scholarly journals Altered Affinity Maturation in Primary Response to (4-hydroxy-3-nitrophenyl) Acetyl (NP) after Autologous Reconstitution of Irradiated C57BL/6 Mice

2002 ◽  
Vol 9 (3) ◽  
pp. 119-125
Author(s):  
Carl De Trez ◽  
Annette Van Acker ◽  
Georgette Vansanten ◽  
Jacques Urbain ◽  
Maryse Brait
Keyword(s):  
Immune Responses ◽  
Single Gene ◽  
Gene Segment ◽  
Keyhole Limpet Hemocyanin ◽  
Primary Response ◽  
Affinity Maturation ◽  
Germinal Center Reaction ◽  
High Affinity ◽  
Primary Antibody Response ◽  
Vh Genes

Immune responses developing in irradiated environment are profoundly altered. The memory anti-arsonate response of A/J mice is dominated by a major clonotype encoded by a single gene segment combination called CRIA. In irradiated and autoreconstituted A/J mice, the level of anti-ARS antibodies upon secondary immunization is normal but devoid of CRIA antibodies. The affinity maturation process and the somatic mutation frequency are reduced. Isotype switching and development of germinal centers (GC) are delayed.The primary antibody response of C57BL/6 mice to the hapten (4-hydroxy-3-nitrophenyl) acetyl (NP)-Keyhole Limpet Hemocyanin (KLH) is dominated by antibodies encoded by a family of closely related VH genes associated with the expression of the λ1 light chain.We investigated the anti-NP primary response in irradiated and autoreconstituted C57BL/6 mice. We observed some splenic alterations as previously described in the irradiated A/J model. Germinal center reaction is delayed although the extrafollicular foci appearance is unchanged. Irradiated C57BL/6 mice are able to mount a primary anti-NP response dominated by λ1 positive antibodies but fail to produce high affinity NP-binding IgGl antibodies. Following a second antigenic challenge, irradiated mice develop enlarged GC and foci. Furthermore, higher affinity NP-binding IgG1 antibodies are detected.

scholarly journals In Situ Studies of the Primary Immune Response to (4-Hydroxy-3-Nitrophenyl)Acetyl. V. Affinity Maturation Develops in Two Stages of Clonal Selection

1998 ◽  
Vol 187 (6) ◽  
pp. 885-895 ◽  
Author(s):  
Yoshimasa Takahashi ◽  
Pinaki R. Dutta ◽  
Douglas M. Cerasoli ◽  
Garnett Kelsoe
Keyword(s):  
Immune Response ◽  
Clonal Selection ◽  
Cd40 Ligand ◽  
Primary Response ◽  
Affinity Maturation ◽  
Primary Immune Response ◽  
Cellular Interactions ◽  
Serum Antibodies ◽  
High Affinity ◽  
Selection Of

To examine the role of germinal centers (GCs) in the generation and selection of high affinity antibody-forming cells (AFCs), we have analyzed the average affinity of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific AFCs and serum antibodies both during and after the GC phase of the immune response. In addition, the genetics of NP-binding AFCs were followed to monitor the generation and selection of high affinity AFCs at the clonal level. NP-binding AFCs gradually accumulate in bone marrow (BM) after immunization and BM becomes the predominant locale of specific AFCs in the late primary response. Although the average affinity of NP-specific BM AFCs rapidly increased while GCs were present (GC phase), the affinity of both BM AFCs and serum antibodies continued to increase even after GCs waned (post-GC phase). Affinity maturation in the post-GC phase was also reflected in a shift in the distribution of somatic mutations as well as in the CDR3 sequences of BM AFC antibody heavy chain genes. Disruption of GCs by injection of antibody specific for CD154 (CD40 ligand) decreased the average affinity of subsequent BM AFCs, suggesting that GCs generate the precursors of high affinity BM AFCs; inhibition of CD154-dependent cellular interactions after the GC reaction was complete had no effect on high affinity BM AFCs. Interestingly, limited affinity maturation in the BM AFC compartment still occurs during the late primary response even after treatment with anti-CD154 antibody. Thus, GCs are necessary for the generation of high affinity AFC precursors but are not the only sites for the affinity-driven clonal selection responsible for the maturation of humoral immune responses.

scholarly journals OLIGOMERIC IGA: THE MAJOR COMPONENT OF THE IN VITRO PRIMARY RESPONSE OF MOUSE SPLEEN FRAGMENTS

1973 ◽  
Vol 138 (4) ◽  
pp. 973-988 ◽  
Author(s):  
Ichiro Nakamura ◽  
Alex Ray ◽  
O. Mäkelä
Keyword(s):  
Sucrose Gradient ◽  
Culture Media ◽  
Keyhole Limpet Hemocyanin ◽  
Aminocaproic Acid ◽  
Primary Response ◽  
Mouse Spleen ◽  
Primary Antibody Response ◽  
Hydroxyphenylacetic Acid ◽  
The Media

