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Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.
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Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity.
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Autoantígenos , Autoinmunidad , Centro Germinal , Centro Germinal/inmunología , Humanos , Animales , Autoantígenos/inmunología , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Ratones , Lupus Eritematoso Sistémico/inmunología , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos B/inmunologíaRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting a growing number of elderly people. In order to improve the early and differential diagnosis of AD, better biomarkers are needed. Glycosylation is a protein post-translational modification that is modulated in the course of many diseases, including neurodegeneration. Aiming to improve AD diagnosis and differential diagnosis through glycan analytics methods, we report the glycoprotein glycome of cerebrospinal fluid (CSF) isolated from a total study cohort of 262 subjects. The study cohort consisted of patients with AD, healthy controls and patients suffering from other types of dementia. CSF free-glycans were also isolated and analyzed in this study, and the results reported for the first time the presence of 19 free glycans in this body fluid. The free-glycans consisted of complete or truncated N-/O-glycans as well as free monosaccharides. The free-glycans Hex1 and HexNAc1Hex1Neu5Ac1 were able to discriminate AD from controls and from patients suffering from other types of dementia. Regarding CSF N-glycosylation, high proportions of high-mannose, biantennary bisecting core-fucosylated N-glycans were found, whereby only about 20% of the N-glycans were sialylated. O-Glycans and free-glycan fragments were less sialylated in AD patients than in controls. To conclude, this comprehensive study revealed for the first time the biomarker potential of free glycans for the differential diagnosis of AD.
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Enfermedad de Alzheimer , Biomarcadores , Polisacáridos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Humanos , Biomarcadores/líquido cefalorraquídeo , Polisacáridos/líquido cefalorraquídeo , Polisacáridos/química , Masculino , Femenino , Anciano , Glicosilación , Persona de Mediana Edad , Anciano de 80 o más Años , Glicoproteínas/líquido cefalorraquídeo , Estudios de Casos y ControlesRESUMEN
The role of antibody affinity in plasma cell (PC) differentiation from germinal centers (GCs) remains contested. Parallel studies by Sprumont et al. and Sutton and Gao et al. show that PCs emerging from GCs produce antibodies with a diverse range of affinities and lack signatures of affinity-based selection. Therefore, commitment to the PC lineage is affinity independent.
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Linfocitos B , Centro Germinal , Humanos , Activación de Linfocitos , Linaje de la Célula , Diferenciación Celular , Células PlasmáticasRESUMEN
Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.
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Mutación con Ganancia de Función , Quinasa I-kappa B , Linfocitos T Reguladores , Animales , Ratones , Factores de Transcripción Forkhead/genética , Quinasa I-kappa B/genética , Inflamación/genéticaRESUMEN
PURPOSE OF REVIEW: This review aims to provide an overview of the genes and molecular pathways involved in monogenic lupus, the implications for genome diagnosis, and the potential therapies targeting these molecular mechanisms. RECENT FINDINGS: To date, more than 30 genes have been identified as contributors to monogenic lupus. These genes are primarily related to complement deficiency, activation of the type I interferon (IFN) pathway, disruption of B-cell and T-cell tolerance and metabolic pathways, which reveal the multifaceted nature of systemic lupus erythematosus (SLE) pathogenesis. SUMMARY: In-depth study of the causes of monogenic lupus can provide valuable insights into of pathogenic mechanisms of SLE, facilitate the identification of effective biomarkers, and aid in developing therapeutic strategies.
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Interferón Tipo I , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/terapia , Lupus Eritematoso Sistémico/tratamiento farmacológico , Proteínas del Sistema Complemento , Interferón Tipo I/metabolismo , BiomarcadoresRESUMEN
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.
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Autoinmunidad , Lupus Eritematoso Sistémico , Animales , Humanos , Ratones , Autoinmunidad/genética , Factor Activador de Células B/metabolismo , Linfocitos B , Lupus Eritematoso Sistémico/genética , Células Precursoras de Linfocitos BRESUMEN
Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.
