T-cell function is critical for murine cholesterol gallstone formation.
OBJECTIVE
The formation of cholesterol gallstones is a complex process involving contributions from genes and environmental factors. Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown.


METHODS
The role of adaptive immunity in cholesterol cholelithogenesis was analyzed utilizing immunocompetent Helicobacter spp.-infected and -uninfected BALB/c and congenic immunodeficient Rag2(-/-) (Rag) mice. Lymphocyte transfer studies were performed to determine which cellular subset was responsible for cholesterol gallstone formation. Also, gallbladder inflammation was quantified to determine the nature of the inflammatory response associated with cholelilithogenesis.


RESULTS
When fed a lithogenic diet for 8 weeks, wild-type mice developed significantly more cholesterol gallstones (27%-80% prevalence) than Rag mice ( approximately 5%, P < .05). Helicobacter spp.-infected BALB/cJ mice displayed statistically significant increases in cholesterol gallstone prevalence compared with uninfected mice (81% vs. 39%; P < .05). Transfer of splenocytes or T lymphocytes to Rag2(-/-) mice increased stone prevalence markedly (26% and 40% respectively; P < .05), whereas transfer of B cells was not appreciably cholelithogenic (13%). The adaptive immune response increased the expression of gallbladder Muc genes and accumulation of mucin gel. In addition, T cells and cholesterol monohydrate crystals induced proinflammatory gene expression in the gallbladder, which likely contributes to gallbladder dysfunction.


CONCLUSIONS
These studies indicate that T cells are critical in murine cholesterol cholelithogenesis. Furthermore, cholesterol monohydrate crystals induce expression of proinflammatory cytokines in a T-cell-dependent fashion. Acquired immunity and inflammation are likely to be crucial factors in cholesterol gallstone pathogenesis, rather then merely the result of cholelithogenesis.
Maurer
Kirk J
KJ
Department of Biological Engineering, Massachusetts Institute of Technology, Boston, Massachusetts, USA. kmaurer@mit.edu
Rao
Varada P
VP
Ge
Zhongming
Z
Rogers
Arlin B
AB
Oura
Trisha J
TJ
Carey
Martin C
MC
Fox
James G
JG
D019264:Adoptive Transfer; D000818:Animals; D002764:Cholecystitis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D002769:Cholelithiasis / Q000150:complications / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D002791:Cholesterol, Dietary / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005704:Gallbladder / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D044923:Helicobacter hepaticus; D007111:Immunity, Cellular; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009077:Mucins / Q000378:metabolism; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000637:transplantation
D002791:Cholesterol, Dietary; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D009077:Mucins; C499308:Rag2 protein, mouse