Impaired T-Lymphocyte Subpopulations and Deranged Profile of Immunologic Activation in Patients with Gaucher Disease Type I

Abstract

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<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.