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Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes.

ABSTRACT: Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric forms of MBL carry only a single MASP homodimer. This prompted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand surfaces. We demonstrate that intercomplex activation occurs between discrete PRM/MASP complexes. PRM ligand binding does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation. Our results support a clustering-based mechanism of activation, fundamentally different from the conformational model suggested for the classical pathway of complement.

SUBMITTER: Degn SE

PROVIDER: S-EPMC4169954 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes.

Degn Søren E SE Kjaer Troels R TR Kidmose Rune T RT Jensen Lisbeth L Hansen Annette G AG Tekin Mustafa M Jensenius Jens C JC Andersen Gregers R GR Thiel Steffen S

Proceedings of the National Academy of Sciences of the United States of America 20140902 37

Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric ...[more]

PMID: 25197071

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Project description:B cells represent a critical component of the adaptive immune response whose development and differentiation are determined by antigen-dependent and antigen-independent interactions. In this study, we explored the effects of IL-4 and pattern-recognition receptor (PRR) ligands on B cell development and differentiation by investigating their capacity to drive the in vitro maturation of human transitional B cells. In the presence of IL-4, ligands for TLR7/8, TLR9, and NOD1 were effective in driving the in vitro maturation of cord blood transitional B cells into mature, naïve B cells as measured by CD23 expression, ABCB1 transporter activation and upregulation of sIgM and sIgD. In addition, several stimulation conditions, including TLR9 ligand alone, favored an expansion of CD27+ IgM memory B cells. Transitional B cells stimulated with TLR7/8 ligand + IL-4 or TLR9 ligand, with or without IL-4, induced a significant subpopulation of CD23+CD27+ B cells expressing high levels of sIgM and sIgD, a minor B cell subpopulation found in human peripheral blood. These studies illustrate the heterogeneity of the B cell populations induced by cytokine and PRR ligand stimulation. A comparison of transitional and mature, naïve B cells transcriptomes to identify novel genes involved in B cell maturation revealed that mature, naïve B cells were less transcriptionally active than transitional B cells. Nevertheless, a subset of differentially expressed genes in mature, naïve B cells was identified including genes associated with the IL-4 signaling pathway, PI3K signaling in B lymphocytes, the NF-κB signaling pathway, and the TNFR superfamily. When transitional B cells were stimulated in vitro with IL-4 and PRR ligands, gene expression was found to be dependent on the nature of the stimulants, suggesting that exposure to these stimulants may alter the developmental fate of transitional B cells. The influence of IL-4 and PRR signaling on transitional B cell maturation illustrates the potential synergy that may be achieved when certain PRR ligands are incorporated as adjuvants in vaccine formulations and presented to developing B cells in the context of an inflammatory cytokine environment. These studies demonstrate the potential of the PRR ligands to drive transitional B cell differentiation in the periphery during infection or vaccination independently of antigen mediated BCR signaling.

Project description:Rationale: Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disorder in which inflammation and immunity have emerged as critical early pathogenic elements. Although proinflammatory processes in PH and pulmonary arterial hypertension (PAH) are the focus of extensive investigation, the initiating mechanisms remain elusive.Objectives: We tested whether activation of the complement cascade is critical in regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and can serve as a prognostic biomarker of outcome in human PAH.Methods: We used immunostaining of lung tissues from experimental PH models and patients with PAH, analyses of genetic murine models lacking specific complement components or circulating immunoglobulins, cultured human pulmonary adventitial fibroblasts, and network medicine analysis of a biomarker risk panel from plasma of patients with PAH.Measurements and Main Results: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH and PAH in experimental animal models and humans. In experimental hypoxic PH, proinflammatory and pro-proliferative responses were dependent on complement (alternative pathway and component 5), and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identified Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of patients with PAH, we demonstrated that complement signaling can serve as a prognostic factor for clinical outcome in PAH.Conclusions: This study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating proinflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH and demonstrates complement signaling as a critical determinant of clinical outcome in PAH.

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Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes.

Publications

Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes.

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