scholarly journals Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte.

1989 ◽  
Vol 170 (4) ◽  
pp. 1211-1230 ◽  
Author(s):  
T Manser
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Somatic Mutation ◽  
High Efficiency ◽  
Clonal Expansion ◽  
Isotype Switching ◽  
Cell Clones ◽  
Short Period ◽  
V Region ◽  
Neutral Mutations

Changes in the structure and function of antibodies occur during the course of an immune response due to variable (V) region gene somatic mutation and isotype switch recombination. While the end products of both these processes are now well documented, their mechanisms, timing, and regulation during clonal expansion remain unclear. Here I describe the characterization of antibodies expressed by a large number of hybridomas derived from single B cell clones at an intermediate stage of an immune response. These data provide new insights into the mechanism, relative timing, and potential of V gene mutation and isotype switching. The data suggest that somatic mutation and isotype switching are completely independent processes that may, but need not, occur simultaneously during clonal expansion. In addition, the results of this analysis demonstrate that individual B cell clones are far more efficient than previously imagined at generating and fixing particular V region somatic mutations that result in increased affinity for the eliciting epitope. Models to account for this high efficiency are discussed. Taken together with previous data, the results of this analysis also suggest that the "somatic evolution" of V region structure to a single epitope takes place in two stages; the first in which particular mutations are sustained and fixed by antigen selection in the CDR regions of the V region genes expressed in a clone over a short period of clonal expansion, and the second in which these selected CDR mutations are maintained in the growing clone, deleterious mutations are lost, and selectively neutral mutations accumulate throughout the length of V genes over long periods of clonal expansion.

scholarly journals Somatic mutation and clonal expansion of B cells in an antigen-driven immune response.

1985 ◽  
Vol 4 (2) ◽  
pp. 345-350 ◽  
Author(s):  
F. Sablitzky ◽  
G. Wildner ◽  
K. Rajewsky
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Somatic Mutation ◽  
Clonal Expansion

scholarly journals Survival and Clonal Expansion of Mutating “Forbidden” (Immunoglobulin Receptor–Deficient) Epstein-Barr Virus–Infected B Cells in Angioimmunoblastic T Cell Lymphoma

2001 ◽  
Vol 194 (7) ◽  
pp. 927-940 ◽  
Author(s):  
Andreas Bräuninger ◽  
Tilmann Spieker ◽  
Klaus Willenbrock ◽  
Philippe Gaulard ◽  
Hans-Heinrich Wacker ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Clonal Expansion ◽  
Barr Virus ◽  
Cell Clones ◽  
Epstein Barr

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

scholarly journals Interleukin 4 causes isotype switching to IgE in T cell-stimulated clonal B cell cultures.

1988 ◽  
Vol 168 (3) ◽  
pp. 853-862 ◽  
Author(s):  
D A Lebman ◽  
R L Coffman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Cultures ◽  
Heavy Chain ◽  
Clonal Expansion ◽  
Precursor Cells ◽  
Interleukin 4 ◽  
Isotype Switching ◽  
Th Cell ◽  
Clonal Cultures

Although it has been established that IL-4 enhances both IgG1 and IgE secretion in LPS-stimulated B cell cultures, these studies failed to determine whether IL-4 preferentially induces isotype switching or preferentially allows for the maturation of precommitted precursor cells. To distinguish between these possibilities, it is necessary to ascertain the effect of IL-4 on the isotypes secreted by individual precursor cells during clonal expansion. Therefore, clonal cultures of B cells stimulated with a Th2 helper cell line specific for rabbit Ig and rabbit anti-mouse IgM were established. The majority of B cells are capable of undergoing clonal expansion under these conditions. To vary the level of IL-4 present, either IL-4 or anti-IL-4 was added to cultures. In the presence of IL-4 there was an increase in the proportion of clones that secreted IgE and a decrease in the proportion of clones that secreted IgM. The addition of IL-4 to cultures also increased the amount of IgE secreted by individual clones. Thus, these experiments definitively prove that IL-4 causes specific heavy chain class switching to IgE in Th2-stimulated B cell cultures. In contrast, IL-4 does not affect the proportion of clones secreting IgG1, suggesting that other consequences of Th cell-B cell interactions play a role in the generation of an IgG1 response.

scholarly journals BCR signal through α4 is involved in S6 kinase activation and required for B cell maturation including isotype switching and V region somatic hypermutation

2002 ◽  
Vol 14 (2) ◽  
pp. 177-187 ◽  
Author(s):  
Seiji Inui ◽  
Kazuhiko Maeda ◽  
Ding Rong Hua ◽  
Takeshi Yamashita ◽  
Hideyuki Yamamoto ◽  
...  
Keyword(s):  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Maturation ◽  
Isotype Switching ◽  
S6 Kinase ◽  
Kinase Activation ◽  
B Cell Maturation ◽  
V Region

scholarly journals ICAMs support B cell interactions with T follicular helper cells and promote clonal selection

2017 ◽  
Vol 214 (11) ◽  
pp. 3435-3448 ◽  
Author(s):  
Irina Zaretsky ◽  
Ofir Atrakchi ◽  
Roei D. Mazor ◽  
Liat Stoler-Barak ◽  
Adi Biram ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Clonal Expansion ◽  
Cell Interactions ◽  
Antigen Uptake ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Clones ◽  
Wide Range

The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T–B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh–B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.