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Autoinmunidad , Linfocitos B , Diferenciación Celular , Regulación de la Expresión Génica , Lupus Eritematoso Sistémico , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Animales , Humanos , Ratones , Autoinmunidad/genética , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Haploinsuficiencia , Envejecimiento/inmunología , Modelos Animales de Enfermedad , FemeninoRESUMEN
Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the ß-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αß and γδ T cells, even in the absence of transforming growth factor-ß. Consistent with DECTIN-1's Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.
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Haploinsuficiencia , Lectinas Tipo C , Animales , Humanos , Ratones , Autoinmunidad , Antígeno CTLA-4/genética , Lectinas Tipo C/genéticaRESUMEN
Aim: Thorough diagnostics are a prerequisite for the optimal treatment of Alzheimer's disease (AD). Biomarker-based diagnostics are standard in academia, data on practitioners' diagnostic workups is scarce. Materials & methods: Surveys in German and US healthcare providers (HCP) were conducted regarding diagnostics in presumed AD patients. A subsample of 153 German and 88 US professionals was analyzed in detail. Results: Fewer German physicians conduct AD diagnostics themselves compared with US colleagues (67% vs 99%; p < 0.0001). German doctors more often order diagnostics at other institutions (65% vs 45%; p < 0.005). No significant differences were found regarding the type of diagnostics ordered at other institutions. Conclusion: Diagnostic routines for suspected AD patients differ between German and US-American healthcare providers.
It is important to conduct the best-possible tests to come to a correct diagnosis of Alzheimer's disease (AD). This ensures choosing the optimal treatment. In academic surroundings such as specialized memory clinics, so called biomarkers (found for example in blood) are an important component in finding the correct diagnosis. However, there is limited data on the methods healthcare providers (HCP) use in their everyday clinical practice. With this study, we aimed to get a clearer picture of the differences in the diagnostic routines for potential AD patients implemented by HCPs in two high-income countries, Germany and the USA. We conducted two surveys in 500 German and 100 US HCPs on their AD-diagnostic routines. A comparable subsample of 153 German and 88 US professionals was analyzed in detail. We found that fewer German physicians conduct AD diagnostics themselves compared with their USAmerican colleagues (67% vs 99%). The other way around, German doctors more often order diagnostics at other institutions (65% vs 45%). However, there were no significant differences in the type of diagnostic procedures ordered at other institutions. In conclusion, diagnostic routines for suspected AD patients differ between German and USAmerican healthcare providers, such as biomarker-based diagnostics, which German physicians significantly perform less often.
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Enfermedad de Alzheimer , Médicos , Humanos , Estados Unidos , Enfermedad de Alzheimer/diagnóstico , Atención Primaria de SaludRESUMEN
TANK-binding kinase 1 (TBK1) is a key signalling component in the production of type-I interferons, which have essential antiviral activities, including against SARS-CoV-2. TBK1, and its homologue IκB kinase-ε (IKKε), can also induce pro-inflammatory responses that contribute to pathogen clearance. While initially protective, sustained engagement of type-I interferons is associated with damaging hyper-inflammation found in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKε signalling through destabilisation of TBK1/IKKε protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation.
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COVID-19 , Interferón Tipo I , Animales , Ratones , Quinasa I-kappa B , Modelos Animales de Enfermedad , SARS-CoV-2 , InflamaciónRESUMEN
Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-ß induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.
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Apoptosis , Proteínas Quinasas , Humanos , Animales , Ratones , Fosforilación , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Membrana Celular/metabolismo , Mutación , Factores de Transcripción/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Background: We analyzed differences in protein concentrations in human blood serum depending on the tube material and the immunoassay platform used. Materials & methods: Blood samples from study participants were collected in glass and polypropylene tubes (n = 292). Serum concentrations of six proteins (BDNF, IGF-1, VEGF-A, TGF-ß1, MCP-1 and IL-18) were assessed by using ELISAs (all biomarkers), as well as a novel fully automated immunoassay platform (all but IGF-1, n = 211). Bland-Altman analyses were conducted to investigate intrasample variability of protein concentrations. Results: Tube comparison resulted in mean biases of between -0.45 and -70.64%. Platform comparison revealed mean biases of between 21.04 and -128.10%. Conclusion: Protein concentrations can vary significantly depending on the types of tube and immunoassay used, with protein-specific differences.
