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1.
J Clin Immunol ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33284430

RESUMO

Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68+, S100+, and CD1a- histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFNγ were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms "type I IFN," "IFNγ signaling pathway," and "immune responses" as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFNγ signature. These findings may help find better therapeutic options for this rare disorder.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33338534

RESUMO

BACKGROUND: As of November 2020, SARS-CoV-2 has resulted in 55 million infections worldwide and over 1.3 million deaths from COVID-19. Outcomes following SARS-CoV-2 infection in individuals with primary immunodeficiency or symptomatic secondary immunodeficiency remain uncertain. OBJECTIVES: To document the outcomes of individuals with primary or symptomatic secondary immunodeficiency following COVID-19 in the United Kingdom. METHODS: At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network (UK PIN) established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. RESULTS: 100 patients had been enrolled by 1st July 2020, 60 with primary immunodeficiency (PID), 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency and 33 with symptomatic secondary immunodeficiency (SID). In individuals with PID, 53.3% (n=32/60) were hospitalized, the infection fatality rate (IFR) was 20.0% (n=12/60), the case fatality rate (CFR) was 31.6% (n=12/38) and the inpatient mortality 37.5% (n=12/32). Individuals with SID had worse outcomes than those with PID. 75.8% (n=25/33) were hospitalized, the IFR was 33.3% (n=11/33), the CFR was 39.2% (n=11/28), and inpatient mortality 44.0% (n=11/25). CONCLUSIONS: In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus.

4.
BMJ Open ; 10(10): e035793, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004384

RESUMO

OBJECTIVES: To develop a behavioural intervention package to support clinicians and patients to amend incorrect penicillin allergy records in general practice. The intervention aimed to: (1) support clinicians to refer patients for penicillin allergy testing (PAT), (2) support patients to attend for PAT and (3) support clinicians and patients to prescribe or consume penicillin, when indicated, following a negative PAT result. METHODS: Theory-based, evidence-based and person-based approaches were used in the intervention development. We used evidence from a rapid review, two qualitative studies, and expert consultations with the clinical research team to identify the intervention 'guiding principles' and develop an intervention plan. Barriers and facilitators to the target behaviours were mapped to behaviour change theory in order to describe the proposed mechanisms of change. In the final stage, think-aloud interviews were conducted to optimise intervention materials. RESULTS: The collated evidence showed that the key barriers to referral of patients by clinicians were limited experience of referral and limited knowledge of referral criteria and PAT. Barriers for patients attending PAT were lack of knowledge of the benefits of testing and lack of motivation to get tested. The key barriers to the prescription and consumption of first-line penicillin following a negative test result were patient and clinician beliefs about the accuracy of PAT and whether taking penicillin was safe. Intervention materials were designed and developed to address these barriers. CONCLUSIONS: We present a novel behavioural intervention package designed to address the multiple barriers to uptake of PAT in general practice by clinicians and patients. The intervention development details how behaviour change techniques have been incorporated to hypothesise how the intervention is likely to work to help amend incorrect penicillin allergy records. The intervention will go on to be tested in a feasibility trial and randomised controlled trial in England.

5.
Eur J Hosp Pharm ; 27(6): 367-368, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33097621

RESUMO

INTRODUCTION: Due to perceived risk of anaphylaxis, home treatment with omalizumab has been limited. Within the UK, most centres administer omalizumab in a hospital setting. However, the reported prevalence of anaphylaxis is low and in December 2018 home treatment became licensed. A home treatment pathway was previously reported by one UK centre, and this update describes three UK centres' experience of home omalizumab treatment. METHODS: The medical records of omalizumab patients were retrospectively reviewed. RESULTS: A total of 137 adult patients have received home omalizumab treatment; home treatment duration 0-44 months. There was no increase in adverse effects seen in patients treated at home. There were no reported adherence issues and no reduction in efficacy. Patients report they prefer home treatment due to increased flexibility and reduced impact on daily life/work. CONCLUSION: Home treatment with omalizumab is a safe and effective alternative to hospital administration.