The primary antibody response elicited from mouse spleen explants by conjugates of the 3-nitro-5-iodo-4-hydroxyphenylacetic acid (NIP) hapten consisted mostly of the IgA class. Poly-L-lysine, pneumococcal polysaccharide Type SIII, keyhole limpet hemocyanin, and sheep erythrocytes were effective carriers in this system, whereas chicken globulin was not. The anti-NIP response against all of the immunogenic conjugates was detectable in culture media 4 days after explantation and immunization, and reached peak titers by 8–10 days. IgA was identified by sucrose gradient velocity centrifugation in conjunction with the use of a class-specific antiserum. The media collected at 4 days contained low titers of IgM antibody, whereas the peak response at 8 days consisted almost entirely of IgA. The primary response IgA secreted by the spleen fragments was characterized as polymeric by its sedimentation rate through a sucrose gradient, and as polyvalent by its drastically greater avidity for NIP14BSA than for free NIP-aminocaproic acid. Its haptenated phage-inactivating activity was abolished by treatment with 0.1 M 2-mercaptoethanol. These experiments indicate that precursor cells existing in the spleen before primary immunization can give rise to production of polymeric IgA.

scholarly journals Essential role of immobilized chemokine CXCL12 in the regulation of the humoral immune response

2017 ◽  
Vol 114 (9) ◽  
pp. 2319-2324 ◽  
Author(s):  
Aleksandr Barinov ◽  
Lingjie Luo ◽  
Pamela Gasse ◽  
Vannary Meas-Yedid ◽  
Emmanuel Donnadieu ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Affinity Maturation ◽  
Humoral Immune ◽  
Germinal Center Reaction ◽  
Humoral Immune Responses ◽  
Binding Domains ◽  
Chemokine Cxcl12

Chemokines control the migration of a large array of cells by binding to specific receptors on cell surfaces. The biological function of chemokines also depends on interactions between nonreceptor binding domains and proteoglycans, which mediate chemokine immobilization on cellular or extracellular surfaces and formation of fixed gradients. Chemokine gradients regulate synchronous cell motility and integrin-dependent cell adhesion. Of the various chemokines, CXCL12 has a unique structure because its receptor-binding domain is distinct and does not overlap with the immobilization domains. Although CXCL12 is known to be essential for the germinal center (GC) response, the role of its immobilization in biological functions has never been addressed. In this work, we investigated the unexplored paradigm of CXCL12 immobilization during the germinal center reaction, a fundamental process where cellular traffic is crucial for the quality of humoral immune responses. We show that the structure of murine germinal centers and the localization of GC B cells are impaired when CXCL12 is unable to bind to cellular or extracellular surfaces. In such mice, B cells carry fewer somatic mutations in Ig genes and are impaired in affinity maturation. Therefore, immobilization of CXCL12 is necessary for proper trafficking of B cells during GC reaction and for optimal humoral immune responses.

Photoperiod controls the induction, retention, and retrieval of antigen-specific immunological memory

2004 ◽  
Vol 286 (1) ◽  
pp. R54-R60 ◽  
Author(s):  
Brian J. Prendergast ◽  
Staci D. Bilbo ◽  
Randy J. Nelson
Keyword(s):  
Immune Responses ◽  
Keyhole Limpet Hemocyanin ◽  
Immunological Memory ◽  
Day Length ◽  
Secondary Response ◽  
Delayed Type Hypersensitivity ◽  
Secondary Antibody ◽  
Initial Exposure ◽  
Siberian Hamsters ◽  
Primary Antibody Response

Changes in day length affect several measures of immunity in seasonally breeding mammals. In Siberian hamsters ( Phodopus sungorus), short day lengths suppress specific secondary antibody responses to the keyhole limpet hemocyanin (KLH) antigen and enhance cutaneous delayed-type hypersensitivity (DTH) responses to dinitrofluorobenzene (DNFB). These experiments tested whether day length affects secondary antibody and DTH responses by altering immune function solely during the interval after the initial exposure to each antigen, solely during the interval after the second exposure, or during both stages of the respective immune responses. Adult male Siberian hamsters were exposed to either a long (16 h light/day; LD) or a short (8 h light/day; SD) photoperiod for 7.5 wk before receiving an initial exposure to each antigen (KLH injection, cutaneous DNFB treatment; separate groups of animals for each antigen). A subset of LD hamsters was transferred to the SD photo-period, and a subset of SD hamsters was transferred to the LD photoperiod. Other hamsters remained in LD or SD. Eight weeks later, all hamsters were challenged with a second subcutaneous injection of KLH or a second application of DNFB to the ear, and immune responses were measured. Exposure to SD during the primary antibody response did not affect secondary IgG responses, but SD exposure during the secondary response significantly suppressed IgG production independent of day length during the initial KLH treatment. In contrast, exposure to SD during the DNFB challenge enhanced the ensuing DTH response, but this enhancement depended on the photoperiod prevailing during the initial exposure. Exposure to SD during the sensitization stage did not enhance DTH in hamsters subsequently exposed to LD. The data suggest that short photoperiods have enduring effects on immune responsiveness and on the establishment and retention of immunological memory.

