scholarly journals Monoclonal antibodies from humans with Mycobacterium tuberculosis exposure or latent infection recognize distinct arabinomannan epitopes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Elise Ishida ◽  
Devin T. Corrigan ◽  
Ryan J. Malonis ◽  
Daniel Hofmann ◽  
Tingting Chen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Monoclonal Antibodies ◽  
B Cells ◽  
Latent Infection ◽  
Nontuberculous Mycobacteria ◽  
Antibody Responses ◽  
Human Antibody ◽  
High Affinity ◽  
Latently Infected ◽  
Asymptomatic Individuals

AbstractThe surface polysacharide arabinomannan (AM) and related glycolipid lipoarabinomannan (LAM) play critical roles in tuberculosis pathogenesis. Human antibody responses to AM/LAM are heterogenous and knowledge of reactivity to specific glycan epitopes at the monoclonal level is limited, especially in individuals who can control M. tuberculosis infection. We generated human IgG mAbs to AM/LAM from B cells of two asymptomatic individuals exposed to or latently infected with M. tuberculosis. Here, we show that two of these mAbs have high affinity to AM/LAM, are non-competing, and recognize different glycan epitopes distinct from other anti-AM/LAM mAbs reported. Both mAbs recognize virulent M. tuberculosis and nontuberculous mycobacteria with marked differences, can be used for the detection of urinary LAM, and can detect M. tuberculosis and LAM in infected lungs. These mAbs enhance our understanding of the spectrum of antibodies to AM/LAM epitopes in humans and are valuable for tuberculosis diagnostic and research applications.

scholarly journals Strong Antibody Responses to Mycobacterium tuberculosis PE-PGRS62 Protein Are Associated with Latent and Active Tuberculosis

2009 ◽  
Vol 77 (8) ◽  
pp. 3337-3343 ◽  
Author(s):  
Kah Wee Koh ◽  
Shu E Soh ◽  
Geok Teng Seah
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Infection ◽  
Clinical Status ◽  
Repetitive Sequences ◽  
Antibody Responses ◽  
Specific Immunoglobulin ◽  
Latently Infected ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
Opposite Response

ABSTRACT Mycobacterium tuberculosis has a unique family of PE-PGRS proteins with conserved N-terminal domains (PE) containing site-specific proline-glutamine residues and polymorphic GC-rich repetitive sequences (PGRS). Tuberculosis (TB) patients produce antibodies against some such proteins, but it is not clear whether these responses correlate with disease. Clinical groups with different mycobacterium exposure were studied for their seroreactivity to PE-PGRS17 and PE-PGRS62 proteins and their respective PE domains. There were minimal antibody responses against both PE domains and full-length PE-PGRS17, even in patients with active TB. However, patients with active and latent TB showed significantly higher PE-PGRS62-specific immunoglobulin G antibody responses than treated TB patients and mycobacterium-reactive TB contacts without latent infection. Latently infected persons had high anti-PE-PGRS62 responses but low responses to the 38-kDa antigen commonly used for TB serology, while treated TB cases showed the opposite response. Thus, patterns of seroreactivity to PE-PGRS62 correlate with clinical status and are associated with latent TB infection.

scholarly journals Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus.

1990 ◽  
Vol 171 (1) ◽  
pp. 19-34 ◽  
Author(s):  
Y Ueki ◽  
I S Goldfarb ◽  
N Harindranath ◽  
M Gore ◽  
H Koprowski ◽  
...  
Keyword(s):  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
Rabies Virus ◽  
Gene Segment ◽  
Human Antibody ◽  
Cell Repertoire ◽  
High Affinity ◽  
Clonal Level ◽  
Vh Gene

We quantitated and characterized the changes in the human B cell repertoire, at the clonal level, before and after immunization with rabies virus. Moreover, we generated 10 monoclonal cell lines producing IgM, IgG, and IgA antibodies to the virus. We found that in healthy subjects, not previously exposed to the virus, nearly 2% of the circulating B lymphocytes were committed to the production of antibodies that bound the virus. These B cells expressed the surface CD5 molecule. The antibodies they produced were polyreactive IgM that displayed a relatively low affinity for the virus components (Kd, 1.0-2.4 x 10(-6) g/microliters). After immunization, different anti-virus (IgG and IgA) antibody-producing cells consistently appeared in the circulation and increased from less than 0.005% to greater than 10% of the total B cells committed to the production of IgG and IgA, respectively. Most of such B cells do not express CD5 and produce monoreactive antibodies of high affinity for rabies virus (Kd, 6.5 x 10(-9) to 1.2 x 10(-10) g/microliters). One of these IgG mAbs efficiently neutralized rabies virus in vitro and in vivo, as detailed elsewhere (Dietzschold, B., P. Casali, Y. Ueki, M. Gore, C. E. Rupprecht, A. L. Notkins, and H. Koprowski, manuscript submitted for publication). Hybridization experiments using probes specific for the different human V gene segment families revealed that cell precursors producing low affinity IgM binding to rabies virus utilized a restricted number of VH gene segments (i.e., only members of the VHIIIb subfamily), whereas cell precursors producing high affinity IgG and IgA to rabies virus utilized an assortment of different VH gene segments (i.e., members of the VHI, VHIII, VHIV, and VHVI families and VHIIIb subfamily). In conclusion, our studies show that EBV transformation in conjunction with limiting dilution technology and somatic cell hybridization techniques are useful methods for quantitating, at the B cell clonal level, the human antibody response to foreign Ags and for generating human mAbs of predetermined specificity and high affinity.

