McMurray JC, May JW, Cunningham MW, Jones OY. Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis-A Critical Review of Its Pathogenesis and Treatment. Front Pediatr. 2020 Dec 16;8:626182. doi: 10.3389/fped.2020.626182. PMID: 33425823; PMCID: PMC7793714.

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Banday AZ, Arul A, Vignesh P, Singh MP, Goyal K, Singh S. Kawasaki disease and influenza-new lessons from old associations. Clin Rheumatol. 2021 Jul;40(7):2991-2999. doi: 10.1007/s10067-020-05534-1. Epub 2021 Jan 2. PMID: 33387094; PMCID: PMC7778392.



Borrelli M, Corcione A, Castellano F, Fiori Nastro F, Santamaria F. Coronavirus Disease 2019 in Children. Front Pediatr. 2021 May 28;9:668484. doi: 10.3389/fped.2021.668484. PMID: 34123972; PMCID: PMC8193095.


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Background: Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19.

Methods: We performed highly sensitive indirect immunofluorescence assays to detect antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed up to 1 year after infection, eleven vaccinated individuals, and 41 unexposed controls.

Results: Compared with healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, the paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B-cell compartment after recovery.

Conclusion: Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased antiviral humoral immune responses and inflammatory immune signatures.

Taeschler P, Cervia C, Zurbuchen Y, Hasler S, Pou C, Tan Z, Adamo S, Raeber ME, Bächli E, Rudiger A, Stüssi-Helbling M, Huber LC, Brodin P, Nilsson J, Probst-Müller E, Boyman O. Autoantibodies in COVID-19 correlate with antiviral humoral responses and distinct immune signatures. Allergy. 2022 Aug;77(8):2415-2430. doi: 10.1111/all.15302. Epub 2022 Apr 8. PMID: 35364615; PMCID: PMC9111424.

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Abstract: “Considerable research effort has been made worldwide to decipher the immune response triggered upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, identify the drivers of severe and fatal COVID-19, and understand what leads to the prolongation of symptoms after disease resolution. We review the results of almost 2 years of COVID-19 immunology research and discuss definitive findings and remaining questions regarding our understanding of COVID-19 pathophysiology. We discuss emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome, also known as post-acute sequelae of SARS-CoV-2. We hope that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses, which remain a major unmet need.”

Merad M, Blish CA, Sallusto F, Iwasaki A. The immunology and immunopathology of COVID-19. Science. 2022 Mar 11;375(6585):1122-1127. doi: 10.1126/science.abm8108. Epub 2022 Mar 10. PMID: 35271343.

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Abstract: “Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.”

Zhang Q, Matuozzo D, Le Pen J, Lee D, Moens L, Asano T, Bohlen J, Liu Z, Moncada-Velez M, Kendir-Demirkol Y, Jing H, Bizien L, Marchal A, Abolhassani H, Delafontaine S, Bucciol G; COVID Human Genetic Effort, Bayhan GI, Keles S, Kiykim A, Hancerli S, Haerynck F, Florkin B, Hatipoglu N, Ozcelik T, Morelle G, Zatz M, Ng LFP, Lye DC, Young BE, Leo YS, Dalgard CL, Lifton RP, Renia L, Meyts I, Jouanguy E, Hammarström L, Pan-Hammarström Q, Boisson B, Bastard P, Su HC, Boisson-Dupuis S, Abel L, Rice CM, Zhang SY, Cobat A, Casanova JL. Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia. J Exp Med. 2022 Aug 1;219(8):e20220131. doi: 10.1084/jem.20220131. Epub 2022 Jun 16. PMID: 35708626; PMCID: PMC9206114.

and see also:

Shih HP, Ding JY, Sotolongo Bellón J, Lo YF, Chung PH, Ting HT, Peng JJ, Wu TY, Lin CH, Lo CC, Lin YN, Yeh CF, Chen JB, Wu TS, Liu YM, Kuo CY, Wang SY, Tu KH, Ng CY, Lei WT, Tsai YH, Chen JH, Chuang YT, Huang JY, Rey FA, Chen HK, Chang TW, Piehler J, Chi CY, Ku CL. Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response. J Exp Med. 2022 Sep 5;219(9):e20212126. doi: 10.1084/jem.20212126. Epub 2022 Jul 14. PMID: 35833912; PMCID: PMC9287643.

Abstract: “Anti-interferon (IFN)-γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10-9 M) binding to IFN-γ, but only eight neutralized IFN-γ-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1-IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ-responsive cells.”

