Publications by authors named "Gitta Anne Heinz"

14 Publications

  • Page 1 of 1

SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself.

Nat Commun 2021 03 30;12(1):1961. Epub 2021 Mar 30.

Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself.
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http://dx.doi.org/10.1038/s41467-021-22210-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010106PMC
March 2021

Antigen-driven PD-1 TOX BHLHE40 and PD-1 TOX EOMES T lymphocytes regulate juvenile idiopathic arthritis in situ.

Eur J Immunol 2021 Apr 2;51(4):915-929. Epub 2021 Feb 2.

Deutsches Rheuma-Forschungszentrum (DRFZ), Institute of the Leibniz Association, Berlin, Germany.

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1 TOX EOMES population of CD4 T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1 TOX BHLHE40 population of CD4 , and a mirror population of CD8 T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.
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http://dx.doi.org/10.1002/eji.202048797DOI Listing
April 2021

Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.

Immunity 2020 11;53(5):1015-1032.e8

Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10117 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an institute of the Leibniz Association, 10117 Berlin, Germany. Electronic address:

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6 ILC3 via lymphotoxin-β receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.
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http://dx.doi.org/10.1016/j.immuni.2020.10.012DOI Listing
November 2020

Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus.

N Engl J Med 2020 09;383(12):1149-1155

From the Departments of Rheumatology and Clinical Immunology (L.O., P.G., R.B., U.S., G.B., F. Hiepe, T.A.), Nephrology and Internal Intensive Care Unit (P.E.), Hematology, Oncology and Tumor Immunology (U.R.), and Cardiology and Angiology, Campus Mitte (F.K.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Deutsches Rheuma-Forschungszentrum (DRFZ) Institute of the Leibniz Association (L.O., M.B., P.D., G.A.H., F. Heinrich, A.R., H.E.M., M.-F.M., F. Hiepe, T.A.), German Center for Cardiovascular Research (DZHK) (F.K.), and BIH Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin (M.-F.M.) - all in Berlin; and the Laboratory of Inflammation and Autoimmunity, Biomedical Research Foundation, Academy of Athens, Athens (P.G.).

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).
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http://dx.doi.org/10.1056/NEJMoa2023325DOI Listing
September 2020

Vitamin A controls the allergic response through T follicular helper cell as well as plasmablast differentiation.

Allergy 2021 04 20;76(4):1109-1122. Epub 2020 Sep 20.

Division of Allergy and Immunology, Department of Dermatology, Venereology and Allergy, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

Background: Vitamin A regulates the adaptive immune response and a modulatory impact on type I allergy is discussed. The cellular mechanisms are largely unknown.

Objective: To determine the vitamin A-responding specific lymphocyte reaction in vivo.

Methods: Antigen-specific B and T lymphocytes were analyzed in an adoptive transfer airway inflammation mouse model in response to 9-cis retinoic acid (9cRA) and after lymphocyte-specific genetic targeting of the receptor RARα. Flow cytometry, quantitative PCR, next-generation sequencing, and specific Ig-ELISA were used to characterize the cells functionally.

Results: Systemic 9cRA profoundly enhanced the specific IgA-secreting B-cell frequencies in the lung tissue and serum IgA while reducing serum IgE concentrations. RARα overexpression in antigen-specific B cells promoted differentiation into plasmablasts at the expense of germinal center B cells. In antigen-specific T cells, RARα strongly promoted the differentiation of T follicular helper cells followed by an enhanced germinal center response.

Conclusions: 9cRA signaling via RARα impacts the allergen-specific immunoglobulin response directly by the differentiation of B cells and indirectly by promoting T follicular helper cells.
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http://dx.doi.org/10.1111/all.14581DOI Listing
April 2021

Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow.

Nat Commun 2020 05 22;11(1):2570. Epub 2020 May 22.

Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, 10117, Berlin, Germany.

At present, it is not clear how memory B lymphocytes are maintained over time, and whether only as circulating cells or also residing in particular tissues. Here we describe distinct populations of isotype-switched memory B lymphocytes (Bsm) of murine spleen and bone marrow, identified according to individual transcriptional signature and B cell receptor repertoire. A population of marginal zone-like cells is located exclusively in the spleen, while a population of quiescent Bsm is found only in the bone marrow. Three further resident populations, present in spleen and bone marrow, represent transitional and follicular B cells and B1 cells, respectively. A population representing 10-20% of spleen and bone marrow memory B cells is the only one qualifying as circulating. In the bone marrow, all cells individually dock onto VCAM1 stromal cells and, reminiscent of resident memory T and plasma cells, are void of activation, proliferation and mobility.
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http://dx.doi.org/10.1038/s41467-020-16464-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244721PMC
May 2020

Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells.

Cell 2020 05 6;181(5):1080-1096.e19. Epub 2020 May 6.

Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.

Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.
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http://dx.doi.org/10.1016/j.cell.2020.04.022DOI Listing
May 2020

Specific microbiota enhances intestinal IgA levels by inducing TGF-β in T follicular helper cells of Peyer's patches in mice.

Eur J Immunol 2020 06 27;50(6):783-794. Epub 2020 Feb 27.

Deutsches Rheuma-Forschungszentrum Berlin, a Leibniz Institute (DRFZ), Berlin, Germany.

