The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing.

Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.

Early detection of optic nerve head changes using optical coherence tomography after using mesenchymal stromal cells as intravitreal therapy in rabbit models of ocular hypertension.

Background and Aim: Stem cell therapy is considered a promising treatment for several neurodegenerative diseases. However, there are very few studies on the use of this therapy in glaucoma models. By detecting the changes produced by glaucoma early, cell therapy could help prevent the events that lead to blindness. In this study, early changes in the optic nerve head (ONH) as detected by optical coherence tomography (OCT) after the application of human Wharton's jelly-derived mesenchymal stromal cells (hWJ-MSCs) in an experimental model of ocular hypertension (OH) were evaluated. Materials and Methods: Fifteen New Zealand rabbits were randomly divided into the following three groups: G1: OH, G2: hWJ-MSCs, and G3: OH + hWJ-MSCs. An OH model was constructed, and the intraocular pressure (IOP) was measured regularly. At week 7, 105/100 µL hWJ-MSCs were intravitreally injected. Retinography and OCT were used to evaluate structural changes in ONH. Results: IOP increased significantly in G1 and G3 from week 3 onward. Retinography revealed more significant optic nerve changes, that is, papillary asymmetry suggestive of optic nerve excavation, vascular alterations, and irregular hypopigmentation peripheral to the optic disk margin, in G1 compared with G3. OH locates the hWJ-MSCs solution in the vitreous in front of the optic nerve. OCT revealed retinal nerve fiber layer (RNFL) reduction in all groups, reduced optic cup volume in G2 and G3 between weeks 1 and 9, and significant ganglion cell layer thickness reduction in G1 and a slight increase in G3. Conclusion: Intravitreal hWJ-MSCs injection produced changes in optic cup volume, which were detected early on by OCT; however, RNFL could not be restored in this OH model.

Mesenchymal Stromal Cells from Human Wharton's Jelly Modulate the Intraocular Immune Response in a Glucocorticoid Hypertension Model: An Exploratory Analysis.

INTRODUCTION: Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells. Recent research suggests immunological changes such as cytokine imbalance may affect its pathophysiology. This implies that immunomodulation, like that of mesenchymal cells, could be a potential therapeutic avenue for this disease. However, the effects of intravitreal injections of human Wharton's jelly-derived mesenchymal stromal cells (hWJ-MSCs) on intraocular immune response have not been assessed in ocular hypertension (OH) models. METHODS: We explored this by measuring cytokine levels and expression of other markers, such as glial fibrillary acidic protein (GFAP) and T cells, in 15 randomly divided New Zealand rabbits: G1: OH, G2: hWJ-MSCs, and G3: OH+hWJ-MSCs. We analyzed the aqueous humor (IL-6, IL-8, and TNF-α) and vitreous humor (IFN-γ, IL-10, and TGF-ß) using ELISA and flow cytometry (cell populations), as well as TCD3+, TCD3+/TCD4+, and TCD3+/TCD8+ lymphocytes, and GFAP in the retina and optic nerve through immunohistochemistry. RESULTS: We found a decrease in TNF-α, IL-6, IFN-γ, IL-10, and IL-8 in G3 compared to G1 and an increase in TGF-ß in both G2 and G3. TCD3+ retinal infiltration in all groups was primarily TCD8+ rather than TCD4+ cells, and strong GFAP expression was observed in both the retina and optic nerves in all groups. CONCLUSION: Our results suggest that cellular and humoral immune responses may play a role in glaucomatous optic neuropathy and that intravitreal hWJ-MSCs can induce an immunosuppressive environment by inhibiting proinflammatory cytokines and enhancing regulatory cytokines.

Predictors of mortality in hospitalised patients with COVID-19: a 1-year case-control study.

