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PubMed1992

Questions concerning plasma cell leukaemia.

The classical concept of plasma cell leukaemia (PCL) is reviewed. This disease invariably concerns myeloma, either in its terminal phase (secondary PCL) or particularly rapid and aggressive (primary PCL). A more precise definition of primary PCL would be given by the term leukaemic myelomatosis. Characterization of the membrane antigen CD 56, responsible for the cytoadhesion of malignant plasmocytes in the bone marrow, today offers a convincing pathogenic hypothesis to elucidate this affection which would now appear to be no more than a variant form of myeloma. Acute immunoblastic-plasmoblastic leukaemia and mature cell leukaemic lymphoma would seem to be pathologically related to PCL. Finally, the problems posed by the "enigmatic" plasmacytoid monocyte are discussed.

Antigens, CD↗

PubMed1993

Leukemia-associated marker combinations in acute leukemia suitable for detection of minimal residual disease.

In the absence of truly leukemia-specific antigen, antigen combinations were identified in leukemia cells that are absent or extremely rare among normal hemopoietic cells. Some of the studied combinations related to the simultaneous surface and cytoplasmic marker expression, others, expressed mainly on cell surface membrane, represented atypical or aberrant combinations. Comparing membrane (m) and cytoplasmic (c) antigen expression (followed in 23 acute leukemia cases), we observed that CD3 could be detected in cytoplasm in the majority of T-ALL cells, while was absent on cell surface membrane where simultaneous expression of more immature T cell markers, such as CD7 and CD5, could be detected. Combination of mCD7/cCD3 could be regarded as a suitable marker of individual T-ALL cells. In cases of B-precursors of acute leukemia cells, leukemia-related combination of mCD19/cCD22 was found, which could characterize a single leukemia cell. The cells in one of 11 AML followed cases were positive for CD13 in cytoplasm, but not on cell surface membrane, where CD33 and other myeloid antigens were expressed. The cells in another two AML cases were positive for CD11 in cytoplasm but not on cell surface membrane, where CD13 or CD33 were expressed. Again, marker combinations of mCD33/cCD13 and mCD13 or mCD33/cCD11, respectively, represent a leukemia-related feature, suitable for tracing single leukemia cells in double immunofluorescence. Acute leukemia defined by the coexpression on most blast cells of antigens classically attributed to different lineages (referred as atypical/aberrant marker combinations) remains a rare event. We isolated a series of 27 (12%) such cases of 225 acute leukemia patients whose cells were immunophenotyped at diagnosis. Myeloid markers were present in T-ALL of two cases, T and B markers were coexpressed in 13 cases, markers of B and myeloid lineage were associated in one case, and T cell and myeloid antigens were found in 10 AML cases; in one AML case (M3 according to FAB classification) an aberrant nuclear coexpression of TdT was observed. In one case of the last group an interesting antigen combination of CD4/CD34 present in AML with monocytic differentiation was observed. When 5 patients with leukemia-associated (aberrant) markers were again analyzed at relapse, the relevant antigen combinations were retained in all of them. In summary, 44 of 50 cases (88%) from our acute leukemia series studied for leukemia-associated antigen combination, both with surface membrane and cytoplasmic marker combinations and those with aberrant markers coexpression allow the detection of minimal residual disease.

Adult↗

PubMed1986

Familial steroid-responsive neuropathy.

A hereditary sensory neuropathy different from any of the four classic types was diagnosed in three members of one family. Biopsy in one of the patients revealed histologic inflammatory cell infiltration and the presence of perivascular cuffing in muscle, similar to that seen in nerves affected by idiopathic polyneuritis. The response to steroids was dramatic, unlike that noted with nonvasculitic neuropathies. Signs of vasculitis may suggest reversibility.

Adult↗

PubMed2004

Cholesterol absorption inhibitor Ezetimibe blocks uptake of oxidized LDL in human macrophages.

