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1.
Front Immunol ; 13: 732197, 2022.
Article in English | MEDLINE | ID: covidwho-1686479

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a severe pulmonary disease, which is one of the major complications in COVID-19 patients. Dysregulation of the immune system and imbalances in cytokine release and immune cell activation are involved in SARS-CoV-2 infection. Here, the inflammatory, antigen, and auto-immune profile of patients presenting COVID-19-associated severe ARDS has been analyzed using functional proteomics approaches. Both, innate and humoral responses have been characterized through acute-phase protein network and auto-antibody signature. Severity and sepsis by SARS-CoV-2 emerged to be correlated with auto-immune profiles of patients and define their clinical progression, which could provide novel perspectives in therapeutics development and biomarkers of COVID-19 patients. Humoral response in COVID-19 patients' profile separates with significant differences patients with or without ARDS. Furthermore, we found that this profile can be correlated with COVID-19 severity and results more common in elderly patients.


Subject(s)
Autoantigens/immunology , Autoimmunity/immunology , COVID-19/immunology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , Autoantibodies/immunology , COVID-19/complications , Humans , SARS-CoV-2/immunology
2.
Hum Immunol ; 83(2): 130-133, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1509823

ABSTRACT

The stimulation of AT1R (Angiotensin II Receptor Type 1) by Angiotensin II has, in addition to the effects on the renin-angiotensin system, also pro-inflammatory effects through stimulation of ADAM17 and subsequent production of INF-gamma and Interleukin-6. This pro-inflammatory action stimulate the cytokine storm that characterizes the most severe forms of SARS-CoV-2 infection. We studied the effect of AT1Rab on the AT1R on 74 subjects with SARS-CoV-2 infection with respiratory symptoms requiring hospitalization. We divided the patients into 2 groups: 34 with moderate and 40 with severe symptoms that required ICU admission. Hospitalized subjects showed a 50% reduction in the frequency of AT1Rab compared to healthy reference population. Of the ICU patients, 33/40 (82.5%) were AT1Rab negative and 16/33 of them (48.5%) died. All 7 patients positive for AT1Rab survived. These preliminary data seem to indicate a protective role played by AT1R autoantibodies on inflammatory activation in SARS-CoV-2 infection pathology.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Receptor, Angiotensin, Type 1/immunology , Adult , Aged , Aged, 80 and over , Autoantigens/immunology , Female , Hospitalization , Humans , Italy , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/immunology
3.
J Neuroimmunol ; 361: 577739, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1505871

ABSTRACT

We report the case of a patient with symptoms of myelopathy following acute SARS-CoV-2 infection. MRI documented a longitudinally extensive transverse myelitis and further investigation was unremarkable with the exception of positivity for MOG-IgG in serum. This report extends the spectrum of post-COVID-19 neurological syndromes, and documents a very significant improvement to long-term oral corticosteroid therapy in this setting. Further prospective studies are needed to establish the risk of recurrence in this subset of patients.


Subject(s)
Autoantibodies/immunology , COVID-19/complications , Myelin-Oligodendrocyte Glycoprotein/immunology , Myelitis, Transverse/virology , Adult , Autoantigens/immunology , COVID-19/immunology , Humans , Male , Myelitis, Transverse/immunology , Myelitis, Transverse/pathology , SARS-CoV-2
6.
Nat Commun ; 12(1): 5417, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1410404

ABSTRACT

COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Antinuclear/blood , Antibodies, Antinuclear/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoantibodies/blood , Autoantigens/immunology , Connective Tissue Diseases/immunology , Cytokines/immunology , Female , Hospitalization , Humans , Immunoglobulin G/blood , Male , Middle Aged , SARS-CoV-2/pathogenicity , Viral Proteins/immunology
7.
Int J Mol Sci ; 22(16)2021 Aug 20.
Article in English | MEDLINE | ID: covidwho-1367847

ABSTRACT

While first and foremost considered a respiratory infection, COVID-19 can result in complications affecting multiple organs. Immune responses in COVID-19 can both protect against the disease as well as drive it. Insights into these responses, and specifically the targets being recognised by the immune system, are of vital importance in understanding the side effects of COVID-19 and associated pathologies. The body's adaptive immunity recognises and responds against specific targets (antigens) expressed by foreign pathogens, but not usually to target self-antigens. However, if the immune system becomes dysfunctional, adaptive immune cells can react to self-antigens, which can result in autoimmune disease. Viral infections are well reported to be associated with, or exacerbate, autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In COVID-19 patients, both new onset MS and SLE, as well as the occurrence of other autoimmune-like pathologies, have been reported. Additionally, the presence of autoantibodies, both with and without known associations to autoimmune diseases, have been found. Herein we describe the mechanisms of virally induced autoimmunity and summarise some of the emerging reports on the autoimmune-like diseases and autoreactivity that is reported to be associated with SARS-CoV-2 infection.


Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/virology , COVID-19/immunology , Adaptive Immunity , Arthritis, Rheumatoid/immunology , Autoantibodies/immunology , Autoantigens/immunology , Autoimmunity , COVID-19/virology , Humans , Lupus Erythematosus, Systemic/immunology , SARS-CoV-2/immunology
8.
Circulation ; 144(6): 471-484, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1365256

ABSTRACT

Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age.


Subject(s)
Autoantigens/immunology , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Myocarditis/chemically induced , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Biomarkers , COVID-19/epidemiology , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Female , Humans , Male , Molecular Mimicry/immunology , Myocarditis/immunology , Sex Factors
9.
Clin Neurol Neurosurg ; 208: 106834, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1333310

ABSTRACT

Several neurological presentations have been reported following coronavirus 2019 (COVID-19) infection. This case report describes three myasthenia gravis (MG) patients presented following COVID-19 infection. We report three adult patients with myasthenic Gravis and COVID-19 infection. The patients are between 38 and 61 years old. Case 1 is a 61-year-old woman with progressive dysphagia, nasal speech, ocular ptosis, diplopia, and proximal muscle weakness for 10 days. She had a COVID-19 infection 6 weeks ago. Case 2 is a 57-year-old man with clinical symptoms of muscular fatigability, diplopia, ptosis, and dysphagia for a week and a positive COVID-19 infection 10 days ago. Case 3 is a 38-year-old woman with fatigability, ptosis, dysphagia, and a diagnosis of COVID-19 infection 4 weeks ago. All patients had a positive RT-PCR for COVID-19 infection by nasopharyngeal swab test and a high-level acetylcholine receptor antibody in the serum. All patients were treated with pyridostigmine and prednisolone with a favorable outcome. MG may appear following COVID-19 infection, and the role of molecular mimicry and latent MG activation should be considered the cause of the disease onset.


Subject(s)
COVID-19/complications , Myasthenia Gravis/virology , Adult , Anti-Inflammatory Agents/therapeutic use , Autoantibodies/blood , Autoantibodies/immunology , Autoantigens/immunology , COVID-19/immunology , Cholinesterase Inhibitors/therapeutic use , Female , Humans , Male , Middle Aged , Myasthenia Gravis/drug therapy , Myasthenia Gravis/immunology , Prednisolone/therapeutic use , Receptors, Cholinergic/immunology , SARS-CoV-2/immunology
10.
Circulation ; 144(6): 471-484, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1318235

ABSTRACT

Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age.


Subject(s)
Autoantigens/immunology , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Myocarditis/chemically induced , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Biomarkers , COVID-19/epidemiology , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Female , Humans , Male , Molecular Mimicry/immunology , Myocarditis/immunology , Sex Factors
11.
J Autoimmun ; 123: 102706, 2021 09.
Article in English | MEDLINE | ID: covidwho-1309270

ABSTRACT

Autoimmune phenomena and clinically apparent autoimmune diseases, including autoimmune hepatitis, are increasingly been reported not only after natural infection with the SARS-CoV-2 virus, but also after vaccination against it. We report the case of a 63-year old man without a history of autoimmunity or SARS-CoV-2 natural infection who experienced acute severe autoimmune-like hepatitis seven days after the first dose of the mRNA-1273 SARS-CoV-2 vaccine. Liver histology showed inflammatory portal infiltrate with interface hepatitis, lobular and centrilobular inflammation with centrilobular necrosis, in absence of fibrosis and steatosis. Serum immunoglobulin G was slightly elevated. Autoimmune liver serology showed an indirect immunofluorescence pattern on triple rodent tissue compatible with anti-mitochondrial antibody (AMA), but, unexpectedly, this pattern was not mirrored by positivity for primary biliary cholangitis (PBC)-specific molecular tests, indicating that this antibody is different from classical AMA. Anti-nuclear antibody (ANA) was also positive with a rim-like indirect immunofluorescence pattern on liver and HEp2 cell substrates, similar to PBC-specific ANA; however, anti-gp210 and a large panel of molecular-based assays for nuclear antigens were negative, suggesting a unique ANA in our patient. He carries the HLA DRB1*11:01 allele, which is protective against PBC. Response to prednisone treatment was satisfactory. The clinical significance of these novel specificities needs to be further evaluated in this emerging condition.


