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Cureus Aug 2023Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but fatal complication of blood transfusion that usually develops two to 30 days following a blood... (Review)
Review
Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but fatal complication of blood transfusion that usually develops two to 30 days following a blood transfusion giving rise to graft versus host disease (GVHD) clinical features that are consisting of fever, skin rash, jaundice, diarrhea, and pancytopenia. The disease is fulminant in most patients with a mortality rate of >90% of cases. The main aim of this review is to enhance awareness among medical practitioners about this fatal disease. Data were extracted manually from the main medical databases (Medline, Scopus, and Google Scholar) after the revision of selected articles and assessed for their contribution to the knowledge of TA-GVHD. TA-GVHD occurs when the viable donor T-cells in the blood or blood products attack the recipient's tissues which his/her immune system is incapable to destroy due to several reasons. The recipient's tissues that are usually involved in TA-GVHD include the liver, intestine, skin, lungs, and bone marrow. Any blood component either whole blood, packed red blood cells (RBCs), platelets, or fresh non-frozen plasma that contains viable T lymphocytes can cause TA-GVHD. Host immunodeficiency, transfusion of fresh blood, and partial human leukocyte antigen (HLA) matching between the donors and the recipients represent the major risk factors of TA-GVHD. Partial HLA matching includes immunocompetent recipients who receive blood from a first-degree relative also, seen in genetically homogenous populations because of high rates of consanguineous marriage. The diagnosis of TA-GVHD is mainly suspected based on clinical manifestations. However, a histopathological study of either skin or rectal biopsy is diagnostic. The treatment of TA-GVHD is generally not effective, unless the patient received emergency stem cell transplantation, while prevention via irradiation of blood or blood products represents the standard of care for this disease. In conclusion, medical practitioners should have a high index of suspicion for this disease. Moreover, future clinical trials targeting and comparing the outcomes of the different therapeutic options for TA-GVHD are required.
PubMed: 37753040
DOI: 10.7759/cureus.44148 -
Proceedings of the National Academy of... Sep 2023Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood...
Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC. We identified that scleroderma skin grafts contained both skin and bone marrow-derived human CD4 and CD8 T cells along with human endothelial cells and pericytes. Unlike healthy skin, fibroblasts in scleroderma skin were depleted and replaced by mouse fibroblasts. Furthermore, HSC engraftment alleviated multiple signatures of fibrosis, including expression of collagen and interferon genes, and proliferation and activation of human T cells. Fibrosis improvement correlated with reduced markers of T cell activation and expression of human IL-6 by mesenchymal cells. Mechanistic studies supported a model whereby IL-6 trans-signaling driven by CD4 T cell-derived soluble IL-6 receptor complexed with fibroblast-derived IL-6 promoted excess extracellular matrix gene expression. Thus, MISTRG6 mice transplanted with scleroderma skin demonstrated multiple fibrotic responses centered around human IL-6 signaling, which was improved by the presence of healthy bone marrow-derived immune cells. Our results highlight the importance of IL-6 trans-signaling in pathogenesis of scleroderma and the ability of healthy bone marrow-derived immune cells to mitigate disease.
Topics: Humans; Animals; Mice; Scleroderma, Localized; Interleukin-6; Endothelial Cells; Skin; Disease Models, Animal; Basidiomycota
PubMed: 37669366
DOI: 10.1073/pnas.2306965120 -
JCI Insight Oct 2023Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function...
Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs), and donor-specific Abs. We generated Tregs expressing HLA-A2-specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation, and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR, but not 4-1BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no costimulatory domain. These data revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti-HLA-A2 alloantibodies. This study reveals a dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.
Topics: Mice; Animals; Receptors, Chimeric Antigen; CD28 Antigens; T-Lymphocytes, Regulatory; Transplantation, Homologous; Allografts
PubMed: 37669115
DOI: 10.1172/jci.insight.167215 -
Annals of Dermatology Oct 2023Vitiligo is a disease caused by the acquired depletion of melanocytes and/or melanocyte precursor cells in response to genetic and environmental factors, resulting in... (Review)
Review
Vitiligo is a disease caused by the acquired depletion of melanocytes and/or melanocyte precursor cells in response to genetic and environmental factors, resulting in depigmentation of the entire body. It is roughly divided into segmental and non-segmental vitiligo, and it has been found that abnormalities of melanocytes themselves and dysregulation of autoimmune responses to melanocytes are greatly involved in the pathology of non-segmental vitiligo. Segmental vitiligo pathology is largely unknown; however, it has been suggested that it may be caused by skin or melanocyte mosaicism. Treatments for vitiligo include topical therapy, ultraviolet therapy, and surgical transplantation, and it is extremely important to correctly understand the pathology to perform optimal treatment. In recent years, the development of vitiligo treatments using Janus kinase (JAK) inhibitors has progressed rapidly. We herein outline the latest pathology of vitiligo, from general vitiligo treatment to the progress of clinical trials using JAK inhibitors, along with what clinicians should consider in archiving precision medicine, including my own ideas thereon.
PubMed: 37830414
DOI: 10.5021/ad.23.065 -
Journal of the American Academy of... Sep 2023The Ehlers-Danlos syndromes (EDSs) comprise a group of connective tissue disorders that manifest with skin hyperextensibility, easy bruising, joint hypermobility and... (Review)
Review
BACKGROUND
The Ehlers-Danlos syndromes (EDSs) comprise a group of connective tissue disorders that manifest with skin hyperextensibility, easy bruising, joint hypermobility and fragility of skin, soft tissues, and some organs. A correct assessment of cutaneous features along with the use of adjunct technologies can improve diagnostic accuracy.