scholarly journals CD4+T Cells Promote Antibody Production but Not Sustained Affinity Maturation during Borrelia burgdorferi Infection

2014 ◽  
Vol 83 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Rebecca A. Elsner ◽  
Christine J. Hastey ◽  
Nicole Baumgarth
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Content Type ◽  
High Affinity

CD4 T cells are crucial for enhancing B cell-mediated immunity, supporting the induction of high-affinity, class-switched antibody responses, long-lived plasma cells, and memory B cells. Previous studies showed that the immune response toBorrelia burgdorferiappears to lack robust T-dependent B cell responses, as neither long-lived plasma cells nor memory B cells form for months after infection, and nonswitched IgM antibodies are produced continuously during this chronic disease. These data prompted us to evaluate the induction and functionality ofB. burgdorferiinfection-induced CD4 TFHcells. We report that CD4 T cells were effectively primed and TFHcells induced afterB. burgdorferiinfection. These CD4 T cells contributed to the control ofB. burgdorferiburden and supported the induction ofB. burgdorferi-specific IgG responses. However, while affinity maturation of antibodies against a prototypic T-dependentB. burgdorferiprotein, Arthritis-related protein (Arp), were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells or a strong induction of regulatory T cells.In vitroT-B cocultures demonstrated that T cells isolated fromB. burgdorferi-infected but notB. burgdorferi-immunized mice supported the rapid differentiation of B cells into antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived instead of long-lived T-dependent antibody responsesin vivo. The data further suggest thatB. burgdorferiinfection drives the humoral response away from protective, high-affinity, and long-lived antibody responses and toward the rapid induction of strongly induced, short-lived antibodies of limited efficacy.

scholarly journals B–cell memory and the persistence of antibody responses

2000 ◽  
Vol 355 (1395) ◽  
pp. 345-350 ◽  
Author(s):  
Ian C. M. MacLennan ◽  
Carola García de Vinuesa ◽  
Montserrat Casamayor-Palleja
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibody ◽  
Viral Envelope ◽  
Antibody Responses ◽  
Variable Regions ◽  
Autoreactive B Cells ◽  
High Affinity ◽  
B Cell Memory ◽  
Selection Mechanisms

Antigens such as viral envelope proteins and bacterial exotoxins induce responses which result in the production of neutralizing antibody. These responses persist for years and provide highly efficient defence against reinfection. During these antibody responses a proportion of participating B cells mutate the genes that encode their immunoglobulin variable regions. This can increase the affinity of the antibody, but can also induce autoreactive B cells. Selection mechanisms operate which allow the cells with high affinity for the provoking antigen to persist, while other B cells recruited into the response die.

scholarly journals Paired heavy and light chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

2021 ◽  
Author(s):  
Bailey B. Banach ◽  
Gabriele Cerutti ◽  
Ahmed S. Fahad ◽  
Chen-Hsiang Shen ◽  
Matheus Oliveira de Souza ◽  
...  
Keyword(s):  
B Cells ◽  
Light Chain ◽  
Sequence Similarity ◽  
Molecular Study ◽  
Antibody Responses ◽  
Human Antibody ◽  
List Type ◽  
Receptor Binding Site ◽  
Healthy Human ◽  
Antibody Class

SummaryUnderstanding protective mechanisms of antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We discovered a new antibody, 910-30, that targets the SARS-CoV-2 ACE2 receptor binding site as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. We performed sequence and structural analyses to explore how antibody features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer revealed its binding interactions and ability to disassemble spike. Despite heavy chain sequence similarity, biophysical analyses of IGHV3-53/3-66 antibodies highlighted the importance of native heavy:light pairings for ACE2 binding competition and for SARS-CoV-2 neutralization. We defined paired heavy:light sequence signatures and determined antibody precursor prevalence to be ~1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These data reveal key structural and functional neutralization features in the IGHV3-53/3-66 public antibody class to accelerate antibody-based medical interventions against SARS-CoV-2.HighlightsA molecular study of IGHV3-53/3-66 public antibody responses reveals critical heavy and light chain features for potent neutralizationCryo-EM analyses detail the structure of a novel public antibody class member, antibody 910-30, in complex with SARS-CoV-2 spike trimerCryo-EM data reveal that 910-30 can both bind assembled trimer and can disassemble the SARS-CoV-2 spikeSequence-structure-function signatures defined for IGHV3-53/3-66 class antibodies including both heavy and light chainsIGHV3-53/3-66 class precursors have a prevalence of 1:44,000 B cells in healthy human antibody repertoires

scholarly journals Primary Immune Responses and Affinity Maturation Are Controlled by IgD

