Thymus and autoimmunity

AbstractThe thymus prevents autoimmune diseases through mechanisms that operate in the cortex and medulla, comprising positive and negative selection and the generation of regulatory T-cells (Tregs). Egress from the thymus through the perivascular space (PVS) to the blood is another possible checkpoint, as shown by some autoimmune/immunodeficiency syndromes. In polygenic autoimmune diseases, subtle thymic dysfunctions may compound genetic, hormonal and environmental cues. Here, we cover (a) tolerance-inducing cell types, whether thymic epithelial or tuft cells, or dendritic, B- or thymic myoid cells; (b) tolerance-inducing mechanisms and their failure in relation to thymic anatomic compartments, and with special emphasis on human monogenic and polygenic autoimmune diseases and the related thymic pathologies, if known; (c) polymorphisms and mutations of tolerance-related genes with an impact on positive selection (e.g. the gene encoding the thymoproteasome-specific subunit, PSMB11), promiscuous gene expression (e.g. AIRE, PRKDC, FEZF2, CHD4), Treg development (e.g. SATB1, FOXP3), T-cell migration (e.g. TAGAP) and egress from the thymus (e.g. MTS1, CORO1A); (d) myasthenia gravis as the prototypic outcome of an inflamed or disordered neoplastic ‘sick thymus’.

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Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms22147536 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7536

Author(s):

Inez Wens ◽

Ibo Janssens ◽

Judith Derdelinckx ◽

Megha Meena ◽

Barbara Willekens ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Diseases ◽

Stromal Cells ◽

Mononuclear Cells ◽

Treatment Options ◽

Cell Types ◽

Peripheral Blood Mononuclear ◽

Tailored Treatment ◽

Key Issues ◽

The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

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The Ontogeny of Thymic Myoid Cells in the Chicken. (chick/thymus/myoid cells/development/immunohistochemistry)

Development Growth & Differentiation ◽

10.1111/j.1440-169x.1986.00185.x ◽

1986 ◽

Vol 28 (2) ◽

pp. 185-190 ◽

Cited By ~ 2

Author(s):

HARUKAZU NAKAMURA ◽

KENSUKE E. NAKANO ◽

MINEO YASUDA

Keyword(s):

Myoid Cells ◽

Thymic Myoid Cells

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Stable transfer and restricted expression of a cloned class I gene encoding a secreted transplantation-like antigen

Molecular and Cellular Biology ◽

10.1128/mcb.5.6.1295-1300.1985 ◽

1985 ◽

Vol 5 (6) ◽

pp. 1295-1300

Author(s):

Y Barra ◽

K Tanaka ◽

K J Isselbacher ◽

G Khoury ◽

G Jay

Keyword(s):

Molecular Mechanisms ◽

Cell Types ◽

Class I ◽

Regulatory Sequences ◽

Transcriptional Enhancer ◽

Gene Encoding ◽

Specific Expression ◽

Tissue Specific ◽

Functional Studies ◽

I Gene

The identification of a unique major histocompatibility complex class I gene, designated Q10, which encodes a secreted rather than a cell surface antigen has led to questions regarding its potential role in regulating immunological functions. Since the Q10 gene is specifically activated only in the liver, we sought to define the molecular mechanisms which control its expression in a tissue-specific fashion. Results obtained by transfection of the cloned Q10 gene, either in the absence or presence of a heterologous transcriptional enhancer, into a variety of cell types of different tissue derivations are consistent with the Q10 gene being regulated at two levels. The first is by a cis-dependent mechanism which appears to involve site-specific DNA methylation. The second is by a trans-acting mechanism which would include the possibility of an enhancer binding factor. The ability to efficiently express the Q10 gene in certain transfected cell lines offers an opportunity to obtain this secreted class I antigen in quantities sufficient for functional studies; this should also make it possible to define regulatory sequences which may be responsible for the tissue-specific expression of Q10.