Subject(s)
Autoantibodies/immunology , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , HLA-DRB1 Chains/immunology , Hepatitis, Autoimmune/etiology , Mitochondria/immunology , SARS-CoV-2/immunology , Vaccination/adverse effects , Animals , Antibodies, Antinuclear/immunology , Antibody Specificity , Autoantigens/immunology , Cell Line , Fluorescent Antibody Technique, Indirect , Hepatitis, Autoimmune/drug therapy , Hepatitis, Autoimmune/immunology , Hepatitis, Autoimmune/pathology , Humans , Immunosuppressive Agents/therapeutic use , Liver/immunology , Liver/pathology , Male , Middle Aged , Prednisone/therapeutic use , Rosuvastatin Calcium/adverse effects , Rosuvastatin Calcium/therapeutic use
12.
Mol Immunol ; 137: 105-113, 2021 09.
Article in English | MEDLINE | ID: covidwho-1294069

ABSTRACT

Underlying mechanisms of multi-organ manifestations and exacerbated inflammation in COVID-19 are yet to be delineated. The hypothesis of SARS-CoV-2 triggering autoimmunity is gaining attention and, in the present study, we have identified 28 human proteins harbouring regions homologous to SARS-CoV-2 peptides that could possibly be acting as autoantigens in COVID-19 patients displaying autoimmune conditions. Interestingly, these conserved regions are amongst the experimentally validated B cell epitopes of SARS-CoV-2 proteins. The reported human proteins have demonstrated presence of autoantibodies against them in typical autoimmune conditions which may explain the frequent occurrence of autoimmune conditions following SARS-CoV-2 infection. Moreover, the proposed autoantigens' widespread tissue distribution is suggestive of their involvement in multi-organ manifestations via molecular mimicry. We opine that our report may aid in directing subsequent necessary antigen-specific studies, results of which would be of long-term relevance in management of extrapulmonary symptoms of COVID-19.


Subject(s)
Autoantigens/immunology , Autoimmune Diseases/complications , COVID-19/etiology , Epitopes, B-Lymphocyte/immunology , SARS-CoV-2/immunology , Autoantibodies/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/virology , Autoimmunity/immunology , COVID-19/immunology , COVID-19/pathology , Humans , Molecular Mimicry/immunology
13.
Front Immunol ; 12: 646894, 2021.
Article in English | MEDLINE | ID: covidwho-1285286

ABSTRACT

The origin and the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) in early 2020 was accompanied by high rates of mortality in regions belonging to the ancient silk road, such as the south of China, Iran, Turkey and the northern parts of Italy. However, children seem to be spared in the epidemic as very small percentage worldwide being ill. The protection of children and neonates suggests the involvement of a specific component of adaptive immunity present at early development. Native immunoglobulin belonging to the class of IgM is abundantly present in neonates and children and is known for its recognition of self- and altered self-antigens. Native IgM may be able to neutralize virus by the recognition of endogenous "danger signal" encoded in the viral envelope and originally imprinted in the membranes of infected and stressed cells. Noteworthy, thrombosis and vasculitis, two symptoms in severely affected adult and pediatric patients are shared between COVID-19 and patients with Behcet's disease, an autoimmune disorder exhibiting a region-specific prevalence in countries of the former silk road. Molecular mechanisms and clinical indicators suggest reactive oxygen species as trigger factor for severe progression of COVID-19 and establish a link to the innate immune defense against bacteria. The selective pressure exerted by bacterial pathogens may have shaped the genetics of inhabitants at this ancient trade route in favor of bacterial defense, to the detriment of severe COVID-19 progression in the 21th century.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Models, Immunological , SARS-CoV-2/physiology , Adult , Angiotensin-Converting Enzyme 2/metabolism , Autoantigens/immunology , COVID-19/epidemiology , Child , Disease Susceptibility , Humans , Immunoglobulin M/metabolism , Pathogen-Associated Molecular Pattern Molecules/immunology , Prevalence , Risk , Socioeconomic Factors
14.
J Autoimmun ; 122: 102682, 2021 08.
Article in English | MEDLINE | ID: covidwho-1275428

