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Nature Communications Dec 2023Centromeres are epigenetically defined via the presence of the histone H3 variant CENP-A. Contacting CENP-A nucleosomes, the constitutive centromere associated network...
Centromeres are epigenetically defined via the presence of the histone H3 variant CENP-A. Contacting CENP-A nucleosomes, the constitutive centromere associated network (CCAN) and the kinetochore assemble, connecting the centromere to spindle microtubules during cell division. The DNA-binding centromeric protein CENP-B is involved in maintaining centromere stability and, together with CENP-A, shapes the centromeric chromatin state. The nanoscale organization of centromeric chromatin is not well understood. Here, we use single-molecule fluorescence and cryoelectron microscopy (cryoEM) to show that CENP-A incorporation establishes a dynamic and open chromatin state. The increased dynamics of CENP-A chromatin create an opening for CENP-B DNA access. In turn, bound CENP-B further opens the chromatin fiber structure and induces nucleosomal DNA unwrapping. Finally, removal of CENP-A increases CENP-B mobility in cells. Together, our studies show that the two centromere-specific proteins collaborate to reshape chromatin structure, enabling the binding of centromeric factors and establishing a centromeric chromatin state.
Topics: Chromatin; Centromere Protein A; Cryoelectron Microscopy; Chromosomal Proteins, Non-Histone; Centromere; Nucleosomes; DNA; Autoantigens
PubMed: 38086807
DOI: 10.1038/s41467-023-43739-5 -
Frontiers in Immunology 2020Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by recognition of pancreatic β-cell proteins as self-antigens, called autoantigens (AAgs),... (Review)
Review
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by recognition of pancreatic β-cell proteins as self-antigens, called autoantigens (AAgs), followed by loss of pancreatic β-cells. (Pre-)proinsulin ([P]PI), glutamic acid decarboxylase (GAD), tyrosine phosphatase IA-2, and the zinc transporter ZnT8 are key molecules in T1D pathogenesis and are recognized by autoantibodies detected in routine clinical laboratory assays. However, generation of new autoantigens (neoantigens) from β-cells has also been reported, against which the autoreactive T cells show activity. Heat shock proteins (HSPs) were originally described as "cellular stress responders" for their role as chaperones that regulate the conformation and function of a large number of cellular proteins to protect the body from stress. HSPs participate in key cellular functions under both physiological and stressful conditions, including suppression of protein aggregation, assisting folding and stability of nascent and damaged proteins, translocation of proteins into cellular compartments and targeting irreversibly damaged proteins for degradation. Low HSP expression impacts many pathological conditions associated with diabetes and could play a role in diabetic complications. HSPs have beneficial effects in preventing insulin resistance and hyperglycemia in type 2 diabetes (T2D). HSPs are, however, additionally involved in antigen presentation, presenting immunogenic peptides to class I and class II major histocompatibility molecules; thus, an opportunity exists for HSPs to be employed as modulators of immunologic responses in T1D and other autoimmune disorders. In this review, we discuss the multifaceted roles of HSPs in the pathogenesis of T1D and in autoantigen-specific immune protection against T1D development.
Topics: Animals; Autoantigens; Autoimmune Diseases; Diabetes Mellitus, Type 1; Heat-Shock Proteins; Humans; T-Lymphocytes
PubMed: 33584694
DOI: 10.3389/fimmu.2020.612584 -
Immunotherapy 2015CD4(+)CD25(+)Foxp3(+)regulatory T cells (Treg cells) are extremely important in maintaining immune tolerance. Manipulation of Treg cells, especially autoantigen-specific... (Review)
Review
CD4(+)CD25(+)Foxp3(+)regulatory T cells (Treg cells) are extremely important in maintaining immune tolerance. Manipulation of Treg cells, especially autoantigen-specific Treg cells is a promising approach for treatments of autoimmune disease since Treg cells may provide the advantage of antigen specificity without overall immune suppression. However, the clinical application of Treg cells has long been limited due to low numbers of Treg cells and the difficulty in identifying their antigen specificity. In this review, we summarize studies that demonstrate regression of autoimmune diseases using Treg cells as therapeutics. We also discuss approaches to generate polyclonal and autoantigen-specific Treg cells in vitro and in vivo. We also discuss our recent study that describes a novel approach of generating autoantigen-specific Treg cells in vivo and restoring immune tolerance by two steps apoptosis-antigen therapy.