This study investigated the impact of blood tube materials and measuring platforms on protein concentrations in blood samples. We collected blood serum from up to 292 study participants using glass and polypropylene tubes. The concentrations of six proteins were analyzed using a common laboratory technique called ELISA, as well as an automated platform, Ella™. The choice of tube material had small effects on two proteins (IGF-1 and IL-18), with differences of less than 1%. However, the concentrations of four other proteins (VEGF-A, MCP-1, TGF-ß1 and BDNF) varied significantly more depending on the tube material used, with differences ranging from -32.17 to -70.64%. With the two testing methods, two proteins (VEGF-A and TGF-ß1) showed only small differences, with variations of -7.68 and 11.74%, respectively. For the other four proteins, the differences were larger, from 21.04 to -128.10%. The study demonstrates the importance of having consistent, standardized methods for measuring protein levels in blood samples. The tubes and testing methods used can both change the results significantly, depending on the specific protein being measured. To make sure the measurements are accurate, we suggest creating specific guidelines for each testing method and protein. By following these guidelines, scientists can ensure that the measurements of protein levels in liquid biopsy samples are dependable and consistent.
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The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.
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The past few years have provided important insights into the genetic architecture of systemic autoimmunity through aggregation of findings from genome-wide association studies (GWAS) and whole-exome or whole-genome sequencing studies. In the prototypic systemic autoimmune disease systemic lupus erythematosus (SLE), monogenic disease accounts for a small fraction of cases but has been instrumental in the elucidation of disease mechanisms. Defects in the clearance or digestion of extracellular or intracellular DNA or RNA lead to increased sensing of nucleic acids, which can break B cell tolerance and induce the production of type I interferons leading to tissue damage. Current data suggest that multiple GWAS SLE risk alleles act in concert with rare functional variants to promote SLE development. Moreover, introduction of orthologous variant alleles into mice has revealed that pathogenic X-linked dominant and recessive SLE can be caused by novel variants in TLR7 and SAT1, respectively. Such bespoke models of disease help to unravel pathogenic pathways and can be used to test targeted therapies. Cell type-specific expression data revealed that most GWAS SLE risk genes are highly expressed in age-associated B cells (ABCs), which supports the view that ABCs produce lupus autoantibodies and contribute to end-organ damage by persisting in inflamed tissues, including the kidneys. ABCs have thus emerged as key targets of promising precision therapeutics.
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Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico , Animales , Ratones , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Autoinmunidad , Autoanticuerpos , ADN , Predisposición Genética a la EnfermedadRESUMEN
As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57+ CD4+ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples. Circulating CD57+ CD4+ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4+ T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection.
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Linfocitos B , Linfocitos T CD4-Positivos , Linfocitos B/metabolismo , Antígenos CD57/metabolismo , Diferenciación Celular , Antígeno CTLA-4 , HumanosRESUMEN
Although all multicellular organisms have germ line-encoded innate receptors to sense pathogen-associated molecular patterns, vertebrates also evolved adaptive immunity based on somatically generated antigen receptors on B and T cells. Because randomly generated antigen receptors may also react with self-antigens, tolerance checkpoints operate to limit but not completely prevent autoimmunity. These two systems are intricately linked, with innate immunity playing an instrumental role in the induction of adaptive antiviral immunity. In this work, we review how inborn errors of innate immunity can instigate B cell autoimmunity. Increased nucleic acid sensing, often resulting from defects in metabolizing pathways or retroelement control, can break B cell tolerance and converge into TLR7-, cGAS-STING-, or MAVS-dominant signaling pathways. The resulting syndromes span a spectrum that ranges from chilblain and systemic lupus to severe interferonopathies.