BACKGROUND: A paucity of predictive models assessing risk factors for COVID-19 mortality that extend beyond age and gender in Latino population is evident in the current academic literature. OBJECTIVES: To determine the associated factors with mortality, in addition to age and sex during the first year of the pandemic. DESIGN: A case-control study with retrospective revision of clinical and paraclinical variables by systematic revision of clinical records was conducted. Multiple imputations by chained equation were implemented to account for missing variables. Classification and regression trees (CART) were estimated to evaluate the interaction of associated factors on admission and their role in predicting mortality during hospitalisation. No intervention was performed. SETTING: High-complexity centre above 2640 m above sea level (masl) in Colombia. PARTICIPANTS: A population sample of 564 patients admitted to the hospital with confirmed COVID-19 by PCR. Deceased patients (n=282) and a control group (n=282), matched by age, sex and month of admission, were included. MAIN OUTCOME MEASURE: Mortality during hospitalisation. MAIN RESULTS: After the imputation of datasets, CART analysis estimated 11 clinical profiles based on respiratory distress, haemoglobin, lactate dehydrogenase, partial pressure of oxygen to inspired partial pressure of oxygen ratio, chronic kidney disease, ferritin, creatinine and leucocytes on admission. The accuracy model for prediction was 80.4% (95% CI 71.8% to 87.3%), with an area under the curve of 78.8% (95% CI 69.63% to 87.93%). CONCLUSIONS: This study discloses new interactions between clinical and paraclinical features beyond age and sex influencing mortality in COVID-19 patients. Furthermore, the predictive model could offer new clues for the personalised management of this condition in clinical settings.

Corrigendum: Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population.

[This corrects the article DOI: 10.3389/fimmu.2023.1241038.].

Metabolic fingerprinting of systemic sclerosis: a systematic review.

Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Methods: Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Results: Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. Discussion: The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population.

The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern.

Molecular mimicry and autoimmunity in the time of COVID-19.

Infectious diseases are commonly implicated as potential initiators of autoimmune diseases (ADs) and represent the most commonly known factor in the development of autoimmunity in susceptible individuals. Epidemiological data and animal studies on multiple ADs suggest that molecular mimicry is one of the likely mechanisms for the loss of peripheral tolerance and the development of clinical disease. Besides molecular mimicry, other mechanisms such as defects in central tolerance, nonspecific bystander activation, epitope-determinant spreading, and/or constant antigenic stimuli, may also contribute for breach of tolerance and to the development of ADs. Linear peptide homology is not the only mechanism by which molecular mimicry is established. Peptide modeling (i.e., 3D structure), molecular docking analyses, and affinity estimation for HLAs are emerging as critical strategies when studying the links of molecular mimicry in the development of autoimmunity. In the current pandemic, several reports have confirmed an influence of SARS-CoV-2 on subsequent autoimmunity. Bioinformatic and experimental evidence support the potential role of molecular mimicry. Peptide dimensional analysis requires more research and will be increasingly important for designing and distributing vaccines and better understanding the role of environmental factors related to autoimmunity.

Guillain-Barré Syndrome Following Zika Virus Infection Is Associated With a Diverse Spectrum of Peripheral Nerve Reactive Antibodies.

BACKGROUND AND OBJECTIVES: Recent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurologic side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4,000 ZIKV cases. Whether the neurologic symptoms of ZIKV infection are immune mediated is unclear. We used rodent and human live cellular models to screen for anti-peripheral nerve reactive IgG and IgM autoantibodies in the sera of patients with ZIKV with and without GBS. METHODS: In this study, 52 patients with ZIKV-GBS were compared with 134 ZIKV-infected patients without GBS and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens were validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array. RESULTS: Overall, IgG antibody reactivities to rat Schwann cells (SCs) (6.5%) and myelinated cocultures (9.6%) were significantly higher, albeit infrequent, in the ZIKV-GBS group compared with all controls. IgM antibody immunoreactivity to dorsal root ganglia neurones (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared with other controls, whereas IgM reactivity to cocultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from 1 patient were confirmed to react with neurofascin 155 and 186. Serum from a ZIKV-infected patient without GBS displayed strong myelin-binding and putative antilipid antigen reaction characteristics. There was, however, no significant association of ZIKV-GBS with any known antiglycolipid antibodies. DISCUSSION: Autoantibody responses in ZIKV-GBS target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection.

