The expansion of myeloma cells is regulated by cytokines, among which IL-6 is a major growth factor. It has been recently suggested that serum transforming growth factor beta 1 (TGF beta 1), a cytokine found in large amounts in alpha-granules of platelets, might play a role in multiple myeloma (MM). It was the purpose of this study to determine serum TGF beta 1 levels in MM patients and to seek a correlation with disease parameters. Measurements were done by ELISA. We studied 35 MM patients (19 stage II, 16 stage III, 20 IgG, 8 IgA and 6 BJ, 1 IgD) in different phases of the disease, 27 healthy individuals and 17 thrombocytopenic patients with other haematological diseases (three MDS, three congenital thrombocytopenia, 11 ITP). Overall samples from MM patients were included: 10 at diagnosis, 18 in remission and 32 in relapse. In normal controls TGF beta 1 serum levels ranged from 1 to 33 ng/ml (median 16.5 ng/ml). In both thrombocytopenic controls with other diseases and thrombocytopenic MM patients (seven samples), TGF beta 1 serum levels were very low (median 3.2 and 4.5 ng/ml respectively). In MM patients with PLT > 100 x 10(9)/L (53 samples), TGF beta 1 serum levels were in the normal range in patients without immunoparesis (1 to 27 ng/ml, median 16.6 ng/ml), whereas they were higher in patients with immunoparesis (polyclonal immunoglobulins (Igs) below lower normal reference values) ranging from 10.2 to 45 ng/ml (median 26.8 ng/ml) (P < 0.01). Serum TGF beta 1 levels fluctuated in the same patient at different times but not according to relapse or remission. Correlation was found only between serum TGF beta 1 levels and immunoparesis and not between serum TGF beta 1 levels and disease stage or Ig subtype nor with prognostic factors for MM (serum CRP, beta 2M or IL-6). This finding suggests that the remaining normal plasma cells are sensitive to the inhibitory action of TGF beta 1 on Ig production. In conclusion TGF beta 1 serum levels are very low in thrombocytopenic patients confirming that platelets are the major source of this cytokine. Furthermore, a strong correlation was found between TGF beta 1 serum levels and immunoparesis in MM patients.

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We investigated peripheral blood T-lymphocyte subpopulations and intracellular expression of IFN-g, IL-4, IL-10, and IL-13, by whole blood flow cytometry, in 22 type I Gaucher disease (GD) patients. Results were compared with those of 19 sex-and age-matched controls. Patients with GD exhibited decreased frequencies and absolute numbers of CD3+/CD4+ helper T lymphocytes (40.8 AE 9.8% vs. 49.4 AE 5.7%, p ¼ 0.002, and 0.77 AE 0.33 vs. 1.04 AE 0.28 Â 10 9 /mL, p ¼ 0.011), as well as increased frequencies of CD3+CD8+ suppressor T lymphocytes (23.8 AE 8.0% vs. 18.4 AE 3.8%, p ¼ 0.010), resulting in a significantly decreased CD4/CD8 cell ratio (p < 0.001). Moreover, they had significantly increased percentages of IFNg-producing both CD4+ and CD8+ T cells (p ¼ 0.0003 and p ¼ 0.023, respectively), implying a TH-1 polarization pattern. Finally, patients with GD had decreased percentages and absolute numbers of CD4 +CD25 dim T lymphocytes (p ¼ 0.033 and p ¼ 0.007, respectively), of CD4+CD25 high T lymphocytes (p ¼ 0.039 and p ¼ 0.016, respectively), and of CD4+CD25 high FOXP3+ regulatory T cells (p ¼ 0.036 and p ¼ 0.019, respectively). Our results demonstrate that patients with GD have a significant numerical impairment of T-helper lymphocytes and a constitutive TH1 direction pattern of activation of both CD4+ and CD8+ cells, associated with a significant decrease of T-regs. Ineffective T-cell control may explain the chronic inflammatory reaction and the increased incidence of lymphoid malignancies, which have been repeatedly reported among patients with GD.

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Patients with Gaucher disease exhibit substantial evidence of impairment of their immune system, namely, increased serum levels of proinflammatory cytokines and immunoglobulins, and increased incidence of B-cell malignancies, such as non-Hodgkin’s lymphoma, MGUS and multiple myeloma. We investigated peripheral blood T-lymphocyte subpopulations with dual color flow cytometry, as well as the direction of T-lymphocyte activation, by using intracytoplasmic immunostaining for IL-2, IL-4, IL-10 and IFN-gamma, on resting CD4+ and CD8+ T-lymphocytes and following activation with PMA- 1 with the presence of Brefeldin-A. Evaluations were performed on 16 patients with type I Gaucher disease and on 17 healthy controls. Patients had significantly decreased absolute lymphocyte count (1621±684 vs 2148±566/mm3, p=0.013), CD3+ (1197±478 vs 1508±431/mm3, p=0.045) and CD4+ T-lymphocytes (658±245 vs 945±253/mm3, p=0.021), but not CD8+ T-lymphocytes (491±331 vs 486±189/mm3, p: n.s.), resulting in a significant reduction of the CD4/CD8 ratio (1.59±0.68 vs 2.16±0.83, p=0.041). The populations of naive CD4+CD45RA+ and of memory CD4+CD45RO+ T-lymphocytes were also significantly decreased (218±128 vs 432±179/mm3, p=0.0005 and 484±185 vs 631±231/mm3, p=0.056 respectively), however, CD8+CD45RA+ and CD8+CD45RO+ subpopulations did nor differ significantly, when compared to controls. CD3−CD56+, but not CD3+CD56+ lymphocytes were also decreased (131±82 vs 199±97/mm3, p=0.037). Patients had higher percentages of CD8+ (29.2±9.7 vs 23.5±6.8%, p=0.042), CD8+CD45RA+ (22.1±6.2 vs 18.3±5.0%, p=0.046) and CD8+CD45RO+ T-lymphocytes (13.2±6.2 vs 9.6±3.7%, p=0.027), as well as of activated CD8+HLA-DR+ (0.93±0.68 vs 0.48±0.21%, p=0.008) and CD4+HLA-DR+ T-lymphocytes (1.77±0.93 vs 1.09±0.48%, p=0.008). Moreover, although both, the absolute number and the percentage of CD20+ B-lymphocytes were similar, patients exhibited significantly increased absolute number and percentage of CD5+CD20+ B-lymphocytes (1.63±0.55 vs 0.64±0.37% p=0.00002 and 29±20 vs 13±8/mm3, p=0.011, respectively). Finally, patients with Gaucher disease had significantly increased resting TH2-polarized CD4+T-lymphocytes (CD4+IL-10+: 0.41±0.29 vs 0.24±0.11%, p=0.045) and TH1-polarized CD8+ T-lymphocytes (CD8+IFNγ+: 0.15±0.07 vs 0.08±0.04%, p=0.005, CD8+IL10+: 0.22±0.08 vs 0.32±0.014, p=0.052, and IFNγ+/IL4+ ratio among the CD8+ population 2.54±2.1 vs 1.08±0.91, p=0.018). Following mitogenic activation a very significant impairment of obtaining the TH1 phenotype was observed (CD4+IL2+ lymphocytes 33.7±17.1 vs 65.4±6.1%, p&lt;0.00001). The above findings suggest that in patients with Gaucher disease there is a significant numerical impairment of T-helper lymphocytes and a shift towards TH-2 direction of lymphocyte activation. These findings may explain the rarity of autoimmune manifestations despite the chronic inflammatory reaction, as well as the increased incidence of lymphoid malignancies, which has been reported among patients suffering from this disease.