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1.
Pathophysiology ; 29(2): 243-280, 2022 Jun 03.
Article in English | MEDLINE | ID: covidwho-1884302

ABSTRACT

In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called "the autoimmune virus." We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.

2.
Nat Commun ; 13(1): 1220, 2022 03 09.
Article in English | MEDLINE | ID: covidwho-1735246

ABSTRACT

COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Receptors, G-Protein-Coupled/immunology , Renin-Angiotensin System/immunology , Autoantibodies/blood , Autoimmunity , Biomarkers/blood , COVID-19/blood , COVID-19/classification , Cross-Sectional Studies , Female , Humans , Machine Learning , Male , Multivariate Analysis , Receptor, Angiotensin, Type 1/immunology , Receptors, CXCR3/immunology , SARS-CoV-2 , Severity of Illness Index
3.
J Allergy Clin Immunol Pract ; 9(9): 3331-3338.e2, 2021 09.
Article in English | MEDLINE | ID: covidwho-1693328

ABSTRACT

BACKGROUND: The complex relationship between clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and individual immune responses is not fully elucidated. OBJECTIVE: To examine phenotypes of symptomatology and their relationship with positive anti-SARS-CoV-2 IgG antibody responses. METHODS: An observational study was performed of adults (≥18 years) from 5 US states. Participants completed an electronic survey and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody between May and July 2020. Latent class analysis was used to identify characteristic symptom clusters. RESULTS: Overall, 9507 adults (mean age, 39.6 ± 15.0 years) completed the survey; 6665 (70.1%) underwent antibody testing for anti-SARS-CoV-2 IgG. Positive SARS-CoV-2 antibodies were associated with self-reported positive SARS-CoV-2 nasal swab result (bivariable logistic regression; odds ratio [95% CI], 5.98 [4.83-7.41]), household with 6 or more members (1.27 [1.14-1.41]) and sick contact (3.65 [3.19-4.17]), and older age (50-69 years: 1.55 [1.37-1.76]; ≥70 years: 1.52 [1.16-1.99]), but inversely associated with female sex (0.61 [0.55-0.68]). Latent class analysis revealed 8 latent classes of symptoms. Latent classes 1 (all symptoms) and 4 (fever, cough, muscle ache, anosmia, dysgeusia, and headache) were associated with the highest proportion (62.0% and 57.4%) of positive antibodies, whereas classes 6 (fever, cough, muscle ache, headache) and 8 (anosmia, dysgeusia) had intermediate proportions (48.2% and 40.5%), and classes 3 (headache, diarrhea, stomach pain) and 7 (no symptoms) had the lowest proportion (7.8% and 8.5%) of positive antibodies. CONCLUSIONS: SARS-CoV-2 infections manifest with substantial diversity of symptoms, which are associated with variable anti-SARS-CoV-2 IgG antibody responses. Prolonged fever, anosmia, and receiving supplemental oxygen therapy had strongest associations with positive SARS-CoV-2 IgG.


Subject(s)
COVID-19 , Adult , Aged , Antibodies, Viral , Cross-Sectional Studies , Female , Humans , Immunoglobulin G , Middle Aged , SARS-CoV-2
4.
EBioMedicine ; 75: 103812, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1639102

ABSTRACT

BACKGROUND: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19. METHODS: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy. FINDINGS: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury. INTERPRETATION: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2. FUNDING: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health.


Subject(s)
Blood Coagulation Disorders/metabolism , COVID-19/metabolism , Down-Regulation , Endothelium, Vascular/metabolism , Hypoxia/metabolism , Lung/metabolism , SARS-CoV-2/metabolism , Thrombomodulin/biosynthesis , Aged , Aged, 80 and over , Blood Coagulation Disorders/pathology , COVID-19/pathology , Endothelial Cells/metabolism , Endothelial Cells/ultrastructure , Endothelium, Vascular/ultrastructure , Female , Humans , Hypoxia/pathology , Lung/ultrastructure , Male , Middle Aged
5.
Invest Ophthalmol Vis Sci ; 62(7): 6, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1388618

ABSTRACT

Purpose: To investigate the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 in human retina. Methods: Human post-mortem eyes from 13 non-diabetic control cases and 11 diabetic retinopathy cases were analyzed for the expression of ACE2. To compare the vascular ACE2 expression between different organs that involve in diabetes, the expression of ACE2 was investigated in renal specimens from nondiabetic and diabetic nephropathy patients. Expression of TMPRSS2, a cell-surface protease that facilitates SARS-CoV-2 entry, was also investigated in human nondiabetic retinas. Primary human retinal endothelial cells (HRECs) and primary human retinal pericytes (HRPCs) were further used to confirm the vascular ACE2 expression in human retina. Results: We found that ACE2 was expressed in multiple nonvascular neuroretinal cells, including the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptor outer segments in both nondiabetic and diabetic retinopathy specimens. Strikingly, we observed significantly more ACE2 positive vessels in the diabetic retinopathy specimens. By contrast, in another end-stage organ affected by diabetes, the kidney, ACE2 in nondiabetic and diabetic nephropathy showed apical expression of ACE2 tubular epithelial cells, but no endothelial expression in glomerular or peritubular capillaries. Western blot analysis of protein lysates from HRECs and HRPCs confirmed expression of ACE2. TMPRSS2 expression was present in multiple retinal neuronal cells, vascular and perivascular cells, and Müller glia. Conclusions: Together, these results indicate that retina expresses ACE2 and TMPRSS2. Moreover, there are increased vascular ACE2 expression in diabetic retinopathy retinas.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Diabetic Retinopathy/enzymology , Receptors, Virus/metabolism , Retina/enzymology , SARS-CoV-2/physiology , Adult , Aged , Aged, 80 and over , Binding Sites , Blotting, Western , Cells, Cultured , Diabetic Nephropathies/enzymology , Diabetic Nephropathies/pathology , Diabetic Nephropathies/virology , Diabetic Retinopathy/pathology , Diabetic Retinopathy/virology , Endothelium, Vascular/enzymology , Endothelium, Vascular/virology , Female , Fluorescent Antibody Technique, Indirect , Humans , Immunohistochemistry , Male , Middle Aged , Pericytes/enzymology , Pericytes/virology , Retinal Vessels/enzymology , Retinal Vessels/pathology , Retinal Vessels/virology , Serine Endopeptidases/metabolism
6.
JAMA Netw Open ; 4(3): e212816, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1125118

