Genetical control of B-cell responses. IV. Inheritance of the unresponsiveness to lipopolysaccharides.

Abstract

Two parameters of the unresponsiveness to lipopolysaccharides from Escherichia coli (LPS) displayed by C3H/HeJ mice, namely endotoxemia and the intraperitoneal extravascular leukocyte responses to small doses of LPS, have been studied by Sultzer and found to be under polygenic control (1, 2) . Recently, however, Watson and Riblet (3) presented evidence interpreted as indicating that a single gene was responsible for influencing both mitogenic (polyclonal) and immunogenic (specific) responses to LPS, by analysing crosses between LPS low-responder mice and high-responder strains. Since the B-cell unresponsiveness of C3H/HeJ mice has been shown to depend upon a pure defect in the subpopulation of B cells which interacts with and responds to LPS in the conventional strains,' the finding of Watson and Riblet is of great importance . Thus, it seems possible that the defective gene in C3H/HeJ mice would code for the B-cell surface structure involved in cell triggering, both in polyclonal (4) and in specific (3, 5, 6) antibody responses. According to our current view in B-cell activation, such "mitogen receptor" is the only structure on the B-cell surface which is competent to deliver activating signals to the resting cell (7). If this were the case, C3H/HeJ mice would be of great importance for elucidating the molecular mechanisms governing the generation and delivery of triggering signals. We report in this paper evidence on the inheritance of the genetical defect displayed by C3H/HeJ mice with regard to the direct B-cell responses to LPS as evidenced by polyclonal and specific responses as well . Materials and MethodsC3H/HeJ (H-2') mice were obtained from Jackson Laboratories, Bar Harbor, Maine, and bred in our colony for the last 3 yr. Other mice obtained from that source were also directly used in some experiments . The high-responder strains used in these experiments were C3H/Tif (H-2'°) obtained from Bomholtgaard, Rye, Denmark, and B10.5M (H-2°) from our own colony .LPS from Escherichia coli 055:135 obtained by phenol-water extraction (8) was used throughout these experiments . The hapten (4-hydroxy-3,5-dinitrophenyl)acetyl (NNP) was conjugated to LPS as previously described (9) and the biological characterization of the conjugate used in the present

Genetic basis for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice

“…In fact, the likelihood of the mutations being independent, and consequently different, appears to be strengthened by the distinct behavior of the defective trait in F1 hybrids between either of the nonresponder strains with several responder parents. Thus, although the present results demonstrate that unresponsiveness in B10Cr is inherited as a recessive trait, we had previously found that the defect in C3H/HeJ is codominantly expressed in F 1 hybrids with responder strains (Coutinho et al 1975b). This observation, which was later confirmed by others (Sultzer 1976, Kelly andWatson 1977), led us to hypothesize allelic exclusion for this locus (Coutinho et al 1975b(Coutinho et al , 1978.…”

Immunological unresponsiveness to thymus-independent antigens: two fundamentally different genetic mechanisms of B-cell unresponsiveness to dextran

“…In one case (C3H/HeJ), the gene(s) determine(s) the presence of the nonimmunoglobulin receptors on B cells for' lipopolysaccharide, which are responsible for B-cell activation. The genes are codominantly expressed (3,4) and localized on chromosome 4 in the mousey They do not code for the variable part of the immunoglobulin receptors. Another nonresponding strain to certain TI antigens (CBA/N) lacks PBA receptors or receptor-bearing cells capable of reacting to, for example, Ficoll, and cannot mount an immune response to any hapten coupled to this TI carrier (5).…”

Lipopolysaccharide‐Induced Mediators Assisting the Proliferative Response of C3H/HeJ Thymocytes to Concanavalin A

“…Subsequently, it was clarified that this unresponsiveness of the spleen cells of C3H/HeJ mice to LPS was due to some intrinsic defect of the B cells (26). Genetic analysis indicates that the inability of C3H/HeJ mice to respond to LPS is the consequence of a single gene defect which has been mapped between the major urinary protein locus and the locus coding for polysyndactyl on chromosome 4 (7,8,12,27,32).…”