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Special Issue "Advances in the Pathogenesis and Treatment of Immune-Mediated Inflammatory Diseases"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 September 2021).

Special Issue Editors

Dr. Sander W. Tas
E-Mail Website
Guest Editor
Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology and Laboratory for Experimental Immunology, Academic Medical Center/University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Interests: immune-mediated inflammatory diseases; molecular regulation of inflammation; signal transduction; B cells; dendritic cells; endothelial cells/angiogenesis
Dr. Jan Piet van Hamburg
E-Mail Website
Guest Editor
Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology and Laboratory for Experimental Immunology, Academic Medical Center/University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Interests: immune-mediated inflammatory diseases; molecular regulation of inflammation; lymphocytes; stromal cells; NF-κB signaling

Special Issue Information

Dear Colleagues,

This Special Issue will focus on the rapidly evolving field of immune-mediated inflammatory diseases (IMIDs) and the achievements that were made over the last 10 years. With the advent of novel technologies such as single-cell RNA sequencing and state-of-the-art imaging techniques, researchers in our field have made tremendous progress in unraveling the pathogenesis of autoimmune diseases such as rheumatoid arthritis, vasculitis, and systemic lupus erythematosus, as well as autoinflammatory diseases such as spondyloarthritis and fever syndromes. This has also provided new insights into the contribution of specific (subsets of) immune cells and stromal cells to the inflammatory response, as well as the molecular pathways associated with the pathological processes involved. These advances have led to the identification of promising new therapeutic targets for these diseases and paved the way for novel treatments. However, for rare IMIDs, we are far from fully understanding the underlying mechanisms leading to the development and progression of disease, as well as the response to therapy. A better understanding of the molecular and cellular signatures of these diseases may inform us about potential new treatment options that could be explored.

This Special Issue of IJMS will focus on the molecular, cellular, and clinical advances in the pathogenesis and treatment of IMIDs. We will consider original research, review, or methods manuscripts related to this subject and the keywords below.

Dr. Sander W. Tas
Dr. Jan Piet van Hamburg
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • autoimmunity
  • inflammation
  • immune cells
  • stromal cells
  • lymphoid organs
  • inflammatory mediators
  • signal transduction
  • state-of-the-art technology, including (sc)RNAseq and (imaging)CyTOF
  • molecular imaging and advanced microscopy
  • animal models

Published Papers (7 papers)

