The paracaspase MALT1 in psoriasis

Abstract Psoriasis is a frequent autoimmune-related skin disease, which involves various cell types such as T cells, keratinocytes and dendritic cells. Genetic variations, such as mutations of CARD14, can promote the development of the disease. CARD14 mutations as well as the stimulation of immune and cytokine receptors activate the paracaspase MALT1, a potent activator of the transcription factors NF-κB and AP-1. The disease-promoting role of MALT1 for psoriasis is mediated by both its protease activity as well as its molecular scaffold function. Here, we review the importance of MALT1-mediated signaling and its therapeutic implications in psoriasis.

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Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

Molecular Brain ◽

10.1186/s13041-019-0532-6 ◽

2019 ◽

Vol 12 (1) ◽

Author(s):

Meng-ge Yang ◽

Li Sun ◽

Jinming Han ◽

Chao Zheng ◽

Hudong Liang ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Dendritic Cells ◽

Transcription Factor ◽

Immune Cell ◽

Demyelinating Disease ◽

Cell Types ◽

Lymphoid Organ ◽

Therapeutic Implications

AbstractTranscription factor RelB is a member of the nuclear factror-kappa B (NF-κB) family, which plays a crucial role in mediating immune responses. Plenty of studies have demonstrated that RelB actively contributes to lymphoid organ development, dendritic cells maturation and function and T cells differentiation, as well as B cell development and survival. RelB deficiency may cause a variety of immunological disorders in both mice and humans. Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system which involves a board of immune cell populations. Thereby, RelB may exert an impact on MS by modulating the functions of dendritic cells and the differentiation of T cells and B cells. Despite intensive research, the role of RelB in MS and its animal model, experimental autoimmune encephalomyelitis, is still unclear. Herein, we give an overview of the biological characters of RelB, summarize the updated knowledge regarding the role of RelB in different cell types that contribute to MS pathogenesis and discuss the potential RelB-targeted therapeutic implications for MS.

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Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells.

Journal of Experimental Medicine ◽

10.1084/jem.173.3.549 ◽

1991 ◽

Vol 173 (3) ◽

pp. 549-559 ◽

Cited By ~ 118

Author(s):

M Inaba ◽

K Inaba ◽

M Hosono ◽

T Kumamoto ◽

T Ishida ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

B Cells ◽

Cell Types ◽

Cell Sorter ◽

Histocompatibility Complex ◽

Different Types ◽

Induced Tolerance ◽

Antigen Presenting

To assess the role of different types of antigen-presenting cells (APC) in the induction of tolerance, we isolated B cells, macrophages, and dendritic cells from thymus and spleen, and injected these into neonatal BALB/c mice across an Mls-1 antigenic barrier. One week after injection of APC from Mls-1-incompatible mice or from control syngeneic mice, we measured the number of thymic, Mls-1a-reactive, V beta 6+ T cells and the capacity of thymocytes to induce a graft-vs.-host (GVH) reaction in popliteal lymph nodes of Mls-1a mice. Injection of thymic but not spleen B cells deleted thymic, Mls-1a-reactive V beta 6+ T cells and induced tolerance in the GVH assay. The thymic B cells were primarily of the CD5+ type, and fluorescence-activated cell sorter-purified CD5+ thymic B cells were active. Injection of dendritic cells from spleen or thymus also induced tolerance, but the V beta 6 cells were anergized rather than deleted. Macrophages from thymus did not induce tolerance. Dendritic cells and thymic B cells were also effective in inducing tolerance even when injected into Mls-, major histocompatibility complex-incompatible, I-E- mice, but only thymic B cells depleted V beta 6-expressing T cells. Therefore, different types of bone marrow-derived APC have different capacities for inducing tolerance, and the active cell types (dendritic cells and CD5+ thymic B cells) can act by distinct mechanisms.

