The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Associations between HLA class II alleles and IgE sensitization to allergens in the Qatar Biobank cohort.

Background: Allergic disorders are the consequence of IgE sensitization to allergens. Population studies have shown that certain human leukocyte antigen (HLA) alleles are associated with increased or decreased risk of developing allergy. Objective: We aimed to characterize the relationship between HLA class II allelic diversity and IgE sensitization in an understudied Arab population. Methods: We explored associations between IgE sensitization to 7 allergen mixes and mesquite (comprising 41 food or aeroallergens) and 45 common classical HLA class II alleles in a well-defined cohort of 797 individuals representing the general adult population of Qatari nationals and long-term residents. To do so, we performed HLA calling from whole genome sequencing data at 2-field resolution using 2 independent algorithms. We then applied 3 different regression models to assess either each allergen mix independently, in the context of IgE sensitization to other allergens tested, or polysensitization. Results: More than half (n = 447) of the study participants showed IgE sensitization to at least 1 allergen, most of them (n = 400) to aeroallergens (Phadiatop). We identified statistically significant negative and positive associations with 24 HLA class II alleles. These have been reported to confer risk or protection from variety of diseases; however, only a few have previously been associated with allergy in other populations. Conclusions: Our study reveals several new risk and protective genetic markers for allergen-specific IgE sensitization. This is a first and essential step toward a better understanding of the origins of allergic diseases in this understudied population.

The Effect of High-Dose Methyl Vitamin B12 Therapy on Epileptogenesis in Rats: An In Vivo Study.

Introduction Epileptogenesis has been considered one of the most prevalent diseases affecting significant numbers of individuals worldwide. Since vitamin B12 has been reported to possess antiepileptic effects, this supports that vitamin B12 deficiency is correlated to seizure occurrence. Hence, this study aimed to evaluate the neuroprotective effects of vitamin B12 injection on pentylenetetrazole (PTZ)-induced rats. Methods The study was performed using 40 adult female Sprague-Dawley rats (~250 g). A 45 mg/kg PTZ was intraperitoneally injected into rat models to induce seizure effects. Different groups of rat models received methyl vitamin B12 therapy at different dosages, a low dosage of 45 µg/kg and a high dosage of 85 µg/kg, at different pre-treatment periods, one day and two weeks prior to PTZ injection. A control group, which received only PTZ injection, served as a reference. The seizure latency, seizure intensity, and differences in the quality of seizures and their characteristics, from simple twitches to complete seizures, were observed after 30 minutes of PTZ injection. Results In general, the latency to convulsion significantly increased when vitamin B12 pre-treatment was employed. The longest latency time (LT) of 520.63±73.83 seconds was observed when a high dosage of vitamin B12 at 85 µg/kg was injected one day prior to PTZ inoculation, which was significantly higher than that of the control group at 176.88±62.67 seconds (P<0.001). Moreover, the duration of convulsion significantly decreased in which the lowest duration time (DT) of 7.00±4.68 seconds was observed when a high dosage of vitamin B12 at 85 µg/kg was injected two weeks prior to PTZ inoculation, which was significantly lower than that of the control group at 257.75±41.93 seconds (P<0.001). Lastly, the percentage of the population with PTZ-induced convulsion generally decreased after vitamin B12 pre-treatment in which majority showed more of simple less aggressive twitches rather than tonic-clonic seizures. Conclusion The results showed that vitamin B12 pre-treatment alleviates the seizure occurrence among PTZ-kindled rat models. These findings then suggest that vitamin B12 is a potential strategy and treatment for epilepsy and other related epileptogenesis activities.

Attitudes Towards Artificial Intelligence Among Dermatologists Working in Saudi Arabia.

INTRODUCTION: Artificial intelligence (AI) and its applications are among the most discussed modern technologies today. Despite the rapidly expanding use of AI in medicine, and specifically in dermatology, only a few studies have studied the attitude of physicians toward AI. OBJECTIVE: To recognize the attitudes towards AI among dermatologists in the Kingdom of Saudi Arabia. METHODS: A cross-sectional survey was done among dermatologists in Saudi Arabia. Questionnaires were distributed through several online channels. RESULTS: Overall, 103 dermatologists filled out the survey. The majority saw very strong or strong potential for AI in the automated detection of skin diseases based on dermatological clinical images (50.9%), dermoscopic images (66.6%) and within dermatopathology (66.6%). In regard to results of attitudes towards AI, 56.6% and 52. 8% agreed that AI will revolutionize medicine and dermatology, respectively. However, many of the respondents disagreed that AI will replace physicians (41.5%) and human dermatologists (39.6%) in the future. Age did not impact the overall attitude of dermatologists. CONCLUSION: Dermatologists in Saudi Arabia showed an optimistic attitude towards AI in dermatology and medicine. However, dermatologists believe that AI will not replace humans in the future.