ABSTRACT

The variability in resolution of SARS-CoV-2-infections between individuals neither is comprehended, nor are the long-term immunological consequences. To assess the long-term impact of a SARS-CoV-2-infection on the immune system, we conducted a prospective study of 80 acute and former SARS-CoV-2 infected individuals and 39 unexposed donors to evaluate autoantibody responses and immune composition. Autoantibody levels against cyclic citrullinated peptide (CCP), a specific predictor for rheumatoid arthritis (RA), were significantly (p = 0.035) elevated in convalescents only, whereas both acute COVID-19 patients and long-term convalescents showed critically increased levels of anti-tissue transglutaminase (TG), a specific predictor of celiac disease (CD) (p = 0.002). Both, anti-CCP and anti-TG antibody levels were still detectable after 4-8 months post infection. Anti-TG antibodies occurred predominantly in aged patients in a context of a post-SARS-CoV-2-specific immune composition (R2 = 0.31; p = 0.044). This study shows that increased anti-CCP and anti-TG autoantibody levels can remain long-term after recovering even from mildly experienced COVID-19. The inter-relationship of the lung as viral entry side and RA- and CD-associated autoimmunity indicates that a SARS-CoV-2-infection could be a relevant environmental factor in their pathogenesis.


Subject(s)
Autoantibodies/blood , COVID-19/immunology , Peptides, Cyclic/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Citrullinated Protein Antibodies/blood , Anti-Citrullinated Protein Antibodies/immunology , Arthritis, Rheumatoid/immunology , Autoantibodies/immunology , Autoantigens/immunology , Celiac Disease/immunology , Female , Humans , Male , Middle Aged , Prevalence , Prospective Studies , SARS-CoV-2 , Transglutaminases/immunology , Young Adult
15.
J Autoimmun ; 122: 102683, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267726

ABSTRACT

The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; rPearson = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Autoantibodies/blood , Autoantigens/immunology , COVID-19/immunology , Receptor, Angiotensin, Type 1/immunology , Aged , Autoantibodies/immunology , COVID-19/blood , Female , Humans , Male , Middle Aged , Renin-Angiotensin System/immunology , SARS-CoV-2
16.
Hypertens Res ; 44(9): 1047-1053, 2021 09.
Article in English | MEDLINE | ID: covidwho-1260939

ABSTRACT

There is currently a respiratory disease outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After rapid development, RNA vaccines and adenoviral vector vaccines were approved within a year, which has demonstrated the strong impact of preventing infectious diseases using gene therapy technology. Furthermore, intensive immunological analysis has been performed to evaluate the efficiency and safety of these vaccines, potentially allowing for rapid progress in vaccine technology. After the coronavirus disease 2019 (COVID-19) era, the novel vaccine technology developed will expand to other vaccines. We have been developing vaccines for chronic diseases, such as hypertension, for >10 years. Regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. Therefore, the epitope vaccine approach has been proposed to induce antibody production in response to a combination of a B cell epitope and exogenous T cell epitopes through major histocompatibility complex molecules. When these vaccines are established as therapeutic options for hypertension, their administration regimen, which might be a few times per year, will replace daily medication use. Thus, therapeutic vaccines for hypertension may be a novel option to control the progression of cerebrovascular diseases. Hopefully, the accumulation of immunological findings and vaccine technology advances due to COVID-19 will provide a novel concept for vaccines for chronic diseases.


Subject(s)
Autoantigens/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Hypertension/therapy , SARS-CoV-2/immunology , Vaccines/therapeutic use , Chronic Disease , Humans
17.
IUBMB Life ; 73(6): 843-854, 2021 06.
Article in English | MEDLINE | ID: covidwho-1219298

ABSTRACT

The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer. Cell surface GRP78 (csGRP78) associates with the major histocompatibility complex class I (MHC-I), and is the port of entry for several viruses, including the predictive binding of the novel SARS-CoV-2. Furthermore, csGRP78 is found in association with partners as diverse as the teratocarcinoma-derived growth factor 1 (Cripto), the melanocortin-4 receptor (MC4R) and the DnaJ-like protein MTJ-1. CsGRP78 also serves as a receptor for a large variety of ligands including activated α2 -macroglobulin (α2 M*), plasminogen kringle 5 (K5), microplasminogen, the voltage-dependent anion channel (VDAC), tissue factor (TF), and the prostate apoptosis response-4 protein (Par-4). In this review, we discuss the mechanisms involved in the translocation of GRP78 from the ER to the cell surface, and the role of secreted GRP78 and its autoantibodies in cancer and neurological disorders.


