Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARαand T- and B-cell targeting

A hallmark of B-cell immunity is the generation of a diverse repertoire of antibodies from a limited set of germline V(D)J genes. This repertoire is usually defined in terms of amino acid composition. However, variable domains may also acquire N-linked glycans, a process conditional on the introduction of consensus amino acid motifs (N-glycosylation sites) during somatic hypermutation. High levels of variable domain glycans have been associated with autoantibodies in rheumatoid arthritis, as well as certain follicular lymphomas. However, the role of these glycans in the humoral immune response remains poorly understood. Interestingly, studies have reported both positive and negative effects on antibody affinity. Our aim was to elucidate the role of variable domain glycans during antigen-specific antibody responses. By analyzing B-cell repertoires by next-generation sequencing, we demonstrate that N-glycosylation sites are introduced at positions in which glycans can affect antigen binding as a result of a specific clustering of progenitor glycosylation sites in the germline sequences of variable domain genes. By analyzing multiple human monoclonal and polyclonal (auto)antibody responses, we subsequently show that this process is subject to selection during antigen-specific antibody responses, skewed toward IgG4, and positively contributes to antigen binding. Together, these results highlight a physiological role for variable domain glycosylation as an additional layer of antibody diversification that modulates antigen binding.

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Antiviral Protection and Germinal Center Formation, But Impaired B Cell Memory in the Absence of CD19

Journal of Experimental Medicine ◽

10.1084/jem.188.1.145 ◽

1998 ◽

Vol 188 (1) ◽

pp. 145-155 ◽

Cited By ~ 49

Author(s):

Thomas Fehr ◽

Robert C. Rickert ◽

Bernhard Odermatt ◽

Jürgen Roes ◽

Klaus Rajewsky ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Antibody Responses ◽

B Cell Activation ◽

Protein Antigens ◽

Cell Memory ◽

B Cell Memory

Coligation of CD19, a molecule expressed during all stages of B cell development except plasmacytes, lowers the threshold for B cell activation with anti-IgM by a factor of 100. The cytoplasmic tail of CD19 contains nine tyrosine residues as possible phosphorylation sites and is postulated to function as the signal transducing element for complement receptor (CR)2. Generation and analysis of CD19 gene–targeted mice revealed that T cell–dependent (TD) antibody responses to proteinaceous antigens were impaired, whereas those to T cell–independent (TI) type 2 antigens were normal or even augmented. These results are compatible with earlier complement depletion studies and the postulated function of CD19. To analyze the role of CD19 in antiviral antibody responses, we immunized CD19−/− mice with viral antigens of TI-1, TI-2, and TD type. The effect of CD19 on TI responses was more dependent on antigen dose and replicative capacity than on antigen type. CR blocking experiments confirmed the role of CD19 as B cell signal transducer for complement. In contrast to immunization with protein antigens, infection of CD19−/− mice with replicating virus led to generation of specific germinal centers, which persisted for >100 d, whereas maintenance of memory antibody titers as well as circulating memory B cells was fully dependent on CD19. Thus, our study confirms a costimulatory role of CD19 on B cells under limiting antigen conditions and indicates an important role for B cell memory.

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Virus-Specific Antibody Secreting Cell, Memory B-cell, and Sero-Antibody Responses in the Human Influenza Challenge Model

The Journal of Infectious Diseases ◽

10.1093/infdis/jit650 ◽

2014 ◽

Vol 209 (9) ◽

pp. 1354-1361 ◽

Cited By ~ 34

Author(s):

Kuan-Ying Arthur Huang ◽

Chris Ka-Fai Li ◽

Elizabeth Clutterbuck ◽

Cecilia Chui ◽

Tom Wilkinson ◽

...

Keyword(s):

B Cell ◽

Specific Antibody ◽

Antibody Responses ◽

Human Influenza ◽

Secreting Cell ◽

Cell Memory ◽

Memory B Cell ◽

Antibody Secreting Cell ◽

Virus Specific Antibody

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gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.

Journal of Experimental Medicine ◽

10.1084/jem.180.1.157 ◽

1994 ◽

Vol 180 (1) ◽

pp. 157-163 ◽

Cited By ~ 277

Author(s):

T M Foy ◽

J D Laman ◽

J A Ledbetter ◽

A Aruffo ◽

E Claassen ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Germinal Centers ◽

Antibody Responses ◽

Cell Memory ◽

Specific Memory ◽

B Cell Memory ◽

Germinal Center Formation

gp39, the ligand for CD40 expressed on activated CD4+ T helper cells, is required for the generation of antibody responses to T-dependent (TD) antigens. Treatment of mice with anti-gp39 in vivo inhibits both primary and secondary antibody formation to TD, but not T-independent antigens. However, the role of this receptor-ligand pair in the development of germinal centers and the generation of B cell memory is as yet undefined. Using an antibody to gp39, this study examines the in vivo requirement for gp39-CD40 interactions in the induction of germinal center formation, as well as in the generation of B cell memory. Animals were immunized, treated in vivo with anti-gp39, and evaluated using immunohistochemical staining for the presence of splenic germinal centers 9-11 d after immunization. The results demonstrate that the formation of germinal centers was completely inhibited as a result of treatment with anti-gp39. Moreover, adoptive transfer experiments demonstrate that the generation of antigen-specific memory B cells is also inhibited as a consequence of blocking gp39-CD40 interactions. Taken together, the data demonstrate that gp39-CD40 interactions are critical not only for the generation of antibody responses, but also in the development of B cell memory.

