Peripheral T-cell lymphomas consist of a clinically heterogeneous group of malignant disorders whose immunophenotype usually corresponds to that of normal mature T cells. We describe and correlate ...the clinical, histopathologic, phenotypic, and genotypic findings in two patients with malignant lymphoma presenting with hepatosplenic disease. The morphologic pattern of lymphoma was that of a sinusal/sinusoidal infiltration in spleen, marrow, and liver. This morphologic characteristic was associated with the presence of a productive clonal rearrangement of the T-cell receptor (TCR) delta gene. Lymphoma cells expressed a CD3-TCR-gamma delta- phenotype. They were also double negative (ie, CD4-CD8-) and lacked the CD5 and CD7 antigens. In one patient, tumor progression was associated with phenotypic changes that resulted in a CD3-TCR-gamma delta- phenotype with the same delta-gene rearrangement as initially. These observations suggest the existence of a new type of peripheral T-cell lymphoma characterized by its hepatosplenic presentation, and by the sinusal/sinusoidal tropism and the TCR-gamma delta phenotype of the malignant cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It is now widely accepted that polymerase chain reaction (PCR) analysis of cutaneous T-cell clonality is of diagnostic value in cutaneous T-cell lymphomas (CTCLs) and most helpful in the diagnosis of ...mycosis fungoides (MF). However, the diagnostic and prognostic value of circulating clonal T cells remains unclear. We studied T-cell clonality in the peripheral blood (PB) and the cutaneous lesion, sampled at the same time, in 363 consecutively seen patients with a clinical suspicion of cutaneous lymphoma. Using a PCR technique providing a specific imprint of T-cell clones (PCRγ–denaturing gradient gel electrophoresis), we found that detection of identical circulating and cutaneous T-cell clones was associated with the diagnosis of CTCL (P < .001). Detection of circulating tumor cells in patients with MF was infrequent (12.5%), except in those with erythrodermic MF (42%; P = .003). Moreover, among the 46 patients who had identical circulating and cutaneous T-cell clones, 25 (56%) had erythroderma. The finding of a dominant clone in the PB but not in the skin was frequent, regardless of the clinicohistologic classification; it occurred in 30% of patients with CTCL, 41% with non-CTCL malignant infiltrates, and 34% with benign infiltrates. This pattern was significantly more frequent in patients over 60 years of age (P < .002), even in the CTCL group (P < .01). In conclusion, dominant T-cell clones detected in the PB of patients with MF by using a routine PCR technique are rarely tumoral and are more often related to age. A multicenter prospective study is under way to establish the prognostic value of circulating tumor cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anti-Hu syndrome is a paraneoplastic neurologic disease seemingly associated with an efficient antitumoral immune response against HuD protein expressed by both small cell lung cancer (SCLC) and ...neurons. Since anti-Hu antibodies are not pathogenic, and oligoclonal CD8
+ T cells infiltrate neoplastic and nervous tissues, we examined MHC class I-restricted immunogenicity of human HuD. Among 14 HuD-derived peptides potentially immunogenic in HLA-A*0201 restriction, 10 had actual in vitro binding capacity to the HLA molecule, 8 elicited specific cytotoxic T lymphocyts (CTLs) in a humanized murine model after peptidic vaccination, 2 also elicited specific CTLs in healthy humans, and 1 was naturally processed and presented to the immune system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To determine whether idiopathic sensory neuropathies could be associated with circulating dominant T-cell clones, a T-cell equivalent to monoclonal gammopathy of unknown significance.
A number of ...predominantly sensory neuropathies remain of unknown etiology. Circulating dominant T-cell clones may be observed in the elderly, in autoimmune disorders, and in chronic viral infections.
Twenty patients with chronic sensory or predominantly sensory neuropathies considered idiopathic after intensive investigation were evaluated for the presence of dominant T-cell clones in blood using PCR amplification of the variable region of the T-cell receptor gamma-chain gene. They were classified as chronic idiopathic axonal polyneuropathy (CIAP) or sensory neuronopathy, i.e., chronic idiopathic ataxic neuropathy (CIAN), according to clinical and electrophysiologic criteria.
Occurrence of clonal expansions of T cells was strikingly high in patients with idiopathic sensory neuropathies (16/20, 80%), with a similar proportion in CIAP (12/15, 80%) and CIAN (4/5, 80%), as compared with elderly normal controls (2/10, 20%), elderly controls with degenerative neurologic diseases (2/10, 20%), and elderly patients with idiopathic chronic inflammatory demyelinating polyneuropathy (2/10, 20%) (all p < 0.005).
Both CIAN and CIAP are associated with dominant T-cell clones of unknown significance that cannot simply be attributed to the age of patients. Relevance of T-cell clones to the pathogenesis of idiopathic sensory neuropathies remains to be determined.
