Literatura científica selecionada sobre o tema "Immunte tolerance breakdown"

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.

Autoimmune diseases arise when the adaptive immune system mistakenly targets self-antigens, leading to chronic inflammation and tissue damage. This review explores the mechanisms by which adaptive immunity, particularly T and B lymphocyte responses, contributes to the development and persistence of autoimmune diseases. It examines the underlying factors that influence autoreactivity, including genetic susceptibility, environmental triggers, and breakdowns in immune tolerance. Additionally, we discuss the role of T cells, B cells, and autoantibodies in various autoimmune diseases, with emphasis on rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and multiple sclerosis. Insights into the molecular and cellular pathways driving autoimmunity have informed current therapeutic strategies, including immune modulation and targeted biologics. This review highlights the challenges of restoring tolerance in autoimmune disease management and outlines future directions for research and therapeutic development. Keywords: Adaptive immunity, autoimmunity, T cells, B cells, immune tolerance, autoimmune diseases

Abstract The skin epithelium covers our body and serves as a vital interface with the external environment. Here, we review the context-specific interactions between immune cells and the epithelium that underlie barrier fitness and function. We highlight the mechanisms by which these two systems engage each other and how immune–epithelial interactions are tuned by microbial and inflammatory stimuli. Epithelial homeostasis relies on a delicate balance of immune surveillance and tolerance, breakdown of which results in disease. In addition to their canonical immune functions, resident and recruited immune cells also supply the epithelium with instructive signals to promote repair. Decoding the dialogue between immunity and the epithelium therefore has great potential for boosting barrier function or mitigating inflammatory epithelial diseases.

Background and ObjectivesParaneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis.MethodsUsing clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs.ResultsYo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G–plasma cells.DiscussionThese data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.

Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensivein vitroandin vivostudies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.

Abstract In autoimmune rheumatic diseases, immune hyperactivity and chronic inflammation associate with immune dysregulation and the breakdown of immune self-tolerance. A continued, unresolved imbalance between effector and regulatory immune responses further exacerbates inflammation that ultimately causes tissue and organ damage. Many treatment modalities have been developed to restore the immune tolerance and immmunoregulatory balance in autoimmune rheumatic diseases, including the use of peptide-based therapeutics or the use of nanoparticles-based nanotechnology. This review summarizes the state-of-the-art therapeutic use of peptide-based therapies in autoimmune rheumatic diseases, with a specific focus on lupus.