Somatic mutation of bcl-6 genes can occur in the absence of VH mutations in chronic lymphocytic leukemia

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3534-3540 ◽  
Author(s):  
Surinder S. Sahota ◽  
Zadie Davis ◽  
Terry J. Hamblin ◽  
Freda K. Stevenson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
V Genes ◽  
History Of ◽  
Vh Genes ◽  
V Region

Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated VH genes consistent with a naive B cell, and the other with mutated VH genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5′ noncoding region of thebcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in VH and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated VH genes, with 4 of 10 cases clearly showing mutations inbcl-6. In those CLLs defined by somatically mutated VH genes, 4 of 9 cases predictively showed bcl-6mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of VH genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the VH and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.

scholarly journals Different epitope structures select distinct mutant forms of an antibody variable region for expression during the immune response.

1991 ◽  
Vol 173 (3) ◽  
pp. 665-672 ◽  
Author(s):  
S Fish ◽  
M Fleming ◽  
J Sharon ◽  
T Manser
Keyword(s):  
Immune Response ◽  
Amino Acid ◽  
Somatic Mutation ◽  
Amino Acid Substitution ◽  
Variable Region ◽  
Single Amino Acid ◽  
Amino Acid Residues ◽  
V Region ◽  
Mutant Forms ◽  
Selection Of

Antibody variable (V) regions that initially differ from one another by only single amino acid residues at VH-D and D-JH segment junctions (termed canonical V regions) can be elicited in strain A/J mice by three different haptens. Among such V regions an amino acid substitution due to somatic mutation is recurrently observed at VH CDR2 position 58, regardless of which of these haptens is used for immunization. This substitution confers upon a canonical V region a generic increase in affinity for all the haptens. Conversely, the type of amino acid substitution at VH position 59 resulting from somatic mutation that is recurrently observed among such V regions changes with the eliciting hapten, in a manner that correlates directly with the cognate affinity increases (or decreases) for hapten conferred by the observed substitutions. This small subregion of VH CDR2 therefore plays a major role in determining both affinity and specificity for antigen. The data confirm that affinity for antigen is of pivotal importance in determining the degree of selection of different mutant forms of a V region. Moreover, during an immune response a sufficiently diverse mutant repertoire can be generated from a single canonical V region to allow adaptation to increase affinity for three different epitopes.

scholarly journals Frequencies of mitogen-reactive B cells in the mouse. II. Frequencies of B cells producing antibodies which lyse sheep or horse erythrocytes, and trinitrophenylated or nitrodophenylated sheep erythrocytes

1977 ◽  
Vol 145 (6) ◽  
pp. 1520-1530 ◽  
Author(s):  
J Andersson ◽  
A Coutinho ◽  
F Melchers
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plaque Assay ◽  
Spleen Cells ◽  
Cell Clones ◽  
Total Pool ◽  
V Gene ◽  
V Region ◽  
Precursor B Cells ◽  
Limiting Dilution

The B-cell mitogens LPS and lipoprotein stimulate 20-35 percent of all B cells in the spleen of 6- to 8-wk old C3H/Tif mice, as determined by limiting dilution analysis of precursors. Each reactive cell grows to a clone of IgM-secreting PFC, enumerated in a hemolytic plaque assay detecting all IgM secreting cells, regardless of v-region specificity. We have used these mitogens to reveal the total repertoire of Ig specificities produced by these mitogen-reactive B cells. We have determined in plaque assays with six different target erythrocytes the number of spleen cells limiting to one the number of mitogen-reactive B cells detected as specific IgM-secreting clones in each of these plaque assays. By this method, the absolute frequencies of precursor B cells with defined v-gene specificities could be calculated, for at least, one third of all B cells. The frequencies of specific IgM-plaque-forming B-cell clones within the total pool of mitogen-reactive B cells was 1 in 10 for NIP(12),-SRC, 1 in 50 for TNP(12)- SRC, 1 in 100 for NIP(1)-SRC, 1 in 160 for TNP(3)- SRC, 1 in 500 for HRC, and 1 in 1,000 for SRC. These frequencies were the same in the LPS- and in the lipoprotein-reactive B-cell population for TNP(30)- SRC and SRC.

scholarly journals Sustained antibody response to ZIKV infection induced by NS1 protein is accompanied by the progressive appearance of autoreactive antibodies and cross-reactive B cell clones

2020 ◽  
Author(s):  
Cecilia B. Cavazzoni ◽  
Vicente B. T. Bozza ◽  
Lucas Tostes ◽  
Bruno Maia ◽  
Luka Mesin ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Humoral Immune Response ◽  
Zika Virus ◽  
Cross Reactivity ◽  
Ns1 Protein ◽  
Structural Protein ◽  
Humoral Immune ◽  
Autoreactive Antibodies ◽  
Cell Clones

AbstractAntibodies are key players in controlling viral infections. However, in addition to antigen-specific responses to viral antigens, humoral immune response can generate polyreactive and autoreactive antibodies of unknown function. Dengue and Zika virus infections have been linked to autoimmune disorders including Guillain-Barrè syndrome. A unique feature of flaviviruses is the secretion of non-structural protein 1 (NS1) by infected cells. NS1 is highly immunogenic and antibodies targeting NS1 can have both protective and pathogenic roles. In the present study, we investigated the humoral immune response to Zika virus NS1 and found NS1 to be an immunodominant viral antigen correlated to the presence of autoreactive antibodies. Through single B cell cultures, we coupled binding assays and BCR sequencing, confirming the immunodominance of NS1 and the presence of self-reactive clones in germinal centers both after infection and immunization, some of which were cross-reactivity with NS1. Anti-NS1 B cell clones showed features related to pathogenic autoreactive antibodies. Our findings demonstrate NS1 immunodominance at the cellular level as well as a potential role for NS1 in ZIKV associated autoimmune manifestations.

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