TLR4-mediated sensing of Campylobacter jejuni by dendritic cells is determined by sialylation.
In Guillain-Barré syndrome (GBS), ganglioside mimicry of Campylobacter jejuni lipo-oligosaccharide (LOS) drives the production of cross-reactive Abs to peripheral nerve gangliosides. We determined whether sialic acid residues in C. jejuni LOS modulate dendritic cell (DC) activation and subsequent B cell proliferation as a possible mechanism for the aberrant humoral immune response in GBS. Highly purified sialylated LOS of C. jejuni isolates from three GBS patients induced human DC maturation and secretion of inflammatory cytokines that were inhibited by anti-TLR4 neutralizing Abs. The extent of TLR4 signaling and DC activation was greater with LOS of the wild type isolates than with nonsialylated LOS of the corresponding sialyltransferase gene knockout (cst-II mutant) strains, indicating that sialylation boosts the DC response to C. jejuni LOS. Supernatants of LOS-activated DCs induced B cell proliferation after cross-linking of surface Igs in the absence of T cells. Lower B cell proliferation indices were found with DC supernatants after DC stimulation with cst-II mutant or neuraminidase desialylated LOS. This study showed that sialylation of C. jejuni LOS enhances human DC activation and subsequent B cell proliferation, which may contribute to the development of cross-reactive anti-ganglioside Abs found in GBS patients following C. jejuni infection.
Department of Neurology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.
Mark L
ML
Kuijf
Janneke N
JN
Samsom
Wouter
W
van Rijs
Marieke
M
Bax
Ruth
R
Huizinga
Astrid P
AP
Heikema
Pieter A
PA
van Doorn
Alex
A
van Belkum
Yvette
Y
van Kooyk
Peter C
PC
Burgers
Theo M
TM
Luider
Hubert P
HP
Endtz
Edward E S
EE
Nieuwenhuis
Bart C
BC
Jacobs
D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D016123:Campylobacter jejuni / Q000737:chemistry / Q000276:immunology*; D002240:Carbohydrate Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D002474:Cell-Free System / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D055879:Gene Knock-In Techniques; D020275:Guillain-Barre Syndrome / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D012794:Sialic Acids / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D016207:Cytokines; D008070:Lipopolysaccharides; D012794:Sialic Acids; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C023023:lipid-linked oligosaccharides; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase