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Article ; Online: Efficient Identification of High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Plasma Samples by Pooling Method.

Nguyen, Khoa D / Wirz, Oliver F / Röltgen, Katharina / Pandey, Suchitra / Tolentino, Lorna / Boyd, Scott D / Pham, Tho D

Archives of pathology & laboratory medicine

2021 Volume 145, Issue 10, Page(s) 1221–1227

Abstract: Context.—: The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited a surge in demand for serologic testing to identify previously infected individuals. In particular, antibody testing is ... ...

Abstract	Context.—: The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited a surge in demand for serologic testing to identify previously infected individuals. In particular, antibody testing is crucial in identifying COVID-19 convalescent plasma, which has been approved by the Food and Drug Administration under the Emergency Use Authorization for use as passive immunotherapy for hospitalized patients infected with COVID-19. Currently, high-titer COVID-19 convalescent plasma can be qualified by Ortho's Vitros COVID-19 IgG antibody test. Objective.—: To explore the use of an efficient testing method to identify high-titer COVID-19 convalescent plasma for use in treating COVID-19-infected patients and track COVID-19 positivity over time. Design.—: We evaluated an enzyme-linked immunosorbent assay (ELISA)-based method that detects antibodies specific to the SARS-CoV-2 receptor binding domain (RBD) with individual and pooled plasma samples and compared its performance against the Vitros COVID-19 IgG antibody test. Using the pooled RBD-ELISA (P-RE) method, we also screened more than 10 000 longitudinal healthy blood donor samples to assess seroprevalence. Results.—: P-RE demonstrates 100% sensitivity in detecting Food and Drug Administration-defined high-titer samples when compared with the Vitros COVID-19 IgG antibody test. Overall sensitivity of P-RE when compared with the Vitros COVID-19 IgG antibody test and our individual sample RBD-ELISA (I-RE) were 83% and 56%, respectively. When screening 10 218 healthy blood donor samples by P-RE, we found the seroprevalence correlated with the local infection rates with a correlation coefficient of 0.21 (P < .001). Conclusions.—: Pooling plasma samples can be used to efficiently screen large populations for individuals with high-titer anti-RBD antibodies, important for COVID-19 convalescent plasma identification.
MeSH term(s)	Antibodies, Viral/blood ; Antibodies, Viral/immunology ; Blood Donors/statistics & numerical data ; COVID-19/diagnosis ; COVID-19/epidemiology ; COVID-19/virology ; COVID-19 Serological Testing/methods ; Enzyme-Linked Immunosorbent Assay/methods ; Humans ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Pandemics/prevention & control ; Reproducibility of Results ; SARS-CoV-2/immunology ; SARS-CoV-2/physiology ; Sensitivity and Specificity ; Seroepidemiologic Studies
Chemical Substances	Antibodies, Viral ; Immunoglobulin G
Language	English
Publishing date	2021-06-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2021-0215-SA
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Article ; Online: Impaired innate and adaptive immune responses to BNT162b2 SARS-CoV-2 vaccination in systemic lupus erythematosus.

JCI insight

2024 Volume 9, Issue 5

Abstract: Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive ... ...

Abstract	Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.
MeSH term(s)	Humans ; BNT162 Vaccine ; COVID-19 Vaccines ; SARS-CoV-2 ; COVID-19/prevention & control ; Lupus Erythematosus, Systemic ; Vaccination
Chemical Substances	BNT162 Vaccine ; COVID-19 Vaccines
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.176556
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Article ; Online: Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy.

van de Veen, Willem / Wirz, Oliver F / Globinska, Anna / Akdis, Mübeccel

Current opinion in immunology

2017 Volume 48, Page(s) 74–81

Abstract: Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a clinical tolerance-inducing and immune tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through ... ...

Abstract	Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a clinical tolerance-inducing and immune tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms including early desensitization of basophils and mast cells, regulating T-cell and B-cell responses, changing antibody isotypes, and decreasing activation, mediator release and affected tissue migration of eosinophils, basophils, and mast cells. Similar molecular and cellular mechanisms have been observed in subcutaneous AIT, sublingual AIT and peptide immunotherapy as well as natural tolerance to high doses of allergen exposure in beekeepers and cat owners.
Language	English
Publishing date	2017-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2017.08.012
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Article: Two Distinct Pathways in Mice Generate Antinuclear Antigen-Reactive B Cell Repertoires.

