scholarly journals Light chain skewing in autoantibodies and B-cell receptors of the citrullinated antigen-binding B-cell response in rheumatoid arthritis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247847
Author(s):  
Linda M. Slot ◽  
Rochelle D. Vergroesen ◽  
Priscilla F. Kerkman ◽  
Ellen Staudinger ◽  
Sanne Reijm ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Cell Response ◽  
World Population ◽  
Antigen Binding ◽  
Cell Repertoire ◽  
Citrullinated Antigen ◽  
B Cell Response

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1% of the world population. RA is associated with the presence of autoantibodies, of which anti-citrullinated protein antibodies (ACPA) are most prominent. ACPA are produced by citrullinated antigen-binding B cells that have presumably survived tolerance checkpoints. So far, it is unclear how and when such autoreactive B cells emerge. Light chain (LC) rearrangement and mutation rates can be informative with regard to selection steps during B-cell development. Therefore, we studied LC characteristics of ACPA-expressing B cells and secreted ACPA with the aim to better understand the development of this disease-specific, autoreactive B-cell response. Paired ACPA-IgG and ACPA-depleted IgG were isolated from serum (n = 87) and synovial fluid (SF, n = 21) of patients with established RA. We determined the LC composition for each fraction by ELISA using kappa(Igκ)- and lambda(Igλ) LC-specific antibodies. Cellular LC expression was determined using flow cytometry. In addition, we used a B-cell receptor (BCR)-specific PCR to obtain LC variable region sequences of citrullinated antigen- and tetanus toxoid (TT)-binding B cells. In serum, we observed an increased frequency of lambda LC in ACPA-IgG (1.64:1) compared to control IgG (2.03:1) and to the κ/λ ratio reported for healthy individuals (2:1). A similar trend towards higher frequencies of lambda LCs was observed for ACPA-IgG in SF (1.84:1). Additionally, the percentage of Igλ-expressing B cells was higher for citrullinated antigen-binding B cells (51%) compared to TT-specific (43%) and total CD19+CD20+ B cells (36%). Moreover, an increased Igλ percentage was observed in BCR-sequences derived from ACPA-expressing (49%) compared to TT-specific B cells (34%). Taken together, we report an enhanced frequency of lambda LCs in the secreted ACPA-IgG repertoire and, on the cellular level, in BCR sequences of ACPA-expressing B cells compared to control. This skewing in the autoreactive B-cell repertoire could reflect a process of active selection.

scholarly journals Hemolysis Inhibits Humoral B Cell Responses and Modulates Alloimmunization Risk in Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Author(s):  
Mouli Pal ◽  
Weili Bao ◽  
Rikang Wang ◽  
Yunfeng Liu ◽  
Xiuli An ◽  
...  
Keyword(s):  
B Cells ◽  
Sickle Cell Disease ◽  
B Cell ◽  
Sickle Cell ◽  
Cell Response ◽  
Cell Activity ◽  
Immunomodulatory Activity ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
B Cell Response

Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B cell plasmablast/plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas non-alloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were non-responsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B cell response to hemolysis, we found elevated B cell basal levels of DOCK8 and higher HO-1-mediated inhibition of activated B cells in non-alloimmunized compared to alloimmunized SCD patients. To overcome the alloimmunized B cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B cell activity, reversing the resistance to heme suppression in alloimmunized patients. B cell inhibition by quinine only occurred in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B cell response and that B cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. Quinine by restoring B cell heme sensitivity may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.

Molecular Analysis of Immunoglobulin Variable Genes in HIV-Related Non-Hodgkin Lymphoma: Implications for Disease Pathogenesis and Histogenesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 330-330
Author(s):  
Daniela Capello ◽  
Eva Berra ◽  
Michaela Cerri ◽  
Annunziata Gloghini ◽  
Davide Rossi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Molecular Analysis ◽  
Light Chain ◽  
Mutation Frequency ◽  
Aggressive Lymphoma ◽  
Antigen Binding ◽  
High Affinity ◽  
Aggressive Lymphomas ◽  
Selection For