ABSTRACT

Importance: Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in the United States are still emerging. Objective: To elucidate SARS-CoV-2 seroprevalence and symptom onset in a culturally linked community across 5 states in the United States. Design, Setting, and Participants: This cross-sectional study included adults (aged ≥18 years) recruited from the orthodox Jewish community across 5 states (California, Connecticut, Michigan, New Jersey, and New York) in 3 geographically distinct areas of the United States between May 13 and July 6, 2020. Participants completed an online survey and underwent SARS-CoV-2 antibody testing. Main Outcomes and Measures: Seroprevalence and date of symptom onset of SARS-CoV-2. Results: Overall, 9507 adults (mean [SD] age, 39.6 [15.0] years; 3777 [39.7%] women) completed the SARS-CoV-2 survey, of whom 6665 (70.1%) had immunoglobin G anti-SARS-CoV-2 antibody levels assessed. A high seroprevalence of SARS-CoV-2 antibodies was observed across all communities, with the highest proportion of positive testing observed in New Jersey (1080 of 3323 [32.5%]) and New York (671 of 2196 [30.6%]). Most individuals with a positive SARS-CoV-2 immunoglobin G antibody test reported a date of symptom-onset between March 9 and March 31, 2020 (California: 135 of 154 [87.7%]; Connecticut: 32 of 34 [94.1%]; Michigan: 44 of 50 [88.0%]; New Jersey: 964 of 1168 [82.5%]; New York: 571 of 677 [84.3%]). This start date was coincident with the Jewish festival of Purim, celebrated March 9 to 10, 2020, with extensive intracommunity spread in the weeks following (mean and mode of peak symptom onset, March 20, 2020), occurring in the absence of strong general and culture-specific public health directives. Conclusions and Relevance: This cross-sectional study of orthodox Jewish adults across the US found that socioculturally bound communities experienced early parallel outbreaks in discrete locations, notably prior to substantive medical and governmental directives. Further research should clarify optimal national, local, community-based, and government policies to prevent outbreaks in social and cultural communities that traditionally gather for holidays, assemblies, and festivals.


Subject(s)
COVID-19/epidemiology , Culturally Competent Care , Disease Transmission, Infectious , Holidays , Jews/statistics & numerical data , Minority Groups , Public Health , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/transmission , COVID-19 Serological Testing , California/epidemiology , Connecticut/epidemiology , Cross-Sectional Studies , Disease Outbreaks , Female , Humans , Judaism , Male , Michigan/epidemiology , Middle Aged , New Jersey/epidemiology , New York/epidemiology , Residence Characteristics , SARS-CoV-2 , Seroepidemiologic Studies , United States/epidemiology , Young Adult
7.
Cell Rep ; 34(11): 108863, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1108116

ABSTRACT

It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Immunity/immunology , Adult , Aged , Aged, 80 and over , Apoptosis/immunology , Caspases/immunology , Caspases/metabolism , Female , Humans , Lymphopenia/immunology , Lymphopenia/metabolism , Male , Middle Aged , Mitochondria/immunology , Mitochondria/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , SARS-CoV-2/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Voltage-Dependent Anion Channel 1/metabolism , Young Adult
8.
medRxiv ; 2020 Oct 05.
Article in English | MEDLINE | ID: covidwho-915966

ABSTRACT

It remains unclear why some patients infected with SARS-CoV-2 readily resolve infection while others develop severe disease. To address this question, we employed a novel assay to interrogate immune-metabolic programs of T cells and myeloid cells in severe and recovered COVID-19 patients. Using this approach, we identified a unique population of T cells expressing high H3K27me3 and the mitochondrial membrane protein voltage-dependent anion channel (VDAC), which were expanded in acutely ill COVID-19 patients and distinct from T cells found in patients infected with hepatitis c or influenza and in recovered COVID-19. Increased VDAC was associated with gene programs linked to mitochondrial dysfunction and apoptosis. High-resolution fluorescence and electron microscopy imaging of the cells revealed dysmorphic mitochondria and release of cytochrome c into the cytoplasm, indicative of apoptosis activation. The percentage of these cells was markedly increased in elderly patients and correlated with lymphopenia. Importantly, T cell apoptosis could be inhibited in vitro by targeting the oligomerization of VDAC or blocking caspase activity. In addition to these T cell findings, we also observed a robust population of Hexokinase II+ polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC), exclusively found in the acutely ill COVID-19 patients and not the other viral diseases. Finally, we revealed a unique population of monocytic MDSC (M-MDSC) expressing high levels of carnitine palmitoyltransferase 1a (CPT1a) and VDAC. The metabolic phenotype of these cells was not only highly specific to COVID-19 patients but the presence of these cells was able to distinguish severe from mild disease. Overall, the identification of these novel metabolic phenotypes not only provides insight into the dysfunctional immune response in acutely ill COVID-19 patients but also provide a means to predict and track disease severity as well as an opportunity to design and evaluate novel metabolic therapeutic regimens.

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