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Abstract:  “Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. IFNG gene encoding interferon (IFN)-γ, produced by natural killer cells and T cells, has been suggested to play an important role in the immunopathogenesis of Kawasaki disease. The aim of this study was to examin the correlation of gene polymorphisms of the IFNG gene and plasma levels of IFN-γ in KD patients and their outcomes.A total of 950 subjects (381 KD and 569 controls) were recruited. Three tagging single-nucleotide polymorphisms (rs2069718, rs1861493, rs2069705) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL), coronary artery aneurysms (CAA) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Plasma IFN-γ levels were also measured with an enzyme-linked immunosorbent assay.Polymorphisms of the IFNG gene were significantly different between the normal controls and KD patients. The G allele of rs1861493 conferred a better response to IVIG treatment in KD patients. AA allele frequencies of rs1861493 were also associated with a significantly higher risk of CAA in KD patients. Furthermore, the plasma IFN-γ level was lower in the AA allele than in the GG allele of rs1861493 both before and after IVIG treatment in KD patients.This study provides the first evidence supporting an association between IFNG gene polymorphisms, susceptibility of KD, IVIG responsiveness, and plasma IFN-γ levels in KD patients.”

Huang YH, Hsu YW, Lu HF, Wong HS, Yu HR, Kuo HC, Huang FC, Chang WC, Kuo HC. Interferon-gamma Genetic Polymorphism and Expression in Kawasaki Disease. Medicine (Baltimore). 2016 Apr;95(17):e3501. doi: 10.1097/MD.0000000000003501. PMID: 27124053; PMCID: PMC4998716.

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Abstract:  “Adult-onset immunodeficiency syndrome due to anti-interferon (IFN)-γ autoantibodies has attracted much attention in recent years. It usually occurs in previously healthy people and usually presents as chronic, recurrent, and hard-to-control infections that can be effectively treated with aggressive antibiotic therapy. Adult-onset immunodeficiency syndrome is also referred to as AIDS-like syndrome. Anti-type I IFN (IFN-I) autoantibodies have been reported to play a significant role in the pathogenesis of coronavirus disease 2019 (COVID-19) and preexisting anti-IFN-I autoantibodies are associated with an increased risk of severe COVID-19. This review summarizes the effects of anti-IFN autoantibodies on the susceptibility and severity of various infectious diseases, including SARS-CoV-2 infection. In addition, we discuss the role of anti-IFN autoantibodies in the pathogenesis of autoimmune diseases that are characterized by recurrent infections.”

Chen LF, Yang CD, Cheng XB. Anti-Interferon Autoantibodies in Adult-Onset Immunodeficiency Syndrome and Severe COVID-19 Infection. Front Immunol. 2021 Dec 22;12:788368. doi: 10.3389/fimmu.2021.788368. PMID: 35003106; PMCID: PMC8727472.



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Abstract:  “SARS-CoV-2 infection intrigued medicine with diverse outcomes ranging from asymptomatic to severe acute respiratory syndrome (SARS) and death. After more than two years of pandemic, reports of reinfection concern researchers and physicists. Here, we will discuss potential mechanisms that can explain reinfections, including the aggravated ones. The major topics of this hypothesis paper are the disbalance between interferon and antibodies responses, HLA heterogeneity among the affected population, and increased proportion of cytotoxic CD4+ T cells polarization in relation to T follicular cells (Tfh) subtypes. These features affect antibody levels and hamper the humoral immunity necessary to prevent or minimize the viral burden in the case of reinfections.“

Costa Silva RCM, Bandeira-Melo C, Paula Neto HA, Vale AM, Travassos LH. COVID-19 diverse outcomes: Aggravated reinfection, type I interferons and antibodies. Med Hypotheses. 2022 Oct;167:110943. doi: 10.1016/j.mehy.2022.110943. Epub 2022 Sep 9. PMID: 36105250; PMCID: PMC9461281.

See also:

Robertson SJ, Bedard O, McNally KL, Lewis M, Clancy C, Shaia C, Broeckel RM, Chiramel AI, Sturdevant GL, Forte E, Preuss C, Baker CN, Harder J, Brunton C, Munger S, Sturdevant DE, Martens C, Holland SM, Rosenthal NA, Best SM. Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation and cytokine responses in COVID-19. bioRxiv [Preprint]. 2022 Feb 24:2021.09.17.460664. doi: 10.1101/2021.09.17.460664. PMID: 35233576; PMCID: PMC8887079.

Abstract: Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19), with effective versus dysregulated responses influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the diverse genetic backgrounds of the Collaborative Cross founder strains crossed to K18-hACE2 transgenic mice that confers high susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, survival was associated with early type I interferon (IFN) expression and a phased proinflammatory response distinct from mice with severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding antiviral immunity and evaluating countermeasures.


Bastard P, Rosen LB, … Casanova JL.: Autoantibodies against type I IFNs in patients with life threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585. doi: 10.1126/science.abd4585. Epub 2020 Sep 24. PMID: 32972996; PMCID: PMC7857397.

Abstract: Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

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