We studied de novo protein biosynthesis in platelets of normal adult donors and in newly formed platelets isolated from splenectomized patients with idiopathic thrombocytopenic purpura (ITP). After ...metabolic labelling of platelet proteins, performed with different radiolabelled amino acids or carbohydrates, a tenfold increase in incorporation of radioactivity into trichloroacetic‐acid‐precipitable material was obtained with ITP platelets compared to control platelets. Electron microscopic studies of ITP platelets revealed the presence of rough endoplasmic reticulum and polyribosomes, providing morphological evidence for protein synthesis. SDS‐PAGE of radiolabelled ITP platelet proteins followed by autoradiography showed that 35Smethionine and 3Hleucine were incorporated into almost all Coomassie‐blue‐stained proteins whereas 3Hcarbohydrates only labelled a few bands. Using crossed‐immunoelectrophoresis we identified some of the labelled platelet compounds and demonstrated that major membrane glycoproteins (GPIb, IIb, IIIa) and alpha‐granule proteins, such as fibrinogen, thrombospondin, albumin and von Willebrand factor, were synthesized in newly formed circulating platelets.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Non-Hodgkin's lymphomas (NHLs) are clonal proliferation of B or T lymphocytes. Assessment of clonality in lymphoid proliferations uses immunochemistry and, recently, molecular biology. The aim of our ...study is to assess the role of immunoglobulin gene rearrangement analysis on bronchoalveolar lymphocytes to aid in the diagnosis of B-cell pulmonary NHL.
The study took place in a university hospital. There were seven consecutive patients with B-cell-type pulmonary lymphoma and nine control subjects. Gene rearrangement analysis using polymerase chain reaction (PCR) technique was performed on alveolar lymphocytes recovered by BAL.
Analysis of the immunoglobulin heavy chain gene rearrangement showed a predominant clonal alveolar lymphocyte population in six of seven patients while all control subjects showed germline pattern.
Gene rearrangement analysis by PCR of alveolar lymphocytes would appear to be sensitive in patients with B-cell pulmonary NHL (six of seven patients) and specific (zero of nine in the control group). This simple test should be added only in the analysis of cells recovered by BAL in patients with suspected primary and secondary B-cell pulmonary NHL.
Therapeutic vaccination aims at a strong stimulation of antigen-specific CD8(+) T-cells, so that they differentiate into effectors active in vivo against antigenic targets. Two adenovirus vectors ...(Ad) encoding two HLA-A*0201-restricted HIV epitope sequences (pol 476 and pol 589) were constructed. The Ad differ by the presence or absence of a ubiquitin monomer sequence (AdUb(+) and AdUb(-)). The effect of transgene product ubiquitination was analyzed on (1) in vivo, the immunization of Ad vaccinated HLA-A*0201 humanized HHD mice and (2) in vitro, the presentation of the transgene encoded peptides by transduced human dendritic cells (DC). In vivo, we found that immunization of humanized HHD mice with AdUb(+) elicited a transgene product-specific interferon (INF)-gamma CD8(+) T-cell response detectable by enzyme-linked immunospot (ELISPOT), whereas the AdUb(-) construction did not. Antigen-specific cytotoxic T lymphocytes (CTL) were also generated in HHD mice immunized with AdUb(+) and not with AdUb(-). In vitro, using human AdUb(+)-transduced DC, a sizeable expansion of pol 476 and pol 589 tetramer positive CD8(+) T cells as well as CD8(+) CTL were obtained in healthy donors. Compared to AdUb(-)-transduced DC, AdUb(+)-transduced DC triggered a higher number of pol 476-specific IFN-gamma-secreting CD8(+) T cells. In agreement, AdUb(+) transduced DC, used as target in a (51)Cr-release assay, were more efficiently lysed by peptide-specific CTL than AdUb(-)-transduced DC. In conclusion, the addition of an ubiquitin sequence to the adenoviral transgene, used as an antigen source, resulted in both in vivo enhanced CD8(+) T-cell immunogenicity in HHD mice and in vitro increased HLA class I-restricted presentation of encoded peptides by human DC.
It is frequently difficult to determine whether a neuromuscular disorder (NMD) related to a lymphoproliferative disease is neoplastic, paraneoplastic, or incidental. This may explain why ...neuromuscular complications of chronic lymphoid leukemia (CLL), a frequent disorder, have been rarely reported. We describe 7 patients with CLL and neuromuscular involvement in whom phenotypic and genotypic characterization of infiltrating lymphoid cells was carried out by immunocytochemistry and PCR-amplification of immunoglobulin heavy chain locus. One patient had massive neoplastic infiltration of muscle, and six presented with inflammatory-like NMDs (dermatomyositis: 2, polymyositis: 1, vasculitic mononeuropathy: 2; inflammatory demyelinating neuropathy: 1). Immunocytochemistry on nerve and muscle frozen sections showed a monotypic lymphoid cell population in 3 cases and failed in 4 cases. The PCR analysis of immunoglobulin heavy chain gene (FR3-FR4) rearrangement detected clonal B-cells in all biopsy specimens. There are arguments suggesting that incidental or paraneoplastic inflammatory NMDs may progress to neoplastic infiltration in CLL patients, as a result of the traffic of tumor B-cells from circulation to nerve and muscle tissues. This may question the traditional distinction between inflammatory and neoplastic NMDs in patients with lymphoid cell proliferations.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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