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Role of a nonimmunoglobulin cell surface determinant in the activation of B lymphocytes by thymus-independent antigens.

Journal of Experimental Medicine ◽

10.1084/jem.149.2.495 ◽

1979 ◽

Vol 149 (2) ◽

pp. 495-506 ◽

Cited By ~ 45

Author(s):

B Subbarao ◽

D E Mosier ◽

A Ahmed ◽

J J Mond ◽

I Scher ◽

...

Keyword(s):

Cell Surface ◽

B Cell ◽

B Lymphocytes ◽

Selective Inhibition ◽

Antibody Responses ◽

Antigenic Determinants ◽

Functional Assay ◽

Induce Antibody

Lyb 5 is a B-cell alloantigen which is expressed on 50-60% of B cells. It was defined originally on the basis of cytotoxicity. We have described a new reactivity within the anti-Lyb 5 serum on the basis of selective inhibition of antibody responses in vitro by this antiserum in the absence of complement. This inhibitory activity of anti-Lyb 5.1 serum appears to be due to recognition of antigenic determinants different from the prototype antigens detected in the cytotoxicity assay. Anti-Lyb 5 serum incorporated into spleen cell cultures selectively inhibits antibody responses to a class of thymus-independent antigens (TI-2) previously characterized by their failure to elicit antibody formation in immature mice or in the defective CBA/N strain. Responses to optimal concentrations of TI-1 antigens, which can induce antibody synthesis in these mice, are unaffected by the addition of anti-Lyb 5.1 serum. The B-cell alloantigen defined by this functional assay is designated tentatively Lyb 7 and it is shown to be distinct from cell surface immunoglobulins. Lyb 7 appears to have a role in the activation of B lymphocytes by the TI-2 class of thymus-independent antigens.

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Expansion of SARS-CoV-2-specific Antibody-secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients

10.1101/2020.05.28.118729 ◽

2020 ◽

Cited By ~ 1

Author(s):

Renata Varnaitė ◽

Marina García ◽

Hedvig Glans ◽

Kimia T. Maleki ◽

John Tyler Sandberg ◽

...

Keyword(s):

B Cell ◽

Specific Antibody ◽

Neutralizing Antibodies ◽

Cell Activation ◽

Neutralizing Antibody ◽

Antibody Responses ◽

B Cell Activation ◽

Immunological Parameters ◽

Antibody Secreting Cell ◽

Antibody Levels

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19, and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers, suggesting that SARS-CoV-2-specific antibody levels may reflect the titers of neutralizing antibodies in COVID-19 patients during the acute phase of infection. Lastly, we showed that interleukin 6 (IL-6) and C-reactive protein (CRP) concentrations were higher in serum of patients who were hospitalized for longer, supporting the recent observations that IL-6 and CRP could be used to predict COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in twenty COVID-19 patients, with a focus on B cell and antibody responses, and provides tools to study immune responses to SARS-CoV-2 infection and vaccination.

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Recombinant antibodies containing an engineered B-cell epitope capable of eliciting conformation-specific antibody responses

Vaccine ◽

10.1016/0264-410x(95)00140-v ◽

1995 ◽

Vol 13 (18) ◽

pp. 1770-1778 ◽

Cited By ~ 12

Author(s):

J Cook

Keyword(s):

B Cell ◽

Specific Antibody ◽

Cell Epitope ◽

Recombinant Antibodies ◽

Antibody Responses ◽

B Cell Epitope

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ROLE OF COMPLEMENT IN INDUCTION OF ANTIBODY PRODUCTION IN VIVO

Journal of Experimental Medicine ◽

10.1084/jem.140.1.126 ◽

1974 ◽

Vol 140 (1) ◽

pp. 126-145 ◽

Cited By ~ 249

Author(s):

M. B. Pepys

Keyword(s):

B Cells ◽

Antibody Response ◽

B Cell ◽

Antibody Production ◽

Antibody Responses ◽

Cobra Venom ◽

Sheep Erythrocytes ◽

C3 Receptors

In an in vivo study in mice, suppression by the C3-cleaving protein of cobra venom (CoF), and other C3-reactive agents (zymosan, aggregated IgG, anti-C3 antibodies, and type III pneumococcal polysaccharide) of the thymus-dependent antibody responses to sheep erythrocytes, ovalbumin, and human IgG was demonstrated. The thymus-independent antibody response to polyvinyl-pyrrolidone was however unaffected by CoF. These and other published observations suggest that there may be a requirement for functional C3 in induction of thymus-dependent but not thymus-independent antibody production. A model for the role of C3 in lymphocyte cooperation is proposed based on these data analyzed in the light of existing knowledge of this process. It is postulated that fixed C3 interacting with macrophage See PDF for Structure and B-cell C3 receptors might enhance or facilitate T-dependent presentation of antigen to B cells.

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