Safety and efficacy of convalescent plasma for severe COVID-19: a randomized, single blinded, parallel, controlled clinical study.

BACKGROUND: Convalescent plasma (CP) has been widely used to treat COVID-19 and is under study. However, the variability in the current clinical trials has averted its wide use in the current pandemic. We aimed to evaluate the safety and efficacy of CP in severe coronavirus disease 2019 (COVID-19) in the early stages of the disease. METHODS: A randomized controlled clinical study was conducted on 101 patients admitted to the hospital with confirmed severe COVID-19. Most participants had less than 14 days from symptoms onset and less than seven days from hospitalization. Fifty patients were assigned to receive CP plus standard therapy (ST), and 51 were assigned to receive ST alone. Participants in the CP arm received two doses of 250 mL each, transfused 24 h apart. All transfused plasma was obtained from "super donors" that fulfilled the following criteria: titers of anti-SARS-CoV-2 S1 IgG ≥ 1:3200 and IgA ≥ 1:800 antibodies. The effect of transfused anti-IFN antibodies and the SARS-CoV-2 variants at the entry of the study on the overall CP efficacy was evaluated. The primary outcomes were the reduction in viral load and the increase in IgG and IgA antibodies at 28 days of follow-up. The per-protocol analysis included 91 patients. RESULTS: An early but transient increase in IgG anti-S1-SARS-CoV-2 antibody levels at day 4 post-transfusion was observed (Estimated difference [ED], - 1.36; 95% CI, - 2.33 to - 0.39; P = 0.04). However, CP was not associated with viral load reduction in any of the points evaluated. Analysis of secondary outcomes revealed that those patients in the CP arm disclosed a shorter time to discharge (ED adjusted for mortality, 3.1 days; 95% CI, 0.20 to 5.94; P = 0.0361) or a reduction of 2 points on the WHO scale when compared with the ST group (HR adjusted for mortality, 1.6; 95% CI, 1.03 to 2.5; P = 0.0376). There were no benefits from CP on the rates of intensive care unit admission (HR, 0.82; 95% CI, 0.35 to 1.9; P = 0.6399), mechanical ventilation (HR, 0.66; 95% CI, 0.25 to 1.7; P = 0.4039), or mortality (HR, 3.2; 95% CI, 0.64 to 16; P = 0.1584). Anti-IFN antibodies and SARS-CoV-2 variants did not influence these results. CONCLUSION: CP was not associated with viral load reduction, despite the early increase in IgG anti-SARS-CoV-2 antibodies. However, CP is safe and could be a therapeutic option to reduce the hospital length of stay. Trial registration NCT04332835.

Autoimmunity is a hallmark of post-COVID syndrome.

Autoimmunity has emerged as a characteristic of the post-COVID syndrome (PCS), which may be related to sex. In order to further investigate the relationship between SARS-CoV-2 and autoimmunity in PCS, a clinical and serological assessment on 100 patients was done. Serum antibody profiles against self-antigens and infectious agents were evaluated by an antigen array chip for 116 IgG and 104 IgM antibodies. Thirty pre-pandemic healthy individuals were included as a control group. The median age of patients was 49 years (IQR: 37.8 to 55.3). There were 47 males. The median post-COVID time was 219 (IQR: 143 to 258) days. Latent autoimmunity and polyautoimmunity were found in 83% and 62% of patients, respectively. Three patients developed an overt autoimmune disease. IgG antibodies against IL-2, CD8B, and thyroglobulin were found in more than 10% of the patients. Other IgG autoantibodies, such as anti-interferons, were positive in 5-10% of patients. Anti-SARS-CoV-2 IgG antibodies were found in > 85% of patients and were positively correlated with autoantibodies, age, and body mass index (BMI). Few autoantibodies were influenced by age and BMI. There was no effect of gender on the over- or under-expression of autoantibodies. IgG anti-IFN-λ antibodies were associated with the persistence of respiratory symptoms. In summary, autoimmunity is characteristic of PCS, and latent autoimmunity correlates with humoral response to SARS-CoV-2.

