Browsing by Author "Jacob, J"
Now showing 1 - 3 of 3
- Results Per Page
- Sort Options
Item Open Access In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations.(J Exp Med, 1991-05-01) Jacob, J; Kassir, R; Kelsoe, GAfter primary immunization with an immunogenic conjugate of (4-hydroxy-3-nitrophenyl)acetyl, two anatomically and phenotypically distinct populations of antibody-forming cells arise in the spleen. As early as 2 d after immunization, foci of antigen-binding B cells are observed along the periphery of the periarteriolar lymphoid sheaths. These foci expand, occupying as much as 1% of the splenic volume by day 8 of the response. Later, foci grow smaller and are virtually absent from the spleen by day 14. A second responding population, germinal center B cells, appear on day 8-10 and persist at least until day 16 post-immunization. Individual foci and germinal centers represent discrete pauciclonal populations that apparently undergo somatic evolution in the course of the primary response. We suggest that foci may represent regions of predominantly interclonal competition for antigen among unmutated B cells, while germinal centers are sites of intraclonal clonal competition between mutated sister lymphocytes.Item Open Access In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers.(J Exp Med, 1992-09-01) Jacob, J; Kelsoe, GIn the genetically restricted response that follows immunization with (4-hydroxy-3-nitrophenyl)acetyl coupled to protein carriers, two distinct populations of B cells are observed in the spleens of C57BL/6 mice. By 48 h postimmunization, foci of antigen-binding B cells appear along the periphery of the periarteriolar lymphoid sheaths. These foci expand to contain large numbers of antibody-forming cells that neither bind the lectin, peanut agglutinin, nor mutate the rearranged immunoglobulin variable region loci. Germinal centers containing peanut agglutinin-positive B cells can be observed by 96-120 h after immunization. Although specific for the immunizing hapten, these B cells do not produce substantial amounts of antibody, but are the population that undergoes somatic hypermutation and affinity-driven selection. Both focus and germinal center populations are pauciclonal, founded, on average, by three or fewer B lymphocytes. Despite the highly specialized roles of the focus (early antibody production) and germinal center (higher affinity memory cells) B cell populations, analysis of VH to D to JH joins in neighboring foci and germinal centers demonstrate that these B cell populations have a common clonal origin.Item Open Access In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.(J Exp Med, 1993-10-01) Jacob, J; Przylepa, J; Miller, C; Kelsoe, GIn the murine spleen, germinal centers are the anatomic sites for antigen-driven hypermutation and selection of immunoglobulin (Ig) genes. To detail the kinetics of Ig mutation and selection, 178 VDJ sequences from 16 antigen-induced germinal centers were analyzed. Although germinal centers appeared by day 4, mutation was not observed in germinal center B cells until day 8 postimmunization; thereafter, point mutations favoring asymmetrical transversions accumulated until day 14. During this period, strong phenotypic selection on the mutant B lymphocytes was inferred from progressively biased distributions of mutations within the Ig variable region, the loss of crippling mutations, decreased relative clonal diversity, and increasingly restricted use of canonical gene segments. The period of most intense selection on germinal center B cell populations preceded significant levels of mutation and may represent a physiologically determined restriction on B cells permitted to enter the memory pathway. Noncanonical Ig genes recovered from germinal centers were mostly unmutated although they probably came from antigen-reactive cells. Together, these observations demonstrate that the germinal center microenvironment is rich and temporally complex but may not be constitutive for somatic hypermutation.