Evidence against a key role for transforming growth factor-beta1 in cytomegalovirus-induced bone marrow aplasia.

Dobonici, M; Podlech, J; Steffens, Hans-Peter; Maiberger, S; Reddehase, Matthias J.

doi:10.1099/0022-1317-79-4-867

Cited by 15 publications

(7 citation statements)

References 39 publications

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“…Bioactive TGF may derive from the circulation, the juxtaglomerular apparatus, or the glomerular cells themselves during infections and inflammation (30,31). In the latter cases, the latent pool of TGF␤ constitutively secreted as inactive forms is attenuated by the production of a postulated "inducer" from the glomerular cells (32,33). TGF␤1 induces the expression, and thus the deposition, of type IV collagen as well as aberrant fetal laminin ␣1, ␣2, and ␤1 chains, into the GBM (12).…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Olin

Mörgelin

Truedsson

et al. 2014

Arthritis & Rheumatology

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Objective. Apoptotic nucleosomes are structurally and immunologically involved in lupus nephritis. The purpose of this study was to examine the expression and function of laminins and their interactions with nucleosomes in the kidneys of patients with lupus nephritis, using surface plasmon resonance (SPR) analysis.Methods. SPR interaction analysis was used to quantify the strength of laminin-nucleosome interactions. Electron microscopy techniques were used to determine in vivo colocalization of IgG, chromatin, and laminin ␤1, as well as to characterize nucleosomelaminin interactions in vitro.Results. Nucleosomes were found to possess high affinity for laminin ␤1-containing laminins and to have the potential to form stable molecular complexes with these structures. In vivo, laminin ␤1 was aberrantly expressed in the glomerular basement membrane (GMB) of lupus nephritis patients, and in situ, it acted as a nucleosome ligand, selectively colocalizing with nucleosomes within electron-dense deposits (EDDs). Normal adult laminin 11, which contains laminin ␤2, did not bind nucleosomes, and it did not colocalize in vivo with the nucleosomes in the nephritic GBM. In addition, TGF␤1 was expressed by the glomerular mesangium, glomerular endothelial cells, and by podocytes in patients with lupus nephritis. It was trapped in situ within EDDs by an as-yet-unknown ligand. As was recently described in a transgenic mouse model, paracrine kidney glomerular TGF␤1 may thereby contribute to the development of glomerulopathy via the induction of laminin ␤1 incorporation in the GBM, whereas systemic blood vessel-derived TGF␤1 could be trapped during filtration.Conclusion. Our findings of the specific highaffinity binding of nucleosomes to aberrantly expressed laminin ␤1 in the GBM and their colocalization in the GBM may explain important features of the initial steps in the pathogenesis of lupus nephritis, the planted antigen hypothesis.

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Section: Discussionmentioning

confidence: 99%

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Olin

Mörgelin

Truedsson

et al. 2014

Arthritis & Rheumatology

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“…The infection of the liver and liver tissue infiltration by adoptively-transferred antiviral T cells of the m164 epitope-specific CTL line (see above) was analyzed in the microanatomical context by 2-color immunohistochemistry (2C-IHC) specific for the intranuclear viral protein IE1 (red staining) and the membrane-localizing CD3ε component of the T-cell receptor complex (black staining), respectively. Infected cells in the BM stroma were detected after bone decalcification with trichloroacetic acid in thin-sections of sternum and vertebra by red staining of the IE1 protein (Dobonici et al, 1998). Sections were routinely counterstained with hematoxylin.…”

Section: Quantification Of Infected Tissue Cells and Of Tissue-infiltmentioning

confidence: 99%

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Renzaho

Podlech

Kühnapfel

et al. 2020

Front. Cell. Infect. Microbiol.