scholarly journals COVID-19: Mechanisms of Vaccination and Immunity

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 404 ◽  
Author(s):  
Daniel E. Speiser ◽  
Martin F. Bachmann
Keyword(s):  
Immune Responses ◽  
Clinical Management ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Public Life ◽  
High Affinity ◽  
Vaccination Strategies ◽  
Detailed Evaluation ◽  
Pros And Cons

Vaccines are needed to protect from SARS-CoV-2, the virus causing COVID-19. Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management, complemented with detailed evaluation of safety and immune responses. Here, we review the pros and cons of available vaccine platforms and options to accelerate vaccine development towards the safe immunization of the world’s population against SARS-CoV-2. Favorable vaccines, used in well-designed vaccination strategies, may be critical for limiting harm and promoting trust and a long-term return to normal public life and economy.

scholarly journals Sequential class switching is required for the generation of high affinity IgE antibodies

2012 ◽  
Vol 209 (2) ◽  
pp. 353-364 ◽  
Author(s):  
Huizhong Xiong ◽  
Jayashree Dolpady ◽  
Matthias Wabl ◽  
Maria A. Curotto de Lafaille ◽  
Juan J. Lafaille
Keyword(s):  
Affinity Maturation ◽  
Class Switching ◽  
Ige Antibodies ◽  
High Affinity ◽  
Low Concentrations ◽  
Ige Response

IgE antibodies with high affinity for their antigens can be stably cross-linked at low concentrations by trace amounts of antigen, whereas IgE antibodies with low affinity bind their antigens weakly. In this study, we find that there are two distinct pathways to generate high and low affinity IgE. High affinity IgE is generated through sequential class switching (μ→γ→ε) in which an intermediary IgG phase is necessary for the affinity maturation of the IgE response, where the IgE inherits somatic hypermutations and high affinity from the IgG1 phase. In contrast, low affinity IgE is generated through direct class switching (μ→ε) and is much less mutated. Mice deficient in IgG1 production cannot produce high affinity IgE, even after repeated immunizations. We demonstrate that a small amount of high affinity IgE can cause anaphylaxis and is pathogenic. Low affinity IgE competes with high affinity IgE for binding to Fcε receptors and prevents anaphylaxis and is thus beneficial.

Shark Attack: High affinity binding proteins derived from shark vNAR domains by stepwise in vitro affinity maturation

2014 ◽  
Vol 191 ◽  
pp. 236-245 ◽  
Author(s):  
Stefan Zielonka ◽  
Niklas Weber ◽  
Stefan Becker ◽  
Achim Doerner ◽  
Andreas Christmann ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Affinity Maturation ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
High Affinity

scholarly journals The Structural Basis of Repertoire Shift in an Immune Response to Phosphocholine

2000 ◽  
Vol 191 (12) ◽  
pp. 2101-2112 ◽  
Author(s):  
McKay Brown ◽  
Maria A. Schumacher ◽  
Gregory D. Wiens ◽  
Richard G. Brennan ◽  
Marvin B. Rittenberg
Keyword(s):  
Immune Response ◽  
Light Chain ◽  
Indirect Effects ◽  
Somatic Mutations ◽  
Variable Region ◽  
Primary Response ◽  
Structural Basis ◽  
Antibody Repertoire ◽  
High Affinity

The immune response to phosphocholine (PC)–protein is characterized by a shift in antibody repertoire as the response progresses. This change in expressed gene combinations is accompanied by a shift in fine specificity toward the carrier, resulting in high affinity to PC–protein. The somatically mutated memory hybridoma, M3C65, possesses high affinity for PC–protein and the phenyl-hapten analogue, p-nitrophenyl phosphocholine (NPPC). Affinity measurements using related PC–phenyl analogues, including peptides of varying lengths, demonstrate that carrier determinants contribute to binding affinity and that somatic mutations alter this recognition. The crystal structure of an M3C65–NPPC complex at 2.35-Å resolution allows evaluation of the three light chain mutations that confer high-affinity binding to NPPC. Only one of the mutations involves a contact residue, whereas the other two have indirect effects on the shape of the combining site. Comparison of the M3C65 structure to that of T15, an antibody dominating the primary response, provides clear structural evidence for the role of carrier determinants in promoting repertoire shift. These two antibodies express unrelated variable region heavy and light chain genes and represent a classic example of the effect of repertoire shift on maturation of the immune response.

scholarly journals Germinal center reutilization by newly activated B cells

2009 ◽  
Vol 206 (13) ◽  
pp. 2907-2914 ◽  
Author(s):  
Tanja A. Schwickert ◽  
Boris Alabyev ◽  
Tim Manser ◽  
Michel C. Nussenzweig
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Anatomical Structures ◽  
Class Switch ◽  
Cell Clones ◽  
T Cell Help ◽  
Activated B Cells

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude that GCs are dynamic anatomical structures that can be reutilized by newly activated B cells during immune responses.

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