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J Clin Invest ; 2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1495792


Acute coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Disease Association (AARDA) Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10 to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

Mol Med ; 26(1): 103, 2020 11 09.
Article in English | MEDLINE | ID: covidwho-1388721


The response to viral infection generally includes an activation of the adaptive immune response to produce cytotoxic T cells and neutralizing antibodies. We propose that SARS-CoV-2 activates the innate immune system through the renin-angiotensin and kallikrein-bradykinin pathways, blocks interferon production and reduces an effective adaptive immune response. This model has therapeutic implications.

Betacoronavirus/immunology , Coronavirus Infections/immunology , Immunity, Innate , Pneumonia, Viral/immunology , Animals , Bradykinin/metabolism , COVID-19 , Humans , Kallikreins/metabolism , Models, Immunological , Pandemics , Renin-Angiotensin System , SARS-CoV-2
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Article in English | MEDLINE | ID: covidwho-1276011


Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1ß, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.

Cell Hypoxia/immunology , Hypoxia-Inducible Factor 1, alpha Subunit/immunology , Monocytes/immunology , COVID-19/immunology , Cells, Cultured , Cytokines/immunology , Humans , Interferon Regulatory Factors/metabolism , Interferon Type I/immunology , Interferon Type I/metabolism , Interleukin-1beta/metabolism , Monocytes/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism , Oxygen/metabolism , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism
J Exp Med ; 217(8)2020 08 03.
Article in English | MEDLINE | ID: covidwho-607919


The renin-angiotensin system (RAS) has long been appreciated as a major regulator of blood pressure, but has more recently been recognized as a mechanism for modulating inflammation as well. While there has been concern in COVID-19 patients over the use of drugs that target this system, the RAS has not been explored fully as a druggable target. The abbreviated description of the RAS suggests that its dysregulation may be at the center of COVID-19.

Coronavirus Infections/physiopathology , Lung Diseases/physiopathology , Lung/virology , Pneumonia, Viral/physiopathology , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Blood Coagulation Disorders/virology , COVID-19 , Coronavirus Infections/etiology , Coronavirus Infections/metabolism , Cytokines/metabolism , Humans , Hypertension/physiopathology , Lung/metabolism , Lung/physiopathology , Lung Diseases/metabolism , Lung Diseases/virology , Obesity/physiopathology , Pandemics , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/etiology , Pneumonia, Viral/metabolism , Receptor, Angiotensin, Type 1/metabolism , Severity of Illness Index