2021 ◽  
Vol 12 ◽  
Author(s):  
Timm Amendt ◽  
Omar El Ayoubi ◽  
Alexandra T. Linder ◽  
Gabriele Allies ◽  
Marc Young ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Autoimmune Diabetes ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Cell Functions ◽  
High Affinity ◽  
Deficient Mice

Mature B cells co-express IgM and IgD B cell antigen receptors (BCR) on their surface. While IgM BCR expression is already essential at early stages of development, the role of the IgD-class BCR remains unclear as most B cell functions appeared unchanged in IgD-deficient mice. Here, we show that IgD-deficient mice have an accelerated rate of B cell responsiveness as they activate antibody production within 24h after immunization, whereas wildtype (WT) animals required 3 days to activate primary antibody responses. Strikingly, soluble monovalent antigen suppresses IgG antibody production induced by multivalent antigen in WT mice. In contrast, IgD-deficient mice were not able to modulate IgG responses suggesting that IgD controls the activation rate of B cells and subsequent antibody production by sensing and distinguishing antigen-valences. Using an insulin-derived peptide we tested the role of IgD in autoimmunity. We show that primary autoreactive antibody responses are generated in WT and in IgD-deficient mice. However, insulin-specific autoantibodies were detected earlier and caused more severe symptoms of autoimmune diabetes in IgD-deficient mice as compared to WT mice. The rapid control of autoimmune diabetes in WT animals was associated with the generation of high-affinity IgM that protects insulin from autoimmune degradation. In IgD-deficient mice, however, the generation of high-affinity protective IgM is delayed resulting in prolonged autoimmune diabetes. Our data suggest that IgD is required for the transition from primary, highly autoreactive, to secondary antigen-specific antibody responses generated by affinity maturation.

scholarly journals BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1440-1449 ◽  
Author(s):  
Felix M. Wensveen ◽  
Ingrid A. M. Derks ◽  
Klaas P. J. M. van Gisbergen ◽  
Alex M. de Bruin ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Influenza Infection ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Booster Immunization ◽  
High Affinity ◽  
Activated B Cells

Abstract The efficiency of humoral immune responses depends on the selective outgrowth of B cells and plasmacells that produce high affinity antibodies. The factors responsible for affinity maturation of B cell clones in the germinal center (GC) have been well established but selection mechanisms that allow clones to enter the GC are largely unknown. Here we identify apoptosis, regulated by the proapoptotic BH3-only member Noxa (Pmaip1), as a critical factor for the selection of high-affinity clones during B cell expansion after antigen triggering. Noxa is induced in activated B cells, and its ablation provides a survival advantage both in vitro and in vivo. After immunization or influenza infection, Noxa−/− mice display enlarged GCs, in which B cells with reduced antigen affinity accumulate. As a consequence, Noxa−/− mice mount low affinity antibody responses compared with wild-type animals. Importantly, the low affinity responses correlate with increased immunoglobulin diversity, and cannot be corrected by booster immunization. Thus, normal elimination of low affinity cells favors outgrowth of the remaining high-affinity clones, and this is mandatory for the generation of proper antibody responses. Manipulation of this process may alter the breadth of antibody responses after immunization.

scholarly journals Characterization of the Secreted MPT53 Antigen ofMycobacterium tuberculosis

2001 ◽  
Vol 69 (9) ◽  
pp. 5936-5939 ◽  
Author(s):  
Sadie Johnson ◽  
PierNatale Brusasca ◽  
Konstantin Lyashchenko ◽  
John S. Spencer ◽  
Harald G. Wiker ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Mycobacterium Avium ◽  
Specific Antibody ◽  
Nontuberculous Mycobacteria ◽  
Polyclonal Antibodies ◽  
Antibody Responses ◽  
Delayed Type Hypersensitivity ◽  
Secreted Protein

ABSTRACT MPT53 is a secreted protein of Mycobacterium tuberculosis. Southern transfer and hybridization showed mpt53 to be conserved in the M. tuberculosis complex and to have homology with DNA fromMycobacterium avium and other nontuberculous mycobacteria. However, anti-MPT53 polyclonal antibodies detected no antigen in the culture filtrates of M. avium and other nontuberculous mycobacteria. MPT53 of M. tuberculosisinduced strong, tuberculosis-specific antibody responses in guinea pigs but induced no delayed-type hypersensitivity. Involvement in immune responses during human tuberculosis was very modest.

scholarly journals Mycobacterium tuberculosis progresses through two phases of latent infection in humans

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Roberto Colangeli ◽  
Aditi Gupta ◽  
Solange Alves Vinhas ◽  
Uma Deepthi Chippada Venkata ◽  
Soyeon Kim ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Generation Time ◽  
Latent Infection ◽  
Physiological State ◽  
Latency Period ◽  
Continuous Variable ◽  
Quiescent State ◽  
Latently Infected ◽  
Latent Tb Infection ◽  
Latency Duration

Abstract Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis, with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria.

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