Immunomodulation: Immunoglobulin Preparations Suppress Hyperinflammation in a COVID-19 Model via FcγRIIA and FcαRI

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and “cytokine storm”. The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response.

[1]  A. Casadevall,et al.  Markers of Polyfunctional SARS-CoV-2 Antibodies in Convalescent Plasma , 2021, mBio.

[2]  L. Valsecchi,et al.  IL-1 Receptor Antagonist Anakinra in the Treatment of COVID-19 Acute Respiratory Distress Syndrome: A Retrospective, Observational Study , 2021, The Journal of Immunology.

[3]  H. Ljunggren,et al.  High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19 , 2021, Proceedings of the National Academy of Sciences.

[4]  B. G. Rao,et al.  Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19 , 2021, Frontiers in Pharmacology.

[5]  R. Balk,et al.  COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions , 2021, mBio.

[6]  M. Fartoukh,et al.  Bacterial coinfection in critically ill COVID-19 patients with severe pneumonia , 2021, Infection.

[7]  M. van Egmond,et al.  IgA and FcαRI: Versatile Players in Homeostasis, Infection, and Autoimmunity , 2021, ImmunoTargets and therapy.

[8]  Hassan Mahmoudi Bacterial co-infections and antibiotic resistance in patients with COVID-19 , 2020, GMS hygiene and infection control.

[9]  J. Mestecky,et al.  Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection , 2020, Frontiers in Immunology.

[10]  You-Wen He,et al.  A Potential Role of Interleukin 10 in COVID-19 Pathogenesis , 2020, Trends in Immunology.

[11]  S. Ciesek,et al.  Analysis of Humoral Immune Responses in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection , 2020, The Journal of Infectious Diseases.

[12]  A. Andiappan,et al.  Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19 , 2020, Nature Communications.

[13]  Yang Wang,et al.  Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity , 2020, Cell Reports Medicine.

[14]  Salleh N. Ehaideb,et al.  Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review , 2020, Critical Care.

[15]  G. Gorochov,et al.  When Therapeutic IgA Antibodies Might Come of Age. , 2020, Pharmacology.

[16]  K. Stiasny,et al.  Kinetics of SARS-CoV-2 specific antibodies (IgM, IgA, IgG) in non-hospitalized patients four months following infection , 2020, Journal of Infection.

[17]  M. Farcet,et al.  No SARS-CoV-2 Neutralization by Intravenous Immunoglobulins Produced From Plasma Collected Before the 2020 Pandemic , 2020, The Journal of infectious diseases.

[18]  Robert A. Campbell,et al.  Cytokine release syndrome in COVID-19: Innate immune, vascular, and platelet pathogenic factors differ in severity of disease and sex , 2020, Journal of leukocyte biology.

[19]  Xueying Zheng,et al.  Decline of SARS-CoV-2-specific IgG, IgM and IgA in convalescent COVID-19 patients within 100 days after hospital discharge , 2020, Science China Life Sciences.

[20]  S. Pancani,et al.  Closing the serological gap in the diagnostic testing for COVID‐19: The value of anti‐SARS‐CoV‐2 IgA antibodies , 2020, Journal of medical virology.

[21]  P. Jorth,et al.  The Unrecognized Threat of Secondary Bacterial Infections with COVID-19 , 2020, mBio.

[22]  G. Natoli,et al.  Persistence of Anti-SARS-CoV-2 Antibodies in Non-Hospitalized COVID-19 Convalescent Health Care Workers , 2020, medRxiv.

[23]  Kira L. Newman,et al.  Distinct Early Serological Signatures Track with SARS-CoV-2 Survival , 2020, Immunity.

[24]  N. Zhong,et al.  Characteristics and roles of severe acute respiratory syndrome coronavirus 2‐specific antibodies in patients with different severities of coronavirus 19 , 2020, Clinical and experimental immunology.

[25]  N. Maturo,et al.  Administration of Immunoglobulins in SARS-CoV-2-Positive Patient Is Associated With Fast Clinical and Radiological Healing: Case Report , 2020, Frontiers in Medicine.

[26]  Aaron M. Rosenfeld,et al.  Comprehensive mapping of immune perturbations associated with severe COVID-19 , 2020, Science Immunology.

[27]  W. Cao,et al.  High-Dose Intravenous Immunoglobulins in the Treatment of Severe Acute Viral Pneumonia: The Known Mechanisms and Clinical Effects , 2020, Frontiers in Immunology.