Ezetimibe belongs to a group of selective and very effective 2-azetidione cholesterol absorption inhibitors which act on the level of cholesterol entry into enterocytes. Recent data indicated that the drug prevents the formation of a heterocomplex consisting of annexin-2 and caveolin-l and leads to specific inhibition of an NPCILI-dependent cholesterol uptake pathway required for uptake of micellar cholesterol into enterocytes. Earlier studies have shown that caveolin-l and annexin-2 are also expressed in human macro-phages and we show in this study that human macrophages express NPC1L1. Moreover in human macrophages, Ezetimibe(SCH58235) and its analogue, SCH354909, are bound to specific cell surface receptors followed by endocytosis via the classical endocytic pathway. SCH58235 had no effect on uptake and/or processing of acetylated LDL (Ac-LDL). In contrast, the compound inhibited uptake of oxidized LDL (Ox-LDL) by -50% in a dose-dependent manner. SCH58235 blocked the lipid-induced induction of LXR/RXR target genes ABCAI, ABCGI, and apolipoprotein E distinctively more effectively in macrophages loaded with Ox-LDL than in those loaded with Ac-LDL. Based on these findings, we presume that the caveolin-l-, annexin-2-, and NPClLI-dependent cholesterol uptake system that is operating in enterocytes may also contribute to class B scavenger receptor-dependent uptake of Ox-LDL in human monocyte-derived macrophages.

Anticholesteremic Agents↗

PubMed2006

Total and differential leukocytes counts, but not hsCRP, ESR, and five fractioned serum proteins have significant potency to predict stable coronary artery disease.

BACKGROUND: The role and diagnostic value of markers of inflammation is well recognized in acute coronary syndromes but it is uncertain in patients with stable coronary artery disease (CAD). This study was done to investigate the association of markers of inflammation with the occurrence and severity of CAD and to evaluate their predictive values. METHODS: Markers of inflammation, electrophoresis serum protein fractions, serum (apo)lipoproteins and classical risk factors were determined in 270 angiographically documented subjects. The subjects were classified as CAD cases and controls according to angiography. The severity of CAD was scored on the basis of the number and extent of lesions. RESULTS: The counts of total leukocytes (7.14+/-1.86 cell/nl vs. 6.58+/-1.62, p<or=0.02), neutrophils (3.95+/-1.42 vs. 3.59+/-1.07, p<or=0.05) and eosinophils (0.25+/-0.28 vs. 0.19+/-0.24, p<or=0.03) were increased significantly, whereas the concentrations of high-sensitivity C-reactive protein (hsCRP, 2.03 (0.0-32.0) mg/l vs.1.72 (0.09-11.36), p<or=0.07) changed modestly in CAD patients relative to controls. There were no significant differences in the counts of monocytes and lymphocytes and the concentrations of erythrocyte sedimentation rate (ESR) and any five fractions of serum proteins between two groups. The counts of total leukocytes, neutrophils and eosinophils, but not hsCRP and ESR exhibited significant associations with the severity of CAD. In univariate logistic regression analysis, leukocytes count associated significantly (OR=1.97, p<or=0.01) whereas hsCRP modestly (OR=1.76, p<or=0.06) with the occurrence of CAD. The association was lessened by diabetes mellitus in multivariable adjustment. Receiver operating characteristic (ROC) analysis showed that, only total leukocyte and differential counts had significant potency to predict CAD (area under curve, AUC=0.60+/-0.04, p<or=0.02). CONCLUSIONS: The total leukocytes count and its subgroups are associated with the presence and severity of CAD, but the associations were not independent. The efficiency was questioned for hsCRP, ESR and five fractioned serum proteins to identify stable CAD.

Adult↗

PubMed1995

Chemokines, a family of chemotactic cytokines.

Chemokines are low-molecular-weight proteins that stimulate recruitment of leukocytes. They are secondary pro-inflammatory mediators that are induced by primary pro-inflammatory mediators such as interleukin-1 (IL-1) or tumor necrosis factor (TNF). The physiologic importance of this family of mediators is derived from their specificity. Unlike the classic leukocyte chemo-attractants, which have little specificity, members of the chemokine family induce recruitment of well-defined leukocyte subsets. Thus, chemokine expression can account for the presence of different types of leukocytes observed in various normal or pathologic states. There are two major chemokine sub-families based upon the position of cysteine residues, i.e., CXC and CC. All members of the CXC chemokine sub-family have an intervening amino acid between the first two cysteines; members of the CC chemokine sub-family have two adjacent cysteines. As a general rule (with some notable exceptions), members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and a small sub-set of lymphocytes. This review discusses the potential role of chemokines in inflammation and focuses on the two best-characterized chemokines, monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, and interleukin-8 (IL-8), a member of the CXC chemokine sub-family.

Chemokine CCL2↗

PubMed2003

Multigene expression from a replicating adenovirus using native viral promoters.