Abstract Molecular analysis of immunoglobulin variable region (IGV) genes can provide insights into the histogenesis and clonal history of B-cell NHL. We investigated 67 HIV-related NHL (HIV-NHL), including 30 HIV-diffuse large B cell lymphomas (DLBCL), 21 HIV-Burkitt lymphoma (BL), 6 HIV-primary effusion lymphomas (PEL) and 10 HIV-plasmablastic lymphomas (PBL) for usage, mutation frequency and intratumoral heterogeneity of clonal IGV rearrangements as well as mutation profile and CDR3 structure of IGHV, IGKV and IGLV genes. Results were compared to 200 IGV rearrangements from aggressive lymphomas of immunocompetent hosts and to the normal B-cell repertoire. We identified a total of 65 IGHV and 56 IGV light chain rearrangements in HIV-NHL. A functional IGHV rearrangement was found in 60/67 (90%) cases, a functional IGKV chain rearrangement in 17/38 (44.7%) cases and a functional IGLV rearrangement in 21/38 cases (55.3%). Fifty-three of 60 HIV-NHL (88.3%) showed somatic hypermutation in IGHV and/or IGV light chain genes. The average mutation frequency was 9.42% (median 7.50%, range 2.04%–23.3%) for IGHV genes and 5.42% (median 4.20%, range 2.01%–12.5%) for IGV light chain genes. IGV germline rearrangements selectively associated with HIV-PBL (p<0.001). Among mutated cases, average mutation frequencies did not differ among HIV-NHL groups. HIV-NHL showed a significant overrepresentation of the IGHV4 family (28/60; 46.6%) and a significant underrepresentation of IGHV3 family (18/60, 30.0%) compared to aggressive lymphomas of immunocompetent hosts (p<0.05) and to normal B-cells (p<0.05). IGHV4–34 was the IGHV gene most frequently rearranged (17/60; 28.3%) and was overrepresented in HIV-NHL versus aggressive lymphoma of immunocompetent hosts (17%; p<0.03) and normal B-cells (4%; p<0.001). IGHV4-34 expressing cells preferentially associated with lambda chain rearrangements (70%). The IGKV4-1 gene was the IGKV segment most frequently rearranged (6/17; 35.3%) and its usage was biased in HIV-NHL compared to normal B-cells (5.30; p<0.001). The single IGLV gene most frequently encountered was IGLV1-44 (6/17; 35,3%). Distribution of replacement and silent mutations in IGHV sequences showed tendency to conserve FR sequences and maintain antigen binding in 34/52 (65.4%) cases. A higher than expected number of CDR replacement mutations, suggesting selection for high affinity antigen binding, occurred in 17/52 (32.7%) cases. Analysis of intraclonal heterogeneity showed the presence of ongoing mutations in only 1 HIV-BL and 2 HIV-DLBCL. Implications of these data are multifold. First, most HIV-NHL derive from B-cells persistently subjected to GC reaction, suggesting a potential role for antigen stimulation in the pathogenesis of these lymphomas. This hypothesis is supported by the finding of antigen binding preservation in the majority of HIV-NHL and selection for high affinity antigen binding in a fraction of cases. Second, the preferential usage of IGHV4-34 and IGKV4-1 genes in a fraction of HIV-NHL may suggest a role for stimulation of pre-neoplastic B-cells with polyreactive and/or autoreactive antigens. Finally, at variance with NHL of immucompetent hosts, the presence of intraclonal heterogeneity is a rare finding in HIV-NHL, suggesting a derivation from B-cells that have concluded the GC-reaction.

scholarly journals B-Cell Response during Protozoan Parasite Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
María C. Amezcua Vesely ◽  
Daniela A. Bermejo ◽  
Carolina L. Montes ◽  
Eva V. Acosta-Rodríguez ◽  
Adriana Gruppi
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Plasma Cells ◽  
Protozoan Parasite ◽  
Parasite Infections ◽  
Protozoan Infections ◽  
Induced Apoptosis ◽  
Cellular Immune ◽  
B Cell Response

In this review, we discuss how protozoan parasites alter immature and mature B cell compartment. B1 and marginal zone (MZ) B cells, considered innate like B cells, are activated during protozoan parasite infections, and they generate short lived plasma cells providing a prompt antibody source. In addition, protozoan infections induce massive B cell response with polyclonal activation that leads to hypergammaglobulnemia with serum antibodies specific for the parasites and self and/or non related antigens. To protect themselves, the parasites have evolved unique ways to evade B cell immune responses inducing apoptosis of MZ and conventional mature B cells. As a consequence of the parasite induced-apoptosis, the early IgM response and an already establish humoral immunity are affected during the protozoan parasite infection. Moreover, some trypanosomatides trigger bone marrow immature B cell apoptosis, influencing the generation of new mature B cells. Simultaneously with their ability to release antibodies, B cells produce cytokines/quemokines that influence the characteristic of cellular immune response and consequently the progression of parasite infections.

