Indolent natural killer (NK) cell lymphoproliferative disorders include a heterogeneous group of patients in whom persistent expansions of mature, typically CD56 ؉ , NK cells in the absence of any clonal marker are present in the peripheral blood. In the present study we report on the clinical, hematological, immunophenotypic, serological, and molecular features of a series of 26 patients with chronic large granular NK cell lymphocytosis, whose NK cells were either CD56 ؊ or expressed very low levels of CD56 (CD56 ؊/؉dim NK cells), in the context of an aberrant activation-related mature phenotype and proved to be monoclonal using the human androgen receptor gene polymerase chain reaction-based assay. As normal CD56 ؉ NK cells, CD56 ؊/؉dim NK cells were granzyme B ؉ , CD3 ؊ , TCR␣␤/ ␥␦ ؊ , CD5 ؊ , CD28 ؊ , CD11a ؉bright , CD45RA ؉bright , CD122 ؉ , and CD25 ؊ and they showed variable and heterogeneous expression of both CD8 and CD57. Nevertheless, they displayed several unusual immunophenotypic features. Accordingly, besides being CD56 ؊/؉dim , they were CD11b ؊/؉dim (heterogeneous), CD7 ؊/؉dim (heterogeneous), CD2 ؉ (homogeneous), CD11c ؉bright (homogeneous), and CD38 ؊/؉dim (heterogeneous). Moreover, CD56 ؊/؉dim NK cells heterogeneously expressed HLA-DR. In that concerning the expression of killer receptors, CD56 ؊/؉dim NK cells showed bright and homogeneous CD94 expression, and dim and heterogeneous reactivity for CD161, whereas CD158a and NKB1 expression was variable. From the functional point of view, CD56 ؊/؉dim showed a typical Th1 pattern of cytokine production (interferon-␥ ؉ , tumor necrosis factor-␣ ؉ ). From the clinical point of view, these patients usually had an indolent clinical course, progression into a massive lymphocytosis with lung infiltration leading to death being observed in only one case. Despite this, they frequently had associated cytopenias as well as neoplastic diseases and/or viral infections. In summary, we describe a unique and homogeneous group of monoclonal chronic large granular NK cell lymphocytosis with an aberrant activation-related CD56 ؊/؉dim /CD11b ؊/؉dim phenotype and an indolent clinical course, whose main clinical features are related to concomitant diseases. (Am J

ABSTRACT:In the present study we have compared the immunophenotypic characteristics of the CD56 ϩlo and CD56ϩhi NK-cell subsets in a group of normal healthy adults. Our results show that CD56 ϩhi NK-cells display greater light-scatter properties than CD56ϩlo NK-cells at the same time they have higher levels of CD25 and CD122 IL-2 chains, together with a higher reactivity for HLA-DR and CD45RO and lower levels of CD45RA, supporting that, as opposed to the majority of the CD56 ϩlo population, CD56 ϩhi NK-cells might correspond to a subset of activated circulating NK-lymphocytes. Higher expression of the CD2 and CD7 costimulatory molecules found for the CD56ϩhi NK-cells would support their greater ability to respond to various stimuli. In addition, CD56ϩhi NK-cells expressed higher levels of several adhesion molecules such as CD2, CD11c, CD44, CD56, and CD62L compared to CD56ϩlo NK-cells, supporting a particular ability of these cells to migrate from blood to tissues and/or a potential advantage to form conjugates with target cells. Interestingly, CD56ϩlo and CD56ϩhi NK-cells showed a different pattern of expression of killer receptors that might determine different activation requirements for each of these NK-cell subsets. For instance, absence or low levels of CD16 expression might explain the lower antibody-dependent cytotoxicity activity of CD56 ϩhi NK-cells. On the other hand, the virtual absence of expression of the CD158a and NKB1 immunoglobulin-like and the greater reactivity for the CD94 lectin-like killer receptors on CD56 ϩhi in comparison to CD56 ϩlo NK-cells might determine different MHC-class I specificities for both NK-cell subsets, a possibility that deserves further studies to be confirmed.