Les syndromes neurologiques paranéoplasiques (SNP) associés aux anticorps Hu sont, généralement, associés à des cancers du poumon à petites cellules (CPPC). Le spectre clinique des Hu-SNP est très hétérogène, et la base immunologique de cette hétérogénéité n’est pas connue. De plus, seule une minorité de patients CPPC développent des Hu-SNP, la raison en est également inconnue. Ce projet de thèse vise à phénotyper les patients Hu-SNP et à explorer leurs caractéristiques biologiques, ainsi que les spécificités génomiques et transcriptomiques de leurs CPPC. Dans un premier temps, une classification hiérarchique a identifié trois groupes chez 466 individus Hu-SNP: atteinte du système nerveux central (SNC), neuropathie isolée et phénotypes mixtes SNC/périphériques. La survie était similaire dans les trois groupes, principalement déterminée par l’évolution du cancer, mais la dysautonomie influençait la mortalité neurologique. Les atteintes du tronc cérébral entraînaient une dysautonomie cardiovasculaire fatale ou une hypoventilation centrale, tandis que l'atteinte neurologique périphérique entraînait des troubles gastro-intestinaux ou sécrétoires, sans risque accru de mortalité. Nous avons aussi étudié des patients ayant développé des Hu-SNP après un traitement par inhibiteurs de checkpoint immunitaire (ICI). Ces patients, cliniquement indistinguables des cas spontanés, suggéraient que les ICI pourraient induire des Hu-SNP. Dans une deuxième partie, le génotypage de 100 patients a confirmé une association avec l'haplotype DR3~DQ2, essentiellement chez les patients avec neuropathie sensitive et absent chez les patients ayant une atteinte exclusive du SNC. Le séquençage par immunoprécipitation de phages a évalué la réactivité des épitopes des anticorps Hu ainsi que d'autres autoanticorps dans le sérum et/ou LCR de 210 patients. Aucune association n'a été trouvée avec l'épitote dominant Hu, mais la réactivité des épitopes différait entre le sérum et le LCR chez 75 % des échantillons appariés. Cette variation était liée au moment du prélèvement et au phénotype: les patients avec des épitopes divergents avaient des LCR prélevés plus tard, tandis que ceux avec des épitopes similaires avaient toujours une atteinte du SNC. Nous avons aussi identifié des réactivités contre d'autres protéines, certaines dans le sérum et/ou LCR, et certaines étaient corrélées à des phénotypes cliniques spécifiques. Enfin, nous avons examiné les caractéristiques moléculaires du CPPC de patients Hu-, GABAbR-SNP et témoins. Nous n’avons trouvé aucune mutation, gain, délétion ou surexpression dans les gènes Hu des patients Hu-SNP. Cependant, un profil transcriptomique distinct, avec des gènes surexprimés liés aux processus immunitaires, caractérisait les tumeurs des Hu-SNP. Nous avons aussi identifié des gènes spécifiquement surexprimés dans le CPPC des patients avec neuropathie sensitive, certains liés à l'axonogenèse et au développement de la neuropathie. Nos résultats suggèrent que plusieurs facteurs contribuent à la variabilité clinique des Hu-SNP, notamment un large spectre d'autoantigènes. Ceux-ci peuvent être liés aux profils d'expression génique dans le CPPC, certains gènes associés à l'axonogenèse étant surexprimés chez les patients ayant une neuropathie sensitive. Une prédisposition génétique pourrait également favoriser certains phénotypes, comme l'indique l'association DR3~DQ2 avec la neuropathie sensitive. La compartimentation au sein du système nerveux pourrait également contribuer: la plupart des patients ciblaient différents épitopes Hu dans leur sérum et dans leur LCR, avec certains autoantigènes plus spécifiques au LCR. Enfin, les altérations des gènes Hu dans le CPPC ne semblent pas participer à la rupture de tolérance immune, mais un profil transcriptomique distinct et les ICI pourraient y contribuer. Ce travail fait progresser la compréhension des Hu-SNP et ouvre la voie de futures recherches sur les mécanismes de l'immunité paranéoplasique
Hu antibodies, the most common in paraneoplastic neurological syndromes (PNS), strongly indicate small-cell lung cancer (SCLC). The clinical spectrum of Hu-PNS is diverse, most patients develop multifocal central, peripheral, and/or autonomic nervous system dysfunction. Despite extensive research, questions remain, namely regarding the immunological basis of clinical heterogeneity and why only a minority of SCLC patients develop Hu-PNS. Our PhD project aims to phenotype Hu-PNS patients, explore the immunogenetics and humoral responses underlying neurological phenotypes, and the genomic and transcriptomic features of their SCLC. First, we described 466 Hu-PNS patients. Hierarchical clustering identified three groups: patients with central nervous system (CNS) involvement; isolated neuropathy; and mixed CNS/peripheral phenotypes. Overall survival was similar across groups, primarily determined by cancer, but dysautonomia, present in 26% of patients, significantly influenced neurological mortality. Prominent CNS dysfunction led to fatal cardiovascular dysautonomia or central hypoventilation, while peripheral involvement was associated with gastrointestinal or secretomotor alterations, without increased mortality risk. We also characterized patients who developed neurological syndromes with Hu antibodies after immune checkpoint inhibitor (ICI) treatment. These patients were clinically indistinguishable from spontaneous cases and shared a strong association with SCLC, suggesting ICIs may induce Hu-PNS. Second, we immunologically investigated neurological phenotypes using two approaches. HLA genotyping of 100 patients confirmed an association with the DR3~DQ2 haplotype, particularly in patients with sensory neuropathy, and absent in those with only CNS involvement. Phage immunoprecipitation sequencing was used to evaluate Hu antibody epitope reactivity and other autoantibodies in serum and/or CSF of 210 patients. We found no direct clinical association with the Hu dominant epitope, but epitope reactivity differed between serum and CSF in 75% of patients with paired samples. This variation correlated with sample timing and phenotype: CSF from patients with differing serum/CSF epitopes was collected later after PNS onset, while patients with serum/CSF consistent epitope reactivity always had CNS phenotypes. In addition, we identified reactivities to other proteins, some more specific to serum or CSF, and a subset linked to specific phenotypes. Third, we examined SCLC molecular features of Hu-, GABAbR-PNS and control patients. Next-generation sequencing, copy number variation analysis, and bulk-RNA sequencing revealed no mutations, gains, deletions, or overexpression in the Hu gene family of Hu-PNS SCLC. However, a distinct transcriptomic profile with upregulated genes largely related to immune system processes characterized these tumors. We also identified specific genes upregulated in the SCLC of patients with sensory neuropathy, some of which were linked to axonogenesis and neuropathy development. Our findings suggest multiple factors contribute to Hu-PNS clinical variability, particularly a broad range of additional autoantigens. These may be partly driven by gene expression patterns in SCLC, as some upregulated genes in patients with sensory neuropathy were linked to axonogenesis. Genetic predisposition may also favor specific phenotypes, as the DR3~DQ2 haplotype was associated with sensory neuropathy. Compartmentalization within the nervous system could further contribute, as most patients targeted different Hu epitopes in serum and CSF, and some autoantigens were more specific to CSF. Finally, Hu genes alterations in SCLC are unlikely causes of neoantigenicity, while a distinct immune-related gene profile and ICIs could contribute to immune tolerance breakdown. This work advances understanding of Hu-PNS complexity and paves the way for further studies into the immunological and molecular drivers of paraneoplastic immunity

Dysfunction within the endocrine system can lead to a variety of diseases with autoimmune attack against individual components being some of the most common. Endocrine autoimmunity encompasses a spectrum of disorders including, e.g., common disorders such as type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, and rarer disorders including Addison’s disease and the autoimmune polyendocrine syndromes type 1 (APS 1) and type 2 (APS 2) (see Table 1.6.1). Autoimmune attack within each of these diseases although aimed at different endocrine organs is caused by a breakdown in the immune system’s ability to distinguish between self and nonself antigens, leading to an immune response targeted at self tissues. Investigating the mechanisms behind this breakdown is vital to understand what has gone wrong and to determine the pathways against which therapeutics can be targeted. Before discussing how self-tolerance fails, we first have to understand how the immune system achieves self-tolerance.

Abstract The classical paradigm of the loss of tolerance as a breakdown in the discrimination between self and non-self and as central to the development of autoimmune disease has been challenged by more recent insights into the innate immune system . Rather than positing recognition of non-self as opposed to self as the pivotal event in an acquired immune response, the distinctions between infectious/non-infectious and between dangerous/not dangerous may be the critical elements 3–6. These distinctions, often made by components of the innate immune system7–10, regulate the delivery of a ‘second signal’ to T cells that is required for development of an acquired immune response. Given the central role of innate immunity in this perspective, a re-consideration of the contributions of the neutrophil, as well as those of macrophages and natural killer cells, to autoimmunity and chronic inflammatory diseases such as rheumatoid arthritis is timely.