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Defective repair of

Persistence of Oe-DNA

Of

'-methylguanine-DNA

(carcinogenetic)

Another translocation, t(ll;14), is observed in most cases of mantle cell lymphoma (MCL), involving the immunoglobulin heavy chain locus and the bcl-1 gene on the long arm of the chromosome 11. This translocation results in overexpression of PRAD1 gene, which encodes for cyclin Dl, a cell-cycle protein that is not normally expressed in lymphoid cells [36]. Mucossa-associated lymphoid tissue (MALT) and monocytoid B-cell lymphomas (MBCL) may exhibit a third chromosomal abnormality the trisomy 3, in 50% of the cases [37],

Finally, mutations of the tumor-suppresser activity gene p53 have been observed in lymphomas and have been associated with progression of low-grade MALT lymphoma to high-grade [38], and Guo et al. [39] described recently that a defective repair of 06-methylguanine-DNA in patients with primary SS predisposed to lymphoma. 06-methylguanine mis-pairs with thymine, then DNA replication leads to propagation of a G-to-A transition mutation, a known mechanism of human oncogene activation and tumor suppresser gene inactivation. The persistence of 06-methylguanine-DNA in lymphocytes seems to be carcinogenic and theses lymphoid cells are at risk for transformation to the malignant phenotype.

4.1.2. Infectious Agents

Infectious agents, mainly viruses, may play a etiopathogenic role in the development of lymphoma. Two distinct types of interactions with lymphoid cells may contribute to lymphomagenesis. First, oncogenic viruses such as EBV and HCV can directly infect B cells and drive their proliferation through the expression of virus-encoded transforming proteins. Second, infectious agents can be the source of antigenic de terminants which, in the case of persistent infections, may induce and sustain the proliferation of B cells.

4.1.2.1. Epstein-Barr virus

The EBV, a ubiquitous herpesvirus found in humans, can infect B cells and cause transformation, outgrowth and polyclonal immunoglobulin secretion [40]. It has been shown to be the causative agent in infectious mononucleosis and to be associated with Burkitt's lymphoma, nasopharyngeal carcinoma and X-linked lymphoproliferative syndrome. EBV replicates in the salivary glands and nasopharyngeal epithelia during primary infection and remains latent for the rest of the host's life [41],

A possible role of the EBV in the lymphomagenesis observed in patients with SS has been postulated by several authors, that have found a higher frequency of EBV genes or protein expression in labial salivary gland biopsies from patients with SS in comparison with control subjects [42, 43]. Other authors have found increased levels of EBV DNA in the saliva of SS patients with pseudolymphoma [43] and increased levels of antibodies against EBV early antigen in their sera [44]. Some reports detected EBV in lymphoma-tous tissues. Fox et al. [45] found EBV DNA in 2 out of 5 cervical node NHL's in SS, Jeffers et al. [46] in 3 out of 6 SS associated MALT lymphomas, Royer et al.

[47] in 1 out of 4 parotid lymphomas, Fox et al. [48] in 1 out of 14 NHL in SS patients and Freimark et al. [49] in 1 out of 9 lymphomas arising in the setting of SS. Other authors have not found evidence of EBV in low-grade NHL complicating SS [46].

The EBV is latent in the ductal epithelium of the salivary and lacrimal glands and B cells can be reactivated in patients with SS due to the defective T-cell regulation, and possibly to mutated EBV that escapes recognition by EBV-specific cytotoxic cells [45]. Salivary gland epithelial cells in SS patients express high levels of HLA-DR antigens and may present EBV-associated antigens to immune T cells in patients with SS. Intrinsic, but unknown abnormalities of SS B cells may also contribute to a potent and persistent production of EBV, and the selective expansion of a certain subset of B cells may cause monoclonal lymphopro-liferation [50], SS may represent a situation in which genetically predisposed individuals (i.e., HLA-DR3-DQA4-DQB2) have a persistent but ineffectual T-cell immune response against EBV at its site of latency

4.1.2.2. Human herpes virus-6

The recent isolation of a new member of the herpes virus family (human herpes virus-6, HHV-6) from patients with lymphoproliferative diseases prompted several authors to examine this virus in tissue samples [45] and saliva [51] from patients with primary SS who developed NHL. Jarrett et al. [52] analyzed tissue samples from a patient with a B-cell lymphoma occurring in the context of SS, and found the presence of HHV-6-specific DNA sequences. Fox et al. [53] found HHV-6 DNA in lymph nodes of 1 out of 14 patients.

