Diagnosis 71 Detection of MIgs

MIgs represent the unique product of a single clone of relatively mature B lymphocytes or plasma cells. The presence of an MIg does not in itself demonstrate the existence of a malignant B-cell lymphoproliferative disorder and only indicates the presence of one or more clonal population(s) of B cells able to produce a homogeneous immunoglobulin. Screening for

MIgs is commonly performed by serum protein electrophoresis on cellulose acetate or agarose gel, that in the majority of cases allows the detection of an electrophoretically homogeneous band resulting from the accumulation in the serum of immunoglobulin molecules with restricted electric charge heterogeneity, which thus migrate within a narrow zone on the electrophoretogram.

Over the past several years, it has been demonstrated that the essential characteristic of the transition process from the autoimmune state to malignant lym-phoproliferation is the presence of MIgs in the sera and urine of patients with SS before the development of an overt lymphoma. High resolution electrophore-sis/immunofixation has proven to be of great value in the screening and characterization of serum and urine MIgs associated with SS [153, 154], Moutsopoulos et al. [154] disclosed in 1983 that patients with SS have a high incidence of circulating monoclonal free light chains in the serum. In those cases in which lymphoma develops, the level of urinary free light chains may correlate with disease activity [97], In SS, the value of serum and/or urine MIgs in predicting the risk of developing lymphoma has been clearly demonstrated [97], The detection of MIgs or light chains showed that a B-cell clonal expansion may be present early in a number of patients with SS, coexisting with a polyclonal B-cell activation [7, 105, 155].

The monoclonal origin of the monotypic plasma cells in autoimmune sialadenitis has been confirmed by immunoglobulin gene rearrangement studies [49, 90] but evidence of monoclonality does not represent necessarily the existence of lymphoid malignancy. Several studies showed that oligoclonal B-cell expansion is present in the early minor salivary lesions of patients with SS in the absence of progression to pseudolymphoma or lymphoma. Pablos et al. [101] studied 13 unselected SS patients with early minor salivary lesions and disclosed B-cell clonal expansion in all of them. In the follow-up, all were free of lymphoproliferative disease. Bahler et al. [156] found that different biopsies from the same patient may contain distinct clones indicates that some myoepithelial sialadenitis (MESA) associated does have not yet evolved to malignant lymphomas. This finding contrasts with the view of B-cell clonal expansion as an early marker of malignancy, and therefore does not support the use of aggressive therapy in these patients [97, 157, 158],

7.1.1. Monoclonal rheumatoid factor

Most patients with SS present high levels of RF in their sera [20,159]. Previous studies, using polyclonal anti-idiotypes have shown that monoclonal RF share cross-reactive idiotypes (CRI) [160, 161] that had been originally classified into three CRI groups, Wa and Po, that include 60 and 20% of monoclonal RF, respectively [160], and the Bla group, which defines a minor subgroup [161]. Furthermore, with the use of the hibrydoma technology, monoclonal antibodies to idiotypic determinants on intact light or heavy chains of human monoclonal RF were developed [162-164].

The majority of SS patients express a CRI on the k chains of their RF molecules that is defined by a monoclonal antibody (MoAb 17-109) [43]. The 17-109 MoAb reacts with monoclonal RF which belong to the Wa idiotypic family and bear remarkably similar x light-chain variable regions belonging to the VxIIIbx-L chain subgroup and more specifically to a highly conserved humkv 325 gene [165]. In addition, the prevalence of 17-109 reactive B-lymphocytes within the infiltrated salivary glands of patients with SS are approximately 10-fold higher than that of lymph modes from age matched [43]. In patients with SS, the high levels of 17-109-positive RF molecules may reflect intrinsic B- or T-cell defects, or both. Intrinsic B-cell defects could result in preferential selection of a particular light-chain variable region gene [166] and/or the failure to diversify this gene by subsequent somatic mutations [167], T-cell defects might include excessive T helper-cell function or the failure to suppress particular B-cell clones. The increased frequency of B cells reactive with MoAb 17-109 in SS may be part of a generalized disorder in immunoregulation, because these patients have a high incidence of free light chains [154] and paraproteins in their sera and urine [168-170], and, in most cases, IgM monoclonal RF from the sera, and cryoprecipitates of patients with SS expressed the epitope associated with the Vklllb variable region. This expression was evident in the early stages of the disease and persisted during the disease course [171].

7.1.2. Monoclonal cryoglobulins

Mixed cryoglobulins are cold precipitable proteins containing IgG and anti-IgG rheumatoid factor, usually an IgM of monoclonal (type II) or polyclonal (type

Ill) origin [172] . Cryoglobulins have been observed in a wide variety of diseases, including malignancies, infections and systemic autoimmune diseases [173]. Since the first report of cryoglobulinemia in a patient with S S [174], some studies on the prevalence and clinical significance of cryoglobulins in primary SS patients have been performed. The prevalence of cryoglobulinemia in primary SS has ranged from 5 to 61% [104, 154, 175-179], Further characterization of the cryoprecipitates demonstrated a IgMk monoclonal RF in most of the cryoglobulins that presented the SS patients [27, 175, 179], We have found [179] that the presence of leukocytoclastic cutaneous vasculitis, hypocomplementemia and HCV infection are independently associated with the presence of cryoglobulins in the sera of patients with SS.

In patients with SS-associated type II cryoglobulinemia, the same monoclonal k light-chain B cells have been observed in salivary glands [104], Mout-sopoulos et al. [104] described that over half of the patients with circulating IgMk monoclonal cryoglobulins (type II) have an increased proportion of cells expressing k light chains in their minor salivary gland infiltrates. Tzioufas et al. [180] analyzed the phenotypic expression of the plasma cells infiltrating the minor salivary glands of patients with SS and found that these cells were predominantly k positive, while patients without cryoglobulins or with polyclonal cryoglobulins had an equal number of k and 1 expressing plasma cells [49]. Therefore, it is possible to conclude that the presence of type II cryoglobulin with an IgM monoclonal RF could be considered an early sign of oligoclonal/monoclonal B-cell selection in patients with SS.

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  • ruth
    What is migs disorder?
    8 years ago

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