[28]  R. Sanders,et al.  Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses , 2020, bioRxiv.

[29]  V. Martel-Laferrière,et al.  Decline of Humoral Responses against SARS-CoV-2 Spike in Convalescent Individuals , 2020, mBio.

[30]  A. Didangelos COVID-19 Hyperinflammation: What about Neutrophils? , 2020, mSphere.

[31]  H. Xiong,et al.  Immune‐related factors associated with pneumonia in 127 children with coronavirus disease 2019 in Wuhan , 2020, Pediatric pulmonology.

[32]  Jian-yong Li,et al.  Potential Treatments for COVID-19 Related Cytokine Storm - Beyond Corticosteroids , 2020, Frontiers in Immunology.

[33]  O. Schwartz,et al.  IgA dominates the early neutralizing antibody response to SARS-CoV-2 , 2020, Science Translational Medicine.

[34]  H. Anders,et al.  Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19 , 2020, Cells.

[35]  J. Pačes,et al.  COVID-19 and the immune system. , 2020, Physiological research.

[36]  Yajuan Li,et al.  Serum IgA, IgM, and IgG responses in COVID-19 , 2020, Cellular & Molecular Immunology.

[37]  D. Hoffmann,et al.  Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19 , 2020, Frontiers in Immunology.

[38]  Paweł P. Łabaj,et al.  Altered cytokine levels and immune responses in patients with SARS-CoV-2 infection and related conditions , 2020, Cytokine.

[39]  M. Lanza,et al.  Successful intravenous immunoglobulin treatment in severe COVID-19 pneumonia , 2020, IDCases.

[40]  H. Hakonarson,et al.  Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients , 2020, European Respiratory Journal.

[41]  B. Zhu,et al.  Co-infection with respiratory pathogens among COVID-2019 cases , 2020, Virus Research.

[42]  Douglas R. McDonald,et al.  Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution!☆ , 2020, Clinical Immunology.

[43]  M. Merad,et al.  Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages , 2020, Nature Reviews Immunology.

[44]  R. Dudley,et al.  Immunomodulation in COVID-19 , 2020, The Lancet Respiratory Medicine.

[45]  G. Di Gennaro,et al.  Editorial - High dose intravenous immunoglobulins as a therapeutic option for COVID-19 patients. , 2020, European review for medical and pharmacological sciences.

[46]  P. Matricardi,et al.  IgA-Ab response to spike glycoprotein of SARS-CoV-2 in patients with COVID-19: A longitudinal study , 2020, Clinica Chimica Acta.

[47]  Leiliang Zhang,et al.  A potential inhibitory role for integrin in the receptor targeting of SARS-CoV-2 , 2020, Journal of Infection.

[48]  D. McGonagle,et al.  The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease , 2020, Autoimmunity Reviews.

[49]  A. Singanayagam,et al.  Immunosuppression for hyperinflammation in COVID-19: a double-edged sword? , 2020, The Lancet.

[50]  Ying Wang,et al.  COVID-19 infection: the perspectives on immune responses , 2020, Cell Death & Differentiation.

[51]  Qi Jin,et al.  Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19) , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[52]  Mandeep R. Mehra,et al.  COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal , 2020, The Journal of Heart and Lung Transplantation.

[53]  A. Walls,et al.  Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein , 2020, Cell.

[54]  Chunlin Cai,et al.  Short-term Moderate-dose Corticosteroid Plus Immunoglobulin Effectively Reverses Covid-19 Patients Who Have Failed Low-dose Therapy , 2020 .

[55]  Yuntao Wu,et al.  Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools , 2020, Virologica Sinica.

[56]  P. Mehta,et al.  COVID-19: consider cytokine storm syndromes and immunosuppression , 2020, The Lancet.

[57]  T. Bai,et al.  High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019 , 2020, Open forum infectious diseases.

[58]  F. Lu,et al.  Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia , 2020, medRxiv.

[59]  Zunyou Wu,et al.  Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. , 2020, JAMA.

[60]  Shuye Zhang,et al.  Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses , 2020, bioRxiv.

[61]  Suxin Wan,et al.  Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP) , 2020, medRxiv.

[62]  Y. Hu,et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China , 2020, The Lancet.

[63]  W. Cao,et al.  Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia , 2020, Emerging microbes & infections.

[64]  R. Liu,et al.  Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors , 2020, Emerging microbes & infections.