4.1.2.3. Hepatitis C virus

A possible relationship between HCV—a virus that can be excreted in saliva—and SS was postulated in 1992 by Haddad et al. [54], They reported the occurrence of histologic changes characteristic of SS in salivary glands of patients with HCV infection. Recently, two clinical studies, performed in large series of patients, described the clinical and immunological features of this subset of patients with SS and HCV infection [55, 56]. Furthermore, Koike et al. [57] reported the first experimental evidence of the relationship between SS and HCV infection. These authors found an exocrinopathy resembling SS in the salivary and lacrimal glands of transgenic mice that carry the HCV envelope genes [58]. Taken these findings together, it is conceivable that there is a direct pathogenetic link between SS and HCV infection. On the other hand, the relationship between HCV and lym-phoproliferation has been postulated in recent years, although in 1971 Heimann [59] described the frequent association between liver cirrhosis and lymphoproliferative disorders, suggesting the possible role of hepatotropic viruses in the pathogenesis of both conditions. Twenty-three years later, in 1994, the presence of HCV ongoing replication in both serum and peripheral lymphocytes was first demonstrated in one-third of Italian patients with unselected B-cell NHL, regardless of their different grades of malignancy [60, 61]. Subsequent studies confirmed this higher incidence of HCV infection in NHL [62, 63]. Additional support for the possible association of clonal B-cell expansion and HCV infection has been provided by Franzin et al. [64], who found a high frequency of clonal B-cell expansion in HCV-infected patients, even in the absence of cryoglobulinemia. Finally, the first attempts to localize HCV within the malignant NHL lesion are quite recent [65-66].

De Vita et al. [67] characterized the B-cell lymphomas observed in 35 consecutive patients with HCV infection. They found a definite clinical picture of mixed cryoglobulinemia or SS preceding NHL onset in 5 patients and, when comparing the sites of NHL involvement at onset in patients with primary extran-odal NHL (HCV infected vs. HCV uninfected), liver and salivary involvement were significantly more frequent in HCV-infected patients. Both the liver and the major salivary glands are targets of HCV infection, and their involvement seems to be significantly over-represented in NHL-HCV infected patients, whereas, the localization in these primary organs is extremely uncommon in unselected series of B-cell NHLs [6870],

In summary, HCV may infect and actively replicate within the hepatocytes [71, 72] as well as in the salivary gland epithelium [65], and HCV RNA can be detected in the peripheral blood mononuclear cells of patients with chronic hepatitis C [73]. According to their lympho-, syalo- and hepatotropism, HCV may exert its oncogenic potential in two different directions, leading to B-cell neoplasms (in some cases, there is a previous development of SS or mixed cryo-globulinamia) and liver cancer (Fig. 1). Therefore, it is more appropriate to consider chronic HCV infection as a multisystem clinical syndrome than as a simple liver disease [73-75].

4.1.2.4. Helicobacter pylori

In the last few years, a small Gram negative curved rod denominated Helicobacter pylori has been etio-logically linked to the most important gastroduodenal pathology, including peptic ulcer and gastric carcinoma. Several recent epidemiological and experimental studies have also linked H. pylori to both gastric lymphoid follicles/MALT and MALT lymphoma. Findings reported by different groups demonstrated the dependence of the proliferation of neoplastic lymphoma B cells on the presence of H. pylori specific T cells and the apparent regression of MALT lymphoma after the eradication of H. pylori [76-80], It appears that persistent infection with H. pylori causes organized lymphocyte proliferation which, in turn, can become autonomous and progress to a lymphoproliferative neoplastic disease.

A possible relationship between H. pylori and gastric lymphomagenesis in SS has been recently postulated. Lymphoid accumulation in the gastric mucosa

Salivary glands

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