6.
N Engl J Med ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33108101

RESUMO

BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

7.
Arthritis Rheumatol ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32969189

RESUMO

OBJECTIVES: Monogenic Behçet's Disease (BD)-like conditions are increasingly recognised and to date predominantly involve loss-of-function variants in TNFAIP3. The objective of this study was to identify genetic and pathobiological mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in a three-generation Irish family (n=5 cases; n=5 familial controls). METHODS: Whole exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative RELA expression in peripheral blood mononuclear cells was compared by western blot. Human epithelial and RelA-/- mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to TNF. NF-κB signalling, transcriptional activation, apoptosis and cytokine production was compared between wild-type and truncated RELA in experimental systems and patient samples. RESULTS: A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected members. This mutation results in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting two transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA-/- mouse embryonic fibroblast (MEF) cells expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing RELAWT , however there was no difference in RELA nuclear translocation. In RelA-/- MEF expression of RELAp.His487ThrfsTer7 resulted in 1.98-fold higher ratio of cleaved caspase-3/caspase-3 induced by TNF (p=0.036) compared to RELAWT . CONCLUSIONS: Our data support RELA loss-of-function mutations as causing BD-like autoinflammation and NMO via impaired NF-κB signalling and increased apoptosis.

8.
Clin Exp Allergy ; 50(10): 1166-1175, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735720

RESUMO

BACKGROUND: Real-world evidence describing the benefits of recommended therapies and their impact on the quality of life (QoL) of chronic urticaria (CU) patients is limited. OBJECTIVE: To investigate disease burden, current treatment schedule, and the use of clinical resources by patients with H1 -antihistamine-refractory CU in Europe. METHODS: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global, prospective, non-interventional study in the real-world setting, sponsored by the manufacturer of omalizumab. Disease characteristics, pharmacological treatments, and health-related QoL of patients (N = 2727) ≥18 years of age diagnosed with H1 -antihistamine-refractory chronic spontaneous urticaria (without inducible urticaria) for >2 months are reported here. RESULTS: Of the 2727 patients included, 1232 (45.2%) and 1278 (46.9%) were successfully followed up for any assessment and for the key outcome, the urticaria control test (UCT) score, respectively, and patients with complete remission (14.1%) were excluded from analyses.The proportion of patients with uncontrolled CSU (UCT score <12) dropped from 78% (n/N = 1641/2104) at baseline to 28.7% (n/N = 269/936) after two years of participation in the AWARE study. In addition, the proportion of patients with no impact of CSU on their QoL (assessed by the Dermatological Life Quality Index) increased to 57% (n/N = 664/1164) from 18.7% (n/N = 491/2621) at baseline. Emergency room visits (2.4% [n/N = 7/296] vs 33.5% [n/N = 779/2322]) and hospital stays (1.7% [n/N = 5/296] vs 24.2% [n/N = 561/2322]) reduced at Month 24 vs baseline. Overall, 23.2% (n/N = 26/112) patients on non-sedating H1 -antihistamines (nsAH) and 41.9% (n/N = 44/105) patients on up-dosed nsAH had uncontrolled CSU (UCT <12) at Month 24. In omalizumab-treated patients, 27.1% (n/N = 78/288) had uncontrolled CSU at Month 24. CONCLUSION: These data confirm improvements for most patients with CSU over a 2-year follow-up period. Further studies are needed to understand the differences between guideline recommendations and reported management.

9.
Br J Anaesth ; 125(6): 962-969, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32859363

RESUMO

BACKGROUND: Penicillin allergy is associated with a range of poor health outcomes. Allergy testing can be made simpler by using a direct drug provocation test in patients at low risk of genuine allergy. This approach could allow population-level 'de-labelling'. We sought to determine the incidence and nature of penicillin allergy labels in UK surgical patients and define patient and anaesthetist attitudes towards penicillin allergy testing. METHODS: A prospective cross-sectional questionnaire study was performed in 213 UK hospitals. 'Penicillin allergic' patients were interviewed and risk-stratified. Knowledge and attitudes around penicillin allergy were defined in patients and anaesthetists. RESULTS: Of 21 219 patients, 12% (n=2626) self-reported penicillin allergy; 27% reported low-risk histories potentially suitable for a direct drug provocation test; an additional 40% reported symptoms potentially suitable for a direct drug provocation test after more detailed assessment. Of 4798 anaesthetists, 40% claimed to administer penicillin routinely when they judged the label low risk. Only 47% of anaesthetists would be happy to administer penicillin to a patient previously de-labelled by an allergy specialist using a direct drug provocation test; perceived lack of support was the most common reason for not doing so. CONCLUSIONS: At least 27% of patients with a penicillin allergy label may be suitable for a direct drug provocation test. Anaesthetists demonstrated potentially unsafe prescribing in patients with penicillin allergy labels. More than half of anaesthetists lack confidence in the results of a direct drug provocation tests undertaken by a specialist. Our findings highlight significant barriers to the effective implementation of widespread de-labelling in surgical patients.


