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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331621

ABSTRACT

Post-acute lung sequelae of COVID-19 are challenging many survivors across the world, yet the mechanisms behind are poorly understood. Our results delineate an inflammatory cascade of events occurring along disease progression within fibrovascular niches. It is initiated by endothelial dysfunction, followed by heme scavenging of CD163+ macrophages and production of CCL18. This chemokine synergizes with local CCL21 upregulation to influence the stromal composition favoring endothelial to mesenchymal transition. The local immune response is further modulated via recruitment of CCR7+ T cells into the expanding fibrovascular niche and imprinting an exhausted, T follicular helper like phenotype in these cells. Eventually, this culminates in the formation of tertiary lymphoid structures, further perpetuating chronic inflammation. Thus, our work presents misdirected immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and leads to profound tissue repurposing and chronic inflammation.

2.
Sci Immunol ; 6(60)2021 06 15.
Article in English | MEDLINE | ID: covidwho-1369380

ABSTRACT

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host , Kidney Transplantation , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , COVID-19/immunology , Female , Humans , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Male , Middle Aged , Renal Dialysis , SARS-CoV-2 , Transplant Recipients
3.
Nat Commun ; 12(1): 1961, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1169399

ABSTRACT

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-ß, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-ß. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-ß, and is distracted from itself.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Adult , Aged , Aged, 80 and over , COVID-19/virology , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Interleukins/immunology , Male , Middle Aged , Plasma Cells/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
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