Иммунопатология Ковид-19
Apr. 21st, 2020 09:11 pm![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
chuka_lisХорошо обобщено здесь, и, пожалуй, все же АЗУ в наличии, и может отвечать за часть "тяжелых" случаев.
SARS-CoV-2 infection can activate innate and adaptive immune responses. However, uncontrolled inflammatory innate responses and impaired adaptive immune responses may lead to harmful tissue damage, both locally and systemically. In patients with severe COVID-19, but not in patients with mild disease, lymphopenia is a common feature, with drastically reduced numbers of CD4+ T cells, CD8+ T cells, B cells and natural killer (NK) cells1,2,3,4, as well as a reduced percentage of monocytes, eosinophils and basophils3,5. An increase in neutrophil count and in the neutrophil-to-lymphocyte ratio usually indicates higher disease severity and poor clinical outcome5. In addition, exhaustion markers, such as NKG2A, on cytotoxic lymphocytes, including NK cells and CD8+ T cells, are upregulated in patients with COVID-19.
Most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines including IL-6 and IL-1β, as well as IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1α (also known as CCL3) and TNF, characterized as cytokine storm1,2,3,4. Also, C-reactive protein and D-dimer are found to be abnormally high. High levels of pro-inflammatory cytokines may lead to shock and tissue damage in the heart, liver and kidney, as well as respiratory failure or multiple organ failure. They also mediate extensive pulmonary pathology, leading to massive infiltration of neutrophils and macrophages, diffuse alveolar damage with the formation of hyaline membranes and a diffuse thickening of the alveolar wall. Spleen atrophy and lymph node necrosis were also observed, indicative of immune-mediated damage in deceased patients.
In addition to the cytokine-based pathology in patients with severe COVID-19, complement activation has also been observed, indicating that complement inhibitors, if used at an early stage of the infection, may attenuate the inflammatory damage.
The detection of SARS-CoV-2-specific IgM and IgG in patients provided the basis for disease diagnosis, in conjunction with RT-PCR-based tests. However, two studies, based on the analysis of 222 and 173 patients with COVID-19, respectively, reported that patients with severe disease frequently had an increased IgG response and a higher titre of total antibodies, which was associated with worse outcome5,9. This was suggestive of possible antibody-dependent enhancement (ADE) of SARS-CoV-2 infection.
Worryingly, it was shown that a neutralizing monoclonal antibody targeting the receptor-binding domain of the spike protein of the related Middle East respiratory syndrome (MERS) virus can enhance viral entry. A potential pathogenic effect of antibodies targeted at SARS-CoV-2 would be of major concern for vaccine development and antibody-based therapies. Additional independent large-cohort studies are needed to substantiate or dismiss this possibility.
О подходах к контролю разрушительного иммунного ответа:
A number of studies have trialled strategies to dampen inflammatory responses. Elevated levels of IL-6 were found to be a stable indicator of poor outcome in patients with severe COVID-19 with pneumonia and ARDS. One clinical trial (ChiCTR2000029765), using the IL-6 receptor-targeted monoclonal antibody (mAb) tocilizumab, reported quick control of fever and an improvement of respiratory function in 21 patients with severe COVID-19 treated in Anhui, China. All patients, including two who were critically ill, have recovered and have been discharged from hospital. The efficacy of tocilizumab in treating patients with COVID-19 who develop ARDS needs to be further assessed in larger randomized controlled trials. This encouraging clinical trial indicates that neutralizing mAbs against other pro-inflammatory cytokines may also be of use, with potential targets including IL-1, IL-17 and their respective receptors.
Convalescent plasma containing neutralizing antibodies has been used to treat a small number of patients with severe disease, and preliminary results show clinical improvement in 5 of 5 critically ill patients with COVID-19 who developed ARDS
SARS-CoV-2 infection can activate innate and adaptive immune responses. However, uncontrolled inflammatory innate responses and impaired adaptive immune responses may lead to harmful tissue damage, both locally and systemically. In patients with severe COVID-19, but not in patients with mild disease, lymphopenia is a common feature, with drastically reduced numbers of CD4+ T cells, CD8+ T cells, B cells and natural killer (NK) cells1,2,3,4, as well as a reduced percentage of monocytes, eosinophils and basophils3,5. An increase in neutrophil count and in the neutrophil-to-lymphocyte ratio usually indicates higher disease severity and poor clinical outcome5. In addition, exhaustion markers, such as NKG2A, on cytotoxic lymphocytes, including NK cells and CD8+ T cells, are upregulated in patients with COVID-19.
Most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines including IL-6 and IL-1β, as well as IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1α (also known as CCL3) and TNF, characterized as cytokine storm1,2,3,4. Also, C-reactive protein and D-dimer are found to be abnormally high. High levels of pro-inflammatory cytokines may lead to shock and tissue damage in the heart, liver and kidney, as well as respiratory failure or multiple organ failure. They also mediate extensive pulmonary pathology, leading to massive infiltration of neutrophils and macrophages, diffuse alveolar damage with the formation of hyaline membranes and a diffuse thickening of the alveolar wall. Spleen atrophy and lymph node necrosis were also observed, indicative of immune-mediated damage in deceased patients.
In addition to the cytokine-based pathology in patients with severe COVID-19, complement activation has also been observed, indicating that complement inhibitors, if used at an early stage of the infection, may attenuate the inflammatory damage.
The detection of SARS-CoV-2-specific IgM and IgG in patients provided the basis for disease diagnosis, in conjunction with RT-PCR-based tests. However, two studies, based on the analysis of 222 and 173 patients with COVID-19, respectively, reported that patients with severe disease frequently had an increased IgG response and a higher titre of total antibodies, which was associated with worse outcome5,9. This was suggestive of possible antibody-dependent enhancement (ADE) of SARS-CoV-2 infection.
Worryingly, it was shown that a neutralizing monoclonal antibody targeting the receptor-binding domain of the spike protein of the related Middle East respiratory syndrome (MERS) virus can enhance viral entry. A potential pathogenic effect of antibodies targeted at SARS-CoV-2 would be of major concern for vaccine development and antibody-based therapies. Additional independent large-cohort studies are needed to substantiate or dismiss this possibility.
О подходах к контролю разрушительного иммунного ответа:
A number of studies have trialled strategies to dampen inflammatory responses. Elevated levels of IL-6 were found to be a stable indicator of poor outcome in patients with severe COVID-19 with pneumonia and ARDS. One clinical trial (ChiCTR2000029765), using the IL-6 receptor-targeted monoclonal antibody (mAb) tocilizumab, reported quick control of fever and an improvement of respiratory function in 21 patients with severe COVID-19 treated in Anhui, China. All patients, including two who were critically ill, have recovered and have been discharged from hospital. The efficacy of tocilizumab in treating patients with COVID-19 who develop ARDS needs to be further assessed in larger randomized controlled trials. This encouraging clinical trial indicates that neutralizing mAbs against other pro-inflammatory cytokines may also be of use, with potential targets including IL-1, IL-17 and their respective receptors.
Convalescent plasma containing neutralizing antibodies has been used to treat a small number of patients with severe disease, and preliminary results show clinical improvement in 5 of 5 critically ill patients with COVID-19 who developed ARDS
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