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Nature Communications Apr 2024The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance...
The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance mechanisms, but unknown due to limitations of the currently applied technologies. Here, we introduce an autoantigen-specific liquid chromatography-mass spectrometry-based IgG1 Fab profiling approach using the anti-citrullinated protein antibody (ACPA) repertoire in rheumatoid arthritis (RA) as an example. We show that each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab glycans, and different glycovariants of the same clone can be detected. Together, our data indicate that the autoantibody response in a prominent human autoimmune disease is complex, unique to each patient and dominated by a relatively low number of clones.
Topics: Humans; Autoantibodies; Arthritis, Rheumatoid; Anti-Citrullinated Protein Antibodies; Immunoglobulin G; Autoantigens
PubMed: 38600082
DOI: 10.1038/s41467-024-47337-x -
Frontiers in Immunology 2024The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response....
INTRODUCTION
The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response. Defective ribosomal protein products in tumors are targets of the anti-tumor immune response that is unleashed by immune checkpoint inhibitor (ICI) treatment in cancer patients. We recently described a defective ribosomal product of the insulin gene (INS-DRiP) that is expressed in stressed beta cells and targeted by diabetogenic T cells. T1D patient-derived INS-DRiP specific T cells can kill beta cells and are present in the insulitic lesion. T cells reactive to INS-DRiP epitopes are part of the normal T cell repertoire and are believed to be kept in check by immune regulation without causing autoimmunity.
METHOD
T cell autoreactivity was tested using a combinatorial HLA multimer technology measuring a range of epitopes of islet autoantigens and neoantigen INS-DRiP. INS-DRiP expression in human pancreas and insulinoma sections was tested by immunohistochemistry.
RESULTS
Here we report the induction of islet autoimmunity to INS-DRiP and diabetes after ICI treatment and successful tumor remission. Following ICI treatment, T cells of the cancer patient were primed against INS-DRiP among other diabetogenic antigens, while there was no sign of autoimmunity to this neoantigen before ICI treatment. Next, we demonstrated the expression of INS-DRiP as neoantigen in both pancreatic islets and insulinoma by staining with a monoclonal antibody to INS-DRiP.
DISCUSSION
These results bridge cancer and T1D as two sides of the same coin and point to neoantigen expression in normal islets and insulinoma that may serve as target of both islet autoimmunity and tumor-related autoimmunity.
Topics: Humans; Diabetes Mellitus, Type 1; Autoimmunity; Insulinoma; Autoantigens; Insulin; Epitopes; Immunotherapy; Pancreatic Neoplasms
PubMed: 38596681
DOI: 10.3389/fimmu.2024.1384406 -
Cell Communication and Signaling : CCS Apr 2024Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the...
Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.
Topics: Humans; Mice; Animals; Lupus Nephritis; Toll-Like Receptor 7; Toll-Like Receptor 8; Kidney; Mice, Transgenic; MicroRNAs
PubMed: 38589923
DOI: 10.1186/s12964-024-01601-1 -
Journal of Dermatological Science May 2024Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the...
BACKGROUND
Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce.
OBJECTIVE
To assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics.
METHODS
BP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments.
RESULTS
We demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024-2349 and C3; amino acids 2326-2649), provided the best serological assay for anti-BP230 IgE detection.
CONCLUSION
As a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP.
Topics: Humans; Pemphigoid, Bullous; Immunoglobulin E; Autoantibodies; Male; Female; Aged; Autoantigens; Dystonin; Aged, 80 and over; Non-Fibrillar Collagens; Middle Aged; Enzyme-Linked Immunosorbent Assay; Severity of Illness Index; Immunoglobulin G; Collagen Type XVII; Adult; Blotting, Western
PubMed: 38582700
DOI: 10.1016/j.jdermsci.2024.03.009 -
Frontiers in Immunology 2024Myelin oligodendrocyte glycoprotein antibody (MOG) immunoglobulin G (IgG)-associated disease (MOGAD) has clinical and pathophysiological features that are similar to but...
