Academic literature on the topic 'Immune 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.

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.

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.

Autoimmune diseases (ADs) arise when the immune system erroneously attacks self-tissues, often due to a breakdown in selftolerance. These conditions, influenced by genetic and environmental factors, are increasingly linked to bacterial infections as significant triggers. A healthy immune system protects the body against infections. However, when the immune system malfunctions, it attacks healthy cells, tissues, and organs of the body. This malfunction or dysfunction is called autoimmune disease and can affect any part of the body, impairing psychological function and potentially becoming fatal. This review explores how bacterial pathogens such as Helicobacter pylori, Campylobacter jejuni, and Mycobacterium tuberculosis contribute to autoimmunity through mechanisms like molecular mimicry, bystander activation, and epitope spreading. These processes provoke cross-reactive immune responses, amplify immune dysregulation, and exacerbate tissue damage. Epidemiological and experimental studies reveal strong associations between bacterial infections and diseases like Guillain-Barré syndrome, rheumatoid arthritis, and sarcoidosis. By analyzing the interactions between these pathogens and immune mechanisms, the review highlights the pivotal role of bacteria in disrupting immune tolerance and driving autoimmune disease progression. Moreover, therapeutic strategies such as antibiotics, immunomodulators, and vaccines targeting bacterial-induced autoimmunity offer promising avenues for prevention and treatment. Understanding the mechanisms of bacterial action provides valuable insights into the development of effective diagnostics, preventive measures, and therapies. This review emphasizes the need for continued research on bacterial pathogenesis in autoimmunity, particularly among genetically susceptible populations, to refine targeted clinical approaches and improve outcomes in these complex diseases.

Abstract T regulatory cells (Tregs) have a key role in the maintenance of immune homeostasis and the regulation of immune tolerance by preventing the inflammation and suppressing the autoimmune responses. Numerical and functional deficits of these cells have been reported in systemic lupus erythematosus (SLE) patients and mouse models of SLE, where their imbalance and dysregulated activities have been reported to significantly influence the disease pathogenesis, progression and outcomes. Most studies in SLE have focused on CD4+ Tregs and it has become clear that a critical role in the control of immune tolerance after the breakdown of self-tolerance is provided by CD8+ Tregs. Here we review the role, cellular and molecular phenotypes, and mechanisms of action of CD8+ Tregs in SLE, including ways to induce these cells for immunotherapeutic modulation in SLE.

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria,Escherichia Coli, andNosphingobium aromaticivoransare the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.

