Dynamic spectrum of ectopic lymphoid B cell activation and hypermutation in the RA synovium characterized by NR4A nuclear receptor expression.
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ABSTRACT:
SUBMITTER: Meednu N
PROVIDER: S-EPMC9234997 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundFollicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium.Methods and findingsUsing immunohistochemistry (IHC) and quantitative Taqman real-time PCR (QT-PCR) in synovial tissue from 55 patients with RA, we demonstrated that FDC+ structures invariably expressed AID with a distribution resembling secondary lymphoid organs. Further, AID+/CD21+ follicular structures were surrounded by ACPA+/CD138+ plasma cells, as demonstrated by immune reactivity to citrullinated fibrinogen. Moreover, we identified a novel subset of synovial AID+/CD20+ B cells outside GCs resembling interfollicular large B cells. In order to gain direct functional evidence that AID+ structures support CSR and in situ manufacturing of class-switched ACPA, 34 SCID mice were transplanted with RA synovium and humanely killed at 4 wk for harvesting of transplants and sera. Persistent expression of AID and Igamma-Cmu circular transcripts (identifying ongoing IgM-IgG class-switching) was observed in synovial grafts expressing FDCs/CD21L. Furthermore, synovial mRNA levels of AID were closely associated with circulating human IgG ACPA in mouse sera. Finally, the survival and proliferation of functional B cell niches was associated with persistent overexpression of genes regulating ectopic lymphoneogenesis.ConclusionsOur demonstration that FDC+ follicular units invariably express AID and are surrounded by ACPA-producing plasma cells provides strong evidence that ectopic lymphoid structures in the RA synovium are functional and support autoantibody production. This concept is further confirmed by evidence of sustained AID expression, B cell proliferation, ongoing CSR, and production of human IgG ACPA from GC+ synovial tissue transplanted into SCID mice, independently of new B cell influx from the systemic circulation. These data identify AID as a potential therapeutic target in RA and suggest that survival of functional synovial B cell niches may profoundly influence chronic inflammation, autoimmunity, and response to B cell-depleting therapies.
| S-EPMC2621263 | biostudies-literature
Project description:Background: Rheumatoid arthritis (RA) is a complex heterogenous autoimmune disease and achieving long term disease remission is an elusive goal for patients, thus implying improvement in drug targeting is necessary. Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in RA. Therefore, oral inhibitors of specific kinases, such as Cyclin Dependent Kinases (CDKs) and Janus Kinase (JAKs), are under development or have been approved. However, the cell signalling mechanisms in treatment naïve RA patients is yet to be explored, which may facilitate targeted therapy stratification. Methods: We undertook phosphoproteome and total proteome analysis of 8 pre-treatment synovial biopsies of RA patients using label-free mass spectrometry. Results: The analysis revealed a clear separation of the phosphoproteome and proteome profile between the lymphoid and myeloid RA pathotypes. Differential expression analysis and function enrichment showed that the degree of inflammatory state and specific signalling activities are associated with different RA pathotypes. The lymphoid pathotype was enriched with immunological pathways and associated with Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted kinases not previously linked to RA, such as Serine/Threonine Protein Kinase N1 (PKN1) in the lymphoid pathotype and Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotypes. Certain phosphosites were also highly correlated with clinical features, such as Disabled Homolog 2 (DAB2)-Ser723 with Disease Activity Score (DAS)-28, and so these may be potential biomarkers of disease progression and response. Conclusions: These data provide evidence that specific phosphoproteome and proteome signatures are associated with different RA pathotypes and may have clinical utility for stratifying patients as part of a personalised medicine approach.
2024-08-08 | PXD044963 | Pride
Project description:Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identified a unique B cell population in the synovium characterized by co-expression of a family of orphan nuclear receptors, NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1), that is highly enriched at both early and late stages of RA. See doi:10.1101/2021.05.14.443150 for details.
2022-02-11 | GSE196150 | GEO
Project description:Neuromyelitis optica spectrum disorders (NMOSDs) are important autoimmune central nervous system (CNS) astrocytopathy causing acute myelitis, optic neuritis (ON), and encephalitis associated with significant morbidities and mortality. It is important to diagnose NMOSDs early as they are treatable. The majority of NMOSDs patients are seropositive for aquaporin-4 IgG (AQP4-IgG) autoantibodies, which target CNS aquaporin-4 (AQP4) expressed abundantly in astrocytic foot processes. We report the novel observation of orbital masses containing ectopic lymphoid follicles with germinal centres (GC) in two patients with AQP4-IgG-positive NMOSD. Both patients had severe extensive myelitis with symptomatic or asymptomatic ON, with the ectopic lymphoid structures detected on initial presentation. Histolopathological studies confirmed that the orbital masses contained reactive lymphoid follicles with GC containing B cells and plasma cells. Our observations support that AQP4-IgG positive NMOSDs patients have underlying AQP4 autoimmunity and suggest that ON (symptomatic or asymptomatic) may trigger formation of orbital ectopic GC contributing to development of high-affinity AQP4-specific memory B cells and plasma cells, which produce highly pathogenic AQP4-IgG.