BACKGROUND
Myelin oligodendrocyte glycoprotein antibody (MOG) immunoglobulin G (IgG)-associated disease (MOGAD) has clinical and pathophysiological features that are similar to but distinct from those of aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (AQP4-NMOSD). MOG-IgG and AQP4-IgG, mostly of the IgG1 subtype, can both activate the complement system. Therefore, we investigated whether the levels of serum complement components, regulators, and activation products differ between MOGAD and AQP4-NMOSD, and if complement analytes can be utilized to differentiate between these diseases.
METHODS
The sera of patients with MOGAD (from during an attack and remission; =19 and =9, respectively) and AQP4-NMOSD (=35 and =17), and healthy controls (=38) were analyzed for C1q-binding circulating immune complex (CIC-C1q), C1 inhibitor (C1-INH), factor H (FH), C3, iC3b, and soluble terminal complement complex (sC5b-9).
RESULTS
In attack samples, the levels of C1-INH, FH, and iC3b were higher in the MOGAD group than in the NMOSD group (all, <0.001), while the level of sC5b-9 was increased only in the NMOSD group. In MOGAD, there were no differences in the concentrations of complement analytes based on disease status. However, within AQP4-NMOSD, remission samples indicated a higher C1-INH level than attack samples (p=0.003). Notably, AQP4-NMOSD patients on medications during attack showed lower levels of iC3b (<0.001) and higher levels of C3 (=0.008), C1-INH (=0.004), and sC5b-9 (<0.001) compared to those not on medication. Among patients not on medication at the time of attack sampling, serum MOG-IgG cell-based assay (CBA) score had a positive correlation with iC3b and C1-INH levels (rho=0.764 and =0.010, and rho=0.629 and =0.049, respectively), and AQP4-IgG CBA score had a positive correlation with C1-INH level (rho=0.836, =0.003).
CONCLUSIONS
This study indicates a higher prominence of complement pathway activation and subsequent C3 degradation in MOGAD compared to AQP4-NMOSD. On the other hand, the production of terminal complement complexes (TCC) was found to be more substantial in AQP4-NMOSD than in MOGAD. These findings suggest a strong regulation of the complement system, implying its potential involvement in the pathogenesis of MOGAD through mechanisms that extend beyond TCC formation.
Topics: Humans; Aquaporin 4; Complement C1q; Complement C3b; Complement System Proteins; Immunoglobulin G; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica
PubMed: 38576611
DOI: 10.3389/fimmu.2024.1320094 -
Multiple Sclerosis and Related Disorders May 2024Clinicians are becoming increasingly aware of the cognitive and psychopathological consequences of neurological diseases, which were once thought to manifest with motor... (Review)
Review
Cognitive and psychopathological features of neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease: A narrative review.
Clinicians are becoming increasingly aware of the cognitive and psychopathological consequences of neurological diseases, which were once thought to manifest with motor and sensory impairments only. The cognitive profile of multiple sclerosis, in particular, is now well-characterised. Similar efforts are being made to better characterise the cognitive profile of other central nervous system inflammatory demyelinating autoimmune disorders. This review discusses the current understanding of the cognitive and psychological features of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Detailed analysis of the cognitive sequelae of the above conditions can not only assist with understanding disease pathogenesis but also can guide appropriate management of the symptoms and consequently, improve the quality of life and long-term outcomes for these patients. This narrative review will also identify research gaps and provide recommendations for future directions in the field.
Topics: Humans; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein; Cognitive Dysfunction; Autoantibodies
PubMed: 38574722
DOI: 10.1016/j.msard.2024.105596 -
Frontiers in Immunology 2024Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful... (Review)
Review
Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful immunotherapy requires epitope spreading, but the slow or inefficient induction of functional antitumoral immunity delays the benefit to patients or causes resistances. Therefore, understanding the key mechanisms that support epitope spreading is essential to improve immunotherapy. In this review, we highlight the major role played by B-cells in breaking immune tolerance by epitope spreading. Activated B-cells are key Antigen-Presenting Cells (APC) that diversify the T-cell response against self-antigens, such as ribonucleoproteins, in autoimmunity but also during successful cancer immunotherapy. This has important implications for the design of future cancer vaccines.
