Monoclonal Selection

Physiologically, humoral immune response to an antigen involves the activation of several B-cell clones producing immunoglobulins with different heavy and light chains. Studies carried out in animal models as well as in humans have shown that the appearance of B-cell clonality may occur in the context of a preexisting polyclonal lymphocyte proliferation, probably induced by continuous exposure to either autoantigens (favored by altered self-tolerance) or exogenous antigens such as those associated with persistent infections (e.g., viruses, malaria, H. pylori) that may be responsible for the induction and sustaining of polyclonal lymphoproliferation. Thus, the direct infection of B cells by oncogenic viruses (EB V, HCV) may also induce the clonal expansion of virus-carrying cells.

Benign lymphoproliferative disorders are generally composed of a mixture of polyclonal B and T cells and small numbers of other mononuclear cell populations. The benign lymphoepitelial lesions that are characteristic of SS are composed of a majority of CD4 T-cell lymphocytes [100] and a minority of B-cell lymphocytes that are often oligoclonal [90, 101],

While peripheral blood B cells from patients with SS do not spontaneously secrete increased amounts of immunoglobulins, B cells infiltrating the target issue (i.e., the epithelial cells of the exocrine glands) produce large amounts of immunoglobulins with RF activity. Previous studies have indicated that the poly-clonally activated B cells in patients with primary SS are mainly localized in the affected exocrine glands [10, 102, 103]. Data obtained by Moutsopoulos et al. [104] indicated that the B cells from minor salivary gland infiltrates of patients with SS have a common idiotype with the MIgs from patients with B-cell lymphoid malignancies, thus suggesting that neoplastic transformation in primary SS may start in the exocrine glands [43]. The finding of an association between serum IgMk monoclonality and an increased proportion of k-positive plasma cells in salivary glands of patients with SS [104] also indicates that the affected exocrine glands are the main area of monoclonal B-cell activity. The reports of Ig- and T-cell antigen receptor-gene rearrengements in salivary gland lymphocytes of patients with SS have confirmed that oligoclonal lymphocyte expansion is a feature of the exocrinopathy, even before any overt malignancy develops.

Although B cells represent a minority of SS tissue lymphoid infiltrates, they may undergo polyclonal activation and oligomonoclonal expansion, which may in turn predispose to an as yet undefined B-cell neoplastic transformation event [105]. Monoclonality in SS arises mainly from salivary glands, but may arise also from visceral organs and lymph nodes. The earlier phases of lymphomagenesis therefore may be characterized by the appearance of a clonal expansion of immortalized but not fully malignant B lymphocytes which may persist in involved tissues for variable periods of time. Subclones characterized by proliferative advantages are then selected within the lesion and are responsible for the shift towards a more malignant phenotype. The lymphomas in SS may home to multiple MALT sites and may be detectable at a very early stage in the salivary glands.

4.3. Monoclonal Overexpansion

The observation that the activated B lymphocyte is located mainly in the salivary glands, in association with other factors which may promote neoplasia in the salivary gland lesion (e.g., the absence of natural killer cells), prompted several studies to determine the monoclonal B-cell subsets in the minor salivary gland infiltrates of SS patients responsible for the production of MIgs [27]. In 1982, Schmid et al. [106] suggested that the benign lymphoepithelial lesion of SS salivary glands with areas of confluent lymphoid proliferation contains plasma cells with cytoplasmic monoclonal IgMk immunoglobulins and represents in situ malignant lymphoma. Subsequent studies [49, 90, 104] suggested that the salivary glands in SS patients may serve as the initial site of B-cell neoplastic transformation.

Fishleder et al. [90] found in benign lymphoepithelial lesions of parotid and submandibular gland, removed two years later from the same patient with SS, that the rearrangements of the heavy chain and the k light chain genes were entirely different, thus making highly unlikely that the B-cell clone identified in the second lesion evolved from the first. Different immunoglobulin gene rearrangements in the same patient with benign lymphoepithelial lesions of different major salivary glands have also been observed by Freimark et al. [49]. However, the observation of Bodeutch et al. [107] that multiple separated minor salivary glands of labial salivary gland tissue biopsy specimen are populated by monotypic plasma cells of the same isotype (IgMk) or even of different isotypes in different glands in one of their patients (IgMk and IgAk) supports the hypothesis that monotypic plasma cell populations in the salivary glands of patients with SS are not the result of a clonal expansion of a single neoplastic changed lymphoid stem cell. All aforementioned observations support the hypothesis that monotypic plasma cell populations appear after a latency period in the labial salivary gland tissue and probably also in other exocrine glands in some patients with SS and with an initial polytypic plasma cellular infiltrate. This switch from a polytypic into a monotypic plasma cell infiltrate in many different glands cannot be attributed to neoplastic changes. A more likely explanation is that the exocrine glands in a subpopulation of patients with SS are homed by primitive B cells, which are liable to homeostatically regulated clonal expansions after prolonged antigenic stimulation by modified parenchymal cells in the target organs, and that this phenomenon is accompanied by an increased risk to develop systemic monoclonal lymphoproliferative disorders.

However, B cells from other organs rather than salivary glands must also be carefully evaluated for the presence of B-cell monoclonal expansion. To better characterize the prelymphomatous stages of B-cell lymphoproliferation in SS, De Vita et al. [108] studied multiple tissue lesions (synchronous from different tissues and metachronous from the same tissue) of 6 consecutive patients with SS who had an associated lymphoproliferative disorder, and evaluated the persistence and dissemination of the same B-cell clone, as well as the estimate of the "size" of the expanded B-cell clone(s) during the disease. By molecular analyses of synchronous biopsy specimens, the local overexpansion of the same B-cell clone may be detected in multiple sites. In contrast, in the majority of SS patients, dominant bands of different molecular weight were observed in synchronous biopsy samples from different tissues, indicating different dominant B-cell clones in different microenvironments. The analysis of the metachronous biopsies have shown that B-cell clonal overexpansion is frequently multifocal and fluctuating in SS, since different clones predominated not only in different tissues (synchronous biopsy tissue), but also in the same affected tissue at different times (metachronous biopsies). The authors provided conclusive evidence that clonal B-cell expansion is a frequent event in SS, but may be either oligoclonal or monoclonal, either smaller or larger in size, either fluctuating or established, or either localized or disseminated. Importantly, these different events conceivably imply a different risk of lymphoma progression, though they may all occur under the same pathologic diagnosis of lymphoproliferative lesion.

In summary, lymphoproliferation in SS patients follows a multistep etiopathological process (Fig. 2). The first step may be a noxious infective agent (EBV, HCV... ). The antigenic stimulus caused by viral infections, which may be attributed to viral antigenic products or, alternatively, to desegregated or cross-reactive autoantigens (for instance through the mechanism of molecular mimicry), may enhance the activity of specific helper T-cell clones and, consequently, may cause the polyclonal activation of B cells. The production of different types of autoantibodies is the result of this polyclonal B-cell hyperactivity, together with the overproduction of soluble immune complexes or cryoglobulins. In the subsequent phase, some B-cell clones may selectively proliferate, thus inducing the production of MIgs—usually IgMk with RF activity—which can be detected in the serum and in type II cryoglobu lins. Minor populations of B or T cells may clonally expand in the salivary gland tissues of SS patients, and such lymphocyte expansions may be controlled by the endogenous immune response and/or medications. However, continued lymphoproliferation in these salivary gland tissues may eventually lead to emergence of a neoplastic clone, maybe a particular B- or T-cell clone with a karyotipic underlying alteration, that escapes immunologic control and develops into a NHL as a result of a multistep process [49],

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