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Reactivation of latent cytomegalovirus (CMV) in recipients of hematopoietic cell transplantation (HCT) not only results in severe organ manifestations, but can also cause "graft failure" resulting in bone marrow (BM) aplasia. This inhibition of hematopoietic stem and progenitor cell engraftment is a manifestation of CMV infection that is long known in clinical hematology as "myelosuppression." Previous studies in a murine model of sex-chromosome mismatched but otherwise syngeneic HCT and infection with murine CMV have shown that transplanted hematopoietic cells (HC) initially home to the BM stroma of recipients but then fail to further divide and differentiate. Data from this model were in line with the hypothesis that infection of stromal cells, which constitute "hematopoietic niches" where hematopoiesis takes place, causes a local deficiency in essential hematopoietins. Based on this understanding, one must postulate that preventing infection of stromal cells should restore the stroma's capacity to support hematopoiesis. Adoptively-transferred antiviral CD8 + T cells prevent lethal CMV disease by controlling viral spread and histopathology in vital organs, such as liver and lungs. It remained to be tested, however, if they can also prevent infection of the BM stroma and thus allow for successful HC engraftment. Here we demonstrate that antiviral CD8 + T cells control stromal infection. By tracking male donor-derived sry + HC in the BM of infected female sry − recipients, we show the CD8 + T cells allow for successful donor HC engraftment and thereby prevent CMV-associated BM aplasia. These data provide a further argument for cytoimmunotherapy of CMV infection after HCT.

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“…Viral pathogenesis, lympho-hematopoietic reconstitution, resolution of the productive infection, and the establisment of latency in HSCT recipients have been analyzed in this model in great detail previously [29,30,[33][34][35][36][37] (for reviews see [25,27,28,38] and the contribution by Erlach et al in this issue of MMI). Importantly, whereas under conditions of low-dose HSCT mCMV-WT.Smith inhibits the engraftment of hematopoietic donor stem and progenitor cells in the recipients' bone marrow stroma with the outcome of a lethal bone marrow aplasia [29,30,33], this pathogenesis is prevented under conditions of high-dose HSCT by the successful reconstitution of protective CD8 T cells [34,35] with the result that acute infection is cleared and viral latency established [36,37].…”

Section: Experimental Regimen Of Serial Hsct To Evaluate Transfer Of mentioning

confidence: 99%

“…Importantly, whereas under conditions of low-dose HSCT mCMV-WT.Smith inhibits the engraftment of hematopoietic donor stem and progenitor cells in the recipients' bone marrow stroma with the outcome of a lethal bone marrow aplasia [29,30,33], this pathogenesis is prevented under conditions of high-dose HSCT by the successful reconstitution of protective CD8 T cells [34,35] with the result that acute infection is cleared and viral latency established [36,37]. High-dose HSCT was therefore chosen here to establish a latent infection in the chimeric primary recipients for answering the speciWc question if viral latency is established in their bone marrow and if latent virus can be transmitted with hematopoietic cells to secondary HSCT recipients.…”

Section: Experimental Regimen Of Serial Hsct To Evaluate Transfer Of mentioning

confidence: 99%

Hematopoietic stem cell transplantation with latently infected donors does not transmit virus to immunocompromised recipients in the murine model of cytomegalovirus infection

Seckert

Renzaho

Reddehase

et al. 2008

Med Microbiol Immunol

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Hematopoietic stem cell transplantation (HSCT) bears a risk of reactivating latent cytomegalovirus (CMV) in either the transplanted hematopoietic donor cells or in parenchymal and stromal tissue cells of the immunocompromised recipient, or in both. While reactivated human CMV in recipients of organ transplantations is frequently the virus variant of the donor, this is not usually the case in HSCT recipients. Here we have used experimental sex-mismatched HSCT in the BALB/c mouse model to test if latent murine CMV from CMV-immune donors is transmitted with bone marrow cells to naive immunocompromised recipients.

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Evidence against a key role for transforming growth factor-beta1 in cytomegalovirus-induced bone marrow aplasia.

Cited by 15 publications

References 39 publications

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Pathogenic Mechanisms in Lupus Nephritis: Nucleosomes Bind Aberrant Laminin β1 With High Affinity and Colocalize in the Electron‐Dense Deposits

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Hematopoietic stem cell transplantation with latently infected donors does not transmit virus to immunocompromised recipients in the murine model of cytomegalovirus infection

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