| S-EPMC5776022 | biostudies-literature
Project description:BackgroundEctopic lymphoid neogenesis (LN) occurs in rheumatoid synovium, where it is thought to drive local antigen-dependent B cell development and autoantibody production. This process involves the expression of specific homing chemokines and the development of high endothelial venules (HEV).ObjectiveTo investigate whether these mechanisms occur in psoriatic arthritis (PsA) synovium, where autoantibodies have not been described and the organisation and function of B cells is not clear, and to analyse their clinical correlates.MethodsArthroscopic synovial biopsy specimens from patients with PsA before and after tumour necrosis factor alpha blockade were characterised by immunohistochemical analysis for T/B cell segregation, peripheral lymph node addressin (PNAd)-positive HEV, and the expression of CXCL13, CCL21 and CXCL12 chemokines in relation to the size of lymphoid aggregates.ResultsLymphoid aggregates of variable sizes were observed in 25 of 27 PsA synovial tissues. T/B cell segregation was often observed, and was correlated with the size of lymphoid aggregates. A close relationship between the presence of large and highly organised aggregates, the development of PNAd+ HEV, and the expression of CXCL13 and CCL21 was found. Large organised aggregates with all LN features were found in 13 of 27 tissues. LN in PsA synovitis was not related to the duration, pattern or severity of the disease. The synovial LN pattern remained stable over time in persistent synovitis, but a complete response to treatment was associated with a regression of the LN features.ConclusionsLN occurs frequently in inflamed PsA synovial tissues. Highly organised follicles display the characteristic features of PNAd+ HEV and CXCL13 and CCL21 expression, demonstrating that the microanatomical bases for germinal centre formation are present in PsA. The regression of LN on effective treatment indicates that the pathogenic and clinical relevance of these structures in PsA merits further investigation.
| S-EPMC1954653 | biostudies-literature
Project description:Self-assembly of amyloid-? (A?) peptides in human brain tissue leads to neurodegeneration in Alzheimer's disease (AD). Amyloid fibrils, whose structures have been extensively characterized by solid state nuclear magnetic resonance (ssNMR) and other methods, are the thermodynamic end point of A? self-assembly. Oligomeric and protofibrillar assemblies, whose structures are less well-understood, are also observed as intermediates in the assembly process in vitro and have been implicated as important neurotoxic species in AD. We report experiments in which the structural evolution of 40-residue A? (A?40) is monitored by ssNMR measurements on frozen solutions prepared at four successive stages of the self-assembly process. Measurements on transient intermediates are enabled by ssNMR signal enhancements from dynamic nuclear polarization (DNP) at temperatures below 30 K. DNP-enhanced ssNMR data reveal a monotonic increase in conformational order from an initial state comprised primarily of monomers and small oligomers in solution at high pH, to larger oligomers near neutral pH, to metastable protofibrils, and finally to fibrils. Surprisingly, the predominant molecular conformation, indicated by (13)C NMR chemical shifts and by side chain contacts between F19 and L34 residues, is qualitatively similar at all stages. However, the in-register parallel ?-sheet supramolecular structure, indicated by intermolecular (13)C spin polarization transfers, does not develop before the fibril stage. This work represents the first application of DNP-enhanced ssNMR to the characterization of peptide or protein self-assembly intermediates.
| S-EPMC5559291 | biostudies-literature
Project description:Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1alpha independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress.
| S-EPMC2901488 | biostudies-literature
Project description:The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent "orphan" nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.
| S-EPMC3461922 | biostudies-literature
Project description:The gene nhr-6 encodes the Caenorhabditis elegans ortholog of the NR4A nuclear receptor. We determined the biological functions of NHR-6 through the isolation and characterization of a deletion allele of nhr-6, lg6001. We demonstrate that nhr-6 has an essential role in the development of the C. elegans somatic gonad. Specifically, nhr-6 is required for the development of the hermaphrodite spermatheca, a somatic gonad organ that serves as the site of sperm storage and oocyte fertilization. Using a variety of spermatheca cell markers, we have determined that loss of nhr-6 function causes severe morphological defects in the spermatheca and associated spermathecal valves. This appears to be due to specific requirements for nhr-6 in regulating cell proliferation and cell differentiation during development of these structures. The improper development of these structures in nhr-6(lg6001) mutants leads to defects in ovulation and significantly reduced fecundity of C. elegans hermaphrodites. The phenotypes of nhr-6(lg6001) mutants are consistent with a role for nhr-6 in organogenesis, similar to the functions of its mammalian homologs.
| S-EPMC3845373 | biostudies-literature
Project description:Single Cell RNA in RA Synovium
| PRJNA803484 | ENA