We have developed a novel therapeutic gene delivery system for oncolytic adenoviruses that takes advantage of the endogenous gene expression machinery (promoters, splicing, polyadenylation signals) of the E3 transcription unit for gene delivery. In this work, we use two sites in the E3 region (6.7 K/gp19K and ADP sites) to demonstrate that (1) multiple therapeutic genes (MCP-3, TNFalpha) can be expressed from a single replicating Ad, (2) timing of expression of these therapeutic genes mimics that of the E3 region genes they replaced, (3) expression of the remaining genes in the complex E3 transcription unit is maintained, and (4) the multigene-expressing virus retains replication competence and ability to induce classical adenovirus cytopathic effects that parallel those of the parental adenovirus (ONYX-320). This system conserves the DNA packaging capacity of the size-constrained viral genome for therapeutic genes and can potentially be used to link therapeutic transgene expression to tumor-restricted viral replication. Potential clinical implications are discussed.

Adenoviridae↗

PubMed1997

Immunohistochemical detection of hog cholera viral glycoprotein 55 in paraffin-embedded tissues.

Formalin-fixed, paraffin embedded tissues obtained from 40 pigs inoculated with a field isolate of hog cholera virus were examined for the presence of Gp55, a major structural protein of the virus envelope, using a monoclonal antibody-based immunohistochemical test with the avidin-biotin-peroxidase complex method. Immunoreactivity was detected in hog cholera virus-infected tissues but not in control pigs tissues, African swine fever virus-infected tissues, or bovine viral diarrhea virus-infected porcine or bovine tissues. The first positive reactions were seen in lymphatic tissues, digestive tract and skin on postinoculation day (pid) 4, respiratory and urinary tissues on pid 5, nervous tissues on pid 6, and endocrine tissues on pid 7. These staining reactions persisted until the last observation on pid 18. Hog cholera virus antigen was not detected in heart tissue at any time. The highest levels of antigen detection were found in tonsils, spleen, and pancreas, although the esophageal mucosa and skin epithelial cells were also intensely and widely stained. The cellular staining pattern of Gp55 had a ubiquitous distribution. It was found in epithelial cells, macrophages and circulating monocytes, endothelial cells, lymphoid cells, and glial cells. The results showed a high specificity and high sensitivity for detecting hog cholera Gp55 in formalin-fixed, paraffin embedded tissue samples. This method allows precise association of Gp55 with specific cells, tissues, and histologic lesions, making the technique suitable for use in routine diagnosis of hog cholera.

Animals↗

PubMed1999

Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients.

Human cytomegalovirus (HCMV) infection plays an important role in transplant patients. Its impact is both direct and indirect. This review focuses on new aspects of HCMV (re)activation and HCMV related pathology, particularly HCMV-associated renal allograft injury. During the last two years we have learned that HCMV is more frequently (re)activated, even in healthy people, than previously expected. Inflammatory as well as stress mediators and some drugs may (re)activate the virus by using distinct intracellular pathways. Commonly, HCMV (re)activation is accompanied by HCMV antigenemia/DNAemia, suggesting that precursor cells in the bone marrow play an important role as a reservoir of latent virus. However, local HCMV (re)activation (colon, lung) without detection of active HCMV infection in the peripheral blood is possible. In healthy people a sufficient type 1 T-cell response controls the active HCMV infection, while in patients with severe immune deficiency (AIDS, high-dose immunosuppression) the virus can spread in an uncontrolled fashion and induce 'classic' HCMV disease. In patients with moderate immune deficiency (e.g. long-term transplant patients on low-dose immunosuppression) virus spreading is controlled but the elimination of cells harboring the active virus may be insufficient. The resulting persistent HCMV antigenemia may induce chronic inflammatory processes leading to tissue injury, particularly in the allograft. Therefore, antiviral therapy may be useful in patients suffering from graft deterioration with otherwise clinically symptomless HCMV infection. HCMV-related immune deficiency with an increased risk of developing bacterial/fungal superinfections is frequently seen in patients with symptomatic HCMV disease but not in asymptomatic CMV antigenemia. The risk of developing superinfections can be predicted by flow-cytometric monitoring of peripheral blood monocytes.

Biomarkers↗

PubMed1987

Leukocyte functions.