Faderl, Martin / Klein, Fabian / Wirz, Oliver F / Heiler, Stefan / Albertí-Servera, Llucia / Engdahl, Corinne / Andersson, Jan / Rolink, Antonius

Frontiers in immunology

2018 Volume 9, Page(s) 16

Abstract: The escape of anti-self B cells from tolerance mechanisms like clonal deletion, receptor editing, and anergy results in the production of autoantibodies, which is a hallmark of many autoimmune disorders. In this study, we demonstrate that both germline ... ...

Abstract	The escape of anti-self B cells from tolerance mechanisms like clonal deletion, receptor editing, and anergy results in the production of autoantibodies, which is a hallmark of many autoimmune disorders. In this study, we demonstrate that both germline sequences and somatic mutations contribute to autospecificity of B cell clones. For this issue, we investigated the development of antinuclear autoantibodies (ANAs) and their repertoire in two different mouse models. First, in aging mice that were shown to gain several autoimmune features over time including ANAs. Second, in mice undergoing a chronic graft-versus-host disease (GVHD), thereby developing systemic lupus erythematosus-like symptoms. Detailed repertoire analysis revealed that somatic hypermutations (SHM) were present in all Vh and practically all Vl regions of ANAs generated in these two models. The ANA B cell repertoire in aging mice was restricted, dominated by clonally related Vh1-26/Vk4-74 antibodies. In the collection of GVHD-derived ANAs, the repertoire was less restricted, but the usage of the Vh1-26/Vk4-74 combination was still apparent. Germline conversion showed that the SHM in the 4-74 light chain are deterministic for autoreactivity. Detailed analysis revealed that antinuclear reactivity of these antibodies could be induced by a single amino acid substitution in the CDR1 of the Vk4-74. In both aging B6 and young GVHD mice, conversion of the somatic mutations in the Vh and Vl regions of non Vh1-26/Vk4-74 using antibodies showed that B cells with a germline-encoded V gene could also contribute to the ANA-reactive B cell repertoire. These findings indicate that two distinct pathways generate ANA-producing B cells in both model systems. In one pathway, they are generated by Vh1-26/Vk4-74 expressing B cells in the course of immune responses to an antigen that is neither a nuclear antigen nor any other self-antigen. In the other pathway, ANA-producing B cells are derived from progenitors in the bone marrow that express B cell receptors (BCRs), which bind to nuclear antigens and that escape tolerance induction, possibly as a result of crosslinking of their BCRs by multivalent determinants of nuclear antigens.
MeSH term(s)	Aging/immunology ; Amino Acid Substitution ; Animals ; Antibodies, Antinuclear/immunology ; Antibodies, Monoclonal/immunology ; Antigens, Nuclear/immunology ; Autoimmunity/genetics ; Autoimmunity/immunology ; B-Lymphocytes/immunology ; Graft vs Host Disease/immunology ; Histones/immunology ; Immune Tolerance/genetics ; Immune Tolerance/immunology ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Heavy Chains/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/genetics ; Receptors, Antigen, B-Cell/immunology
Chemical Substances	Antibodies, Antinuclear ; Antibodies, Monoclonal ; Antigens, Nuclear ; Histones ; Immunoglobulin Heavy Chains ; Receptors, Antigen, B-Cell
Language	English
Publishing date	2018-01-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.00016
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Article ; Online: SARS-CoV-2 RNAemia in a Healthy Blood Donor 40 Days After Respiratory Illness Resolution.

Pham, Tho D / Huang, ChunHong / Wirz, Oliver F / Röltgen, Katharina / Sahoo, Malaya K / Layon, Arlene / Pandey, Suchitra / Foung, Steven K / Boyd, Scott D / Pinsky, Benjamin A

Annals of internal medicine

2020 Volume 173, Issue 10, Page(s) 853–854

MeSH term(s)	Betacoronavirus/genetics ; Betacoronavirus/isolation & purification ; Blood Donors ; COVID-19 ; Coronavirus Infections/blood ; Coronavirus Infections/virology ; Humans ; Immunoglobulin G/blood ; Pandemics ; Pneumonia, Viral/blood ; Pneumonia, Viral/virology ; RNA, Viral/blood ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; SARS-CoV-2 ; Viremia/blood ; Viremia/virology
Chemical Substances	Immunoglobulin G ; RNA, Viral
Keywords	covid19
Language	English
Publishing date	2020-07-17
Publishing country	United States
Document type	Case Reports ; Letter
ZDB-ID	336-0
ISSN	1539-3704 ; 0003-4819
ISSN (online)	1539-3704
ISSN	0003-4819
DOI	10.7326/L20-0725
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Article ; Online: Increased antiviral response in circulating lymphocytes from hypogammaglobulinemia patients.