Topics: Animals; Apoptosis; Autoantigens; Autoimmune Diseases; Autoimmunity; CD4 Antigens; Forkhead Transcription Factors; Humans; Immune Tolerance; Immunosuppression Therapy; Immunotherapy, Adoptive; Interleukin-2 Receptor alpha Subunit; T-Lymphocytes, Regulatory
PubMed: 26568117
DOI: 10.2217/imt.15.79 -
Frontiers in Immunology 2023The DNA-binding peptide LL37 is a suspected autoantigen in psoriasis. It can be found in neutrophil extracellular traps (NETs) which have been suggested to play a role...
BACKGROUND
The DNA-binding peptide LL37 is a suspected autoantigen in psoriasis. It can be found in neutrophil extracellular traps (NETs) which have been suggested to play a role in the pathogenesis of the disease. Citrullination, the conversion of peptidyl-arginine into peptidyl-citrulline, can be implicated in the formation of NETs. We hypothesized that citrullination increases LL37 immunogenicity and that NETs are a source of LL37.
OBJECTIVES
We aimed to characterize cytokine responses of B cells and T cells to native and citrullinated LL37 (citLL37) and determine the prevalence and composition of circulating NETs in patients with psoriasis and healthy blood donors (HDs).
METHODS
Mononuclear cells (MNCs) and serum were isolated from 20 HDs and 20 patients with psoriasis. The MNCs were stimulated with native LL37 and citLL37 and the proportion of cytokine-positive B cells and T cells was determined by flow cytometry. Circulating antibodies against native LL37 and citLL37 as well as circulating NETs were measured by ELISA, as was the content of LL37, citLL37, and IgG in the NETs.
RESULTS
CitLL37, but not native LL37, induced IFN-γ-production by T cells and B cells from psoriasis patients, as well as IL-10-production by the patients' CD4 T cells. Serum from 40% of patients and 55% of HDs contained circulating NETs, of which 63% and 27%, respectively, contained LL37. Only two patients had NETs containing citLL37 and IgG antibodies were found in NETs from three patients and one HD. analysis of the cytokines produced by B cells and T cells after stimulation with citLL37 revealed two clusters of patients consisting of 10 high-responders and 9 low-responders. The high-responders were those that had circulating NETs in combination with an earlier age of onset of the disease.
CONCLUSION
Citrullinated but not native LL37 elicits IFN-γ-responses by T cells and B cells from psoriasis patients, particularly those with circulating NETs and early disease onset, suggesting a role of citLL37 as an autoantigen in this subgroup of patients.
Topics: Humans; Extracellular Traps; Psoriasis; Cytokines; Immunity; Immunoglobulin G; Autoantigens
PubMed: 38173716
DOI: 10.3389/fimmu.2023.1247592 -
Journal of Neuroimmunology May 2024Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have... (Review)
Review
Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.
Topics: Humans; Multiple Sclerosis; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Animals; Autoantigens
PubMed: 38615370
DOI: 10.1016/j.jneuroim.2024.578343 -
Clinical and Experimental Immunology Apr 2019Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of... (Review)
Review
Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4 T cells, the cross-priming of CD8 T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC-T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC-T cell interaction for antigen-specific immunotherapy of RA.
Topics: Animals; Antibody Formation; Antigen Presentation; Arthritis, Rheumatoid; Autoantigens; Autoimmunity; B-Lymphocytes; Cell Communication; Dendritic Cells; Humans; Immune Tolerance; Immunotherapy; Lymphocyte Activation; Peptides; T-Lymphocytes
PubMed: 30589082
DOI: 10.1111/cei.13256 -
Nature Reviews. Neurology Sep 2020A rapidly expanding and clinically distinct group of CNS diseases are caused by pathogenic autoantibodies that target neuroglial surface proteins. Despite immunotherapy,... (Review)
Review
A rapidly expanding and clinically distinct group of CNS diseases are caused by pathogenic autoantibodies that target neuroglial surface proteins. Despite immunotherapy, patients with these neuroglial surface autoantibody (NSAb)-mediated diseases often experience clinical relapse, high rates of long-term morbidity and adverse effects from the available medications. Fundamentally, the autoantigen-specific B cell lineage leads to production of the pathogenic autoantibodies. These autoantigen-specific B cells have been consistently identified in the circulation of patients with NSAb-mediated diseases, accompanied by high serum levels of autoantigen-specific antibodies. Early evidence suggests that these cells evade well-characterized B cell tolerance checkpoints. Nearer to the site of pathology, cerebrospinal fluid from patients with NSAb-mediated diseases contains high levels of autoantigen-specific B cells that are likely to account for the intrathecal synthesis of these autoantibodies. The characteristics of their immunoglobulin genes offer insights into the underlying immunobiology. In this Review, we summarize the emerging knowledge of B cells across the NSAb-mediated diseases. We review the evidence for the relative contributions of germinal centres and long-lived plasma cells as sources of autoantibodies, discuss data that indicate migration of B cells into the CNS and summarize insights into the underlying B cell pathogenesis that are provided by therapeutic effects.
