Objective. To prospectively investigate whether mixed monoclonal cryoglobulinemia (MMC) and monoclonal rheumatoid factor (mRF)-associated crossreactive idiotypes (CRI) serve as predictive factors for the development of lymphoma in patients with primary Sjogren's syndrome (SS).Methods. One hundred three consecutive patients with primary SS were evaluated from 1986 to 1991. In all patients, the amount of cryoglobulin was measured by ultraviolet absorption at 280 nm and 260 nm. The type of cryoglobulinemia was identified by agarose gel electrophoresis, combined with immunofixation. Sera from all patients were evaluated by enzyme-linked immunosorbent assay, using the corresponding monoclonal or polyclonal antibodies, for the presence of immunoglobulins bearing the idiotypes 17109 (VdIIb associated), G-6 (V,1 associated), and 3rd SS (a rabbit polyclonal antibody raised against the Fab fragment of an IgMK mRF' from a patient with primary SS). Data analysis was performed by logistic regression.Results. Eighteen of the patients with primary SS (17.4%) had MMC during the first evaluation. There was a statistically significant correlation between the presence of MMC and a higher prevalence of autoantibodies to Ro/SS-A and LdSS-B, as well as extraglandular manifestations. During a 5-year period, 7 patients developed lymphoma. Six of the 7 (86%) had MMC before the appearance of lymphoma, compared with 12 of 96 (12.4%) of the remainder (r = 0.421, P < 0.0009).Patients who developed lymphoma had higher amounts of cryoglobulin than those who did not (mean f SD 53.4 f 44.7 mg/dl versus 26.8 f 20.6 mg/dl). CRIs 17109 and G-6 were also correlated with lymphoma development (r = 0.321, P < 0.006 and r = 0.22, P < 0.03, respectively). For both CRIs, this correlation was dependent on the presence of MMC, since a stepwise multiple comparison analysis revealed that their individual significance was abolished when their correlation with lymphoma in association with MMC was assessed.Conclusion. The determination of MMC can be used as a laboratory predictive factor for lymphoma development in primary SS. CRIs 17109 and G-6 may also be used to predict lymphoma development, especially when the monoclonal component is absent.

The pattern of cytokine mRNA expression in frozen minor salivary gland tissues from patients with primary Sjögren's syndrome (pSS) (n = 12) and controls (n = 8) using an in situ hybridization technique and oligonucleotide probes of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha and beta (TNF-alpha and TNF-beta), interleukin-6 (IL-6), interleukin-2 (IL-2) and its receptor (IL-2R), interleukin-4 (IL-4), interleukin-10 (IL-10), interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) was examined. In addition to in situ hybridization, immunohistochemistry was used to identify the subset of cells expressing IL-2 and IL-4 mRNA. Mononuclear cells involved in the minor salivary gland lesions of pSS patients were found to express mRNA for pro-inflammatory cytokines such as TNF-alpha and IL-1 beta, and cytokines involved in the regulation of B- and T-cell function (IL-2 and IL-6). In contrast, only three biopsies from patients with pSS express mRNA of inhibitory cytokines such as IFN-gamma and TGF-beta. Furthermore mRNA for IL-6 and IL-1 beta was also detected in the glandular epithelial cells suggesting that these cells may play a role in the pathogenesis of autoimmune lesion in Sjögren's syndrome. IL-10 mRNA was not detected while IL-4 mRNA was primarily detected in naïve T-lymphocytes of patients with a mild and early lesion. These results suggest that local production of cytokines by both mononuclear and epithelial cells may be involved in the immune-mediated destruction of exocrine glands in patients with pSS.

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A comparison of the presence of two idiotypes, one identified by a rabbit polyclonal antiidiotypic antibody, first found on a cryoprecipitable IgM chi rheumatoid factor (RF) from an SS patient (3rd SS) and the 17109 idiotype, identified by a monoclonal antibody was performed in 106 sera and eight minor salivary gland biopsies of Sjögren's syndrome (SS) patients and 125 sera from age-sex matched normal controls. Of 106 of SS patients' sera 36 had immunoglobulins positive for the 3rd SS idiotype. 17109 activity was more prevalent in SS patients positive for the polyclonal anti-idiotype 3rd SS, than those with negative idiotype (9/36 VS 2/70 chi 2 = 12.53 P less than 0.005). Cross inhibition studies, however, revealed that the polyclonal anti-idiotype binding was not inhibited by the 17109 moAb. 3rd SS and 17109 anti-idiotypes were reacted with immunoglobulins in the serum of 3.5% and 1.7% of normal human sera respectively. Immunohistologic studies demonstrated that 4/8 and 2/6 minor salivary gland biopsies had infiltrating plasma cells containing immunoglobulins bearing the 3rd SS and the 17109 idiotypes, respectively. The inheritance of both idiotypes was investigated in sera of 4 SS kindreds. In two kindreds with 3rd SS positive probands, the idiotype was detected in 3 first degree relatives of the same generation. 17109 activity was detected in the serum of a sister of the positive proband who had a high RF titer. These results suggest that the 17109 moAb recognizes a different epitope of that of the 3rd SS. The idiotypes of monoclonal RFs are not inherited and probably are produced by plasma cells infiltrating the labial minor salivary glands of SS patients.

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