Assuntos
Antibacterianos/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Rotulagem de Medicamentos/métodos , Procedimentos Cirúrgicos Eletivos , Penicilinas/efeitos adversos , Adolescente , Adulto , Idoso , Estudos Transversais , Hipersensibilidade a Drogas/prevenção & controle , Rotulagem de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Reino Unido/epidemiologia , Adulto Jovem
10.
RMD Open ; 6(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669454

RESUMO

This clinical case series describes our experience with the use of Janus kinase 1/2 inhibitor baricitinib in two patients suffering from refractory adult-onset Still's disease (AOSD) as well as in one case suffering from AOSD-like autoinflammatory disease in the context of myelodysplastic syndrome. All patients suffered from disease non-responsive to conventional Disease-modifying antirheumatic drugs (DMARDs) as well as biological therapies including interleukin (IL)-1 and IL-6 blockade, relying instead on high daily doses of prednisolone. We also report the first case of Pneumocystis jirovecii infection following baricitinib use.

11.
Int J Immunogenet ; 47(4): 324-328, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32623831

RESUMO

We analysed data from 80 patients who tested positive for SARS-CoV-2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA- DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94-3.22) and infection. A bias towards an increased representation of HLA-A*26, HLA-DRB1*15, HLA-DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA-A*02, HLA-B*44 and HLA-C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS-CoV-2 pandemic and potentially in risk-assessing staff interactions with infected patients.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Predisposição Genética para Doença/genética , Teste de Histocompatibilidade , Pneumonia Viral/imunologia , Alelos , Infecções por Coronavirus/patologia , Frequência do Gene , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Transplante de Órgãos , Pandemias , Pneumonia Viral/patologia , Transplantados
12.
Genes Immun ; 21(4): 260-262, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32606316

RESUMO

Cystic fibrosis (CF) is one of the most common autosomal recessive life-limiting conditions affecting Caucasians. The resulting defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) results in defective chloride and bicarbonate secretion, as well as dysregulation of epithelial sodium channels (ENaC). These changes bring about defective mucociliary clearance, reduced airway surface liquid and an exaggerated proinflammatory response driven, in part, by infection. In this short article we explore the overlap in the pathophysiology of CF and COVID-19 infection and discuss how understanding the interaction between both diseases may shed light on future treatments.


Assuntos
Infecções por Coronavirus/metabolismo , Fibrose Cística/metabolismo , Pneumonia Viral/metabolismo , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Citocinas/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia
13.
Isr Med Assoc J ; 22(6): 335-339, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32558435

RESUMO

BACKGROUND: In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indications in inflammatory skin and joint diseases as well as chronic obstructive pulmonary disease (COPD). Furthermore, multiple animal models demonstrate strong anti-inflammatory effects of PDE4i in respiratory models of viral and bacterial infection and also after chemically mediated lung injury. The rationale for PDE4i use in COVID-19 patients comes from the multimodal mechanism of action with cytokine, chemokine, and other key pathway inhibition all achieved with an excellent safety profile. We highlight how PDE4i could be an overlooked treatment from the rheumatologic and respiratory armamentarium, which has potential beneficial immune-modulation for treating severe COVID-19 pneumonia associated with cytokine storms. The proposed use of PDE4i is also supported by age-related immune changes in inflammation severity in PDE4i modifiable pathways in primate coronavirus disease. In conclusion, over-exuberant anti-viral immune responses in older patients with COVID-19 may pose a substantial risk to patient survival and mitigation against such hyper-inflammation with PDE4i, especially with anti-viral agents, is a strategy that need to be pursed, especially in older patients.