Knowledge concerning leukocyte functions has increased enormously over the last two decades, largely because techniques have become available to assess them. It has provided insights into many disease entities, as well as on immunologic functioning as a whole. In addition to some classical clinical entities, such as severe combined immunodeficiency disease and chronic granulomatous disease, new entities have been discovered and described, in which subtle disturbances in white blood cell function are sufficient to cause disease. Furthermore, much has been learned about the effect of drugs and disease conditions on leukocyte functions. This review is not intended as a comprehensive description of white blood cell function testing, rather, it is meant to provide a practical guide for clinical laboratories. Therefore only those functional tests are presented which have a direct impact on patient management. These are primarily those functional derangements in white cells which either define a disease entity or without which a diagnosis cannot be made. Granulocytes, monocytes, and lymphocytes will be discussed separately. A short review of their physiology and function is presented to provide a context for the further discussion of their dysfunctions. This discussion of dysfunction and the techniques for laboratory testing thereof includes the evaluation of diagnostic usefulness and implications for patient management. Clinically, the most important granulocyte defects involve chemotaxis, respiratory burst, and intracellular microbial killing. Defects of granulocyte chemotaxis define the lazy leukocyte syndrome, Job's syndrome, and a series of relatively rare idiopathic neutrophil disorders. In addition, chemotaxis is a relatively easily measured sign of actin dysfunction. Defective generation of the respiratory burst with consequent impaired microbial killing defines chronic granulomatous disease and its variants as well as glutathione peroxidase deficiency. The most reliable clinical laboratory testing of granulocyte chemotaxis is performed by using granulocyte migration in response to a chemoattractant, either across a filter or in agarose. For clinical testing of respiratory burst, nitroblue tetrazolium (NBT) reduction is simple, quantitative, and has recently been adapted to automated measurement. Direct measurement of microbial killing is generally not indicated, since clinically important defects are recognized by measurement of respiratory burst generation. Although the monocyte's functions are numerous, they are somewhat less well characterized than those of granulocytes and lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2000

Expression of the non-classical HLA-G antigen in tumor cell lines is extremely restricted.

It has been proposed that tumor cells frequently associated with partial or total loss of HLA class Ia expression may abnormally express HLA-G class Ib antigen. Such peculiar HLA class I expression would allow tumor cells to escape not only from CD8+T but also from NK-cell cytotoxicity. We studied the cell surface expression of HLA-G using flow cytometry with two HLA-G specific monoclonal antibodies (87G, 01G). The JEG-3 choriocarcinoma cell line, which constitutively expresses HLA-G antigens was used as a positive control. We did not detect the cell-surface HLA-G antigens in the following 75 tumor cell lines: melanoma (22), neuroblastoma (7), retinoblastoma (1), glioma (2), breast carcinoma (3), ovarian carcinoma (3), cervical carcinoma (1), colon carcinoma (3), bladder carcinoma (2), hepatocarcinoma (1), sarcoma (2) and leukemia cell lines: T-lymphocytes (6), B-lymphocytes (13) and myelo-monocytes (9). We found that some myelomonocytic cell lines express on their surface high affinity FcgammaRI (CD64) that may result in the binding of HLA-G specific mabs to their cell surface even in the absence of HLA-G molecules. Our panel of HLA-G negative tumor cell lines accommodated 62 cell lines for which similar analysis have not been reported and also contained 13 cell lines with total or partial loss of HLA class Ia molecules. Our observation imply that under normal culture conditions the cell surface HLA-G reactive with 87G and 01G mabs is absent in most tumor cell lines of different origin.

Antibodies, Monoclonal↗

PubMed1996

HLA-G transcription studies during the different stages of normal and malignant hematopoiesis.

Specific expression of the non classical class I HLA-G gene on trophoblasts, the only fetal tissue in contact with maternal cells which lack MHC class I antigens, may indicate a role of this gene in fetal-maternal tolerance. We recently reported HLA-G transcription in peripheral blood leukocytes. In this work, we have investigated HLA-G transcription in hematopoietic stem cells, in different hematopoietic lineages and in malignant cells by using a RT-PCR technique. PCR amplification with primers specific to the exon 2 and the 3' untranslated region has enabled to detect HLA-G transcription in B and T cell populations. No transcription was found in CD34+ cells, in thymocytes, in polynuclear cells, in monocytes and in natural killer cells. Among the malignancies analyzed, HLA-G is transcribed in 2 of 13 cases of acute leukemia characterized by a monocytic contingent, in 3 of 6 CLL and in all the cases of B-NHL (n = 6). No HLA-G transcription was detected in myeloma (n = 2). The splicing type does not seem to be linked to a lymphocyte subpopulation nor to a malignant proliferation stage. These results suggest that HLA-G is a marker of mature lymphoid cells and may play an immunological function as a peptide presenting molecule. HLA-G transcription in some cases of malignancy might indicate a contribution to the tumoral progression by blocking natural killing reaction.