OBJECTIVES
To systematically review the cutaneous features and adjunct investigations of EDS.
METHODS
A search of PubMed and Web of Science for EDS-related cutaneous features and additional investigations was undertaken from publication of the 2017 International Classification of EDS until January 15, 2022.
RESULTS
One-hundred-and-forty studies involved 839 patients with EDS. The EDS female-to-male ratio was 1.36:1 (P < .001). A high prevalence of skin hyperextensibility, bruising, and soft skin were noted. Most patients with vascular Ehlers-Danlos syndrome showed venous visibility, skin fragility, and acrogeria. Classical EDS showed subcutaneous spheroids and molluscoid pseudotumours. In patients that underwent skin biopsies, only 30.3% and 71.4% showed features suggestive of EDS using light microscopy and transmission electron microscopy, respectively.
LIMITATIONS
Retrospective study and small cases numbers for some EDS-subtypes.
CONCLUSIONS
An accurate clinical diagnosis increases the chances of a molecular diagnosis, particularly for rarer EDS subtypes, whilst decreasing the need for genetic testing where there is a low clinical suspicion for a monogenic EDS-subtype.
Topics: Humans; Female; Male; Retrospective Studies; Ehlers-Danlos Syndrome; Connective Tissue Diseases
PubMed: 36764582
DOI: 10.1016/j.jaad.2023.01.034 -
Frontiers in Immunology 2023Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for various hematologic malignancies. However, alloimmune response is a double-edged sword that... (Review)
Review
Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for various hematologic malignancies. However, alloimmune response is a double-edged sword that mediates both beneficial graft-versus-leukemia (GVL) effects and harmful graft-versus-host disease (GVHD). Separation of GVL effects from GVHD has been a topic of intense research to improve transplant outcomes, but reliable clinical strategies have not yet been established. Target tissues of acute GVHD are the skin, liver, and intestine, while leukemic stem cells reside in the bone marrow. Tissue specific effector T-cell migration is determined by a combination of inflammatory and chemotactic signals that interact with specific receptors on T cells. Specific inhibition of donor T cell migration to GVHD target tissues while preserving migration to the bone marrow may represent a novel strategy to separate GVL from GVHD. Furthermore, tissue specific GVHD therapy, promoting tissue tolerance, and targeting of the tumor immune microenvironment may also help to separate GVHD and GVL.
Topics: Humans; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; T-Lymphocytes; Hematologic Neoplasms; Immune Tolerance; Tumor Microenvironment
PubMed: 38116007
DOI: 10.3389/fimmu.2023.1296663 -
Journal of Clinical Medicine Oct 2023Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by immune dysregulation and progressive fibrosis, typically affecting the skin, with... (Review)
Review
Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by immune dysregulation and progressive fibrosis, typically affecting the skin, with variable internal organ involvement. Interstitial lung disease (ILD), with a prevalence between 35 and 75%, is the leading cause of death in patients with SSc, indicating that all newly diagnosed patients should be screened for this complication. Some patients with SSc-ILD experience a progressive phenotype, which is characterized by worsening fibrosis on high-resolution computed tomography (HRCT), a decline in lung function, and premature mortality. To assess progression and guide therapeutic decisions, regular monitoring is essential and should include pulmonary function testing (PFT), symptom assessment, and repeat HRCT imaging when indicated. Multidisciplinary discussion allows a comprehensive evaluation of the available information and its consequences for management. There has been a shift in the approach to managing SSc-ILD, which includes the addition of targeted biologic and antifibrotic therapies to standard immunosuppressive therapy (particularly mycophenolate mofetil or cyclophosphamide), with autologous hematopoietic stem-cell transplantation and lung transplantation reserved for refractory cases.
PubMed: 37892818
DOI: 10.3390/jcm12206680 -
Biomolecules Jul 2023Microbiome dysbiosis and cytokine alternations are key features of atopic dermatitis (AD) and psoriasis (PsO), two of the most prevalent and burdensome pruritic skin... (Review)
Review
Microbiome dysbiosis and cytokine alternations are key features of atopic dermatitis (AD) and psoriasis (PsO), two of the most prevalent and burdensome pruritic skin conditions worldwide. Interleukin (IL)-33 and IL-31 have been recognized to be major players who act synergistically in the pathogenesis and maintenance of different chronic inflammatory conditions and pruritic skin disorders, including AD and PsO, and their potential role as therapeutic targets is being thoroughly investigated. The bidirectional interplay between dysbiosis and immunological changes has been extensively studied, but there is still debate regarding which of these two factors is the actual causative culprit behind the aetiopathological process that ultimately leads to AD and PsO. We conducted a literature review on the Pubmed database assessing articles of immunology, dermatology, microbiology and allergology with the aim to strengthen the hypothesis that dysbiosis is at the origin of the IL-33/IL-31 dysregulation that contributes to the pathogenesis of AD and PsO. Finally, we discussed the therapeutic options currently in development for the treatment of these skin conditions targeting IL-31, IL-33 and/or the microbiome.
Topics: Humans; Dermatitis, Atopic; Interleukin-33; Dysbiosis; Psoriasis; Skin; Interleukins; Pruritus; Microbiota
PubMed: 37509136
DOI: 10.3390/biom13071100