INCREASED MUCOSAL B-LYMPHOCYTE APOPTOSIS DURING POLYMICROBIAL SEPSIS IS A FAS LIGAND BUT NOT AN ENDOTOXIN-MEDIATED PROCESS

Sepsis is reported to induce an increase in the rate of apoptosis (A(o )) in immature lymphoid cells residing in hematopoietic tissues such a s the thymus and bone marrow. Alternatively, secondary lymphoid tissue , such as the spleen exhibit little innate (unstimulated) A(o). Howeve r, it is unknown whether or not polymicrobial sepsis has any effects o n the frequency of A(o) in mucosal lymphoid tissue and what, if any, a re the functional consequences of such a change. To assess this, Peyer 's patch cells were harvested from C3H/HeN (endotoxin-sensitive) mice killed 12 or 24 hours after the onset of polymicrobial sepsis (cecal l igation and puncture [CLP]). The results indicate that the percentage of cells that were A(o)+ as determined by flow cytometry were markedly increased at 24 hours, but not at 12 hours post-CLP. This correlates well with evidence of increased DNA fragmentation as well as histologi cal changes observed both at a light and transmission electron microsc opic level of the Peyer's patch A(o). Phenotypically, these changes we re restricted to the B220(+) (B-cell) population that also exhibited a marked increase of Fas/Apo-1 antigen expression. The functional conse quence of this increased apoptosis appears to be associated with the e ndogenous stimulation (activation) of IgA production by mucosal B lymp hocytes and increased nuclear c-Rel expression. Furthermore, we found that Peyer's patch lymphocytes isolated from C3H/HeJ-Fasl(gld) (endoto xin-tolerant/Fas ligand-[FasL] deficient) as opposed to C3H/HeJ (endot oxin-tolerant) inbred mice did not exhibit increased A(o) after CLP. T hese findings indicate that increased B-cell A(o) appears to be a FasL -Fas antigen-mediated process, but is not due to endotoxin sensitivity . In conclusion, we speculate that the increased Fas-associated apopto sis detected in mucosal B cells (as opposed to splenic or bone marrow B cells) may be due to increased luminal antigens other than endotoxin , released due to gut barrier integrity breakdown during sepsis. (C) 1 998 by The American Society of Hematology.