Susceptibility to in vitro tolerance induction of adult B cells from mice with an X-linked B-cell defect.

Abstract

C B A / N mice, a m u t a n t subline of the C B A / C a strain, have an X-linked B l y m p h o c y t e -i m m u n e defect. These mice and F1 male progeny derived from C B A / N females fail to produce specific a n t i b o d y after i m m u n i z a t i o n with certain thymicindependent (TI) antigens (1-4). In addition, these mice fail to produce I g M or IgG responses to either the T I or T -d e p e n d e n t derivatives of the hapten phosphorylcholine (PC) (5, 6). Moreover, analysis of surface m e m b r a n e characteristics indicates that B cells derived from i m m u n e defective mice fail to express determinants that are present on a population of B lymphocytes that appears late in ontogeny. These include minor lymphocyte-stimulating determinants (7), Lyb5 (8), and Lyb3 (9). Furthermore, the B cells of C B A / N mice have unusually high amounts of surface I g M (sIgM) and exhibit a low ratio of surface 8:/~ heavy chains when c o m p a r e d with the B cells of normal mice (10, 11). These surface characteristics are similar to those that are exhibited by neonatal B cells (10). T a k e n together, these findings are consistent with the hypothesis that the i m m u n e defect(s) in C B A / N mice arise from a m a t u r a t i o n a l arrest either in the development of C B A / N B cells or of a subpopulation of these B cells.Previous studies, which used a modification of the in vitro splenic focus technique (12), have suggested that susceptibility to in vitro tolerance induction m a y serve as a functional marker for developing (immature) B cells and B-cell m a t u r a t i o n (12-14). This conclusion is based primarily on the following observations. (a) 2,4-dinitrophenyl (DNP)-and PC-reactive splenic B cells are tolerizable only for the first few days after their initial expression in the murine neonate (12, 13). (b) Neonatal bone marrow B cells can be rendered unresponsive to antigen longer in development than neonatal splenic B cells (13,14). (c) Whereas adult splenic B cells are not susceptible to in vitro tolerance induction, 25% of adult bone marrow B cells are tolerizable (13,14).

Impaired B Cell Receptor Signaling Is Responsible for Reduced TACI Expression and Function in X-Linked Immunodeficient Mice

“…In many ways, XID B cell responses resemble those of newborn mice (67). For example, anti-IgM-induced B cell proliferation can be restored in both age groups by second signals such as LPS, IL-4, CD40L, or CpG (53,54,(68)(69)(70).…”

Role of variable region gene expression and environmental selection in determining the antiphosphorylcholine B cell repertoire.

“…Thus, whereas in normal and conventional mice, <10% of splenic B cells are tolerance susceptible in vitro, >50% of splenic B cells in F~ male defective mice remain tolerance susceptible (26). Since PC is a ubiquitous environmental antigen, it is an interesting possibility that the absence of mature PC-specific B cells in (CBA/N × BALB/c)FI male defective mice is the result of tolerance induction by a normal environmental antigen.…”

“…Previous studies from several laboratories (17)(18)(19)(20)(26)(27)(28) have demonstrated a multifaceted sex-linked immunologic deficiency in CBA/N mice and F1 male mice derived from a CBA/N parent. One of the deficiencies of these mice is an almost total absence, from the primary B cell repertoire, of cells that can respond to PC, even presented on highly immunogenic carriers (17)(18)(19)(20).…”

“…Several years ago, it was noted that one of the immunologic abnormalities associated with the CBA/N defect is an unusual degree of tolerance susceptibility of B cells obtained from defective mice (26,27). Thus, whereas in normal and conventional mice, <10% of splenic B cells are tolerance susceptible in vitro, >50% of splenic B cells in F~ male defective mice remain tolerance susceptible (26).…”

“…It is assumed that at the time of isolation these cells would not yet have interfaced with the environment and, thus, should be representative of the B cell repertoire as it emerges from bone marrow stem cells; it should thereby be reflective of the readout of expressed immunoglobulin variable region genes. Additionally, it is assumed that, within the context of the fragment culture system, such cells can acquire their surface receptors but do so in the presence of antigen and excess carrier-specific T cells that provide a stimulatory milieu and avoid tolerance induction of cells that would otherwise be obligately tolerance susceptible (13,26).…”