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Differential expression of the human gonadotropin alpha gene in ectopic and eutopic cells

Molecular and Cellular Biology ◽

10.1128/mcb.5.11.3157-3167.1985 ◽

1985 ◽

Vol 5 (11) ◽

pp. 3157-3167

Author(s):

R B Darnell ◽

I Boime

Keyword(s):

Hela Cells ◽

Cell Types ◽

Base Pairs ◽

Gene Encoding ◽

Basal Expression ◽

Bacterial Enzyme ◽

Specific Induction ◽

Alpha Gene ◽

Cat Gene ◽

Jar Cells

We have analyzed the regulation of the alpha gonadotropin gene in eutopic placental cells and ectopic tumor cells by constructing a series of plasmid vectors containing alpha genomic 5' flanking DNA placed upstream of the gene encoding the bacterial enzyme chloramphenicol acetyltransferase (CAT). These plasmid DNAs were transfected into a eutopic (JAr) and an ectopic (HeLa) cell line. Both cell types expressed the CAT gene from plasmid constructs containing as much as 1,500 base pairs (bp) and as little as 140 bp of alpha 5' flanking DNA; JAr cells were considerably more efficient than HeLa cells. Ectopic and eutopic cells differed qualitatively in their expression from these alpha-CAT constructs when cells were treated with cAMP or butyrate. Butyrate induced alpha expression in HeLa cells but not in JAr cells, while cAMP induced expression in JAr cells. These results are consistent with and extend previous observations suggesting that there are cell-specific differences in the regulation of alpha gene expression in ectopic and eutopic cells. However, by using deletion constructs of the alpha-CAT gene, we found that the basal expression and cell-specific induction of the alpha gene in ectopic and eutopic cells were dependent on the same 140 bp of alpha 5' flanking DNA. These 140 bp were sequenced and found to contain a 9-bp stretch of DNA homologous with the consensus viral enhancer sequence. Such features of alpha expression common to both ectopic and eutopic cells may be involved in the coordinate expression of the alpha gene and the tumorigenic phenotype observed in each cell type.

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CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M)

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-3910 ◽

2018 ◽

Vol 40 (4) ◽

pp. 333-338

Author(s):

Ester Miranda Pereira ◽

Adalberto Socorro da Silva ◽

Raimundo Nonato da Silva ◽

José Tiburcio Monte Neto ◽

Fernando F. do Nascimento ◽

...

Keyword(s):

Fabry Disease ◽

Cell Types ◽

Control Group ◽

Gene Encoding ◽

Peripheral Blood Mononuclear ◽

Enzyme Replacement ◽

Replacement Treatment ◽

Promising Tool ◽

Potential Marker ◽

Different Cell Types

ABSTRACT Introduction: Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT). Objective: The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). Methods: We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types. Results: A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels. Conclusion: The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

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The developmentally regulated ECM glycoprotein ISG plays an essential role in organizing the ECM and orienting the cells of Volvox

Journal of Cell Science ◽

10.1242/jcs.113.24.4605 ◽

2000 ◽

Vol 113 (24) ◽

pp. 4605-4617

Author(s):

A. Hallmann ◽

D.L. Kirk

Keyword(s):

Critical Role ◽

Somatic Cells ◽

Cell Types ◽

Model System ◽

Swimming Behavior ◽

Truncated Form ◽

Developmentally Regulated ◽

Gene Encoding ◽

Ecm Architecture ◽

Multicellular Organisms

Volvox is one of the simplest multicellular organisms with only two cell types, yet it has a surprisingly complex extracellular matrix (ECM) containing many region-specific morphological components, making Volvox suitable as a model system for ECM investigations. ECM deposition begins shortly after inversion, which is the process by which the embryo turns itself right-side-out at the end of embryogenesis. It was previously shown that the gene encoding an ECM glycoprotein called ISG is transcribed very transiently during inversion. Here we show that the developmentally controlled ISG accumulates at the bases of the flagella right after inversion, before any morphologically recognizable ECM structures have yet developed. Later, ISG is abundant in the ‘flagellar hillocks’ that encircle the basal ends of all flagella, and in the adjacent ‘boundary zone’ that delimits the spheroid. Transgenic Volvox were generated which express a truncated form of ISG. These transgenics exhibit a severely disorganized ECM within which the cells are embedded in a highly chaotic manner that precludes motility. A synthetic version of the C-terminal decapeptide of ISG has a similar disorganizing effect, but only when it is applied during or shortly after inversion. We postulate that ISG plays a critical role in morphogenesis and acts as a key organizer of ECM architecture; at the very beginning of ECM formation ISG establishes an essential initial framework that both holds the somatic cells in an adaptive orientation and acts as the scaffold upon which the rest of the ECM can be properly assembled, assuring that somatic cells of post-inversion spheroids are held in orientations and locations that makes adaptive swimming behavior possible.