scholarly journals Biomaterials direct functional B cell response in a material specific manner

2021 ◽  
Author(s):  
Erika M. Moore ◽  
David R. Maestas ◽  
Chris C. Cherry ◽  
Jordan A. Garcia ◽  
Hannah Y. Comeau ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Tissue Injury ◽  
Breast Implants ◽  
Cell Immune Response ◽  
Biomaterial Scaffold ◽  
Scaffold Materials ◽  
Antigen Presenting ◽  
B Cell Response

AbstractB cells are an adaptive immune target of biomaterials development in vaccine research but despite their role in wound healing have not been studied in tissue engineering and regenerative medicine. We evaluated the B cell response to biomaterial scaffold materials implanted in a muscle wound; a biological extracellular matrix (ECM) and synthetic polyester polycaprolactone. In the local muscle tissue, small numbers of B cells are recruited in response to tissue injury and biomaterial implantation. ECM materials induced plasmablasts in lymph nodes and antigen presentation in the spleen while the synthetic PCL implants delayed B cell migration and induced an antigen presenting phenotype. In muMt− mice lacking B cells, the fibrotic response to the synthetic biomaterials decreased. Immunofluorescence confirmed antigen presenting B cells in fibrotic tissue surrounding silicone breast implants. In sum, the adaptive B cell immune response to biomaterial depends on composition and induces local, regional and systemic immunological changes.

The B cell response to citrullinated antigens in the development of rheumatoid arthritis

2018 ◽  
Vol 14 (3) ◽  
pp. 157-169 ◽  
Author(s):  
Hans Ulrich Scherer ◽  
Tom W. J. Huizinga ◽  
Gerhard Krönke ◽  
Georg Schett ◽  
Rene E. M. Toes
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Cell Response ◽  
B Cell Response

scholarly journals SARS-CoV-2 spike-specific memory B cells express higher levels of T-bet and FcRL5 after non-severe COVID-19 as compared to severe disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261656
Author(s):  
Raphael A. Reyes ◽  
Kathleen Clarke ◽  
S. Jake Gonzales ◽  
Angelene M. Cantwell ◽  
Rolando Garza ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Symptom Onset ◽  
Cell Response ◽  
Severe Disease ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Specific Memory ◽  
Specific Igg ◽  
B Cell Response

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.

scholarly journals Single-Cell Repertoire Analysis Demonstrates that Clonal Expansion Is a Prominent Feature of the B Cell Response in Multiple Sclerosis Cerebrospinal Fluid

2003 ◽  
Vol 171 (5) ◽  
pp. 2725-2733 ◽  
Author(s):  
Gregory P. Owens ◽  
Alanna M. Ritchie ◽  
Mark P. Burgoon ◽  
R. Anthony Williamson ◽  
John R. Corboy ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
B Cell ◽  
Single Cell ◽  
Cell Response ◽  
Clonal Expansion ◽  
Prominent Feature ◽  
Cell Repertoire ◽  
Repertoire Analysis ◽  
B Cell Response

Germ line tumor-associated immunoglobulin VH region peptides provoke a tumor-specific immune response without altering the response potential of normal B cells

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 752-759 ◽  
Author(s):  
Qiang Lou ◽  
Raymond J. Kelleher ◽  
Alessandro Sette ◽  
Jenni Loyall ◽  
Scott Southwood ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Cell Response ◽  
Germ Line ◽  
T Cell Response ◽  
Binding Potential ◽  
Variable Regions ◽  
B Cell Response

AbstractPrevious studies have suggested that murine T cells are tolerant to epitopes derived from germ line variable regions of immunoglobulin (Ig) heavy (VH) or light chains. This has lead to the prediction that germ line VH-region epitopes found in neoplastic B cells cannot be used to provoke an antitumor immune response. To test these assumptions and address the question of how such a vaccine may alter the normal B-cell response, an antibody-forming B-cell hybridoma (1H6) expressing a conserved germ line VH gene with specificity for dextran was generated and used as a tumor model. Using algorithms for predicting major histocompatibility complex (MHC) binding, potential MHC class I and II binding peptides were identified within the 1H6 VH region, synthesized, and tested for MHC binding and immunogenicity. We show that germ line VH peptides, when presented by dendritic cells, are immunogenic in vitro and provoke a tumor-specific protective immune response in vivo. We conclude that (1) it is possible to induce a T-cell response to germ line VH peptides; (2) such peptides can be used to generate a B-cell tumor-specific vaccine; and (3) a vaccine targeting VH peptides expressed by the dominant dextran-specific B-cell clonotype had no effect upon the magnitude of the normal B-cell response to dextran.