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Research

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Article
Fibroblast Activation Protein Targeted Photodynamic Therapy Selectively Kills Activated Skin Fibroblasts from Systemic Sclerosis Patients and Prevents Tissue Contraction
Int. J. Mol. Sci. 2021, 22(23), 12681; https://doi.org/10.3390/ijms222312681 - 24 Nov 2021
Viewed by 254
Abstract
Systemic sclerosis (SSc) is a rare, severe, auto-immune disease characterized by inflammation, vasculopathy and fibrosis. Activated (myo)fibroblasts are crucial drivers of this fibrosis. By exploiting their expression of fibroblast activation protein (FAP) to perform targeted photodynamic therapy (tPDT), we can locoregionally deplete these [...] Read more.
Systemic sclerosis (SSc) is a rare, severe, auto-immune disease characterized by inflammation, vasculopathy and fibrosis. Activated (myo)fibroblasts are crucial drivers of this fibrosis. By exploiting their expression of fibroblast activation protein (FAP) to perform targeted photodynamic therapy (tPDT), we can locoregionally deplete these pathogenic cells. In this study, we explored the use of FAP-tPDT in primary skin fibroblasts from SSc patients, both in 2D and 3D cultures. Method: The FAP targeting antibody 28H1 was conjugated with the photosensitizer IRDye700DX. Primary skin fibroblasts were obtained from lesional skin biopsies of SSc patients via spontaneous outgrowth and subsequently cultured on plastic or collagen type I. For 2D FAP-tPDT, cells were incubated in buffer with or without the antibody-photosensitizer construct, washed after 4 h and exposed to λ = 689 nm light. Cell viability was measured using CellTiter Glo®®. For 3D FAP-tPDT, cells were seeded in collagen plugs and underwent the same treatment procedure. Contraction of the plugs was followed over time to determine myofibroblast activity. Results: FAP-tPDT resulted in antibody-dose dependent cytotoxicity in primary skin fibroblasts upon light exposure. Cells not exposed to light or incubated with an irrelevant antibody-photosensitizer construct did not show this response. FAP-tPDT fully prevented contraction of collagen plugs seeded with primary SSc fibroblasts. Even incubation with a very low dose of antibody (0.4 nM) inhibited contraction in 2 out of 3 donors. Conclusions: Here we have shown, for the first time, the potential of FAP-tPDT for the treatment of fibrosis in SSc skin. Full article
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Article
Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway
Int. J. Mol. Sci. 2021, 22(22), 12580; https://doi.org/10.3390/ijms222212580 - 22 Nov 2021
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Abstract
TGF β-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it [...] Read more.
TGF β-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1β-induced TAK1 phosphorylation—a prerequisite for and indicator of its functional potential—by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs. Full article
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Article
C-Reactive Protein Controls IL-23 Production by Human Monocytes
Int. J. Mol. Sci. 2021, 22(21), 11638; https://doi.org/10.3390/ijms222111638 - 28 Oct 2021
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Abstract
C-reactive protein (CRP) is an acute-phase protein in humans that is produced in high quantities by the liver upon infection and under inflammatory conditions. Although CRP is commonly used as a marker of inflammation, CRP can also directly contribute to inflammation by eliciting [...] Read more.
C-reactive protein (CRP) is an acute-phase protein in humans that is produced in high quantities by the liver upon infection and under inflammatory conditions. Although CRP is commonly used as a marker of inflammation, CRP can also directly contribute to inflammation by eliciting pro-inflammatory cytokine production by immune cells. Since CRP is highly elevated in serum under inflammatory conditions, we have studied the CRP-induced cytokine profile of human monocytes, one of the main innate immune cell populations in blood. We identified that CRP is relatively unique in its capacity to induce production of the pro-inflammatory cytokine IL-23, which was in stark contrast to a wide panel of pattern recognition receptor (PRR) ligands. We show that CRP-induced IL-23 production was mediated at the level of gene transcription, since CRP particularly promoted gene transcription of IL23A (encoding IL-23p19) instead of IL12A (encoding IL-12p35), while PRR ligands induce the opposite response. Interestingly, when CRP stimulation was combined with PRR ligand stimulation, as for example, occurs in the context of sepsis, IL-23 production by monocytes was strongly reduced. Combined, these data identify CRP as a unique individual ligand to induce IL-23 production by monocytes, which may contribute to shaping systemic immune responses under inflammatory conditions. Full article
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Article
Efficient Neutrophil Activation Requires Two Simultaneous Activating Stimuli
Int. J. Mol. Sci. 2021, 22(18), 10106; https://doi.org/10.3390/ijms221810106 - 18 Sep 2021
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Abstract
Neutrophils are abundantly present in the synovium and synovial fluid of patients suffering from arthritis. Neutrophils can be activated by a multitude of stimuli and the current dogma states that this is a two-step process, consisting of a priming step followed by an [...] Read more.
Neutrophils are abundantly present in the synovium and synovial fluid of patients suffering from arthritis. Neutrophils can be activated by a multitude of stimuli and the current dogma states that this is a two-step process, consisting of a priming step followed by an activation step. Considering that neutrophil activation occurs in an inflammatory environment, where multiple stimuli are present, we argue that a two-step process is highly unlikely. Here, we indeed demonstrate that neutrophils require simultaneous ligation of two different receptors for efficient activation. We isolated human peripheral blood neutrophils and cultured them with various combinations of stimuli (GM-CSF, fMLF, TNF, and LPS). Next, we evaluated essential neutrophil functions, including degranulation and ROS production using flow cytometry, mediator release using ELISA, NETosis by a live cell imaging method, phagocytosis by imaging flow cytometry, and extracellular vesicle (EV) release quantified by high-resolution flow cytometry. Exposure of neutrophils to any combination of stimuli, but not to single stimuli, resulted in significant degranulation, and mediator and EV release. Furthermore, ROS production increased substantially by dual stimulation, yet appeared to be more dependent on the type of stimulation than on dual stimulation. Phagocytosis was induced to its maximum capacity by a single stimulus, while NETosis was not induced by any of the used physiological stimuli. Our data indicate that neutrophil activation is tightly regulated and requires activation by two simultaneous stimuli, which is largely independent of the combination of stimuli. Full article
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Review