Persistent Autoimmune Activation and Proinflammatory State in Post-Coronavirus Disease 2019 Syndrome.

BACKGROUND: The immunopathological pathways enabling post-coronavirus disease 2019 (COVID-19) syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition. METHODS: Thirty-three patients were included for longitudinal clinical and autoantibody analyses, 12 of whom were assessed for cytokines and lymphocyte populations. Patients were followed for 7-11 months after acute COVID-19. Autoimmune profile and immunological statuses were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry. RESULTS: Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by up-regulated interferon-α, tumor necrosis factor-α, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-6, IL-1ß, and IL-13, whereas interferon-γ-induced protein 10 (IP-10) was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of immunoglobulin G S1-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies remained elevated over time. CONCLUSIONS: The clinical manifestations of PCS are associated with the persistence of a proinflammatory and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

New insights into the taxonomy of autoimmune diseases based on polyautoimmunity.

OBJECTIVE: The clinical coexistence of two or more autoimmune diseases (ADs) fulfilling classification criteria is termed "overt polyautoimmunity" (PolyA), whereas the presence of autoantibodies unrelated to an index AD, without clinical criteria fulfillment, is known as "latent PolyA". We aimed to explore a new taxonomy of ADs based on PolyA. METHODS: In a cross-sectional study of 292 subjects, we evaluated the presence of PolyA in 146, 45, 29, 17, and 17 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), autoimmune thyroid disease (AITD) and systemic sclerosis (SSc), respectively, and 38 healthy controls. Clinical assessment, autoantibody profile (by autoantigen array chip), lymphocytes immunophenotype and cytokine profile (by flow cytometry) were evaluated simultaneously. A mixed cluster methodology was used to classify ADs. RESULTS: Latent PolyA was more frequent than overt PolyA, ranging from 69.9% in RA to 100% in SSc. Nevertheless, both latent and overt PolyA clustered together. Over-expressed IgG autoantibodies were found to be hallmarks for the identification of index ADs. The combination of autoantibodies allowed high accuracy in the classification of ADs. Three well-defined clusters based on PolyA were observed with distinctive clinical and immunological phenotypes. CONCLUSIONS: This proof-of-concept study indicates that ADs can be classified according to PolyA. PolyA should be considered in all studies dealing with ADs, including epidemiological, genetic, and clinical trials.

Post-COVID syndrome. A case series and comprehensive review.

The existence of a variety of symptoms with a duration beyond the acute phase of COVID-19, is referred to as post-COVID syndrome (PCS). We aimed to report a series of patients with PCS attending a Post-COVID Unit and offer a comprehensive review on the topic. Adult patients with previously confirmed SARS-CoV-2 infection and PCS were systematically assessed through a semi-structured and validated survey. Total IgG, IgA and IgM serum antibodies to SARS-CoV-2 were evaluated by an electrochemiluminescence immunoassay. A systematic review of the literature and meta-analysis were conducted, following PRISMA guidelines. Univariate and multivariate methods were used to analyze data. Out of a total of 100 consecutive patients, 53 were women, the median of age was 49 years (IQR: 37.8-55.3), the median of post-COVID time after the first symptoms was 219 days (IQR: 143-258), and 65 patients were hospitalized during acute COVID-19. Musculoskeletal, digestive (i.e., diarrhea) and neurological symptoms including depression (by Zung scale) were the most frequent observed in PCS patients. A previous hospitalization was not associated with PCS manifestation. Arthralgia and diarrhea persisted in more than 40% of PCS patients. The median of anti-SARS-CoV-2 antibodies was 866.2 U/mL (IQR: 238.2-1681). Despite this variability, 98 patients were seropositive. Based on autonomic symptoms (by COMPASS 31) two clusters were obtained with different clinical characteristics. Levels of anti-SARS-CoV-2 antibodies were not different between clusters. A total of 40 articles (11,196 patients) were included in the meta-analysis. Fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression and impaired concentration were presented in more than 20% of patients reported. In conclusion, PCS is mainly characterized by musculoskeletal, pulmonary, digestive and neurological involvement including depression. PCS is independent of severity of acute illness and humoral response. Long-term antibody responses to SARS-CoV-2 infection and a high inter-individual variability were confirmed. Future studies should evaluate the mechanisms by which SARS-CoV-2 may cause PCS and the best therapeutic options.

