IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.

Download Full-text

Effects of Loigolactobacillus coryniformis K8 CECT 5711 on the Immune Response of Elderly Subjects to COVID-19 Vaccination: A Randomized Controlled Trial

Nutrients ◽

10.3390/nu14010228 ◽

2022 ◽

Vol 14 (1) ◽

pp. 228

Author(s):

Anxo Fernández-Ferreiro ◽

Francisco J. Formigo-Couceiro ◽

Roi Veiga-Gutierrez ◽

Jose A. Maldonado-Lobón ◽

Ana M. Hermida-Cao ◽

...

Keyword(s):

Immune Response ◽

Controlled Trial ◽

Severe Disease ◽

Nursing Home Residents ◽

Vaccination Schedule ◽

Elderly Subjects ◽

Double Blind ◽

Iga Antibody ◽

Specific Igg ◽

Antibody Levels

Elderly people are particularly vulnerable to COVID-19, with a high risk of developing severe disease and a reduced immune response to the COVID-19 vaccine. A randomized, placebo-controlled, double-blind trial to assess the effect of the consumption of the probiotic Loigolactobacillus coryniformis K8 CECT 5711 on the immune response generated by the COVID-19 vaccine in an elderly population was performed. Two hundred nursing home residents >60 yrs that had not COVID-19 were randomized to receive L. coryniformis K8 or a placebo daily for 3 months. All volunteers received a complete vaccination schedule of a mRNA vaccine, starting the intervention ten days after the first dose. Specific IgG and IgA antibody levels were analyzed 56 days after the end of the immunization process. No differences between the groups were observed in the antibody levels. During the intervention, 19 subjects had COVID-19 (11 receiving K8 vs. 8 receiving placebo, p = 0.457). Subgroup analysis in these patients showed that levels of IgG were significantly higher in those receiving K8 compared to placebo (p = 0.038). Among subjects >85 yrs that did not get COVID-19, administration of K8 tended to increase the IgA levels (p = 0.082). The administration of K8 may enhance the specific immune response against COVID-19 and may improve the COVID-19 vaccine-specific responses in elderly populations.

Download Full-text

Human immune response to SARS-CoV-2 infection

Jurnal Teknologi Laboratorium ◽

10.29238/teknolabjournal.v9i1.223 ◽

2020 ◽

Vol 9 (1) ◽

pp. 29-40

Author(s):

Lia Yosaneri Wina Nurtias ◽

Dora Dayu Rahma Turista ◽

Eka Puspitasari

Keyword(s):

Immune Response ◽

Immune Responses ◽

Severe Disease ◽

Adaptive Immune Response ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Reactive Protein ◽

Narrative Literature ◽

Human Immune Response ◽

Narrative Literature Review

COVID-19 is an acute respiratory infection caused by a new type of Coronavirus, SARS-CoV-2, which first appeared in Wuhan, China in December 2019. COVID-19 then became a pandemic in various countries in early 2020. In this article it contains review that discusses the immune response in humans due to SARS-CoV-2 infection, using the narrative literature review method, a total of 36 articles (6 from Elsevier, 24 from PMC, and 6 from Springer). It is known that the pathogenesis of COVID-19 and the manufacture of drugs and vaccines are still under investigation, but in infected patients, innate immune responses in the form of alveolar macrophages, dendritic cells, airway epithelial cells, congenital lymphocytes, and neutrophils work together in the fight against infection. Next comes the adaptive immune response in the form of antibodies (immunoglobulins) which help in fighting infections due to SARS-CoV-2. These immune responses include increasing levels of cytokines, coagulation parameters, C-reactive protein, neutrophils, and decreasing total lymphocytes. It is also known that COVID-19 patients with severe disease often experience higher total antibody, IgM responses, and IgG responses than COVID-19 patients without congenital disease. IgG antibodies are present in the serum, so the serum in COVID-19 patients who have recovered can be used for therapy in COVID-19 patients who have not healed, as long as the drug and vaccine are under investigation.

Download Full-text

IgA Immune Complexes Induce Osteoclast-Mediated Bone Resorption

Frontiers in Immunology ◽

10.3389/fimmu.2021.651049 ◽

2021 ◽

Vol 12 ◽

Author(s):

Annelot C. Breedveld ◽

Melissa M. J. van Gool ◽

Myrthe A. M. van Delft ◽

Conny J. van der Laken ◽

Teun J. de Vries ◽

...