Wirz, Oliver F / Üzülmez, Öykü / Jansen, Kirstin / van de Veen, Willem / Lammela, Auli / Kainulainen, Leena / Vuorinen, Tytti / Breiteneder, Heimo / Akdis, Cezmi A / Jartti, Tuomas / Akdis, Mübeccel

Allergy

2020 Volume 75, Issue 12, Page(s) 3147–3158

Abstract: Background: B cells play a crucial role during rhinovirus (RV) infections by production of virus-neutralizing antibodies. A main feature of common variable immunodeficiency (CVID) is hypogammaglobulinemia (HG). HG patients have severely reduced levels ... ...

Abstract	Background: B cells play a crucial role during rhinovirus (RV) infections by production of virus-neutralizing antibodies. A main feature of common variable immunodeficiency (CVID) is hypogammaglobulinemia (HG). HG patients have severely reduced levels of antibody-producing B cells and suffer from prolonged virus infections. Here, we addressed whether antiviral response of peripheral blood lymphocytes differs between HG patients and healthy individuals during natural RV infection. Methods: Using fluorescence-activated cell sorting, B-cell subsets were analyzed. Simultaneously, CD19 + B cells, CD14 + monocytes, and CD3 + T cells were sorted from frozen peripheral blood mononuclear cells from 11 RV-infected hypogammaglobulinemia patients, 7 RV-infected control subjects, and 14 noninfected control subjects. Real-time PCR was used to study expression of antiviral genes. A pan-RV PCR was used to detect RV genome in all samples. Results: In HG patients, total B-cell numbers, as well as IgA + and IgG + switched memory B cells, were reduced while naïve B cells and T cells were increased. STAT1 expression was increased in HG patients compared to controls in all lymphocyte subsets analyzed. The expression of antiviral genes IFITM1 and MX1 correlated with STAT1 expression in B cells and monocytes. RV RNA was found in 88.9% of monocytes from infected HG patients, 85.7% of monocytes from infected controls, and 7.1% of monocytes from uninfected controls. Conclusions: We demonstrate an increased antiviral response in B cells and monocytes in HG patients and their correlation with STAT1 expression. Monocytes of infected HG patients and infected non-HG controls carry RV RNA.
MeSH term(s)	Agammaglobulinemia ; Antiviral Agents ; B-Lymphocytes ; Common Variable Immunodeficiency ; Humans ; Leukocytes, Mononuclear
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2020-07-16
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.14445
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Article ; Online: Experimental rhinovirus infection induces an antiviral response in circulating B cells which is dysregulated in patients with asthma.

Wirz, Oliver F / Jansen, Kirstin / Satitsuksanoa, Pattraporn / van de Veen, Willem / Tan, Ge / Sokolowska, Milena / Mirer, David / Stanić, Barbara / Message, Simon D / Kebadze, Tatiana / Glanville, Nicholas / Mallia, Patrick / Gern, James E / Papadopoulos, Nikolaos / Akdis, Cezmi A / Johnston, Sebastian L / Nadeau, Kari / Akdis, Mübeccel

Allergy

2021 Volume 77, Issue 1, Page(s) 130–142

Abstract: Background: Rhinoviruses are the predominant cause of respiratory viral infections and are strongly associated with asthma exacerbations. While humoral immunity plays an important role during virus infections, cellular aspects of this response are less ... ...

Abstract	Background: Rhinoviruses are the predominant cause of respiratory viral infections and are strongly associated with asthma exacerbations. While humoral immunity plays an important role during virus infections, cellular aspects of this response are less well understood. Here, we investigated the antiviral response of circulating B cells upon experimental rhinovirus infection in healthy individuals and asthma patients. Methods: We purified B cells from experimentally infected healthy individuals and patients with asthma and subjected them to total RNA-sequencing. Rhinovirus-derived RNA was measured in isolated B cells using a highly sensitive PCR. B cells were stimulated with rhinovirus in vitro to further study gene expression, expression of antiviral proteins and B-cell differentiation in response rhinovirus stimulation. Protein expression of pro-inflammatory cytokines in response to rhinovirus was assessed using a proximity extension assay. Results: B cells isolated from experimentally infected subjects exhibited an antiviral gene profile linked to IFN-alpha, carried viral RNA in vivo and were transiently infected by rhinovirus in vitro. B cells rapidly differentiated into plasmablasts upon rhinovirus stimulation. While B cells lacked expression of interferons in response to rhinovirus exposure, co-stimulation with rhinovirus and IFN-alpha upregulated pro-inflammatory cytokine expression suggesting a potential new function of B cells during virus infections. Asthma patients showed extensive upregulation and dysregulation of antiviral gene expression. Conclusion: These findings add to the understanding of systemic effects of rhinovirus infections on B-cell responses in the periphery, show potential dysregulation in patients with asthma and might also have implications during infection with other respiratory viruses.
MeSH term(s)	Antiviral Agents/therapeutic use ; Asthma ; Cytokines/pharmacology ; Humans ; Interferons ; Picornaviridae Infections ; Rhinovirus
Chemical Substances	Antiviral Agents ; Cytokines ; Interferons (9008-11-1)
Language	English
Publishing date	2021-07-16
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.14985
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Article ; Online: T regulatory cells from atopic asthmatic individuals show a Th2-like phenotype.