scholarly journals High Preexisting Serological Antibody Levels Correlate with Diversification of the Influenza Vaccine Response

2015 ◽  
Vol 89 (6) ◽  
pp. 3308-3317 ◽  
Author(s):  
Sarah F. Andrews ◽  
Kaval Kaur ◽  
Noel T. Pauli ◽  
Min Huang ◽  
Yunping Huang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Influenza Vaccine ◽  
B Cell ◽  
Cell Response ◽  
Vaccine Response ◽  
Trivalent Influenza Vaccine ◽  
Antibody Levels ◽  
Virus Strains ◽  
B Cell Response

ABSTRACTReactivation of memory B cells allows for a rapid and robust immune response upon challenge with the same antigen. Variant influenza virus strains generated through antigenic shift or drift are encountered multiple times over the lifetime of an individual. One might predict, then, that upon vaccination with the trivalent influenza vaccine across multiple years, the antibody response would become more and more dominant toward strains consistently present in the vaccine at the expense of more divergent strains. However, when we analyzed the vaccine-induced plasmablast, memory, and serological responses to the trivalent influenza vaccine between 2006 and 2013, we found that the B cell response was most robust against more divergent strains. Overall, the antibody response was highest when one or more strains contained in the vaccine varied from year to year. This suggests that in the broader immunological context of viral antigen exposure, the B cell response to variant influenza virus strains is not dictated by the composition of the memory B cell precursor pool. The outcome is instead a diversified B cell response.IMPORTANCEVaccine strategies are being designed to boost broadly reactive B cells present in the memory repertoire to provide universal protection to the influenza virus. It is important to understand how past exposure to influenza virus strains affects the response to subsequent immunizations. The viral epitopes targeted by B cells responding to the vaccine may be a direct reflection of the B cell memory specificities abundant in the preexisting immune repertoire, or other factors may influence the vaccine response. Here, we demonstrate that high preexisting serological antibody levels to a given influenza virus strain correlate with low production of antibody-secreting cells and memory B cells recognizing that strain upon revaccination. In contrast, introduction of antigenically novel strains generates a robust B cell response. Thus, both the preexisting memory B cell repertoire and serological antibody levels must be taken into consideration in predicting the quality of the B cell response to new prime-boost vaccine strategies.

Inverse Association Between IgG–Anti-κ and Antierythrocyte Autoantibodies in Patients With Cold Agglutination

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4343-4346
Author(s):  
Peter Terness ◽  
Dan Navolan ◽  
Gerhard Opelz ◽  
Dieter Roelcke
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Cell Response ◽  
Inverse Correlation ◽  
Hinge Region ◽  
Cold Agglutinin ◽  
Inverse Association ◽  
Long Time ◽  
Cell Proliferations

It has been known for a long time that IgG–anti-F(ab′)2 antibodies (Abs) are able to suppress the B-cell response. We showed that natural IgG-anti–F(ab′)2 autoantibodies appear in the serum of patients with cold agglutination. If the anti-F(ab′)2 Ab suppresses cold agglutinin (CA)-producing B cells, one would expect an inverse correlation between the titers of these two Abs. Our study confirmed this correlation. Subsequent experiments showed that some anti-F(ab′)2 Abs bind to the hinge region of IgG. It was difficult to explain how this Ab suppresses CA-producing B cells, which are of IgM isotype. Here we show that patients with cold agglutination have an IgG–anti-κ light chain autoantibody in their serum. This is another member of the anti-F(ab′)2 Ab group. Because the vast majority of CAs are IgM-κ Abs, the anti-κ Ab might suppress CA-producing B cells. If this is the case, there should be an inverse association between the titer of anti-κ Ab and CA. In a group of 302 patients, we found that high titers of the anti-κ Ab correlate with low titers of CA and vice versa (P= .009). Interestingly, this association is found only in patients whose disease is caused by noninfectious agents, including mainly B-cell proliferations (P = .0058). Our data show that the inverse correlation is not confined to a particular CA autoantibody specificity. The results are discussed in the light of recent findings showing that anti-IgM Abs may either inactivate or kill tumoral B cells by apoptosis.

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