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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.
Arthritis Rheumatol ; 74(6): 934-947, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1589171

ABSTRACT

OBJECTIVE: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy are at higher risk of poor COVID-19 outcomes and show substantially impaired humoral immune response to anti-SARS-CoV-2 vaccine. However, the complex relationship between antigen-specific B cells and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown. METHODS: Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 patients with rheumatoid arthritis (RA) or antineutrophil cytoplasmic antibody-associated vasculitis receiving RTX, 12 patients with RA receiving other therapies, and 30 healthy controls after SARS-CoV-2 vaccination with either messenger RNA or vector-based vaccines. RESULTS: A minimum of 10 B cells per microliter (0.4% of lymphocytes) in the peripheral circulation appeared to be required for RTX-treated patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX-treated patients who lacked IgG seroconversion showed reduced receptor-binding domain-positive B cells (P = 0.0005), a lower frequency of Tfh-like cells (P = 0.0481), as well as fewer activated CD4 (P = 0.0036) and CD8 T cells (P = 0.0308) compared to RTX-treated patients who achieved IgG seroconversion. Functionally relevant B cell depletion resulted in impaired interferon-γ secretion by spike-specific CD4 T cells (P = 0.0112, r = 0.5342). In contrast, antigen-specific CD8 T cells were reduced in both RA patients and RTX-treated patients, independently of IgG formation. CONCLUSION: In RTX-treated patients, a minimum of 10 B cells per microliter in the peripheral circulation is a candidate biomarker for a high likelihood of an appropriate cellular and humoral response after SARS-CoV-2 vaccination. Mechanistically, the data emphasize the crucial role of costimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B cell and plasma cell differentiation.


Subject(s)
Arthritis, Rheumatoid , COVID-19 , Antibodies, Viral , Arthritis, Rheumatoid/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Cell Count , Humans , Immunity, Humoral , Immunoglobulin G , Rituximab/therapeutic use , SARS-CoV-2 , Vaccination/methods
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-291487

ABSTRACT

Background: Cervical cancer screening has demonstrated high effectiveness reducing cervical cancer mortality worldwide, however there is still a high rate of under screened women. Pap smear technique is often considered an uncomfortable examination technique that can reduce uptake of the examination. This study explores the perceptions of self sampling and urine sampling versus traditional pap smear in rural settings of Cuenca Ecuador. Methods: A qualitative study with a phenomenological approach was performed. Focus groups were conducted in El Valle parish of Azuay province of Cuenca Ecuador. Women natives of this rural area were included in this research. Results: A total of 45 women, have participated in 7 focus groups, all participants live in rural area. Pap smear technique is considered a painful, intrusive and embarrassing method, however participants believe that is more reliable, compared with self sampling methods, due a direct visualization of the cervix and because other problems could be detected during the examination. Advantages of self-sampling include that it is perceived as comfortable, less painful, participation rate, time-saving, because it can be done at home, and can be made widely available for example through pharmacies or with help of traditional healers . Barriers are related with doubts of the quality of the sample and lack of capability to perform it. Conclusions: This study shows that women consider self sampling methods as a possible solution to overcome barriers that could reduce the uptake of cervical cancer screening;privacy, comfortability and accessibility are major advantages of those methods. Self examination at home reduces waiting times in health centers, with high demand of attention or during Covid pandemic. Barriers are mainly related with doubts in the self proficiency to perform the test and the accuracy of the results. Those doubts are understandable, because self sampling methods are never used before in Ecuador, and could be solved with an adequate training and information for the patients. Further studies that measure acceptability and sensitivity in real application are required to address the utility of self sampling methods in a rural context.

4.
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
5.
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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