Specific and Nonspecific B-Cell Function in the Small Intestines of Patients with Whipple's Disease

Abstract

Whipple's disease is a chronic multisystemic infection caused by Tropheryma whipplei that is characterized by arthritis, weight loss, and diarrhea. The immunological defects in the duodenal mucosa, the site of major replication of the agent underlying the pathogenesis of Whipple's disease, are poorly understood. Mucosal immunoglobulins are essential for the defense against intestinal pathogens; therefore, we analyzed the B-cell response in duodenal specimens and sera of Whipple's disease patients. Whereas systemic immunoglobulin production was affected only marginally, duodenal biopsy specimens of Whipple's disease patients contained reduced numbers of immunoglobulin-positive plasma cells and secreted less immunoglobulin compared to healthy controls but showed a weak secretory IgA response toward T. whipplei. This T. whipplei-specific intestinal immune response was not observed in controls. Thus, we were able to demonstrate that general mucosal immunoglobulin production in Whipple's disease patients is impaired. However, this deficiency does not completely abolish T. whipplei-specific secretory IgA production that nonetheless does not protect from chronic infection.Whipple's disease is a chronic multisystemic infection caused by Tropheryma whipplei (15, 18). The major clinical manifestations of Whipple's disease are arthritis, weight loss, and diarrhea that resolve upon antimicrobial treatment (15).Immunoglobulins, especially IgA, are a major defense mechanism against infections at mucosal surfaces. IgA is secreted into the gut lumen, where it binds infectious agents, thereby blocking their adhesion and entry into the mucosa (9). Moreover, IgA is able to eliminate pathogens from the lamina propria and even binds viral proteins before assembly in the epithelial cells (8).The local immunological defects underlying the pathogenesis of Whipple's disease are poorly understood, and data on mucosal humoral immunity are lacking. We have shown that in the duodenum of Whipple's disease patients the numbers of T cells and unspecific and T. whipplei-specific Th1 reactivity are reduced compared to healthy controls, and that macrophages are alternatively activated (3,10,13,14). Thus, secretory immunity may be also impaired, since Th1 cells play a crucial role in mucosal B-cell differentiation (9). In addition, T. whipplei acquires a glycoproteic biofilm that might inhibit the specific humoral immune response (1). Indeed, in serum samples of Whipple's disease patients, reduced total IgG2 (11) and T. whipplei-specific IgG and IgM have been detected, whereas T. whipplei-specific IgA is enhanced compared to healthy persons (2).However, nothing is known about the quantitative production of immunoglobulins and the specificity of secretory IgA in the duodenal mucosa of Whipple's disease patients, the site of major replication of the pathogen. Thus, we quantified systemic and duodenal production of immunoglobulins and determined T. whipplei-specific secretory IgA in the supernatants of short-term cultured duodenal biopsy specimens to...

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease

“…Thus, reduced Th1 reactivity is explained not only by specifically repressed IFN-␥ expression but also by an overall insufficient T-cell activation. Since the infecting T. whipplei strain does not influence the manifestation of the disease (9), the immunological dysfunctions of antigen-presenting cells of CWD patients and the modulation of regulatory T cells imply that the immunologic reaction of the host is responsible for the tolerance of CD4 ϩ T cells (16,(37)(38)(39). However, while CWD treatment status does not influence the reactivity to T. whipplei antigens, the T cell reaction to SEB is influenced by the clinical manifestation and the treatment status.…”

Role of Dendritic Cells in the Pathogenesis of Whipple's Disease

“…Immunostaining on paraffin sections was performed as previously described (7,8,31). We identified DC populations in tissues by the expression of DC-SIGN (32) and S-100 (31).…”

“…Self-limiting asymptomatic or moderate infections with this agent are common (2,3) and result in a protective humoral and cellular immunity in most individuals (4,5). In contrast, subtle immune defects that occur only rarely seem to predispose for CWD: an HLA association (6) and immunological aberrations point at problems in the axis of antigen processing/presentation/T cell activation (4,(7)(8)(9)(10)(11)(12). These differences include low peripheral interleukin-12 (IL-12) and gamma interferon (IFN-␥) (4,(10)(11)(12), enhanced anti-inflammatory cytokines and regulatory T cells (T reg ) (7,12), and the absence of a T. whipplei-specific Th1 response (4).…”

<b><i>Tropheryma whipplei</i></b>, Immunosuppression and Whipple's Disease: From a Low-Pathogenic, Environmental Infectious Organism to a Rare, Multifaceted Inflammatory Complex

“…Patients exhibit diminished production of Th1 cytokines in response to T. whipplei and other antigens, but there is an increase in functional Th2 responses [15][16][17][18] . CWD patients show higher numbers of CD4+ T regulatory cells (Treg), elevated secretion of IL-10 and TGF-β in the lamina propria, and peripheral Treg of patients were activated [19] .…”

“…Peripheral IgM and IgG2 subclass levels are often decreased, and IgA is increased in acute stages of the disease [12,15,16,24,25] . The observation of decreased IgG2 levels deserves comment.…”