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The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Journal of Virology ◽

10.1128/jvi.73.6.4575-4581.1999 ◽

1999 ◽

Vol 73 (6) ◽

pp. 4575-4581 ◽

Cited By ~ 61

Author(s):

Masahiko Makino ◽

Satoshi Shimokubo ◽

Shin-Ichi Wakamatsu ◽

Shuji Izumo ◽

Masanori Baba

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Virus Type ◽

Spastic Paraparesis ◽

Tropical Spastic Paraparesis ◽

Normal Donor ◽

Dependent Manner ◽

T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

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Eminent role of ICOS costimulation for T cells interacting with plasmacytoid dendritic cells

Immunology ◽

10.1111/j.1365-2567.2006.02379.x ◽

2006 ◽

Vol 118 (3) ◽

pp. 353-360 ◽

Cited By ~ 22

Author(s):

Marko Janke ◽

Esther J. Witsch ◽

Hans W. Mages ◽

Andreas Hutloff ◽

Richard A. Kroczek

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Plasmacytoid Dendritic Cells

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Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-κB2

Journal of Experimental Medicine ◽

10.1084/jem.186.7.999 ◽

1997 ◽

Vol 186 (7) ◽

pp. 999-1014 ◽

Cited By ~ 128

Author(s):

Hideaki Ishikawa ◽

Daniel Carrasco ◽

Estefania Claudio ◽

Rolf-Peter Ryseck ◽

Rodrigo Bravo

Keyword(s):

T Cells ◽

Lymphocyte Proliferation ◽

Cytokine Production ◽

Cell Types ◽

Homozygous Deletion ◽

Binding Activity ◽

Activated T Cells ◽

Physiological Relevance

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-κB, the p100 precursor is believed to function as an inhibitor of Rel/NF-κB activity by cytoplasmic retention of Rel/NF-κB complexes, like other members of the IκB family. However, the physiological relevance of the p100 precursor as an IκB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-κB2 (p100−/−) had marked gastric hyperplasia, resulting in early postnatal death. p100−/− animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear κB–binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-κB complexes in various cell types and its absence cannot be efficiently compensated for by other IκB proteins.

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Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽

10.1182/blood.v97.9.2764 ◽

2001 ◽

Vol 97 (9) ◽

pp. 2764-2771 ◽

Cited By ~ 77

Author(s):

Beth D. Harrison ◽

Julie A. Adams ◽

Mark Briggs ◽

Michelle L. Brereton ◽

John A. Liu Yin

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Dendritic Cells ◽

T Cell ◽

Myeloid Leukemia ◽

T Cell Responses ◽

Cell Responses ◽

Antigen Presenting ◽

Acute Myeloid ◽

Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

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Regulation of Pax-3 expression in the dermomyotome and its role in muscle development

Development ◽

10.1242/dev.120.4.957 ◽

1994 ◽

Vol 120 (4) ◽

pp. 957-971 ◽

Cited By ~ 63

Author(s):

M. Goulding ◽

A. Lumsden ◽

A.J. Paquette

Keyword(s):

Transcription Factors ◽

Muscle Development ◽

Cell Types ◽

Axial Skeleton ◽

Mouse Embryos ◽

Related Gene ◽

Paired Domain ◽

Trunk Musculature ◽

Somitic Mesoderm

The segmented mesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeleton and muscle. A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle.

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Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells

Molecular and Cellular Biology ◽

10.1128/mcb.12.7.3305-3312.1992 ◽

1992 ◽

Vol 12 (7) ◽

pp. 3305-3312

Author(s):

M Izquierdo ◽

J Downward ◽

J D Graves ◽

D A Cantrell

Keyword(s):

T Cells ◽

Protein Kinase C ◽

Protein Kinase ◽

Kinase Inhibitor ◽

Antigen Receptor ◽

Permeabilized Cell ◽

Regulatory Pathways ◽

Kinase C ◽

Stimulation Of

T-lymphocyte activation via the antigen receptor complex (TCR) results in accumulation of p21ras in the active GTP-bound state. Stimulation of protein kinase C (PKC) can also activate p21ras, and it has been proposed that the TCR effect on p21ras occurs as a consequence of TCR regulation of PKC. To test the role of PKC in TCR regulation of p21ras, a permeabilized cell system was used to examine TCR regulation of p21ras under conditions in which TCR activation of PKC was blocked, first by using a PKC pseudosubstrate peptide inhibitor and second by using ionic conditions that prevent phosphatidyl inositol hydrolysis and hence diacylglycerol production and PKC stimulation. The data show that TCR-induced p21ras activation is not mediated exclusively by PKC. Thus, in the absence of PKC stimulation, the TCR was still able to induce accumulation of p21ras-GTP complexes, and this stimulation correlated with an inactivation of p21ras GTPase-activating proteins. The protein tyrosine kinase inhibitor herbimycin could prevent the non-PKC-mediated, TCR-induced stimulation of p21ras. These data indicate that two mechanisms for p21ras regulation coexist in T cells: one PKC mediated and one not. The TCR can apparently couple to p21ras via a non-PKC-controlled route that may involve tyrosine kinases.

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