Umberto Dianzani

CD38: A multi-lineage cell activation molecule with a split personality

SummaryThis review reports the characteristics of the human surface molecule CD38, a structure not linked to a definite line and predominantly expressed in early and activated phenotypes. The CD38 molecule consists of a single chain of 46 kDa, spanning the membrane and with the carboxyl terminus located in the extracellular compartment. The CD38 molecule is also involved in the transduction of activation and proliferation signals, which are line unrestricted. The gene coding for the CD38 antigen has been cloned and used for the construction of simian and mouse transfectants expressing the human molecule. These cell models are used for the analysis of several unanswered issues, mainly concerning the in vivo function of CD38, the existence of a natural ligand and of polymorphism in the population.

Human myeloma: Several subsets of circulating lymphocytes express plasma cell-associated antigens

Peripheral blood lymphocytes from 9 monoclonal gammopathies of undetermined significance (MGUS) and 27 multiple myelomas (MM) were studied with a panel of monoclonal antibodies (MoAb) that recognize B and T lymphocytes and plasma cells. No difference in the percentage of B lymphocytes, identified by B1 and B4 MoAb, was observed in MGUS and MM patients versus normal controls. However, high percentages of circulating lymphocytes expressing plasma cell‐associated antigens were detected in MM (HAN‐PC1 + = 29.4 ± 20.4%; TEC‐T10+ = 27.8 ± 19.2%) whereas they were in the normal range in MGUS (HAN‐PC1 + = 8.8 ± 5.8% p = 0.006; TEC‐T10+ = 5.7 ± 4.7% p<0.001). Almost identical results were obtained using PCA‐1 MoAb in 17 of these patients. TEC‐T10+ and PCA‐1 + lymphocytes were sorted and re‐analyzed with phycoerythrin conjugated MoAb in 3 healthy subjects, 2 MGUS, and 4 MM patients. In normal subjects and in MGUS the majority of PCA‐1 + cells belonged to the B lineage (Leu 2‐, Leu3‐, Leu 15‐, HLA‐Dr +), whereas the majority of TEC‐T10+ cells are represented by activated T cells and NK cells (Leu 15 +). In MM an abnormal expansion of T lymphocytes was chiefly responsible for the high values of lymphocytes expressing plasma cell‐associated antigens. Moreover, in MM a clinical evaluation showed a correlation between the presence of these lymphocytes and an aggressive disease. Indeed, they can be considered a useful prognostic marker.

Defective interleukin-2 induction of lymphokine-activated killer (LAK) activity in peripheral blood T lymphocytes of patients with monoclonal gammopathies.

The recombinant interleukin‐2 (rIL‐2) generation of lymphokine‐activated killer (LAK) cells wasinvestigated in peripheral blood T lymphocytes (PBT) of 16 patients with monoclonal gammopathyof undetermined significance (MGUS) and 32 patients with multiple myeloma (MM). LAK activitywas significantly decreased in MM. but not in MGUS patients, and was partially recovered in MM inthe remission phase. This finding was unexpected, because CD8+ CD11b+ cells, which contain LAKprecursors, are significantly increased in MM. LAK activity was investigated in purifiedCD8+ CD11b+ lymphocytes to discriminate between an intrinsic defect or a defective regulation byother T cell subsets. These cells were intrinsically unable to generate LAK activity fully followingrIL‐2 stimulation. MM showed the more pronounced LAK deficiency, while MGUS patients showedintermediate values. Phenotyping revealed significantly increased proportions of Leu7+ and HLA‐DR+ cells in MM patients. These data reveal another dysregulation of T cell effector functions inpatients with monoclonal gammopathies and offer further evidence of the impairment of their cell‐mediated immunity.