Evolution and Epidemic Spread of SARS-CoV-2 in Colombia: A Year into the Pandemic.

Current efforts to understand the epidemiology, transmission dynamics and emergence of novel SARS-CoV-2 variants worldwide has enabled the scientific community to generate critical information aimed at implementing disease surveillance and control measures, as well as to reduce the social, economic and health impact of the pandemic. Herein, we applied an epidemic model coupled with genomic analysis to assess the SARS-CoV-2 transmission dynamics in Colombia. This epidemic model allowed to identify the geographical distribution, Rt dynamics and predict the course of the pandemic considering current implementation of countermeasures. The analysis of the incidence rate per 100,000 inhabitants carried out across different regions of Colombia allowed visualizing the changes in the geographic distribution of cases. The cumulative incidence during the timeframe March 2020 to March 2021 revealed that Bogotá (8063.0), Quindío (5482.71), Amazonas (5055.68), Antioquia (4922.35) and Tolima (4724.41) were the departments with the highest incidence rate. The highest median Rt during the first period evaluated was 2.13 and 1.09 in the second period; with this model, we identified improving opportunities in health decision making related to controlling the pandemic, diagnostic testing capacity, case registration and reporting, among others. Genomic analysis revealed 52 circulating SARS-CoV-2 lineages in Colombia detected from 774 genomes sequenced throughout the first year of the pandemic. The genomes grouped into four main clusters and exhibited 19 polymorphisms. Our results provide essential information on the spread of the pandemic countrywide despite implementation of early containment measures. In addition, we aim to provide deeper phylogenetic insights to better understand the evolution of SARS-CoV-2 in light of the latent emergence of novel variants and how these may potentially influence transmissibility and infectivity.

Latent rheumatic, thyroid and phospholipid autoimmunity in hospitalized patients with COVID-19.

Autoimmune responses mediated by autoantibodies have been observed in SARS-CoV-2 infection. Herein, we evaluate the presence of rheumatic, thyroid and phospholipid autoantibodies in sera samples from 120 adult hospitalized patients with COVID-19 in comparison to pre-pandemic samples from 100 healthy individuals. In addition, to estimate the frequency of these autoantibodies in COVID-19, a meta-analysis of selected articles was conducted. Hospitalized patients with COVID-19 had latent autoimmunity characterized by a high frequency of anti-thyroid peroxidase antibodies, rheumatoid factor (RF), anti-cyclic citrullinated peptide third generation antibodies, antinuclear antibodies (ANAs), IgM anti-ß2-glycoprotein I (ß2GP1) and IgM anti-cardiolipin antibodies. The meta-analysis confirmed our results, with RF and ANAs being the most common autoantibodies. In addition, cluster analysis revealed that those patients with high frequency of RF, IgM anti-ß2GP1 antibodies and ANAs had a longer hospital stay, required more vasopressors during hospitalization, and were more likely to develop critical disease. These data suggest that latent autoimmunity influences the severity of COVID-19, and support further post-COVID studies in order to evaluate the development of overt autoimmunity.

COVID-19 convalescent plasma composition and immunological effects in severe patients.

