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Absence of Fc?RIII results in increased proinflammatory response in Fc?RIII-KO cardiac recipients.

ABSTRACT: Alloantibody can contribute significantly to rejection of heart transplants by activation of complement and interactions with a variety of effector cells, including macrophages and monocytes through activating Fc?RI, Fc?RIII, Fc?RIV, the inhibitory Fc?RIIB and complement receptors. These receptors link cellular and humoral immunity by bridging the antibody specificity to effector cells. Activating Fc?Rs are also involved in serum amyloid P component (SAP)-mediated clearance of apoptotic bodies.B10.A (H-2a) hearts were transplanted into wild-type (WT) or Fc?RIII-knockout (KO) C57BL/6 (H-2b) mouse recipients. Levels of alloantibodies and SAP in the circulation were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Intragraft cytokine mRNA expression was measured by real-time polymerase chain reaction. Intragraft deposition of C4d, von Willebrand factor, SAP, and activated caspase 3 was visualized by immunochemistry.B10.A hearts in C57BL/6 Fc?RIII-KO recipients were rejected acutely within 6 to 8 days compared with 10 to 14 days in WT. The rejection in Fc?RIII-KO was accompanied by higher levels of circulating IgM/IgG alloantibodies and SAP than in WT recipients. Histology in Fc?RIII-KO cardiac allograft recipients indicated perivascular margination of monocytes and neutrophils, vascular endothelial cell injury, and intense vasculocentric infiltrates with extensive apoptosis. Higher numbers of apoptotic cells, stronger C4d and SAP deposition, and extensive activated caspase 3 were found in areas of dense pockets of apoptotic blebs in Fc?RIII-KO.We propose that absence of Fc?RIII is associated with the lack of efficient SAP-mediated clearance of apoptotic cells through Fc?Rs. Apoptotic cells become immunogenic and induce enhanced inflammation, alloantibody production, and complement activation leading to accelerated cardiac allograft rejection.

SUBMITTER: Erdinc Sunay MM

PROVIDER: S-EPMC3795861 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Absence of FcγRIII results in increased proinflammatory response in FcγRIII-KO cardiac recipients.

Erdinc Sunay Melek M MM Fox-Talbot Karen K Velidedeoglu Ergun E Baldwin William M WM Wasowska Barbara A BA

Transplantation 20131001 7

<h4>Background</h4>Alloantibody can contribute significantly to rejection of heart transplants by activation of complement and interactions with a variety of effector cells, including macrophages and monocytes through activating FcγRI, FcγRIII, FcγRIV, the inhibitory FcγRIIB and complement receptors. These receptors link cellular and humoral immunity by bridging the antibody specificity to effector cells. Activating FcγRs are also involved in serum amyloid P component (SAP)-mediated clearance of ...[more]

PMID: 23903009

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Project description:Background: Desmin is a muscle-specific protein belonging to the intermediate filament family. Desmin mutations are linked to skeletal muscle defects, including inherited myopathies with severe clinical manifestations. The aim of this study was to examine the role of desmin in skeletal muscle remodeling and performance gain induced by muscle mechanical overloading which mimics resistance training. Methods: Plantaris muscles were overloaded by surgical ablation of gastrocnemius and soleus muscles. The functional response of plantaris muscle to mechanical overloading in desmin-deficient mice (DesKO, n = 32) was compared to that of control mice (n = 36) after 7-days or 1-month overloading. To elucidate the molecular mechanisms implicated in the observed partial adaptive response of DesKO muscle, we examined the expression levels of genes involved in muscle growth, myogenesis, inflammation and oxidative energetic metabolism. Moreover, ultrastructure and the proteolysis pathway were explored. Results: Contrary to control, absolute maximal force did not increase in DesKO muscle following 1-month mechanical overloading. Fatigue resistance was also less increased in DesKO as compared to control muscle. Despite impaired functional adaptive response of DesKO mice to mechanical overloading, muscle weight and the number of oxidative MHC2a-positive fibers per cross-section similarly increased in both genotypes after 1-month overloading. However, mechanical overloading-elicited remodeling failed to activate a normal myogenic program after 7-days overloading, resulting in proportionally reduced activation and differentiation of muscle stem cells. Ultrastructural analysis of the plantaris muscle after 1-month overloading revealed muscle fiber damage in DesKO, as indicated by the loss of sarcomere integrity and mitochondrial abnormalities. Moreover, the observed accumulation of autophagosomes and lysosomes in DesKO muscle fibers could indicate a blockage of autophagy. To address this issue, two main proteolysis pathways, the ubiquitin-proteasome system and autophagy, were explored in DesKO and control muscle. Our results suggested an alteration of proteolysis pathways in DesKO muscle in response to mechanical overloading. Conclusion: Taken together, our results show that mechanical overloading increases the negative impact of the lack of desmin on myofibril organization and mitochondria. Furthermore, our results suggest that under these conditions, the repairing activity of autophagy is disturbed. Consequently, force generation is not improved despite muscle growth, suggesting that desmin is required for a complete response to resistance training in skeletal muscle.

Project description:Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (P<0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC=0.88, P<0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (P=0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that non-response to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor. Transcriptional profiles of 40 renal allograft biopsy samples were analyzed using Illumina HumanRef-8 v3.0 BeadChips (Illumina, San Diego, CA). Expression profiles were investigated in total RNA isolated from biopsy samples of 18 patients with steroid responsive acute rejection and 18 patients with steroid resistant acute rejection. Four biopsies, taken during acute decrease of graft function but with no histomorphologic indication of rejection, were included as controls.

Dataset Information

Absence of Fc?RIII results in increased proinflammatory response in Fc?RIII-KO cardiac recipients.

Publications

Absence of FcγRIII results in increased proinflammatory response in FcγRIII-KO cardiac recipients.

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