Topics: Animals; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Central Nervous System Diseases; Humans; Immunotherapy
PubMed: 32724223
DOI: 10.1038/s41582-020-0381-z -
Cell Death and Differentiation Jun 2016The skeletal muscle is an immunologically unique tissue. Leukocytes, virtually absent in physiological conditions, are quickly recruited into the tissue upon injury and... (Review)
Review
The skeletal muscle is an immunologically unique tissue. Leukocytes, virtually absent in physiological conditions, are quickly recruited into the tissue upon injury and persist during regeneration. Apoptosis, necrosis and autophagy coexist in the injured/regenerating muscles, including those of patients with neuromuscular disorders, such as inflammatory myopathies, dystrophies, metabolic and mitochondrial myopathies and drug-induced myopathies. Macrophages are able to alter their function in response to microenvironment conditions and as a consequence coordinate changes within the tissue from the early injury throughout regeneration and eventual healing, and regulate the activation and the function of stem cells. Early after injury, classically activated macrophages ('M1') dominate the picture. Alternatively activated M2 macrophages predominate during resolution phases and regulate the termination of the inflammatory responses. The dynamic M1/M2 transition is increasingly felt to be the key to the homeostasis of the muscle. Recognition and clearance of debris originating from damaged myofibers and from dying stem/progenitor cells, stromal cells and leukocytes are fundamental actions of macrophages. Clearance of apoptotic cells and M1/M2 transition are causally connected and represent limiting steps for muscle healing. The accumulation of apoptotic cells, which reflects their defective clearance, has been demonstrated in various tissues to prompt autoimmunity against intracellular autoantigens. In the muscle, in the presence of type I interferon, apoptotic myoblasts indeed cause the production of autoantibodies, lymphocyte infiltration and continuous cycles of muscle injury and regeneration, mimicking human inflammatory myopathies. The clearance of apoptotic cells thus modulates the homeostatic response of the skeletal muscle to injury. Conversely, defects in the process may have deleterious local effects, guiding maladaptive tissue remodeling with collagen and fat accumulation and promoting autoimmunity itself. There is strong promise for novel treatments based on new knowledge of cell death, clearance and immunity in the muscle.
Topics: Animals; Apoptosis; Autoantigens; Autoimmunity; Humans; Inflammation; Macrophages; Muscle, Skeletal; Regeneration; T-Lymphocytes
PubMed: 26868912
DOI: 10.1038/cdd.2015.171 -
International Journal of Molecular... Feb 2020Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the... (Review)
Review
Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.
Topics: Administration, Oral; Animals; Autoantigens; Chemotherapy, Adjuvant; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Glutamate Decarboxylase; Humans; Injections, Intralymphatic; Injections, Subcutaneous; Insulin; Proinsulin; Vitamin D
PubMed: 32111075
DOI: 10.3390/ijms21051598 -
Clinical and Experimental Immunology Dec 2019In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four...
In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four review articles are presented, which encompass new findings presented at the Immunology of Diabetes Society meeting in London 2018. The articles are focused particularly in 4 related areas of investigation, which include autoantibodies in type 1 diabetes, new autoantigenic targets for CD4 T cells, trafficking of immune cells to the pancreas and islet-immune interactions in the pancreas.
Topics: Autoantibodies; Autoantigens; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Humans; Islets of Langerhans; Pancreas
PubMed: 31729755
DOI: 10.1111/cei.13396