Topics: Humans; Epitopes; T-Lymphocytes; Autoantigens; Autoimmunity; Immunotherapy; Neoplasms
PubMed: 38571942
DOI: 10.3389/fimmu.2024.1382236 -
Heliyon Apr 2024Graves' ophthalmopathy (GO) is an extrathyroidal manifestation of Graves' disease, Orbital fibroblasts (OFs) are recognized as key players in GO pathogenesis, involved...
Graves' ophthalmopathy (GO) is an extrathyroidal manifestation of Graves' disease, Orbital fibroblasts (OFs) are recognized as key players in GO pathogenesis, involved in orbital inflammation, tissue remodeling, and fibrosis. This study offers a primary exploration of cell behavior and characteristics on OFs from GO (GO-OFs), and compared to OFs from healthy control (HC-OFs). Results reveal that GO-OFs exhibit delayed migration from tissue fragments, while no significant difference in cell proliferation is observed between GO-OFs and HC-OFs. Aberrant expression pattern of surface proteins Thy-1, TSHR, and IGF-1R suggests shared autoantigens and pathways between GO and GD, contributing to inflammation and fibrosis. Investigations into cytokine responses unveil elevated secretion of hyaluronic acid (HA) and prostaglandin E2 (PGE2) in GO-OFs, emphasizing their role in tissue remodeling. These findings deepen our understanding of OFs in GO pathogenesis, offering potential therapeutic avenues.
PubMed: 38571651
DOI: 10.1016/j.heliyon.2024.e28397 -
Nature May 2024Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size. As a result, patterns of human...
Human centromeres have been traditionally very difficult to sequence and assemble owing to their repetitive nature and large size. As a result, patterns of human centromeric variation and models for their evolution and function remain incomplete, despite centromeres being among the most rapidly mutating regions. Here, using long-read sequencing, we completely sequenced and assembled all centromeres from a second human genome and compared it to the finished reference genome. We find that the two sets of centromeres show at least a 4.1-fold increase in single-nucleotide variation when compared with their unique flanks and vary up to 3-fold in size. Moreover, we find that 45.8% of centromeric sequence cannot be reliably aligned using standard methods owing to the emergence of new α-satellite higher-order repeats (HORs). DNA methylation and CENP-A chromatin immunoprecipitation experiments show that 26% of the centromeres differ in their kinetochore position by >500 kb. To understand evolutionary change, we selected six chromosomes and sequenced and assembled 31 orthologous centromeres from the common chimpanzee, orangutan and macaque genomes. Comparative analyses reveal a nearly complete turnover of α-satellite HORs, with characteristic idiosyncratic changes in α-satellite HORs for each species. Phylogenetic reconstruction of human haplotypes supports limited to no recombination between the short (p) and long (q) arms across centromeres and reveals that novel α-satellite HORs share a monophyletic origin, providing a strategy to estimate the rate of saltatory amplification and mutation of human centromeric DNA.
Topics: Animals; Humans; Centromere; Centromere Protein A; DNA Methylation; DNA, Satellite; Evolution, Molecular; Genetic Variation; Kinetochores; Macaca; Pan troglodytes; Polymorphism, Single Nucleotide; Pongo; Male; Female; Reference Standards; Chromatin Immunoprecipitation; Haplotypes; Mutation; Gene Amplification; Sequence Alignment; Chromatin; Species Specificity
PubMed: 38570684
DOI: 10.1038/s41586-024-07278-3 -
Translational Medicine @ UniSa 2024Gender medicine is a multidisciplinary science and represents an important perspective for pathophysiological and clinical studies in the third millennium. Here, it is... (Review)
Review
Gender medicine is a multidisciplinary science and represents an important perspective for pathophysiological and clinical studies in the third millennium. Here, it is provided an overview of the topics discussed in a recent course on the Role of Sex and Gender in Ageing and Longevity. The paper highlights three themes discussed in the course, i.e., the interaction of gender/sex with, i) the pathophysiology of age-related diseases; ii), the role of genetics and epigenetics in ageing and longevity and, iii) the immune responses of older people to pathogens, vaccines, autoantigens, and allergens. Although largely unexplored, it is clear that sex and gender are modulators of disease biology and treatment outcomes. It is becoming evident that men and women should no longer be considered as subgroups, but as biologically distinct groups of patients deserving consideration for specific therapeutic approaches.
PubMed: 38560614
DOI: 10.37825/2239-9747.1049