MHC Class II Molecules Control Murine B Cell Responsiveness to Lipopolysaccharide Stimulation

Abstract

LPS is a strong stimulator of the innate immune system and inducer of B lymphocyte activation. Two TLRs, TLR4 and RP105 (CD180), have been identified as mediators of LPS signaling in murine B cells, but little is known about genetic factors that are able to control LPS-induced cell activation. We performed a mouse genome-wide screen that aside from identifying a controlling locus mapping in the TLR4 region (logarithm of odds score, 2.77), also revealed that a locus closely linked to the MHC region (logarithm of odds score, 3.4) governed B cell responsiveness to LPS stimulation. Using purified B cells obtained from MHC congenic strains, we demonstrated that the MHCb haplotype is accountable for higher cell activation, cell proliferation, and IgM secretion, after LPS stimulation, when compared with the MHCd haplotype. Furthermore, B cells from MHC class II−/− mice displayed enhanced activation and proliferation in response to LPS. In addition, we showed that the MHC haplotype partially controls expression of RP105 (a LPS receptor molecule), following a pattern that resembles the LPS responsiveness phenotype. Together, our results strongly suggest that murine MHC class II molecules play a role in constraining the B cell response to LPS and that genetic variation at the MHC locus is an important component in controlling B cell responsiveness to LPS stimulation. This work raises the possibility that constraining of B cell responsiveness by MHC class II molecules may represent a functional interaction between adaptive and innate immune systems.

Chemotactic and Immunoregulatory Properties of Bone Cells are Modulated by Endotoxin-Stimulated Lymphocytes

“…As expected [14,31], T lymphocyte response to LPS pulse was weak, although an early increase in the CD69 expression was found ( Fig 1B). In contrast, a strong increase in the membrane expression of CD69, CD86 and MHC-II within 48 hours following the LPS pulse was confirmed on B lymphocytes (Fig 1C).…”

“…Moreover, LPS-pulsed splenocytes enhanced OCL differentiation, confirming that inflammatory environment lead to bone destruction as a serious complication of bacterial infections of bones or adjacent tissues [6,9,[12][13][14][15][16]37]. In conclusion, our results demonstrate that there is a bidirectional communication during endotoxin-induced inflammation between bone and immune cells.…”

“…LPS promotes bone resorption in mice, by stimulating pro-inflammatory cytokines, antigen presentation and OBL expression of osteoclastogenic cytokines RANKL and tumor necrosis factor (TNF)-α [9][10][11][12]. B lymphocytes, highly susceptible to LPS, additionally contribute to osteoclastogenic effect of LPS in vitro and in vivo [13][14]. T lymphocytes within an inflamed site support bone destruction by stimulating RANKL expression and OCL precursors [15][16].…”

Mapping of quantitative trait loci using the skew-normal distribution

“…As described above (Fig.1), to search genes controlling the percentage of CD19+/CD69+ B-cells that were stimulated with bacterial LPS in mice, a genetic intercross experiment was performed between the C57BL/6 and BALB/c mouse strains (Rodo et al, 2006). From this cross, 139 F 2 mice were generated.…”

“…An example is the data on the percentage of CD19+/CD69+ B-cells that were stimulated with bacterial lipopolysaccharide (LPS) in 139 F 2 mice from an intercross experiment between the C57BL/6 and BALB/c mouse strains (Rodo et al, 2006). The histogram in Fig.1 shows that this phenotype follows a highly skewed distribution.…”