Assuntos
Anti-Inflamatórios/administração & dosagem , Doenças Transmissíveis Emergentes/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Surtos de Doenças , Inibidores da Fosfodiesterase 4/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adulto , Fatores Etários , Idoso , Animais , Betacoronavirus , Doenças Transmissíveis Emergentes/mortalidade , Infecções por Coronavirus/diagnóstico , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Pandemias , Inibidores da Fosfodiesterase 4/farmacologia , Pneumonia Viral/diagnóstico , Prognóstico , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Reino Unido
14.
Blood ; 136(9): 1055-1066, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32518946

RESUMO

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

15.
J Inflamm Res ; 13: 141-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210604

RESUMO

Familial Mediterranean Fever (FMF) is the most prevalent genetic autoinflammatory disorder. In most patients, treatment with colchicine can prevent attacks of fever and inflammation. However, 5%-10% of patients are resistant to colchicine treatment, while a similar percentage cannot tolerate colchicine in doses needed to prevent attacks. For these patients, Canakinumab, a full human antibody against IL-1ß, has been approved recently by the FDA and EMA. In this article, we present a systematic review of the long-term efficacy, safety, and tolerability of Canakinumab in FMF patients who cannot tolerate colchicine or who are resistant to colchicine treatment.

16.
17.
Elife ; 92020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32118580

RESUMO

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1ß, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1ß was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1ß only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1ß and pro-IL-1ß mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

18.
Nat Rev Rheumatol ; 16(4): 222-237, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32107482

RESUMO

Autoinflammation as a distinct disease category was first reported in 1999 as a group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation, known as periodic fever syndromes. Since this original description, the focus has shifted considerably to the inclusion of complex multifactorial conditions with an autoinflammatory basis. Furthermore, the boundaries of what are considered to be autoinflammatory disorders are constantly evolving and currently encompass elements of immunodeficiency and autoimmunity. Notable developments in the intervening 20 years include substantial progress in understanding how the different inflammasomes are activated, how infection is sensed by the innate immune system and how intracellular signalling systems are consequently activated and integrated with many different cellular functions in the autoinflammatory process. With these developments, the field of autoinflammation is moving from a gene-centric view of innate immune-mediated disease towards a systems-based concept, which describes how various convergent pathways, including pyrin and the actin cytoskeleton, protein misfolding and cellular stress, NF-κB dysregulation and interferon activation, contribute to the autoinflammatory process. The development and adoption of a systems-based concept of systemic autoinflammatory diseases is anticipated to have implications for the development of treatments that target specific components of the innate immune system.


Assuntos
Autoimunidade/imunologia , Citoesqueleto/imunologia , Doenças Hereditárias Autoinflamatórias/classificação , Imunidade Inata , Estresse Oxidativo , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos
20.
Front Immunol ; 11: 569006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33424831

RESUMO

The Schnitzler Syndrome (SchS) is an acquired, autoinflammatory condition successfully treated with IL-1 inhibition. The two main defining features of this late-onset condition are neutrophilic urticarial dermatoses (NUD) and the presence of an IgM monoclonal component. While the former aspect has been extensively studied in this disease setting, the enigmatic paraproteinaemia and its potential consequential effects within SchS, has not previously been thoroughly addressed. Previous studies analyzing clonal B cell repertoires have largely focused on autoimmune disorders such as Systemic Lupus Erythematous (SLE) and hematological malignancies such as Chronic Lymphocytic Leukaemia (CLL), where B-cell clonality is central to disease pathology. The present study uses next-generation sequencing to provide detailed insight into aspects of B cell VDJ recombination and properties of the resulting immunoglobulin chains. An overview of IgH regional dynamics in 10 SchS patients, with a particular focus on CDR3 sequences and VDJ gene usage is reported, highlighting the presence of specific B cell expansions. Protein microarray detected a substantial proportion of autoreactive IgM to nuclear target proteins, though a single universal target was not identified. Together, these genetic and functional findings impart new understanding into this rare disorder.

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