Impaired immune functions of monocytes and macrophages in Whipple's disease.
OBJECTIVE
Whipple's disease is a chronic multisystemic infection caused by Tropheryma whipplei. Host factors likely predispose for the establishment of an infection, and macrophages seem to be involved in the pathogenesis of Whipple's disease. However, macrophage activation in Whipple's disease has not been studied systematically so far.


METHODS
Samples from 145 Whipple's disease patients and 166 control subjects were investigated. We characterized duodenal macrophages and lymphocytes immunohistochemically and peripheral monocytes by flow cytometry and quantified mucosal and systemic cytokines and chemokines indicative for macrophage activation. In addition, we determined duodenal nitrite production and oxidative burst induced by T whipplei and by other bacteria.


RESULTS
Reduced numbers of duodenal lymphocytes, increased numbers of CD163(+) and stabilin-1(+), reduced numbers of inducible nitric synthase+ duodenal macrophages, and increased percentages of CD163(+) peripheral monocytes indicated a lack of inflammation and a M2/alternatively activated macrophage phenotype in Whipple's disease. Incubation with T whipplei in vitro enhanced the expression of CD163 on monocytes from Whipple's disease patients but not from control subjects. Chemokines and cytokines associated with M2/alternative macrophage activation were elevated in the duodenum and the peripheral blood from Whipple's disease patients. Functionally, Whipple's disease patients showed a reduced duodenal nitrite production and reduced oxidative burst upon incubation with T whipplei compared with healthy subjects.


CONCLUSIONS
The lack of excessive local inflammation and alternative activation of macrophages, triggered in part by the agent T whipplei itself, may explain the hallmark of Whipple's disease: invasion of the intestinal mucosa with macrophages incompetent to degrade T whipplei.
Moos
Verena
V
Medizinische Klinik I, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany. verena.moos@charite.de
Schmidt
Carsten
C
Geelhaar
Anika
A
Kunkel
Désirée
D
Allers
Kristina
K
Schinnerling
Katina
K
Loddenkemper
Christoph
C
Fenollar
Florence
F
Moter
Annette
A
Raoult
Didier
D
Ignatius
Ralf
R
Schneider
Thomas
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D004386:Duodenum / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009573:Nitrites / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D016897:Respiratory Burst / Q000276:immunology; D054851:Tropheryma / Q000276:immunology*; D008061:Whipple Disease / Q000276:immunology* / Q000382:microbiology*; D055815:Young Adult; D000098902:CD163 Antigen; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015816:Cell Adhesion Molecules, Neuronal; D018932:Chemokine CCL2; D016753:Interleukin-10; D018950:Lipopolysaccharide Receptors; D009573:Nitrites; D011956:Receptors, Cell Surface; D016201:Receptors, Lymphocyte Homing; D000098902:CD163 Antigen; C111835:CCL2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C508609:IL10 protein, human; C449926:STAB1 protein, human