Subject(s)
Autoimmune Diseases of the Nervous System/immunology , COVID-19/transmission , Heat-Shock Proteins/physiology , Neoplasm Proteins/physiology , Nerve Tissue Proteins/physiology , Receptors, Cell Surface/physiology , Receptors, Virus/physiology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Autoantibodies/immunology , Autoantigens/immunology , Autoimmune Diseases of the Nervous System/metabolism , Cell Survival , Endoplasmic Reticulum Stress/physiology , Exosomes , GPI-Linked Proteins/metabolism , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/immunology , Humans , Ligands , Neoplasm Invasiveness , Neoplasm Proteins/immunology , Nerve Tissue Proteins/immunology , Protein Domains , Protein Transport , Signal Transduction , Tumor Microenvironment , Unfolded Protein Response/physiology , Virus Internalization
18.
J Autoimmun ; 120: 102644, 2021 06.
Article in English | MEDLINE | ID: covidwho-1201116

ABSTRACT

We aim to establish a comprehensive COVID-19 autoantigen atlas in order to understand autoimmune diseases caused by SARS-CoV-2 infection. Based on the unique affinity between dermatan sulfate and autoantigens, we identified 348 proteins from human lung A549 cells, of which 198 are known targets of autoantibodies. Comparison with current COVID data identified 291 proteins that are altered at protein or transcript level in SARS-CoV-2 infection, with 191 being known autoantigens. These known and putative autoantigens are significantly associated with viral replication and trafficking processes, including gene expression, ribonucleoprotein biogenesis, mRNA metabolism, translation, vesicle and vesicle-mediated transport, and apoptosis. They are also associated with cytoskeleton, platelet degranulation, IL-12 signaling, and smooth muscle contraction. Host proteins that interact with and that are perturbed by viral proteins are a major source of autoantigens. Orf3 induces the largest number of protein alterations, Orf9 affects the mitochondrial ribosome, and they and E, M, N, and Nsp proteins affect protein localization to membrane, immune responses, and apoptosis. Phosphorylation and ubiquitination alterations by viral infection define major molecular changes in autoantigen origination. This study provides a large list of autoantigens as well as new targets for future investigation, e.g., UBA1, UCHL1, USP7, CDK11A, PRKDC, PLD3, PSAT1, RAB1A, SLC2A1, platelet activating factor acetylhydrolase, and mitochondrial ribosomal proteins. This study illustrates how viral infection can modify host cellular proteins extensively, yield diverse autoantigens, and trigger a myriad of autoimmune sequelae. Our work provides a rich resource for studies into "long COVID" and related autoimmune sequelae.


Subject(s)
Autoantigens/immunology , Autoimmunity , COVID-19/immunology , Lung/immunology , SARS-CoV-2/physiology , Signal Transduction/immunology , Virus Replication/immunology , A549 Cells , COVID-19/pathology , Humans , Lung/pathology , Lung/virology
19.
Rev Neurol ; 72(6): 203-212, 2021 03 16.
Article in English, Spanish | MEDLINE | ID: covidwho-1134737

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic is a major worldwide health disorder. There is an increasing number of neurological complications recognized with COVID-19 including patients with GBS and its variants. DEVELOPMENT: A review of the clinical cases of GBS associated to COVID-19 infection published in the last months has been developed. We included 48 patients (31 men, mean age 56.4 years). The most common COVID-19 symptoms were cough (60.4%) and fever (56.3%). Mean time from COVID-19 symptoms to neurologic manifestations was 12.1 days, but in nine patients (18.8%) developed GBS within seven days. Eleven patients (22.9%) presented cranial nerve involvement in the absence of muscle weakness; 36 presented the classic sensory motor variant (75%) and one had a pure motor variant (2.1%). The electrodiagnostic pattern was considered demyelinating in 82.4% of the generalized variants. The presence of hyposmia/dysgeusia was associated with a latency shorter than seven days to GBS onset of symptoms (30% vs 15.6%), and cranial nerve involvement in the absence of weakness (30.8% vs 17.1%). Most patients (87.5%) were treated with intravenous immunoglobulin. Neurological outcome was favorable in 64.6%; 29.2% had respiratory failure and 4.2% died shortly after being admitted. CONCLUSIONS: GBS in patients with SARS-CoV-2 infection resembles clinically and electrophysiology the classical forms. Further studies are necessary to understand whether GBS frequency is actually increased due to SARS-CoV-2 infection and explore pathogenic mechanisms.