In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine TGF-β, suppressing unwanted immune reactions but also targeting Ig class switching to IgA. It had been suggested that eosinophils promote the generation and maintenance of mucosal IgA-expressing plasma cells. Here, we demonstrate that not eosinophils, but specific bacteria determine mucosal IgA production. Co-housing of eosinophil-deficient mice with mice having high intestinal IgA levels, as well as the intentional microbiota transfer induces TGF-β expression in intestinal T follicular helper cells, thereby promoting IgA class switching in Peyer's patches, enhancing IgA plasma cell numbers in the small intestinal lamina propria and levels of mucosal IgA. We show that bacteria highly enriched for the genus Anaeroplasma are sufficient to induce these changes and enhance IgA levels when adoptively transferred. Thus, specific members of the intestinal microbiota and not the microbiota as such regulate gut homeostasis, by promoting the expression of immune-regulatory TGF-β and of mucosal IgA.
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http://dx.doi.org/10.1002/eji.201948474DOI Listing
June 2020

Single-cell transcriptomes of murine bone marrow stromal cells reveal niche-associated heterogeneity.

Eur J Immunol 2019 09 7;49(9):1372-1379. Epub 2019 Jun 7.

Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.

Bone marrow (BM) stromal cells are important in the development and maintenance of cells of the immune system. Using single cell RNA sequencing, we here explore the functional and phenotypic heterogeneity of individual transcriptomes of 1167 murine BM mesenchymal stromal cells. These cells exhibit a tremendous heterogeneity of gene expression, which precludes the identification of defined subpopulations. However, according to the expression of 108 genes involved in the communication of stromal cells with hematopoietic cells, we have identified 14 non-overlapping subpopulations, with distinct cytokine or chemokine gene expression signatures. With respect to the maintenance of subsets of immune memory cells by stromal cells, we identified distinct subpopulations expressing Il7, Il15 and Tnfsf13b. Together, this study provides a comprehensive dissection of the BM stromal heterogeneity at the single cell transcriptome level and provides a basis to understand their lifestyle and their role as organizers of niches for the long-term maintenance of immune cells.
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http://dx.doi.org/10.1002/eji.201848053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771914PMC
September 2019

CD69 memory T lymphocytes of the bone marrow and spleen express the signature transcripts of tissue-resident memory T lymphocytes.

Eur J Immunol 2019 06 30;49(6):966-968. Epub 2019 Jan 30.

Cell Biology, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), a Leibniz Institute, Berlin, Germany.

It is a matter of current debate whether the bone marrow is a hub for circulating memory T lymphocytes and/or the home of resident memory T lymphocytes. Here we demonstrate for CD69 murine CD8 , and CD69 murine and human CD4 memory T lymphocytes of the bone marrow, making up between 30 and 60% of bone marrow memory T lymphocytes, that they express the gene expression signature of tissue-resident memory T lymphocytes. This suggests that a substantial proportion of bone marrow memory T lymphocytes are resident. It adds to previous evidence that bone marrow memory T cells are resting in terms of mobility and proliferation, and maintain exclusive long-term memory to distinct, systemic antigens.
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http://dx.doi.org/10.1002/eji.201847982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563480PMC
June 2019

MicroRNA-31 Reduces the Motility of Proinflammatory T Helper 1 Lymphocytes.

Front Immunol 2018 6;9:2813. Epub 2018 Dec 6.

Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin, Germany.

Proinflammatory type 1 T helper (Th1) cells are enriched in inflamed tissues and contribute to the maintenance of chronic inflammation in rheumatic diseases. Here we show that the microRNA- (miR-) 31 is upregulated in murine Th1 cells with a history of repeated reactivation and in memory Th cells isolated from the synovial fluid of patients with rheumatic joint disease. Knock-down of miR-31 resulted in the upregulation of genes associated with cytoskeletal rearrangement and motility and induced the expression of target genes involved in T cell activation, chemokine receptor- and integrin-signaling. Accordingly, inhibition of miR-31 resulted in increased migratory activity of repeatedly activated Th1 cells. The transcription factors T-bet and FOXO1 act as positive and negative regulators of T cell receptor (TCR)-mediated miR-31 expression, respectively. Taken together, our data show that a gene regulatory network involving miR-31, T-bet, and FOXO1 controls the migratory behavior of proinflammatory Th1 cells.
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http://dx.doi.org/10.3389/fimmu.2018.02813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291424PMC
October 2019

Stable lines and clones of long-term proliferating normal, genetically unmodified murine common lymphoid progenitors.

Blood 2018 05 23;131(18):2026-2035. Epub 2018 Mar 23.

Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.

Common lymphoid progenitors (CLPs) differentiate to T and B lymphocytes, dendritic cells, natural killer cells, and innate lymphoid cells. Here, we describe culture conditions that, for the first time, allow the establishment of lymphoid-restricted, but uncommitted, long-term proliferating CLP cell lines and clones from a small pool of these cells from normal mouse bone marrow, without any genetic manipulation. Cells from more than half of the cultured CLP clones could be induced to differentiate to T, B, natural killer, dendritic, and myeloid cells in vitro. Cultured, transplanted CLPs transiently populate the host and differentiate to all lymphoid subsets, and to myeloid cells in vivo. This simple method to obtain robust numbers of cultured noncommitted CLPs will allow studies of cell-intrinsic and environmentally controlled lymphoid differentiation programs. If this method can be applied to human CLPs, it will provide new opportunities for cell therapy of patients in need of myeloid-lymphoid reconstitution.
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http://dx.doi.org/10.1182/blood-2017-09-805259DOI Listing
May 2018

Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo.

J Autoimmun 2018 05 1;89:41-52. Epub 2017 Dec 1.

Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Germany. Electronic address:

In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.
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http://dx.doi.org/10.1016/j.jaut.2017.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916452PMC
May 2018

The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes.

Nat Immunol 2010 Nov 10;11(11):1057-62. Epub 2010 Oct 10.

Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.

After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities.
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http://dx.doi.org/10.1038/ni.1945DOI Listing
November 2010