Biochemical and immunologic abnormalities in peripheral blood T lymphocytes of patients with hemophilia A

Subset distribution, ecto‐5′nucleotidase (5′NT) activity, and the generation of allospecific cytotoxic T lymphocytes (CTL) were investigated in peripheral blood T lymphocytes from 39 hemophilia A patients divided into three groups: group A and group B (HIV‐patients with CD4:CD8 ratio < 1 and > 1 respectively), and group C (HIV+ patients). 5′NT activity was significantly decreased compared with healthy controls in groups B and C. In group B, this deficiency was attributable to expansion of CD8+ CD11+ suppressor cells. In group C, activated (HLA‐DR +) CD8+ cells were also present and contributed to 5′NT deficiency. The suppressor cell expansion seemed to be mainly related to AHF infusions, whereas HLA‐DR expression was related to HIV infection. CD11+ and HLA‐DR + cells were also expanded in the CD4+ subpopulation of all three groups, whereas CD4+ CD28+ lymphocytes were significantly decreased in group C only. Lastly, alloreactive cytotoxicity was decreased in group B and was normal in groups A and C.

Amplification of T Cell Activation Induced by CD73 (Ecto-5′Nucleotidase) Engagement

In the last years, the surface 69 kD differentiation antigen CD73 has been demonstrated to play a significant role in the activation of human T cells. Unlike other surface molecules involved in T cell activation, CD73 combines three distinct features: i) it has ecto-5′nucleotidase (5′NT) activity (E.C. 3.1.3.5); ii) it is linked to the cell membrane via a glycosyl phosphatidylinositol (GPI) anchor; iii) it can very effectively amplificate T cell activation even if it is expressed by a minority only (15–25%) of T cells.

Monoclonal Immunoglobulin Gene Rearrangement in Peripheral Lymphocytes of a Patient with Multiple Myeloma

We analyzed the immunoglobulin (Ig) heavy chain gene rearrangement in the peripheral blood lymphocytes of a patient with multiple myeloma (MM). Although the morphological and immunological examination did not reveal the presence of circulating plasma cells, a monoclonal Ig gene rearrangement was detected. This observation indicates that a monoclonal expansion of circulating B cells was present in the peripheral lympocytes of this patient.

Immunologic and virologic findings in hemophiliacs do not correlate with ecto-5′nucleotidase activity of peripheral blood lymphocytes. A difference with homosexual men

It has been recently demonstrated that ecto‐5′nucleotidase (5′NT) activity is significantly decreased in the peripheral blood lymphocytes (PBL) of homosexual men. This paper reports a study of PBL 5′NT activity in 38 hemophiliacs at risk for the acquired immunodeficiency syndrome (AIDS). The enzyme activity was correlated to the immunologic and virologic data. T‐cell subset distribution was unbalanced and directly correlated with the cumulative amount of AHF infused. PBL 5′NT activity, however, was similar to that of healthy controls. 6 patients displayed serum antibodies to the human immunodeficiency virus (HIV) but no decrease in PBL 5′NT activity. In conclusion, these data indicate that both heavily treated and seropositive as well as untreated hemophiliacs have normal PBL 5′NT activity. This striking dissimilarity between homosexual men and hemophiliacs suggests that some immunologic alterations leading to 5′NT deficiency occur in the former only.

Advances in biology of multiple myeloma : cell kinetics, molecular biology and immunology

Bone marrow plasma cell proliferative activity has been evaluated in a large series of multiple myeloma (MM) patients. This kinetic parameter has been shown to be a useful tool for patient management, and contributes to a correct diagnosis and a selection of high‐risk patients who can be offered high‐dose chemotherapy. The role of ras oncogenes has been evaluated in the pathogenesis of MM. A point‐mutated and activated H‐ras oncogene, introduced in a human lymphoblastoid cell line, was able to induce neoplastic transformation and differentiation to plasma cell. Indeed, mutated alleles of ras genes have been detected in a high percentage of myeloma patients in relapse phase. Phenotypical and functional studies have been carried out in T‐lymphocyte subsets and an impaired cellular immunity has been detected. Such an impairment was related to the disease status: marked alterations were detected in relapse phase, whereas a partial recovery was observed during remission phase.