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/ß-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/ß-dependent antiviral immunity.

Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria.

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rß1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium-inducible IFN-γ immunity in both Vδ2+ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ-dependent immunity to Mycobacterium in at least two lymphocyte subsets.

Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αß T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αß and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αß T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αß T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB.

Rate Coefficients for the Gas-Phase Reactions of Nitrate Radicals with a Series of Furan Compounds.

The atmospheric reaction of a series of furan compounds (furan (F), 2-methylfuran (2-MF), 3-methylfuran (3-MF), 2,5-dimethylfuran (2,5-DMF), and 2,3,5-trimethylfuran (2,3,5-TMF)) with nitrate radical (NO3) has been investigated using the relative rate kinetic method in the CHamber for the Atmospheric Reactivity and the Metrology of the Environment (CHARME) simulation chamber at the laboratoire de Physico-Chimie de l'Atmosphere (LPCA) laboratory (Dunkerque, France). The experiments were performed at (294 ± 2) K atmospheric pressure and under dry conditions (relative humidity, RH < 2%) with proton transfer mass reaction-time of flight-mass spectrometer (PTR-ToF-MS) for the chemical analysis. The following rate coefficients (in units cm3 molecule-1 s-1) were determined: furan, k(F) = (1.51 ± 0.38) × 10-12, 2-methylfuran, k(2-MF) = (1.91 ± 0.32) × 10-11, 3-methylfuran, k(3-MF) = (1.49 ± 0.33) × 10-11, 2,5-dimethylfuran, k(2,5-DMF) = (5.82 ± 1.21) × 10-11, and 2,3,5-trimethylfuran, k(2,3,5-TMF) = (1.66 ± 0.69) × 10-10. The uncertainty on the measured rate coefficient (ΔkFC) includes both the uncertainty on the measurement and that on the rate coefficient of the reference molecule. To our knowledge, this work represents the first determination for the rate coefficient of the 2,3,5-TMF reaction with NO3. This work shows that the reaction between furan and methylated furan compounds with nitrate radical (NO3) is the dominant removal pathway during the night with lifetimes between 0.5 and 55 min for the studied molecules.

Detection of Antinuclear Antibodies Targeting Intracellular Signal Transduction, Metabolism, Apoptotic Processes and Cell Death in Critical COVID-19 Patients.

Background and Objectives: The heterogeneity of the coronavirus disease of 2019 (COVID-19) lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) is a leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Results: Initial screening for antinuclear antibodies (ANA) IgG using ELISA revealed that 1.58% (2/126) and 4% (5/126) of intensive care unit (ICU) COVID-19 cases expressed strong and moderate ANA levels, respectively. An additional sample was positive with immunofluorescence assays (IFA) screening. However, all the non-ICU cases (n=273) were ANA negative using both assays. Samples positive for ANA were further confirmed with large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). The majority of the ANA-positive samples showed "speckled" ANA pattern by microscopy and revealed autoantibody specificities that targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death by PhIP-Seq; further denoting reactivity to nuclear and cytoplasmic antigens. Conclusion: Our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of COVID-19.

Human leukocyte antigen class II gene diversity tunes antibody repertoires to common pathogens.

Allelic diversity of human leukocyte antigen (HLA) class II genes may help maintain humoral immunity against infectious diseases. In this study, we investigated germline genetic variation in classical HLA class II genes and employed a systematic, unbiased approach to explore the relative contribution of this genetic variation in the antibody repertoire to various common pathogens. We leveraged a well-defined cohort of 800 adults representing the general Arab population in which genetic material is shared because of the high frequency of consanguineous unions. By applying a high-throughput method for large-scale antibody profiling to this well-defined cohort, we were able to dissect the overall effect of zygosity for classical HLA class II genes, as well as the effects associated with specific HLA class II alleles, haplotypes and genotypes, on the antimicrobial antibody repertoire breadth and antibody specificity with unprecedented resolution. Our population genetic studies revealed that zygosity of the classical HLA class II genes is a strong predictor of antibody responses to common human pathogens, suggesting that classical HLA class II gene heterozygosity confers a selective advantage. Moreover, we demonstrated that multiple HLA class II alleles can have additive effects on the antibody repertoire to common pathogens. We also identified associations of HLA-DRB1 genotypes with specific antigens. Our findings suggest that HLA class II gene polymorphisms confer specific humoral immunity against common pathogens, which may have contributed to the genetic diversity of HLA class II loci during hominine evolution.