Keyword(s):

Bone Resorption ◽

Disease Activity ◽

Immune Complexes ◽

Severe Disease ◽

Neutrophil Extracellular Trap ◽

Peptide Antibody ◽

Activated Monocytes ◽

Antibody Levels ◽

Iga Immune Complexes

ObjectiveAutoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption.MethodsAnti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption.ResultsNET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts.ConclusionIgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

Download Full-text

Efficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination

10.1101/2021.03.11.21253352 ◽

2021 ◽

Author(s):

Amihai Rottenstreich ◽

Gila Zarbiv ◽

Esther Oiknine-Djian ◽

Roy Zigron ◽

Dana G. Wolf ◽

...

Keyword(s):

Cord Blood ◽

Medical Center ◽

Severe Disease ◽

Vaccine Dose ◽

Protein S ◽

Study Cohort ◽

Transplacental Transfer ◽

Serologic Response ◽

Specific Igg ◽

Antibody Levels

AbstractBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy and early infancy can result in severe disease. Evaluating the serologic response after maternal vaccination during pregnancy and subsequent transplacental antibody transfer has important implications for maternal care and vaccination strategies.ObjectiveTo assess maternal and neonatal SARS-CoV-2 antibody levels after antenatal mRNA vaccination.Design, Setting, and ParticipantsThis study took place at Hadassah Medical Center in Jerusalem, Israel in February 2021. Maternal and cord blood sera were collected for antibody measurement from mother/newborn dyads following antenatal vaccination.ExposureSARS-CoV-2 BNT162b2 mRNA vaccination.Main outcome and measuresSpike protein (S) and receptor binding domain (RBD) - specific, IgG levels were evaluated in maternal and cord blood sera.ResultsThe study cohort consisted of 20 parturients, with a median maternal age of 32 y ears and a median gestational age of 393/7 weeks at the time of delivery. The median time lapsed from the first and second doses of vaccine administration until delivery was 33 [IQR 30-37] and 11 [IQR 9-15] days, respectively. Of the 20 dyads, all women an d infants were positive for anti S- and anti-RBD-specific IgG. Anti-S and anti-RBD-specific IgG levels in maternal sera were positively correlated to their respective concentrations in cord blood (ρs= 0.72; P<0.001 and ρs= 0.72; P <0.001, respectively). Anti-S and anti-RBD-specific IgG titers in cord blood were directly correlated with time lapsed since the administration of the first vaccine dose (ρs= 0.71; P =0.001 and ρs= 0.63; P=0.004, respectively).Conclusion and RelevanceIn this study, SARS-CoV-2 mRNA vaccine administered during pregnancy induced adequate maternal serologic response with subsequent efficient transplacental transfer. Our findings highlight that vaccination of pregnant women may provide maternal and neonatal protection from SARS-CoV-2 infection.

Download Full-text

Elevated SARS-CoV-2 Antibodies Distinguish Severe Disease in Early COVID-19 Infection

10.1101/2020.12.04.410589 ◽

2020 ◽

Author(s):

Natalie S. Haddad ◽

Doan C. Nguyen ◽

Merin E. Kuruvilla ◽

Andrea Morrison-Porter ◽

Fabliha Anam ◽

...

Keyword(s):