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

Introduction : Les syndromes neurologiques paranéoplasiques (SNP) sont des maladies auto-immunes rares affectant le système nerveux central, associées à la présence d'un cancer et satellites de la réponse immune anti-tumorale. Ces pathologies sont associées à la présence d’auto-anticorps, dont la détection dans le sang ou le LCR des patients permet de poser le diagnostic. Ces auto-anticorps sont dirigés contre une protéine du soi, exprimée à la fois dans la tumeur et dans le SNC, appelée l'antigène onconeuronal. Les facteurs amenant à la rupture de tolérance immune dans les SNP restent inconnus à ce jour. Des travaux récents dans les cancers de l'ovaire et du sein associés au syndrome Yo ont permis de montrer que les antigènes onconeuronaux Yo sont surexprimés dans la tumeur. De plus, il existe fréquemment des mutations et des gains de nombre de copie des gènes codant pour les antigènes Yo. Ces altérations des antigènes onconeuronaux ne sont pas retrouvées dans les autres SNP (cancers du poumon associé aux anticorps anti-Hu par exemple) et les facteurs déclenchants de la rupture de tolérance immune dans ces cancers sont encore plus mystérieux. Les objectifs de ce travail de thèse sont d'approfondir l'analyse du lien entre la tumeur et l'auto-immunité paranéoplasique. Le premier axe d'étude était la comparaison de deux couples de syndromes associés au même type de cancer (syndrome Ri et Yo associés à des cancers du sein, syndrome RGS8 et DNER associés à des lymphomes de Hodgkin). Le deuxième axe portait sur l'analyse des potentielles altérations des antigènes onconeuronaux dans le syndrome Ri.Méthodes : La première étude de ce travail de thèse portait sur une cohorte de cancers du sein associés au syndrome de Ri, utilisant des données clinico-pathologiques, génomiques et transcriptomiques. La seconde étude portait sur patients atteints du syndrome RGS8 et utilisait des données clinico-pathologiques et le séquençage par immunoprécipitation de Phage (PhIP-seq).Résultats : Les cancers du sein Ri sont d’un sous-type particulier (Luminal B) différent de celui observé dans les cancers Yo (HER2-driven) et présentent des particularités génétiques qui les différencient des tumeurs Luminal B contrôles. Aucune altération des antigènes onconeuronaux n'a été retrouvée dans les tumeurs Ri. En revanche, la réaction immune anti-tumorale, composée majoritairement d’un infiltrat lymphocytaire B intra-tumoral, est comparable à celle observée dans les cancers du sein Ri et Yo.Concernant le syndrome RGS8, deux patients présentent un lymphome de Hodgkin d'un sous-type spécifique rare nodulaire à prédominance lymphocytaire, différents des formes nodulaires-sclérosantes classiques associées au syndrome DNER. Les auto-anticorps détectés chez tous les patients enrichissaient le même épitope sur la protéine RGS8, une protéine intracellulaire physiologiquement exprimée dans les cellules de Purkinje mais dont on retrouve également une expression ectopique dans les cellules de lymphome des patients atteints du syndrome RGS8.Conclusion : chaque syndrome paranéoplasique est associé à un sous-type spécifique de cancer présentant des particularités génétiques. Les altérations de l'antigène (surexpression, variation du nombre de copies et mutation) peuvent déclencher la rupture de la tolérance immune mais ne sont pas présentes dans tous les syndromes paranéoplasiques. L'immunité antitumorale associée aux PNS est atypique du fait de l’importance de l’infiltrat lymphocytaire B. Ces résultats constituent un pas en avant dans notre compréhension de l'immunité paranéoplasique et fournissent des indices sur les marqueurs prédictifs potentiels qui pourraient être utiles pour personnaliser la prise de décision médicale en immunothérapie anti-cancéreuse
Background: Paraneoplastic cerebellar degeneration (PCD) are rare autoimmune disorders affecting an otherwise immune-privileged site: the central nervous system. This autoimmunity is associated with the presence of a cancer and is satellite of the anti-tumor immune response, the B-cell response originating a secretion of autoantibodies that are diagnostic hallmarks of these disorders. These autoantibodies are directed against a protein expressed both in the tumor and in the CNS, the so-called onconeural antigen. The triggers of the immune tolerance breakdown and the exact relationship between the tumor, the immune system and the neurological symptoms are still not totally understood. Recent studies have allowed to show that in some tumors associated with paraneoplastic syndromes (namely ovarian and breast cancers associated with Yo syndrome), the onconeural antigen is overexpressed due to the presence of a gain or amplification in the gene locus and may present mutations while in others, none of these alterations of the onconeural antigen are present (e.g. lung cancers in Hu syndrome). The objectives of this thesis work are to further analyze the link between the tumor and the paraneoplastic autoimmunity by comparing two syndromes associated with the same type of cancer (Ri and Yo syndrome associated with breast cancers, RGS8 and DNER syndrome associated with Hodgkin’s lymphoma) and to search for antigen alterations in another syndrome (Ri syndrome).Methods: we conducted two studies within the frame of this thesis work. A first study on a clinical and pathological cohort of breast cancers associated with Ri-syndrome using clinicopathological data, DNA-sequencing, and whole-transcriptome analysis. A second analysis on three patients with RGS8-syndrome using clinicopathological data and Phage Immunoprecipitation sequencing (PhIP-seq).Results: Ri breast cancers were a subtype different than one observed in Yo with uncommon genetic features that singularize them among their subtype. Neither overexpression nor genetic alteration of the Ri onconeural antigens were found in Ri breast cancers. Conversely, the anti-tumor immune reaction in Ri breast cancers was similar to the one found in Yo: an atypical intratumoral B-cell infiltration.Concerning RGS8 paraneoplastic cerebellar degeneration, two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, whereas DNER is associated with the classical nodular-sclerosing form. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-syndrome.Conclusion: each paraneoplastic syndrome is associated with a specific histomolecular subtype of cancer with uncommon genetic features, which provides the first evidence of a tight link between oncogenesis and paraneoplastic immunity. Alterations of the antigen (overexpression, copy number variation and mutation) may be the mechanism of immune tolerance breakdown in several different syndromes but are not ubiquitous. The antitumor immunity seems to be an atypical B-cell response in several subtypes irrespective of the tumor type and antigen alterations. These results are a step forward in our understanding of paraneoplastic immunity and provide clues on potential predictive markers of paraneoplastic immunity that may be of use in personalizing medical decision of immunotherapy in the field of oncology

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.