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ABSTRACT:To define a dynamic sequence of phenotypic changes related to early and late phases of NK-cell activation, we have analyzed by four-color flow cytometry the immunophenotype of normal blood NK-cells from 12 healthy individuals and compared it with those from 15 patients with acute viral infections and 15 patients with either chronic infections or tumors. Although a great interindividual variability was found, nonstimulated CD56 ϩ NK-cells, present in normal blood samples, usually were CD2 Ϫ/ϩlo , CD7 ϩhi , HLA-DR Ϫ , CD11b ϩ , CD38 ϩ , CD11a ϩhi , CD45RA ϩhi , and CD45RO Ϫ , the expression of CD11c and CD57 being heterogeneous and variable. Recently activated NK-cells, herein corresponding to NK-cells from patients with acute viral infections, displayed a pattern of expression of CD2/CD7 similar to that referred to above, but they typically showed higher levels of CD11a, CD38, and HLA-DR, as well as downregulation of CD11b and CD45RA, accompanied in some cases by coexpression of CD45RO; in addition, these NK-cells were CD11c ϩ and CD57 Ϫ/ϩlo . Late-activated NK-cells, represented by NK-cells present in patients with chronic infections and tumors, converted into a CD2 ϩhi /CD7 Ϫ/ϩlo immunophenotype and expressed heterogeneously low levels of CD38 and CD11b; moreover, they were CD57 ϩ and CD11c Ϫ/ϩ . At this stage, most NK-cells had already reverted into their original CD45RA ϩ /CD45RO Ϫ /HLA-DR Ϫ phenotype. In summary, we show that the patterns of expression of CD2/CD7, CD57/CD11c, CD38/CD11b, CD45RA/CD45RO, and CD11a/HLA-DR may help us to define the immunophenotypic profiles associated with early and late NK-cell activation phases in "in vivo" models. © 2002 Elsevier Science (USA)

erogeneous clinical expression. It is becoming increasingly Hemochromatosis is a hereditary iron-overload disevident that the ''clinical scene'' of diagnosis of hemochromaease linked to HLA. The clinical expression of hemochrotosis is changing 5 with less severe, or even asymptomatic, matosis is influenced by sex and age. However, other forms of the disease becoming increasingly frequent. This factors must account for the notorious heterogeneity of change is in part the result of the existence of an established expression of the disease independent of sex, age, and link between the disease and HLA. 6,7 HLA linkage studies HLA phenotype. The present study attempts to clarify have permitted localization of the putative hemochromatosis some of these additional factors based on exhaustive stagene in a short region around the HLA-A locus. [8][9][10] Therefore, tistical analysis of data collected from 43 selected pa-HLA phenotyping, by permitting the detection of cases tients with hemochromatosis. The statistical analysis fothrough family screening, allows identification of cases much cused on three groups of variables: the first group before the classical clinical symptoms develop. 11 To a certain included variables reflecting the clinical expression of extent, the latter development has exposed further the ignothe disease; the second group represented the biochemirance of the factors underlying the heterogeneity in presentacal and hematological values at the time of diagnosis; tion and progression of the disease. 12 and the third group consisted of the independent variIn the course of our early studies in hemochromatosis, disables sex, age, HLA phenotype, and T-cell subset profile, tinct clinical groups of patients could be defined with the i.e., the percentages and total numbers of CD4/ and different CD4-CD8 ratios and distinct responses to intensive CD8/ cells and the CD4-CD8 ratios. The results show phlebotomy treatment. 3,4 that the relative expansion of the two main T-cell sub-The present study consists of an extensive comparative sets, in the context of the HLA phenotype, correlates analysis of the relative impact of HLA phenotype and CD4-significantly with the clinical expression of hemochro-CD8 ratios on the clinical expression of the disease. Other matosis and the severity of iron overload. The present factors known for some time to influence presentation and findings substantiate further the postulate that T cells course of disease, namely sex and age, were also included. have a role in the regulation of iron metabolism. (HEPA-The results substantiate the existence of a significant associ-TOLOGY 1997;25:397-402.) ation between HLA phenotype, CD4-CD8 ratios, and clinical progression of the disease, illustrating the importance of a A recent study by Amadori et al. 1 showing considerable major histocompatibility complex (MHC) applying the princivariation in CD4-CD8 ratios in the normal population was ples discussed by Amadori et al. 1 to an class I-linked disease, received with a commentary stressing its ''se...