Role of dendritic cells in the pathogenesis of Whipple's disease.
Accumulation of Tropheryma whipplei-stuffed macrophages in the duodenum, impaired T. whipplei-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple's disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC ex vivo or after in vitro maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry in situ. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11c(high) myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype. In vitro-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate T. whipplei-specific Th1 cells. In duodenal and lymphoid tissues, T. whipplei was found within immature DC-SIGN(+) DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of T. whipplei-specific T cells during CWD and that immature DC carrying T. whipplei contribute to the dissemination of the bacterium.
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Katina
K
Schinnerling
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Anika
A
Geelhaar-Karsch
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Kristina
K
Allers
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Julian
J
Friebel
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Kristina
K
Conrad
Institut für Pathologie, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Christoph
C
Loddenkemper
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Anja A
AA
Kühl
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Ulrike
U
Erben
Institut für Tropenmedizin und Internationale Gesundheit, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Ralf
R
Ignatius
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany verena.moos@charite.de.
Verena
V
Moos
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
Thomas
T
Schneider
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D004386:Duodenum / Q000276:immunology / Q000382:microbiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D054400:Receptors, CCR7 / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology*; D054851:Tropheryma / Q000276:immunology / Q000472:pathogenicity; D008061:Whipple Disease / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015703:Antigens, CD; D051940:B7-2 Antigen; D039521:CD11c Antigen; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D053765:Interleukin-12 Subunit p35; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface; D000097802:CD83 Antigen; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C515370:CCR7 protein, human; C497964:CD86 protein, human; C508858:IL12A protein, human