[65]  F. Jönsson,et al.  Expression, Role, and Regulation of Neutrophil Fcγ Receptors , 2019, Front. Immunol..

[66]  L. Koenderman Corrigendum: Inside-Out Control of Fc-Receptors , 2019, Front. Immunol..

[67]  Andreas Radbruch,et al.  Functional Roles of the IgM Fc Receptor in the Immune System , 2019, Front. Immunol..

[68]  M. Benhamou,et al.  Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools , 2019, Front. Immunol..

[69]  J. Jansen,et al.  Potent Fc Receptor Signaling by IgA Leads to Superior Killing of Cancer Cells by Neutrophils Compared to IgG , 2019, Front. Immunol..

[70]  Chuan Qin,et al.  Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. , 2019, JCI insight.

[71]  T. K. van den Berg,et al.  FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils , 2019, Front. Immunol..

[72]  M. Romans Altered , 2019 .

[73]  Lin Qiu,et al.  Understanding the Multifaceted Role of Neutrophils in Cancer and Autoimmune Diseases , 2018, Front. Immunol..

[74]  D. Velissaris,et al.  The use of IgM‐enriched immunoglobulin in adult patients with sepsis , 2018, Journal of critical care.

[75]  Robert M. DiFazio,et al.  Advanced model systems and tools for basic and translational human immunology , 2018, Genome Medicine.

[76]  M. D. de Jonge,et al.  Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections , 2018, Front. Immunol..

[77]  M. Singer,et al.  Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study) , 2018, Intensive Care Medicine.

[78]  J. Cervera,et al.  Imiquimod inhibits growth and induces differentiation of myeloid leukemia cell lines , 2018, Cancer Cell International.

[79]  S. Kaveri,et al.  IVIG-mediated effector functions in autoimmune and inflammatory diseases , 2017, International immunology.

[80]  S. Collins,et al.  A map of gene expression in neutrophil-like cell lines , 2017, bioRxiv.

[81]  J. Benschop,et al.  Peptide mimetics of immunoglobulin A (IgA) and FcαRI block IgA‐induced human neutrophil activation and migration , 2017, European journal of immunology.

[82]  E. Daugas,et al.  Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation , 2017, Nature Communications.

[83]  P. Späth,et al.  Clinical Use and Therapeutic Potential of IVIG/SCIG, Plasma-Derived IgA or IgM, and Other Alternative Immunoglobulin Preparations , 2017, Archivum Immunologiae et Therapiae Experimentalis.

[84]  Colleen B. Jonsson,et al.  A Role for Neutrophils in Viral Respiratory Disease , 2017, Front. Immunol..

[85]  V. Martín,et al.  IL-10: A Multifunctional Cytokine in Viral Infections , 2017, Journal of immunology research.

[86]  H. Naim,et al.  Antimicrobial activity of HL-60 cells compared to primary blood-derived neutrophils against Staphylococcus aureus , 2017, Journal of Negative Results in BioMedicine.

[87]  Marieke H. Heineke,et al.  Immunoglobulin A: magic bullet or Trojan horse? , 2017, European journal of clinical investigation.

[88]  M. Andersen,et al.  Elimination of erroneous results in flow cytometry caused by antibody binding to Fc receptors on human monocytes and macrophages , 2016, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[89]  S. Stehr,et al.  IgM‐enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia , 2015, Acta anaesthesiologica Scandinavica.

[90]  A. Zuercher,et al.  Reversal of Arthritis by Human Monomeric IgA Through the Receptor‐Mediated SH2 Domain–Containing Phosphatase 1 Inhibitory Pathway , 2015, Arthritis & rheumatology.

[91]  D. Baeten,et al.  Control of Cytokine Production by Human Fc Gamma Receptors: Implications for Pathogen Defense and Autoimmunity , 2015, Front. Immunol..

[92]  J. Seoh,et al.  Phenotypic and Functional Analysis of HL-60 Cells Used in Opsonophagocytic-Killing Assay for Streptococcus pneumoniae , 2015, Journal of Korean medical science.

[93]  J. V. van Strijp,et al.  Neutrophil-Mediated Phagocytosis of Staphylococcus aureus , 2014, Front. Immunol..

[94]  P. Bruhns,et al.  Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis. , 2014, The Journal of clinical investigation.

[95]  V. Everts,et al.  IgA Enhances NETosis and Release of Neutrophil Extracellular Traps by Polymorphonuclear Cells via Fcα Receptor I , 2014, The Journal of Immunology.

[96]  M. van Egmond,et al.  Neutrophils as effector cells for antibody-based immunotherapy of cancer. , 2013, Seminars in cancer biology.

[97]  P. Kubes,et al.  Neutrophil recruitment and function in health and inflammation , 2013, Nature Reviews Immunology.

[98]  F. Nimmerjahn,et al.  Intravenous immunoglobulin therapy: how does IgG modulate the immune system? , 2013, Nature Reviews Immunology.

[99]  E. Gelfand Intravenous immune globulin in autoimmune and inflammatory diseases. , 2012, The New England journal of medicine.

[100]  B. Crestani,et al.  IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses. , 2012, Blood.

[101]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[102]  J. Bakema,et al.  The human immunoglobulin A Fc receptor FcαRI: a multifaceted regulator of mucosal immunity , 2011, Mucosal Immunology.

[103]  J. Peiris,et al.  Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH- and Cysteine Protease-Independent FcγR Pathway , 2011, Journal of Virology.

[104]  M. Schilham,et al.  Targeting FcαRI on Polymorphonuclear Cells Induces Tumor Cell Killing through Autophagy , 2011, The Journal of Immunology.

[105]  M. van Egmond,et al.  Immunoglobulin A , 2011, mAbs.

[106]  D. Irvine,et al.  A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples. , 2010, Journal of immunological methods.

[107]  M. Benhamou,et al.  Inhibitory ITAMs as novel regulators of immunity , 2009, Immunological reviews.

[108]  Jae Hoon Kim,et al.  NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26). , 2009, Biochemical and biophysical research communications.

[109]  G. Vidarsson,et al.  Inside-Out Regulation of FcαRI (CD89) Depends on PP2A1 , 2008, The Journal of Immunology.

[110]  R. Fleck,et al.  Use of HL-60 Cell Line To Measure Opsonic Capacity of Pneumococcal Antibodies , 2005, Clinical Diagnostic Laboratory Immunology.

[111]  C. Hughes,et al.  Of Mice and Not Men: Differences between Mouse and Human Immunology , 2004, The Journal of Immunology.

[112]  T. Hudson,et al.  GeneExpression in HL60 Granulocytoids and Human PolymorphonuclearLeukocytes Exposed to Candidaalbicans† , 2004, Infection and Immunity.

[113]  Clinton L White,et al.  Bivalent binding of IgA1 to FcalphaRI suggests a mechanism for cytokine activation of IgA phagocytosis. , 2003, Journal of molecular biology.

[114]  S. Jolles High‐dose intravenous immunoglobulin (hdIVIg) in the treatment of autoimmune blistering disorders , 2002, Clinical and experimental immunology.

[115]  T. van der Poll,et al.  Proinflammatory Effects of IL-10 During Human Endotoxemia1 , 2000, The Journal of Immunology.

[116]  G. Mufti,et al.  Changes in antigen expression on differentiating HL60 cells treated with dimethylsulphoxide, all-trans retinoic acid, alpha1,25-dihydroxyvitamin D3 or 12-O-tetradecanoyl phorbol-13-acetate. , 1998, Leukemia research.

[117]  D. Kraft,et al.  Lack of evidence for IgM-induced ADCC: studies with monoclonal and polyclonal antibodies. , 1981, Immunology.

[118]  Hyun-Dong Chang,et al.  Authentic IgM Fc Receptor (FcμR). , 2017, Current topics in microbiology and immunology.

[119]  Maja O’Connor LONGITUDINAL STUDY , 2013 .

[120]  F. Esen,et al.  IgM-enriched Immunoglobulins in Sepsis , 2009 .

[121]  J. Ravetch,et al.  Fcgamma receptors: old friends and new family members. , 2006, Immunity.

[122]  J. Ravetch,et al.  Fcgamma receptors: old friends and new family members. , 2006, Immunity.

[123]  I. Moura,et al.  Identification of FcαRI as an Inhibitory Receptor that Controls Inflammation: Dual Role of FcRγ ITAM , 2005 .

[124]  J. R. Scotti,et al.  Available From , 1973 .

[125]  D. C. Henckel,et al.  Case report. , 1995, Journal.

[126]  I. D. Wilson,et al.  The effect of heat inactivation of serum on aggregation of immunoglobulins. , 1979, Immunology.