Antibody Response ◽

Severe Disease ◽

Roc Curves ◽

Multiplex Immunoassay ◽

Specific Igg ◽

Critical Patients ◽

Antibody Levels ◽

Kinetics Of

AbstractBackgroundSARS-CoV-2 has caused over 36,000,000 cases and 1,000,000 deaths globally. Comprehensive assessment of the multifaceted anti-viral antibody response is critical for diagnosis, differentiation of severe disease, and characterization of long-term immunity. Initial observations suggest that severe disease is associated with higher antibody levels and greater B cell/plasmablast responses. A multi-antigen immunoassay to define the complex serological landscape and clinical associations is essential.MethodsWe developed a multiplex immunoassay and evaluated serum/plasma from adults with RT-PCR-confirmed SARS-CoV-2 infections during acute illness (N=52) and convalescence (N=69); and pre-pandemic (N=106) and post-pandemic (N=137) healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 Nucleocapsid (N), Spike domain 1 (S1), receptor binding domain (S1-RBD) and S1-N-terminal domain (S1-NTD).ResultsTo diagnose infection, the combined [IgA+IgG+IgM] or IgG for N, S1, and S1-RBD yielded AUC values −0.90 by ROC curves. From days 6-30 post-symptom onset, the levels of antigen-specific IgG, IgA or [IgA+IgG+IgM] were higher in patients with severe/critical compared to mild/moderate infections. Consistent with excessive concentrations of antibodies, a strong prozone effect was observed in sera from severe/critical patients. Notably, mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared to severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 months.ConclusionThis SARS-CoV-2 multiplex immunoassay measures the magnitude, complexity and kinetics of the antibody response against multiple viral antigens. The IgG and combined-isotype SARS-CoV-2 multiplex assay is highly diagnostic of acute and convalescent disease and may prognosticate severity early in illness.One Sentence SummaryIn contrast to patients with moderate infections, those with severe COVID-19 develop prominent, early antibody responses to S1 and N proteins.

Download Full-text

High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages

Science Translational Medicine ◽

10.1126/scitranslmed.abf8654 ◽

2021 ◽

pp. eabf8654

Author(s):

Willianne Hoepel ◽

Hung-Jen Chen ◽

Chiara E. Geyer ◽

Sona Allahverdiyeva ◽

Xue D. Manz ◽

...

Keyword(s):

Inflammatory Response ◽

Critically Ill ◽

Alveolar Macrophages ◽

Inflammatory Responses ◽

Severe Disease ◽

Adaptive Immune Response ◽

Molecule Inhibitor ◽

Igg Receptors ◽

Specific Igg

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.

Download Full-text

Serum C-Reactive Protein and Interleukin-6 Levels as Biomarkers for Disease Severity and Clinical Outcomes in Patients with Idiopathic Granulomatous Mastitis

Journal of Clinical Medicine ◽

10.3390/jcm10102077 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2077

Author(s):

Yi-Min Huang ◽

Chiao Lo ◽

Chiao-Feng Cheng ◽

Cheng-Hsun Lu ◽

Song-Chou Hsieh ◽

...

Keyword(s):

Disease Severity ◽

Severe Disease ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis ◽

Serum Biomarkers ◽

Healthy Controls ◽

Granulomatous Mastitis ◽

C Reactive Protein ◽

Idiopathic Granulomatous Mastitis ◽

Reactive Protein

Idiopathic granulomatous mastitis (IGM) is a rare inflammatory breast disease mimicking breast cancer. Limited research has been conducted on the application of serum biomarkers. This study aims to investigate the association of serum biomarkers with disease severity in patients with IGM. From November 2011 to March 2020, medical records of patients with IGM were reviewed. Serum cytokine levels were measured in patients and healthy controls between July 2018 and March 2020. A total of 41 patients with histologically proven IGM were found. Serum interleukin (IL)-6 level was significantly higher in patients with IGM (n = 11) than healthy controls (n = 7). Serum IL-6 and C-reactive protein (CRP) levels were significantly higher in patients with severe disease than mild and moderate disease. Serum IL-6 (Spearman’s ρ = 0.855; p < 0.001) and CRP (Spearman’s ρ = 0.838; p = 0.001) levels were associated with time to resolution. A higher serum CRP level was associated with a longer time to resolution (B = 0.322; p < 0.001) in multiple linear regression analysis. Serum IL-6 and CRP levels can be used as biomarkers for the evaluation of disease severity in IGM. IL-6 may play a crucial role in the immunopathology of IGM.

Download Full-text

Oxidative burst and phagocytic activity of phagocytes in canine parvoviral enteritis

Journal of Veterinary Diagnostic Investigation ◽

10.1177/10406387211025513 ◽

2021 ◽

pp. 104063872110255

Author(s):

Kelly du Preez ◽

Yolandi Rautenbach ◽

Emma H. Hooijberg ◽

Amelia Goddard

Keyword(s):

