Regulation of V_H gene repertoire and somatic mutation in germinal centre B cells by passively administered antibody

Abstract

Immunization with T-dependent antigens induces a rapid differentiation of B cells to plasmacytes that produce the primary immunoglobulin M (IgM) and IgG antibodies with low affinities for the immunogen. It is proposed that the IgG antibody forms immune complexes with the residual antigen which provide an important stimulus for the formation of germinal centres (GC) and the activation of somatic mutation. This hypothesis was tested by passive administration of hapten-specific antibody into mice shortly after the immunization with nitrophenyl (NP) coupled to chicken gamma globulin (NP-CGG) in an environment of limited T-cell help. Athymic mice that received normal T helper cells at 72 hr after the administration of antigen produced low levels of anti-NP antibody and the splenic GC formation was delayed until day 12 after the antigen administration. The analysis of VDJ segments from NP-reactive GC B cells showed very few mutations in the VH genes. Passive injection of anti-NP IgG1 monoclonal antibody - but, not IgM - stimulated the GC formation up to normal levels and the somatic mutation activity in the GC B cells was fully restored. In addition, GC B cells in the recipients of IgG1 antibody demonstrated a change in the usage of germline-encoded VH genes which was not apparent among the primary antibody-forming cells. These results suggest the existence of a specific feedback mechanism whereby the IgG antibody regulates the GC formation, clonotypic repertoire and somatic mutation in GC B cells.

Immune Complex-Bearing Follicular Dendritic Cells Deliver a Late Antigenic Signal That Promotes Somatic Hypermutation

“…Most ICs will be efficiently trapped and eliminated by phagocytic cells but some are trapped by FDCs in GC light zones and SHM is promoted in GC B cells restimulated by Ag in FDC-ICs after day 6. The sequence of these events is illustrated and summarized in Fig 6. Passive transfer studies indicate that it is important for ICs to be made using IgG to promote SHM (13). SHM is typically not apparent in the first week after primary immunization (10,23,29) and we reason that IgG Ab production, IgG-IC formation leading to trapping by FDCs, takes time and helps explain the delay.…”

Antibody-Mediated Immunomodulation: a Strategy To Improve Host Responses against Microbial Antigens

“…Immunomodulation by antibody can be Fc-dependent or independent and can include increased uptake of antigen via FcR on antigen-presenting cells (66,73), differential engagement of stimulatory versus inhibitory FcR (40,51,53,104,126), FcR-dependent enhancement of MHC class I-restricted cross-presentation (41,98,119), alterations in proteolysis and antigen processing (6,72,73,103,121), a shift in presentation of class II-restricted T-cell determinants (4,5,70), changes in cytokine expression by antigen-presenting cells and/or T cells (3,4,11,12), masking of dominant epitopes by antibody (6,9,10,14,72,121), exposure of cryptic epitopes induced by antibody binding (61,103,121), enhanced germinal center formation and generation of strong recall responses (53,59,60,62,64,91,108), changes in usage of germline-encoded V H genes (85,109), and induction of somatic hypermutation (85,108,109).…”

“…Immunization with IC has been reported to accelerate the development of B memory cells, the formation of GC, and the maturation of antibody affinity compared with immunization by antigen alone (62). In studies designed to analyze how immunization with IC can alter the repertoire of antigen-reactive B cells at the molecular level, the rearranged Ig heavy chain variable (V H ) genes from mouse splenic GC were examined (85,109). While most of the GC B cells in mice that received antigen alone expressed a single variable region gene, B cells of mice immunized with an antigen-MAb complex demonstrated heterogeneous V H gene expression, including nine different germ-line segments.…”

B‐cell clonal diversification and gut‐lymph node trafficking in ulcerative colitis revealed using lineage tree analysis

“…It is as yet unknown how SHM is triggered, although germinal center initiation and its structural organization [23][24][25] are known to require both cognate and co-stimulatory interactions with T cells [26,27], and are assumed to involve B cells that are already participating in the response. SHM may be triggered, and possibly be also maintained in germinal center B cells, by immune complexes formed by IgG antibodies bound to the antigen [15,19,28,29]. It is particularly not clear how the processes of SHM and selection interact dynamically and temporally to shape the memory B-cell repertoire, on which the system depends for fast antigen elimination in subsequent encounters [30][31][32][33], although several models have been suggested based on imaging studies [34][35][36].…”