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Autoinmunidad , Linfocitos B , Interacciones Huésped-Patógeno , Inmunidad Innata , Virosis , Virus , Animales , Inmunidad Adaptativa , Autoinmunidad/genética , Linfocitos B/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , Transducción de Señal , Virosis/inmunología , Virus/inmunología , HumanosRESUMEN
OBJECTIVE: Increased Toll-like receptor 7 (TLR-7) signaling leading to the production of type I interferon (IFN) is an important contributor to human systemic lupus erythematosus (SLE). Protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), a molecule that regulates synaptic vesicle recycling, has been linked to TLR-7/TLR-9-mediated type I IFN production in humans and mice, but the underlying mechanism is unknown. We undertook this study to explore the pathogenicity and underlying mechanism of a de novo PACSIN1 missense variant identified in a child with SLE. METHODS: PACSIN1 Q59K de novo and null variants were introduced into a human plasmacytoid dendritic cell line and into mice using CRISPR/Cas9 editing. The effects of the variants on TLR-7/TLR-9 signaling in human and mouse cells, as well as PACSIN1 messenger RNA and IFN signature in SLE patients, were assessed using real-time polymerase chain reaction and flow cytometry. Mechanisms were investigated using luciferase reporter assays, RNA interference, coimmunoprecipitation, and immunofluorescence. RESULTS: We established that PACSIN1 forms a trimolecular complex with tumor necrosis factor receptor-associated factor 4 (TRAF4) and TRAF6 that is important for the regulation of type I IFN. The Q59K mutation in PACSIN1 augments binding to neural Wiskott-Aldrich syndrome protein while it decreases binding to TRAF4, leading to unrestrained TRAF6-mediated activation of type I IFN. Intriguingly, PACSIN1 Q59K increased TLR-7 but not TLR-9 signaling in human cells, leading to elevated expression of IFNß and IFN-inducible genes. Untreated SLE patients had high PACSIN1 expression in peripheral blood cells that correlated positively with IFN-related genes. Introduction of the Pacsin1 Q59K mutation into mice caused increased surface TLR-7 and TRAIL expression in B cells. CONCLUSION: PACSIN1 Q59K increases IFNß activity through the impairment of TRAF4-mediated inhibition of TLR-7 signaling, possibly contributing to SLE risk.
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Interferón Tipo I , Lupus Eritematoso Sistémico , Niño , Humanos , Ratones , Animales , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Interferón-alfa , Proteína Quinasa C/metabolismo , Factor 4 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Factor 6 Asociado a Receptor de TNF/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Interferón Tipo I/metabolismo , Neuronas/metabolismo , Receptor Toll-Like 9 , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
Follicular T cells including T follicular helper (TFH) and T follicular regulatory (TFR) cells are essential in supporting and regulating the quality of antibody responses that develop in the germinal centre (GC). Follicular T cell migration during the propagation of antibody responses is largely attributed to the chemokine receptor CXCR5, however CXCR5 is reportedly redundant in migratory events prior to formation of the GC, and CXCR5-deficient TFH and TFR cells are still capable of localizing to GCs. Here we comprehensively assess chemokine receptor expression by follicular T cells during a model humoral immune response in the spleen. In addition to the known follicular T cell chemokine receptors Cxcr5 and Cxcr4, we show that follicular T cells express high levels of Ccr6, Ccr2 and Cxcr3 transcripts and we identify functional expression of CCR6 protein by both TFH and TFR cells. Notably, a greater proportion of TFR cells expressed CCR6 compared to TFH cells and gating on CCR6+CXCR5hiPD-1hi T cells strongly enriched for TFR cells. Examination of Ccr6-/- mice revealed that CCR6 is not essential for development of the GC response in the spleen, and mixed bone marrow chimera experiments found no evidence for an intrinsic requirement for CCR6 in TFR cell development or localisation during splenic humoral responses. These findings point towards multiple functionally redundant chemotactic signals regulating T cell localisation in the GC.