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1.
Curr Opin Rheumatol ; 34(2): 125-132, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1691787

ABSTRACT

PURPOSE OF REVIEW: New insight into altered B cell distribution including newly identified subsets and abnormalities in systemic lupus erythematosus (SLE) as well as their role in immune protection are summarized in this review. RECENT FINDINGS: SLE carries characteristic B cell abnormalities, which offer new insights into B cell differentiation and their disturbances including discoveries of pathogenic B cell subsets and intrinsic B cell abnormalities. A recent study in SLE found that antigen-experienced B cell subsets lacking expression of CD27 and IgD defined by their lack of CXCR5 and CD19low expression are expanded in SLE and represent plasmablasts likely escaping proper selection. In terms of therapeutic targeting with broader coverage than rituximab, second-generation anti-CD20, anti-CD38 and CD19-CART treatment experiences have advanced our understanding recently. However, the key role of qualitative and quantitative B cell requirements in connection with T cells became apparent during SARS-Cov2 infection and vaccination, especially in patients with gradual B cell impairments by rituximab, mycophenolate mofetil and cyclophosphamide. SUMMARY: Identification and characterization relevant B cell subsets together with altered regulatory mechanisms in SLE facilitates new approaches in targeting pathogenic B cells but require consideration of preservation of protection.


Subject(s)
COVID-19 , Lupus Erythematosus, Systemic , B-Lymphocytes , Humans , RNA, Viral , SARS-CoV-2
2.
Arthritis Rheumatol ; 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1589171

ABSTRACT

OBJECTIVES: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy are at higher risk for poor COVID-19 outcomes and show substantially impaired humoral anti-SARS-CoV-2 vaccine responses. However, the complex relationship between antigen-specific B 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 rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) patients receiving RTX, 12 RA patients on other therapies and 30 healthy controls after SARS-CoV-2 vaccination with either mRNA or vector based vaccines. RESULTS: A minimum of 10 B cells/µL (0,4% of lymphocytes) in the peripheral circulation appeared to be required in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX patients lacking IgG seroconversion showed reduced RBD+ B cells, lower frequency of TfH-like cells as well as less activated CD4 and CD8 T cells compared to IgG seroconverted RTX patients. Functionally relevant B cell depletion resulted in impaired IFNγ secretion by spike-specific CD4 T cells. In contrast, antigen-specific CD8 T cells were reduced in patients, independently of IgG formation. CONCLUSIONS: In patients receiving RTX, a minimum of 10 B cells/µl in the peripheral circulation candidates as 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 co-stimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B and plasma cell differentiation.

3.
Eur J Immunol ; 52(1): 138-148, 2022 01.
Article in English | MEDLINE | ID: covidwho-1479399

ABSTRACT

The interferon pathway, a key antiviral defense mechanism, is being considered as a therapeutic target in COVID-19. Both, substitution of interferon and JAK/STAT inhibition to limit cytokine storms have been proposed. However, little is known about possible abnormalities in STAT signaling in immune cells during SARS-CoV-2 infection. We investigated downstream targets of interferon signaling, including STAT1, STAT2, pSTAT1 and 2, and IRF1, 7 and 9 by flow cytometry in 30 patients with COVID-19, 17 with mild, and 13 with severe infection. We report upregulation of STAT1 and IRF9 in mild and severe COVID-19 cases, which correlated with the IFN-signature assessed by Siglec-1 (CD169) expression on peripheral monocytes. Interestingly, Siglec-1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe cases compared to mild cases. Contrary to the baseline STAT1 expression, the phosphorylation of STAT1 was enhanced in severe COVID-19 cases, indicating a dysbalanced JAK/STAT signaling that fails to induce transcription of interferon stimulated response elements (ISRE). This abnormality persisted after IFN-α and IFN-γ stimulation of PBMCs from patients with severe COVID-19. Data suggest impaired STAT1 transcriptional upregulation among severely infected patients may represent a potential predictive biomarker and would allow stratification of patients for certain interferon-pathway targeted treatments.


Subject(s)
COVID-19/immunology , Monocytes/immunology , SARS-CoV-2/immunology , STAT1 Transcription Factor/immunology , Signal Transduction/immunology , Up-Regulation/immunology , Adult , Aged , Female , Humans , Interferon Regulatory Factors/immunology , Male , Middle Aged , Patient Acuity , Phosphorylation/immunology
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
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