Biomedical subjects

E Notidis

Publications and source records attributed to E Notidis.

3 recordsLinked to original sources

PubMed1998

Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development.

We analyzed the participation of a predominant B cell clonotype in the anti-arsonate immune response of mice in which Bcl-2 expression was enforced in B cells. Many of the antibodies expressed by the arsonate-induced memory compartment of these mice were "dual-reactive," displaying increased affinity acquired via V region somatic hypermutation for both arsonate and the autoantigen DNA. The hypermutated antibodies expressed by the anti-arsonate memory B cell compartment of normal mice have increased affinity for arsonate but lack measurable affinity for DNA. Thus, interference with apoptotic pathways allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. These data demonstrate that both positive and negative selection, working in concert with V gene somatic hypermutation, result in the "specificity maturation" of the antibody response.

Amino Acid Sequence↗

PubMed1998

The roles of antibody variable region hypermutation and selection in the development of the memory B-cell compartment.

Somatic hypermutation and selection of immunoglobulin (Ig) variable (V)-region genes, working in concert, appear to be essential for memory B-cell development in mammals. There has been substantial progress on the nature of the cis-acting DNA elements that regulate hypermutation. The data obtained suggest that the mechanisms of Ig gene hypermutation and transcription are intimately intertwined. While it has long been appreciated that stringent phenotypic selection forces are imposed on the somatically mutated Ig V regions generated during a T-cell dependent B-cell response, the mechanisms involved in this selection have remained enigmatic. Our studies have questioned the role of foreign antigen deposited on follicular dendritic cells in affinity-based positive selection of V regions, and have shown that this selection takes place in a "clone-autonomous" fashion. In addition, our data strongly suggest that affinity for antigen alone is not the driving force for selection of B-cell clones into the memory compartment. In contrast, we suggest that a combination of positive selection for increased foreign antigen binding, and negative selection of antibody V regions that are autoreactive at the onset of the response, or have acquired autoreactivity via hypermutation, results in the "specificity maturation" of the memory B-cell response.

Animals↗

PubMed1997

Initiation codon scanthrough versus termination codon readthrough demonstrates strong potential for major histocompatibility complex class I-restricted cryptic epitope expression.

Accumulating evidence shows that the repertoire of major histocompatibility complex class I-restricted epitopes extends beyond conventional translation reading frames. Previously, we reported that scanthrough translation, where the initiating AUG of a primary open reading frame is bypassed, is most likely to account for the presentation of cryptic epitopes from alternative reading frames within the influenza A PR/8/34 nucleoprotein gene. Here, we confirm and extend these findings using an epitope cassette construct that features two well-defined CD8(+) T cell (TCD8+) epitopes in alternative reading frames, each preceded by a single start codon. Expression of one epitope depends on scanning of the ribosome over the first AUG with translation initiation occurring at the second AUG. We find that scanthrough translation has great potency in our system, with its impact being modulated, as predicted, by the base composition surrounding the first initiation codon, the number of start codons preceding the point of alternate reading frame initiation, and the efficiency with which the epitope itself is generated. Additionally, we investigated the efficiency of eukaryotic translation termination codons, to assess codon readthrough as a mechanism for cryptic epitope expression from 3' untranslated regions. In contrast with initiation codons, eukaryotic stop codons appear to be highly efficient at preventing expression of epitopes encoded in 3' untranslated regions, suggesting that 3' untranslated regions are not a common source of cryptic epitope substrate. We conclude that scanthrough is a powerful mechanism for the expression of epitopes encoded in upstream alternative open reading frames that may contribute significantly to TCD8+ responses and to tolerance induction.

Animals↗