Antigens, Neoplasm↗

PubMed1996

HLA-G transcription studies during the different stages of normal and malignant hematopoiesis.

HLA Antigens↗

PubMed1994

Cell-surface protein identified on phagocytic cells modulates the C1q-mediated enhancement of phagocytosis.

C1q, a subunit of the first component of the classical C pathway, binds to specific cells of the immune system, triggering a variety of cellular responses. To identify the functional C1qR on phagocytic cells, mAbs were generated by immunization with either C1q-binding proteins isolated from U937 cells or intact U937 cells. Immunoprecipitation followed by Western blot analysis demonstrated that three mAbs, designated R139 (IgG2b), R3 (IgM), and U40.3 (IgG1), recognize the same 100,000 M(r) protein (126,000 M(r) under reducing conditions). These mAbs also co-immunoprecipitate CD43 from detergent extracts of U937, consistent with the possibility that this C1qR is a multi-subunit structure. Two Abs, R3 and R139, but not U40.3, consistently inhibited the enhancement of phagocytosis by monocytes adhered to either C1q or the collagen-like fragment of C1q (C1q-CLF). Interestingly, binding inhibition studies demonstrated that neither R139 nor U40.3 blocked the binding of [125I]C1q-CLF to U937 cells, whereas R3 did inhibit 35 to 45% of the binding of [125I]C1q-CLF to these cells. Thus, the three mAbs recognize distinct epitopes of a 100,000 M(r) polypeptide that is a component of the monocyte C1qR that modulates phagocytosis. All three mAbs recognize the extracellular domain of the molecule on neutrophils, monocytes, and U937 cells, but were not reactive with CEM or RAJI cells, T and B lymphoblastoid cell lines, respectively. Furthermore, none of these three mAbs inhibited or mimicked the C1q-mediated stimulation of superoxide production by neutrophils, suggesting that the C1qR that mediates the enhancement of phagocytosis differs in at least some critical parameter from the C1qR that mediates superoxide generation by the neutrophil.

Antibodies, Monoclonal↗

PubMed1998

Pathophysiology and treatment of idiopathic hypercalciuria.

Nearly 50 years after its initial description by Dr. F. Albright, the term idiopathic hypercalciuria (IH) is still in use. The exact mechanism of hypercalciuria is still unknown despite extensive pathophysiologic investigations; recent advances represent the focus of this review. A precise definition of true IH is proposed, taking into account the various nutritional conditions influencing calcium excretion. The potential pathogenic mechanisms are discussed, and the limits of the classical Pak's pathophysiological classification are recalled. The evidence supporting the role of an increased intestinal calcium absorption, a defect in renal tubular calcium reabsorption, or an increased bone loss as a primary mechanism in IH are successively examined. Since overall available human data indicates that all three mechanisms may be found in IH, the hypothesis that a broader disorder encompassing all these various abnormalities may be involved in IH is discussed. Three global hypotheses to account for IH physiopathology are examined: a diffuse defect in fatty acid content of cell membranes, an increased expression of the vitamin D receptor of the 25(OH) vitamin D 1 alpha-hydroxylase, or of the calcium sensor receptor and a monocyte disease. Finally, the available clinical data justifying the therapeutic approaches are reviewed, and guidelines for dietary recommendations regarding calcium and also animal protein, sodium chloride, alcohol, carbohydrate, phosphate, and potassium intakes are proposed, and drug therapy indications are discussed.

Bone Diseases, Metabolic↗

PubMed2005

Covert human immunodeficiency virus replication in dendritic cells and in DC-SIGN-expressing cells promotes long-term transmission to lymphocytes.

