the inhibitory receptor FcγRIIB, then the beneficial effect of human CRP is abrogated. Also, subcutaneous administration of purified human CRP stalled progression of ongoing EAE in wild-type mice, but similar treatment failed to impede EAE progression in mice lacking FcγRIIB. The results reveal that a CRP → FcγRIIB axis is responsible for protection against EAE in the CRPtg model.

0 Bookmarks
 · 
76 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The pentraxins are an ancient family of proteins with a unique architecture found as far back in evolution as the Horseshoe crab. In humans the two members of this family are C-reactive protein and serum amyloid P. Pentraxins are defined by their sequence homology, their pentameric structure and their calcium-dependent binding to their ligands. Pentraxins function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. They function as opsonins for pathogens through activation of the complement pathway and through binding to Fc gamma receptors. Pentraxins also recognize membrane phospholipids and nuclear components exposed on or released by damaged cells. CRP has a specific interaction with small nuclear ribonucleoproteins whereas SAP is a major recognition molecule for DNA, two nuclear autoantigens. Studies in autoimmune and inflammatory disease models suggest that pentraxins interact with macrophage Fc receptors to regulate the inflammatory response. Because CRP is a strong acute phase reactant it is widely used as a marker of inflammation and infection.
    01/2013; 2013:379040. DOI:10.1155/2013/379040
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.
    Expert Review of Cardiovascular Therapy 12/2011; 9(12):1565-84. DOI:10.1586/erc.11.159
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pentraxins are innate pattern recognition molecules whose major function is to bind microbial pathogens or cellular debris during infection and inflammation and, by doing so, contribute to the clearance of necrotic cells as well as pathogens through complement activations. Fc receptors are the cellular mediators of antibody functions. Although conceptually separated, both pentraxins and antibodies are important factors in controlling acute and chronic inflammation and infections. In recent years, increasing experimental evidence suggests a direct link between the innate pentraxins and humoral Fc receptors. Specifically, both human and mouse pentraxins recognize major forms of Fc receptors in solution and on cell surfaces with affinities similar to antibodies binding to their low affinity Fc receptors. Like immune complex, pentraxin aggregation and opsonization of pathogen result in Fc receptor and macrophage activation. The recently published crystal structure of human serum amyloid P (SAP) in complex with FcγRIIA further illustrated similarities to antibody recognition. These recent findings implicate a much broader role than complement activation for pentraxins in immunity. This review summarizes the structural and functional work that bridge the innate pentraxins and the adaptive Fc receptor functions. In many ways, pentraxins can be regarded as innate antibodies.
    Immunological Reviews 11/2012; 250(1):230-8. DOI:10.1111/j.1600-065X.2012.01162.x · 12.91 Impact Factor

Full-text (4 Sources)

Download
16 Downloads
Available from
May 27, 2014