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Desmoyokin, a 680 kDa keratinocyte plasma membrane-associated protein, is homologous to the protein encoded by human gene AHNAK

Journal of Cell Science ◽

10.1242/jcs.105.2.275 ◽

1993 ◽

Vol 105 (2) ◽

pp. 275-286 ◽

Cited By ~ 1

Author(s):

T. Hashimoto ◽

M. Amagai ◽

D.A. Parry ◽

T.W. Dixon ◽

S. Tsukita ◽

...

Keyword(s):

Southern Blot Analysis ◽

Human Gene ◽

Cell Types ◽

Mrna Levels ◽

Expression Library ◽

Gene Encoding ◽

Beta Sheet Structure ◽

Sheet Structure ◽

Significant Homology ◽

Genomic Dnas

We have obtained a monoclonal antibody (33A-3D) that specifically recognize desmoyokin, a 680 kDa desmosomal plaque protein that is well characterized in bovine muzzle epidermis. A cDNA clone (DY6, 3693 bp) was isolated by immunoscreening a mouse keratinocyte expression library with 33A-3D, and it was confirmed that DY6 has a partial coding sequence for desmoyokin. DY6 consists of highly homologous repeats about 128 residues long. Furthermore, the 128-residue repeats exhibit a quasi seven-residue substructure, which we believe will adopt an antiparallel beta-sheet structure. Surprisingly, the amino acid sequence showed a significant homology with AHNAK, a newly identified human gene encoding a 700 kDa protein, which was suggested to be down-regulated in neuroblastoma. From its extensive homology, the similarity in both size and structure, and the identical patterns on Southern blot analysis of genomic DNAs, desmoyokin and AHNAK protein are thought to be identical. Although the desmoyokin/AHNAK protein is detected in a variety of cell types at both protein and mRNA levels, its distribution in keratinocytes (associated closely with cell membrane) is quite different from that in cells other than keratinocytes (distributed diffusely in the cytoplasm). These findings suggest that the desmoyokin/AHNAK protein is a ubiquitous molecule with a unique structure and appears to have different distributions (and probably different functions) among different cells.

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Identification of human thrombin-activatable fibrinolysis inhibitor in vascular and inflammatory cells

Thrombosis and Haemostasis ◽

10.1160/th10-06-0413 ◽

2011 ◽

Vol 105 (06) ◽

pp. 999-1009 ◽

Cited By ~ 9

Author(s):

Joellen Lin ◽

Mathieu Garand ◽

Branislava Zagorac ◽

Steven Schadinger ◽

Corey Scipione ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Line ◽

Cell Lines ◽

Umbilical Vein ◽

Inflammatory Cells ◽

Cell Types ◽

Rt Pcr ◽

Thrombin Activatable Fibrinolysis Inhibitor ◽

Gene Encoding ◽

Fibrinolysis Inhibitor

SummaryTAFI (thrombin-activatable fibrinolysis inhibitor) is a carboxypeptidase zymogen originally identified in plasma. The TAFI pathway helps to regulate the balance between the coagulation and fibrinolytic cascades. Activated TAFI (TAFIa) can also inactivate certain pro-inflammatory mediators, suggesting that the TAFI pathway may also regulate communication between coagulation and inflammation. Expression in the liver is considered to be the source of plasma TAFI. TAFI has also been identified in platelets and CPB2 (the gene encoding TAFI) mRNA has been detected in megakaryocytic cell lines as well as in endothelial cells. We have undertaken a quantitative analysis of CPB2 mRNA and TAFI protein in extrahepatic cell types relevant to vascular disease. Using RT-PCR and quantitative RT-PCR, we detected CPB2 mRNA in the human megakaryoblastic cell lines MEG-01 and Dami, the human monocytoid cell line THP-1 as well as THP-1 cells differentiated into a macrophage-like phenotype, and in primary human umbilical vein and coronary artery endothelial cells. CPB2 mRNA abundance in MEG-01, Dami, and THP-1 cells was modulated by the state of differentiation of these cells. Using a recently developed TAFIa assay, we detected TAFI protein in the lysates of the human hepatocellular carcinoma cell line HepG2 as well as in MEG-01 and Dami cells and in the conditioned medium of HepG2 cells, differentiated Dami cells, and THP-1 macrophages. We have obtained clear evidence for extrahepatic expression of TAFI, which has clear implications for the physiological and pathophysiological functions of the TAFI pathway.

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