Oxidative Burst ◽

Phagocytic Activity ◽

Severe Disease ◽

Burst Activity ◽

E Coli ◽

Reactive Protein ◽

Oxidative Burst Activity ◽

Healthy Control ◽

Complete Blood Counts ◽

Serum Crp

Canine parvoviral enteritis (CPE) is a severe disease characterized by systemic inflammation and immunosuppression. The function of circulating phagocytes (neutrophils and monocytes) in affected dogs has not been fully investigated. We characterized the functional capacity of canine phagocytes in CPE by determining their oxidative burst and phagocytic activities using flow cytometry. Blood was collected from 28 dogs with CPE and 11 healthy, age-matched, control dogs. Oxidative burst activity was assessed by stimulating phagocytes with opsonized Escherichia coli or phorbol 12-myristate 13-acetate (PMA) and measuring the percentage of phagocytes producing reactive oxygen species and the magnitude of this production. Phagocytosis was measured by incubating phagocytes with opsonized E. coli and measuring the percentage of phagocytes containing E. coli and the number of bacteria per cell. Complete blood counts and serum C-reactive protein (CRP) concentrations were also determined. Serum CRP concentration was negatively and positively correlated with segmented and band neutrophil concentrations, respectively. Overall, no differences in phagocyte function were found between dogs with CPE and healthy control dogs. However, infected dogs with neutropenia or circulating band neutrophils had decreased PMA-stimulated oxidative burst activity compared to healthy controls. Additionally, CPE dogs with neutropenia or circulating band neutrophils had decreased PMA- and E. coli–stimulated oxidative burst activity and decreased phagocytosis of E. coli compared to CPE dogs without neutropenia or band neutrophils. We conclude that phagocytes have decreased oxidative burst and phagocytic activity in neutropenic CPE dogs and in CPE dogs with circulating band neutrophils.

Download Full-text

Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications

Nature Communications ◽

10.1038/s41467-021-21907-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Nan Xiao ◽

Meng Nie ◽

Huanhuan Pang ◽

Bohong Wang ◽

Jieli Hu ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Mononuclear Cells ◽

Inflammatory Responses ◽

Ex Vivo ◽

Rhesus Macaques ◽

Fatal Outcome ◽

Organ Injury ◽

Cytokine Release ◽

Serum Samples ◽

Peripheral Blood Mononuclear

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

Download Full-text

Chronic Induction of C-Reactive Protein by Hemodialysis, but Not by Peritoneal Dialysis Therapy

Peritoneal Dialysis International ◽

10.1177/089686089601600213 ◽

1996 ◽

Vol 16 (2) ◽

pp. 158-162 ◽

Cited By ~ 65

Author(s):

Marion Haubitz ◽

Reinhard Brunkhorst ◽

Eike Wrenger ◽

Peter Froese ◽

Matthias Schulze ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Renal Insufficiency ◽

Chronic Renal Insufficiency ◽

Inflammatory Activity ◽

C Reactive Protein ◽

Dialysis Therapy ◽

Dialysis Treatment ◽

Reactive Protein ◽

Before And After ◽

Patient Groups

Objective Evaluation of the inflammatory activity in patients on chronic peritoneal dialysis (PD) and patients on chronic hemodialysis (HD) in comparison to patients with chronic renal insufficiency without dialysis treatment and healthy volunteers. Design Open, non randomized prospective study. Setting Nephrology Department, including HD and PD therapy in a university hospital. Patients Twenty -four patients on chronic PD, 21 patients on chronic HD therapy using a cuprophan dialyzer, 16 patients with chronic renal insufficiency without dialysis treatment, and 33 healthy volunteers; 8 additional patients before and after initiation of chronic HD therapy. All patients and controls were without infection or immunosuppressive therapy. Main Outcome Measures As a marker of the inflammatory activity in the different patient groups, C-reactive protein (CAP) was measured serially using a sensitive, enzyme-Iinked, immunosorbent assay in order to detect values below the detection limit of standard assays. Results All patient groups had CAP levels higher than the normal controls (p < 0.01). Patients on HD had CAP levels significantly higher than PD patients (p < 0.01) whose levels were comparable to patients without dialysis therapy. Accordingly, longitudinal measurements before and after initiation of chronic HD showed a significant increase in CAP levels after the beginning of HD treatment (p < 0.04). Conclusions The results suggest that induction of the inflammatory activity is lower during PD compared to HD, since stimulation by the dialyzer membrane, dialysate buffer, or bacterial fragments in the dialysate is avoided. This observation might indicate a possible lower risk of long-term complications in patients with PD.

Download Full-text