Jansen, Kirstin / Satitsuksanoa, Pattraporn / Wirz, Oliver F / Schneider, Stephan R / van de Veen, Willem / Tan, Ge / Sokolowska, Milena / Message, Simon D / Kebadze, Tatiana / Glanville, Nicholas / Mallia, Patrick / Akdis, Cezmi A / Moniuszko, Marcin / Johnston, Sebastian L / Nadeau, Kari / Akdis, Mübeccel

Allergy

2021 Volume 77, Issue 4, Page(s) 1320–1324

MeSH term(s)	Asthma ; Humans ; Hypersensitivity, Immediate ; Phenotype ; Th2 Cells
Language	English
Publishing date	2021-12-11
Publishing country	Denmark
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.15193
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Article ; Online: The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T-cell compartment.

Nusser, Anja / Nuber, Natko / Wirz, Oliver F / Rolink, Hannie / Andersson, Jan / Rolink, Antonius

European journal of immunology

2014 Volume 44, Issue 10, Page(s) 2893–2902

Abstract: Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. ...

Abstract	Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4(+) T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4(+) T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features.
MeSH term(s)	Aging/immunology ; Animals ; Antibodies, Antinuclear/blood ; Antibodies, Antinuclear/immunology ; Autoimmunity/immunology ; CD4-Positive T-Lymphocytes/immunology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Fluorescent Antibody Technique, Indirect ; Homeostasis/immunology ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL
Chemical Substances	Antibodies, Antinuclear
Language	English
Publishing date	2014-10
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201344408
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Article ; Online: Role of regulatory B cells in immune tolerance to allergens and beyond.

van de Veen, Willem / Stanic, Barbara / Wirz, Oliver F / Jansen, Kirstin / Globinska, Anna / Akdis, Mübeccel

The Journal of allergy and clinical immunology

2016 Volume 138, Issue 3, Page(s) 654–665

Abstract: Immune tolerance to both self-antigens and innocuous non-self-antigens is essential to protect the host against chronic inflammatory diseases and tissue damage. A wide range of cell types and suppressive molecules are involved in induction and ... ...

Abstract	Immune tolerance to both self-antigens and innocuous non-self-antigens is essential to protect the host against chronic inflammatory diseases and tissue damage. A wide range of cell types and suppressive molecules are involved in induction and maintenance of tolerance. In addition to their key function in the production of immunoglobulins, B cells can regulate immune responses through their surface molecules and secretion of cytokines. Regulatory B (Breg) cells are characterized by their immunosuppressive capacity, which is often mediated through IL-10 secretion. However, IL-35 and TGF-β have also been associated with B cell-mediated immunosuppression. Several types of murine and human Breg cells have been described, such as mouse CD5(+)CD1d(hi) B10 cells, CD21(hi)CD23(hi)CD24(hi) transitional stage 2-like B cells, and CD138(+) plasma cells and plasmablasts. Human Breg cell types include CD27(+)CD24(high) B10 cells, CD24(hi)CD38(hi) immature transitional B cells, and CD73(-)CD25(+)CD71(+) BR1 cells and a subset of plasma cells. Support for the in vivo existence of allergen-specific human Breg cells comes from direct detection of their increase during the course of allergen-specific immunotherapy, as well as their increased expression in nonallergic but high-dose allergen-exposed beekeepers. Human BR1 cells selectively upregulate IgG4 antibodies on differentiation to plasma cells. This suggests an additional immune regulatory role because of the noninflammatory and blocking antibody function of IgG4. Taken together, Breg cells appear to be involved in mediating allergen tolerance, but many open questions remain to be answered.
MeSH term(s)	Allergens/immunology ; Animals ; B-Lymphocytes, Regulatory/immunology ; Humans ; Immune Tolerance ; Infection/immunology ; Inflammation/immunology
Chemical Substances	Allergens
Language	English
Publishing date	2016-09-06
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2016.07.006
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