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Review
The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms
Int. J. Mol. Sci. 2021, 22(23), 12739; https://doi.org/10.3390/ijms222312739 - 25 Nov 2021
Viewed by 191
Abstract
Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation [...] Read more.
Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis. Full article
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Review
Single-Cell RNA Sequencing Reveals Heterogeneity and Functional Diversity of Lymphatic Endothelial Cells
Int. J. Mol. Sci. 2021, 22(21), 11976; https://doi.org/10.3390/ijms222111976 - 05 Nov 2021
Viewed by 475
Abstract
Lymphatic endothelial cells (LECs) line the lymphatic vasculature and play a central role in the immune response. LECs have abilities to regulate immune transport, to promote immune cell survival, and to cross present antigens to dendritic cells. Single-cell RNA sequencing (scRNA) technology has [...] Read more.
Lymphatic endothelial cells (LECs) line the lymphatic vasculature and play a central role in the immune response. LECs have abilities to regulate immune transport, to promote immune cell survival, and to cross present antigens to dendritic cells. Single-cell RNA sequencing (scRNA) technology has accelerated new discoveries in the field of lymphatic vascular biology. This review will summarize these new findings in regard to embryonic development, LEC heterogeneity with associated functional diversity, and interactions with other cells. Depending on the organ, location in the lymphatic vascular tree, and micro-environmental conditions, LECs feature unique properties and tasks. Furthermore, adjacent stromal cells need the support of LECs for fulfilling their tasks in the immune response, such as immune cell transport and antigen presentation. Although aberrant lymphatic vasculature has been observed in a number of chronic inflammatory diseases, the knowledge on LEC heterogeneity and functional diversity in these diseases is limited. Combining scRNA sequencing data with imaging and more in-depth functional experiments will advance our knowledge of LECs in health and disease. Building the case, the LEC could be put forward as a new therapeutic target in chronic inflammatory diseases, counterweighting the current immune-cell focused therapies. Full article
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Review
The Germinal Center Milieu in Rheumatoid Arthritis: The Immunological Drummer or Dancer?
Int. J. Mol. Sci. 2021, 22(19), 10514; https://doi.org/10.3390/ijms221910514 - 29 Sep 2021
Viewed by 615
Abstract
Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, affecting approximately 1% of the general population. To alleviate symptoms and ameliorate joint damage, chronic use of immunosuppressives is needed. However, these treatments are only partially effective and may lead to [...] Read more.
Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, affecting approximately 1% of the general population. To alleviate symptoms and ameliorate joint damage, chronic use of immunosuppressives is needed. However, these treatments are only partially effective and may lead to unwanted side effects. Therefore, a more profound understanding of the pathophysiology might lead to more effective therapies, or better still, a cure. The presence of autoantibodies in RA indicates that B cells might have a pivotal role in the disease. This concept is further supported by the fact that a diverse antibody response to various arthritis-related epitopes is associated with arthritis development. In this context, attention has focused in recent years on the role of Germinal Centers (GCs) in RA. Since GCs act as the main anatomic location of somatic hypermutations, and, thus, contributing to the diversity and specificity of (auto) antibodies, it has been speculated that defects in germinal center reactions might be crucial in the initiation and maintenance of auto-immune events. In this paper, we discuss current evidence that various processes within GCs can result in the aberrant production of B cells that possess autoreactive properties and might result in the production of RA related autoantibodies. Secondly, we discuss various (pre-)clinical studies that have targeted various GC processes as novel therapies for RA treatment. Full article
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