TITLE: Síndrome de Guillain-Barré asociado a infección por COVID-19: revisión de casos publicados.Introducción. La pandemia por la enfermedad por coronavirus 2019 (COVID-19) es un importante problema para la salud mundial. Hay un incremento en las complicaciones neurológicas reconocidas por la COVID-19, incluyendo el síndrome de Guillain-Barré (SGB) y sus variantes. Desarrollo. Se realizó una revisión de los casos publicados en los últimos meses de SGB asociado a infección por COVID-19. Incluimos a 48 pacientes (31 hombres; edad media: 56,4 años). Los síntomas de COVID-19 más comunes fueron tos (60,4%) y fiebre (56,3%). El tiempo promedio entre los síntomas de COVID-19 y el SGB fue de 12,1 días, pero nueve pacientes (18,8%) desarrollaron SGB en menos de siete días. Once pacientes (22,9%) presentaron afectación de los nervios craneales en ausencia de debilidad muscular, 36 presentaron la variante clásica sensitivomotora (75%) y uno tuvo una variante motora pura (2,1%). El patrón electrofisiológico se consideró desmielinizante en el 82,4% de las variantes generalizadas. La presencia de hiposmia/disgeusia estuvo asociada con una latencia menor a los siete días hasta el inicio de los síntomas del SGB (30 frente a 15,6%) y a la afectación de los nervios craneales en ausencia de debilidad (30,8 frente a 17,1%). La mayoría de los pacientes (87,5%) fueron tratados con inmunoglobulina endovenosa. La evolución neurológica fue favorable en el 64,6%, el 29,2% tuvo insuficiencia respiratoria y hubo un 4,2% de muertes. Conclusiones. El SGB en pacientes con infección por SARS-CoV-2 es similar clínica y electrofisiológicamente a las formas clásicas. Se requieren más estudios para comprender si la frecuencia del SGB realmente aumentó debido a la pandemia por COVID-19 y explorar los mecanismos patógenos involucrados.


Subject(s)
COVID-19/complications , Guillain-Barre Syndrome/etiology , Pandemics , SARS-CoV-2 , Adolescent , Adult , Aged , Anosmia/etiology , Autoantibodies/blood , Autoantibodies/immunology , Autoantigens/immunology , Cranial Nerve Diseases/etiology , Dysgeusia/etiology , Female , Gangliosides/immunology , Guillain-Barre Syndrome/cerebrospinal fluid , Guillain-Barre Syndrome/immunology , Guillain-Barre Syndrome/therapy , Humans , Immunoglobulins, Intravenous/therapeutic use , Male , Middle Aged , Plasmapheresis , Respiratory Insufficiency/etiology , Retrospective Studies , Symptom Assessment , Treatment Outcome , Young Adult
20.
J Neuroimmunol ; 353: 577521, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1091758

ABSTRACT

BACKGROUND: Serious neurological complications of SARS-CoV-2 are increasingly being recognized. CASE: We report a novel case of HHV6 myelitis with parainfectious MOG-IgG in the setting of COVID-19-induced lymphopenia and hypogammaglobulinemia. The patient experienced complete neurological recovery with gancyclovir, high dose corticosteroids, and plasma exchange. To our knowledge, this is the first case of HHV6 reactivation in the central nervous system in the setting of COVID19 infection and the first case of MOG-IgG myelitis in the setting of SARS-CoV-2 and HHV6 coinfection. CONCLUSION: Patients with neurological manifestations in the setting of COVID19-related immunodeficiency should be tested for opportunistic infections including HHV6. Viral infection is a known trigger for MOG-IgG and therefore this antibody should be checked in patients with SARS-CoV-2 associated demyelination.


Subject(s)
COVID-19/complications , Coinfection/complications , Lymphopenia/virology , Myelitis, Transverse/virology , Roseolovirus Infections/immunology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Autoantibodies/immunology , Autoantigens/immunology , COVID-19/immunology , Coinfection/immunology , Ganciclovir/therapeutic use , Herpesvirus 6, Human , Humans , Male , Methylprednisolone/therapeutic use , Middle Aged , Myelitis, Transverse/immunology , Myelitis, Transverse/therapy , Plasma Exchange/methods , Roseolovirus Infections/drug therapy , SARS-CoV-2 , Virus Activation/immunology
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