HCV tropism

Lymphocytes

Hepatocytes

Figure 1. Oncogenic potential of the chronic HCV infection. (SS: Sjogren's syndrome, MC: mixed cryoglobulinemia, CH: chronic hepatitis/cirrhosis).

is common in SS but full evidence for an antigen-driven B-cell expansion has not been demonstrated. De Vita et al. [79] described a low-grade gastric lymphoma concomitantly with H. pylori infection in a patient with SS. After H. pylori eradication, a dramatic regression of gastric lymphoma into chronic gastritis was observed, but no amelioration occurred in the parotid and nodal involvement. Multiple molecular analyses showed the expansion of the same B-cell clone in synchronous and metachronous lymph node, parotid, and gastric lesions before and after H. pylori eradication. Other authors [80] studied the gastric tissue in SS in order to define whether the presence of MALT in the stomach is associated with several infectious agents, and showed that H. pylori infection is not more frequent among patient with SS than in controls, and that the abnormal accumulation of MALT may occur in the stomach even in the absence of H. pylori infection. Other studies performed on a limited number of SS patients with simple dyspepsia indicate that clonality may persist for up to six months after the eradication of H. pylori. [81], Thus, although H. pylori may play a crucial role in the local boosting of B-cell lymphoproliferation, the underlying B-cell disorder seems to be a nonmalignant process. [79]

4.1.3. Molecular Pathogenesis

4.1.3.1. Apoptosis

Although interstitial lymphocytes of salivary gland tissue from patients with primary SS may show in situ apoptosis, recent investigations described that these lymphocytes have significantly less apoptosis in spite of a high expression of Fas [24] and that the progression of SS from benign to malignant lymphoproliferation may be related to suppression of apoptotic death by be 1-2 [82]. The possible mechanisms explaining this blocked apoptosis in SS salivary gland are under study and could involve abnormalities in bcl-2-related gene products, cytokines such interleukin (IL)-10, adhesion molecules and costimulatory molecules (CD80/CD28) [83], In order to elucidate the mechanism of the progression from polyclonal to monoclonal lymphoproliferation in patients with SS, Takeshita et al. [84] analyzed the monoclonal nature and the expression of bcl-2 protein in the salivary glands and found that 36 out of 45 patients showed small areas of bcl-2 expression in periductal lymphocytes of lip biopsy specimens. Other authors [82] found that the lymphocytes from the lymphoepithelial lesion in the major salivary glands of patients with SS expressed the oncogene bcl-2 protein. We may conclude that the expression of bcl-2 protein in the cells plays a crucial role in the cells escaping apoptotic cell death, living long and resulting in autoantibody production, and thus producing an increased risk of monoclonal proliferation of the cells [84],

4.1.3.2. Cytokines

Perpetuation of the immune response within the SS glands also depends on production of cytokines by both lymphocytes and epithelial cells. Local cytokine networks probably play a contributory role in the development and evolution of B-cell lymphoprolifer-ation, and continued stimulation of such B cells in the glandular microenvironment may promote their transition to lymphomas. Several cytokines such as IL-1, IL-3, IL-6, IL-10, tumor necrosis factor (TNF)-a and TNF/3 are known to behave like autocrine growth factors for B lymphocytes. Conversely, IL-2, IL-4 and IL-13 stimulate B-cell proliferation almost exclusively in a paracrine fashion [85]. Determination of the relative growth-promoting activities of these cytokines is often difficult since more than one lymphokine may play a role, and the effects on the proliferation of B lymphocytes may vary according to the activation or differentiation state of these cells.

De Vita et al. [86] described a putative pathobio-logical role of the IL-12/IL-4 balance, in the presence of cytokines that may sustain B-cell proliferation (i.e., IL-3, IL-6, IL-10), in prelymphomatous and definite lymphomatous SS lesions (which might be then implicated in lymphoma progression in this disease).

Patients with chronic lymphocytic leukemia (CLL) show a specific circulating B cell that expresses a cell surface marker normally associated with T cells, the CD5+ (Leu-1) molecule [87]. The role of CD5+ B cells in human and murine autoim-mune/lymphoproliferative disorders has recently attracted much interest [88-89], and evidence is emerging that CD5+ B cells belong to a developmental lineage distinct from that of conventional B cells and mainly participate in natural immunity. Since CD5+

B cells are probably the source of rheumatoid factor (RF) in patients with RA [90] and the proliferating cells in CLL [91], it has been suggested that this subgroup of B cells may be implicated in the oligo-clonal/monoclonal expansion seen in S S. In fact, it has been demonstrated that CD5+ B cells are increased in both the peripheral blood [92] and salivary infiltrates of patients with SS [91, 93-98]. B cells, expanded under selective pressure through an antigenic or T-cell-driven process, may represent a precursor of CD5+ lymphomas in SS (i.e., small lymphocytic lymphoma and MCL) [83]. Interestingly, the percentage of these cells has been shown to be higher in primary SS patients with circulating IgMk monoclonal component than in those without [93], and remission of malignant lymphoma in some patients with primary SS has been shown to be accompanied by restoration of CD5+ B-cell levels to normal [94], Perhaps the lympho-proliferation in primary SS is highly selective and a distinct subpopulation of B cells, possibly those expressing the CD5+ molecule. Therefore, CD5+ B lymphocyte may be the element playing the central role in the progression from SS to B-cell lymphoproliferation [99],

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