Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarshi

THE INTERPLAY OF PLATELETS AND TOLL-LIKE RECEPTOR 7 IN PLATELET-NEUTROPHIL COMPLEX FORMATION AND ITS ROLE IN DISEASE MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Ph.DDOCTOR OF PHILOSOPHY (SOM

Takotsubo syndrome and rheumatic diseases - a critical systematic review

10.1093/rheumatology/keaa504RHEUMATOLOGY60111-2

Untitled Reply

10.1002/art.41151ARTHRITIS & RHEUMATOLOGY723509-51

Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside

Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs

Booster COVID-19 Vaccines for Immune-Mediated Inflammatory Disease Patients: A Systematic Review and Meta-Analysis of Efficacy and Safety

Background: Seroconversion and longevity of vaccine-induced immune response is blunted in immune-mediated inflammatory disease (IMID) patients owing to immunosuppressive regimens. COVID-19 booster vaccines after a primary series have been proposed with inconclusive evidence on efficacy to date. Methods: This PROSPERO-registered systematic review (CRD42022302534) was conducted according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, Web of Science, CORD-19, WHO ICTRP, and medRxiv were searched up to 28 February 2022 for eligible studies. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tools. Results: From 6647 records, 17 prospective studies were included for systematic review and 12 in meta-analysis of primary series non-responders. The risk of bias was low. Pooling 340 non-responders, a booster dose proved effective with 0.47 seroconverting (95% CI: 0.32–0.63, I2 = 82%). Rituximab therapy was associated with significant impairment, with risks of 0.25 (95% CI: 0.17–0.36, I2 = 50.7%) versus 0.81 (95% CI: 0.72–0.87, I2 = 0.0%) for those without rituximab therapy. A systematic review of antibody levels against COVID-19 showed several-fold increases across studies. Incidence of local and systemic adverse events, including disease flares, were either comparable or slightly increased after the booster dose compared to primary series. No major events such as myocarditis or death were reported. Conclusion: Our results show that booster doses are effective in eliciting seroconversion in non-responders, bolstering immunity to COVID-19. It has also not been associated with major adverse events

25-Hydroxyvitamin D3 Deficiency Independently Predicts Cognitive Impairment in Patients with Systemic Lupus Erythematosus.

Cognitive dysfunction has been reported in 20-80% of SLE patients. Converging evidence has indicated the importance of vitamin D as a neuroimmunomodulator for cognitive function. In this study, we evaluated the relationship between vitamin D and cognitive dysfunction.Consecutive age- and gender-matched SLE patients and healthy controls (HCs) were administered Automated Neuropsychological Assessment Metrics in this cross-sectional study. The primary outcome was the total throughput score (TTS). Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Levels of 25-hydroxyvitamin D [25(OH)D3 and total 25(OH)D] were measured using Liquid Chromatography-Tandem Mass Spectrometry.In total, 61 SLE patients and 61 HCs were studied. SLE patients scored significantly lower than HCs in the TTS (p = 0.004). There were no statistically significant differences in 25(OH)D3 levels, total 25(OH)D levels and total 25(OH)D deficiency between SLE patients and HCs. However, more SLE patients had 25(OH)D3 deficiency compared to HCs [12 (19.7%) versus 2 (3.3%), p = 0.003]. Deficiency of 25(OH)D3 (β = -63.667, SE = 27.456, p = 0.025), but not other vitamin D variables, independently predicted worse TTS after adjusting for age, education, gender, ethnicity, HADS-Total, duration of SLE, SELENA-SLEDAI, SLICC/ACR Damage Index and cumulative steroid dose in SLE patients. Age (β = -4.261, SE = 0.866, p < 0.001) was the only predictor of TTS after adjusting for education, gender, ethnicity, HADS-Total, vitamin D levels or status in HCs.Deficiency of 25(OH)D3, a potentially modifiable risk factor, independently predicted cognitive impairment in SLE patients

Cognitive Dysfunction in Systemic Lupus Erythematosus: Immunopathology, Clinical Manifestations, Neuroimaging and Management

10.1007/s40744-021-00312-0RHEUMATOLOGY AND THERAPY82651-67

Mean throughput scores in SLE patients and HCs.

<p>Higher scores represent better performance. The individual test data points for each group are connected for illustration purposes only. *P<0.05; **P<0.01.</p

Total throughput scores in relation to 25(OH)D₃ status in SLE patients.

<p>Box represents 25^th and 75^th percentiles, horizontal line represents the median, error bars show the 5^th and 95^th percentile and outside values are shown as dots. F(2,52) = 3.73, p = 0.031.</p