Antibody-defective, genetically susceptible CBA/N mice have an altered Salmonella typhimurium-specific B cell repertoire.

Abstract

CBA/N mice, which express the X-linked immunodeficiency gene xid, are susceptible to Salmonella typhimurium. The basis for this susceptibility is currently unknown. However, previous studies (10) from this laboratory have provided evidence that susceptibility may be due to a defective anti-S. typhimurium antibody response. In that report we hypothesized that the defective antibody response may be a reflection of an altered S. typhimurium-specific B cell repertoire. In the studies described here, we have investigated this hypothesis using a modification of the in vitro splenic focus system. The frequency and characteristics of salmonella-specific B cells in normal, innately resistant, CBA/Ca mice have been compared with those of salmonella-susceptible, anti-S. typhimurium antibody-defective CBA/N mice. The results show that CBA/N mice express no primary or secondary S. typhimurium-specific B cell precursors after stimulation with an acetone-killed and dried (AKD) preparation of S. typhimurium strain TML. However, after three immunizations, the CBA/N tertiary frequency of 15.4 per 10(6) splenic B cells was similar to the primary precursor frequency in immunologically normal CBA/Ca mice, but 23-fold lower than the tertiary precursor frequency in CBA/Ca control mice. Moreover, CBA/N mice had an altered isotype distribution pattern after stimulation with AKD-TML. Greater than 70% of the tertiary CBA/N TML-specific B cells secreted IgG2, in contrast to either nonimmune or primed control mice. In addition, 80% of the CBA/N TML-specific B cells secreted only a single isotype, whereas the majority of B cells from primed normal mice secreted multiple isotypes. Fine specificity analysis of the TML-specific B cells indicated that the array of antigenic determinants to which CBA/N B cells could respond was restricted. Although the majority of primed CBA/Ca and primed CBA/N B cells were specific for LPS, the fine specificity pattern exhibited by CBA/N B cells was similar to that observed in unprimed normal mice, i.e., the vast majority were specific for the O antigen region of the LPS molecule. In contrast, a major portion of the LPS-specific B cells in primed CBA/Ca mice were directed against the KDO/lipid A region of the LPS molecule. Therefore, it appears that CBA/N mice lack or are unable to stimulate the B cell subset that predominates in primed, normal mice. Taken together, these studies indicate that the basis for susceptibility of CBA/N mice to S. typhimurium is multifactorial and suggests that the inability of some animals to respond to some infectious agents may be related to holes in their B cell repertoire.

Chronic giardiasis in B-cell-deficient mice expressing the xid gene

“…However, a variety of studies have indicated a marked inability of xid mice to synthesize antibody to bacterial antigens, particularly polysaccharides (2,5,11). This in turn is associated with the inability of xid mice to develop immune resistance to infection with extracellular microorganisms (10,14,19). In normal mice, antibodies to polysaccharide antigens are preferentially produced within the IgM and IgG3 isotypes (21,30).…”

“…Numerous reports indicate reduced antibody production by these mice to systemically administered T-cell-independent antigens (2,17,29,30) and some T-cell-dependent antigens (5,23,24,28). Female mice that are homozygous or male mice that are hemizygous for xid have reduced resistance to systemic bacterial, protozoan, and viral infections linked to deficient antibody production (10,14,16,18,19). In this study, we compared mice expressing the xid gene with phenotypically normal mice to test our hypothesis that antibody is important for normal elimination of G. muris.…”

Clonal analysis of primary B cells responsive to the pathogenic bacterium Salmonella typhimurium.

“…The results presented here suggest that antibodies to the core polysaccharide region of the LPS molecule are not as important in the memory response to S. typhimurium infections as are anti-O antigen and anti-lipid A antibodies . Interestingly, recent studies from this laboratory suggest that salmonella-susceptible CBA/N mice which have been shown to be antibody defective (18), may have an altered repertoire to these determinants (66).…”

X-Linked Immune Deficiency (xid)

“…However, these mice are known to be extremely susceptible to certain bacterial infections (Duran and Metcalf, 1987).…”