Convalescent plasma (CP) has emerged as a treatment for COVID-19. However, the composition and mechanism of action are not fully known. Therefore, we undertook a two-phase controlled study in which, first the immunological and metabolomic status of recovered and severe patients were evaluated. Secondly, the 28-day effect of CP on the immune response in severe patients was assessed. Nineteen recovered COVID-19 patients, 18 hospitalized patients with severe disease, and 16 pre-pandemic controls were included. Patients with severe disease were treated with CP transfusion and standard therapy (i.e., plasma recipients, n = 9) or standard therapy alone (n = 9). Clinical and biological assessments were done on day 0 and during follow-up on days 4, 7, 14, and 28. Clinical parameters, viral load, total immunoglobulin (Ig) G and IgA anti-S1-SARS-CoV-2 antibodies, neutralizing antibodies (NAbs), autoantibodies, cytokines, T and B cells, and metabolomic and lipidomic profiles were examined. Total IgG and IgA anti-S1-SARS-CoV-2 antibodies were key factors for CP selection and correlated with NAbs. In severe COVID-19 patients, mostly interleukin (IL)-6 (P = <0.0001), IL-10 (P = <0.0001), IP-10 (P = <0.0001), fatty acyls and glycerophospholipids were higher than in recovered patients. Latent autoimmunity and anti-IFN-α antibodies were observed in both recovered and severe patients. COVID-19 CP induced an early but transient cytokine profile modification and increases IgG anti-S1-SARS-CoV-2 antibodies. At day 28 post-transfusion, a decrease in activated, effector and effector memory CD4+ (P < 0.05) and activated and effector CD8+ (P < 0.01) T cells and naïve B cells (P = 0.001), and an increase in non-classical memory B cells (P=<0.0001) and central memory CD4+ T cells (P = 0.0252) were observed. Moreover, IL-6/IFN-γ (P = 0.0089) and IL-6/IL-10 (P = 0.0180) ratios decreased in plasma recipients compared to those who received standard therapy alone. These results may have therapeutic implications and justify further post-COVID-19 studies.

Neutrophil extracellular traps in autoimmune diseases / Trampas extracelulares de neutrófilos en enfermedades autoinmunes

ABSTRACT Neutrophils play an important role in immune defence against several pathogens. These cells actively participate in the innate immune response through different functions, such as chemotaxis, phagocytosis, oxidative burst and degranulation, which have been widely studied. However, in the last few years, a new function has been described; activated neutrophils are able to release web-like chromatin structures known as neutrophil extracellular traps (NETs). These structures formed by DNA, histones, and proteins, immobilize and kill microorganisms. Disruption in NET formation is associated with the pathophysiology of several disorders, including the autoimmune diseases. NETs are an important source of the autoantigens involved in the production of autoantibodies and maintenance of the inflammatory milieu. This review provides a summary of the contribution of NETs to the pathogenesis of anti-neutrophil cytoplasmic antibodies-associated vasculitis, systemic lupus erythematosus, and rheumatoid arthritis. The preliminary findings on NETs components in Sjögren.'s syndrome will also be described.

RESUMEN Los neutrófilos juegan un papel muy importante en la defensa inmune contra diferentes patógenos. Estas células participan activamente en la respuesta inmune innata a través de diferentes funciones como quimiotaxis, fagocitosis, estallido oxidativo y degranulación, las cuales han sido estudiadas ampliamente. Sin embargo, en los últimos años se ha descrito una nueva función; los neutrófilos activados son capaces de liberar redes de cromatina llamadas trampas extracelulares de neutrófilos (NETs). Estas estructuras están formadas por ADN, histonas y proteínas capaces de inmovilizar y matar microorganismos. Alteraciones en la formación de estas NETs están asociadas con la fisiopatología de varios trastornos, incluyendo las enfermedades autoinmunes (EAI). Las NETs son consideradas una fuente de autoantígenos que ayudan a la producción de autoanticuerpos y al mantenimiento de un ambiente inflamatorio. Esta revisión resume la contribución de las NETs a la patogénesis de vasculitis asociada a anticuerpos contra el citoplasma de los neutrófilos, lupus eritematoso sistémico y artritis reumatoide. Adicionalmente, se describirán los resultados preliminares de la detección de componentes de las NETs en pacientes con síndrome de Sjögren.