HIV-1 virions are efficiently captured by monocyte-derived immature dendritic cells (iDCs), as well as by cell lines expressing the lectin DC-SIGN. Viral infectivity can be retained for several days, and even enhanced, before transmission to CD4+ lymphocytes. The role of DC-SIGN in viral retention and enhancement of infection is not fully understood and varies according to the cell line expressing the lectin. We studied here the mechanisms underlying this process. We focused our study on X4-tropic human immunodeficiency virus (HIV) strains, since they were widely believed not to replicate in iDCs. However, we first show that X4 HIV replicates covertly and slowly in iDCs. This is also the case in Raji-DC-SIGN cells, which are classically used to study HIV transmission. We used either single-cycle or replicative HIV and measured viral RT and replication to further demonstrate that transfer of incoming virions from iDCs or DC-SIGN+ cells occurs only on the short-term (i.e., a few hours after viral exposure). There is no long-term storage of original HIV particles in these cells. A few days after viral exposure, replicative viruses, and not single-cycle virions, are transmitted to CD4+ cells. The cell-type-dependent activity of DC-SIGN reflects the ability of HIV to replicate covertly in some cells, and not in others.

B-Lymphocytes↗

PubMed2002

Zwitterionic polysaccharides stimulate T cells by MHC class II-dependent interactions.

Polysaccharides of pathogenic extracellular bacteria commonly have negatively charged groups or no charged groups at all. These molecules have been considered classic T cell-independent Ags that do not elicit cell-mediated immune responses in mice. However, bacterial polysaccharides with a zwitterionic charge motif (ZPSs), such as the capsular polysaccharides of many strains of Bacteroides fragilis, Staphylococcus aureus, and Streptococcus pneumoniae type 1 elicit potent CD4(+) T cell responses in vivo and in vitro. The cell-mediated response to ZPS depends on the presence of both positively charged and negatively charged groups on each repeating unit of the polysaccharide. In this study, we define some of the requirements for the presentation of ZPS to CD4(+) T cells. We provide evidence that direct interactions of T cells with APCs are essential for T cell activation by ZPS. Monocytes, dendritic cells, and B cells are all able to serve as APCs for ZPS-mediated T cell activation. APCs lacking MHC class II molecules do not support this activity. Furthermore, mAb to HLA-DR specifically blocks ZPS-mediated T cell activation, while mAbs to other MHC class II and class I molecules do not. Immunoprecipitation of lysates of MHC class II-expressing cells following incubation with ZPS shows binding of ZPS and HLA-DR. Electron microscopy reveals colocalization of ZPS with HLA-DR on the cell surface and in compartments of the endocytic pathway. These results indicate that MHC class II molecules expressing HLA-DR on professional APCs are required for ZPS-induced T cell activation. The implication is that binding of ZPS to HLA-DR may be required for T cell activation.

Animals↗

PubMed1997

Relationship between proliferation and susceptibility to CD95- and CD2-mediated apoptosis in stimulated primary T lymphocytes: T cells manifesting proliferative unresponsiveness are preferentially susceptible to CD95-mediated apoptosis.

We examined the relationship between proliferation and susceptibility to Fas- and CD2-mediated apoptosis of human peripheral T lymphocytes that had been exposed in primary culture to CD3- or CD2-derived mitogenic stimuli in the presence of monocytes and exogenous IL-2. After 5 days, activated T cells were fractionated into large (F2) and small (F6) cells on Percoll density gradients and analyzed for their susceptibility to apoptosis and for their position in the cell cycle. Most F6 cells displayed a CD45RA+, CD25-, CD2R- phenotype and were unable to incorporate bromodeoxyuridine (BrdUrd) during the entire culture period. However, they were activated to express Fas Ag and some cell cycle regulatory proteins specific to late G1 phase. T cells with proliferative unresponsiveness were sensitive to Fas-mediated apoptosis whether it was triggered by anti-Fas mAb or by Fas ligand, but were almost completely resistant to CD2 apoptotic signaling. In contrast, F2 cells exhibited classical activation markers (CD45RO, CD25, and CD2R), had crossed S phase at least once, and were sensitive to both Fas and CD2 apoptotic signals. In large cells harvested earlier (on day 3), the signals were operative in both BrdUrd+ and BrdUrd- cells. Thus, S phase entry is not required for Fas- and CD2-mediated apoptosis. The profound proliferative unresponsiveness of F6 cells to CD3 and CD2 stimuli (bypassed by ionomycin plus PMA) and the CD2R- conformation of their CD2 molecules suggest that they may be in vivo anergized cells whose elimination, upon restimulation, is highly dependent on the Fas death pathway.

Apoptosis↗