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Biomedical subjects

E S Jaffe

Publications and source records attributed to E S Jaffe.

At least 91 records · Page 5Linked to original sources
PubMed1998

Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor.

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.

Blotting, Southern↗
PubMed1998

Pathological findings in human autoimmune lymphoproliferative syndrome.

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).

Apoptosis↗
PubMed1998

Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T lymphocytes.

Subcutaneous panniculitic T cell lymphoma (SCPTCL) is characterized by primary involvement of the subcutaneous fat in a manner mimicking panniculitis. We studied 16 cases of this lymphoma to define its immunophenotypical profile as well as cellular origin. Involvement of the subcutaneous fat in a lacelike pattern with neoplastic cells rimming individual fat spaces was present in all cases. All 16 cases were of T cell phenotype. Thirteen of the 16 cases were CD8+, whereas three were negative for both CD4 and CD8. Twelve cases were stained for betaF1; of these, eight were betaF1+ and four were betaF1-. Focal staining for CD56 and CD30 was seen in 2 of 13 and two of eight cases, respectively. Intense diffuse positivity for the cytotoxic granular proteins T cell intracellular antigen-1 (TIA-1) and perforin was present in all cases, indicating an origin from cytotoxic T lymphocytes. Ten cases studied for Epstein-Barr viral sequences were negative. Eight of 9 cases with amplifiable DNA showed a clonal TCR gamma gene rearrangement by polymerase chain reaction. Controls included seven cases of benign panniculitis and seven other peripheral T cell lymphomas involving the skin and subcutaneous tissues: two peripheral T cell lymphomas, not otherwise specified (PTL,NOS), four anaplastic large cell lymphomas (ALCL), one T/NK cell lymphoma. The seven cases of panniculitis lacked cytological atypia and were characterized by an admixture of CD4+ and CD8+ cells with interspersed aggregates of L26+ B cells. Only infrequent cells showed staining for TIA-1 and perforin. In the control cases of T cell lymphoma, the infiltrate had a tendency for dermal and sometimes even epidermal involvement, with sheeting out of malignant cells, in contrast to the characteristic subcutaneous localization and rimming of fat spaces noted in SCPTCL. The two PTL, NOS were CD4+ and negative for both TIA-1 and perforin. Although the remaining controls expressed TIA-1 and perforin, in keeping with their cytotoxic T or natural killer (NK) cell origin, histological and other immunophenotypical features allowed distinction from SCPTCL. Five cases of SCPTCL were also stained for apoptosis using a tdt-mediated end labeling kit. All cases showed numerous positive apoptotic bodies, suggesting apoptosis as the mechanism of cell death in these tumors. Our study indicates that SCPTCL constitutes a distinctive clinicopathological entity derived from cytotoxic T lymphocytes and should be differentiated from other benign and malignant lymphoid infiltrates involving the subcutis. The apoptosis seen in these tumors may be mediated by release of cytotoxic granular proteins.

Adult↗
PubMed1998

FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.

Various histological subtypes of leukaemia and lymphoma are associated with diagnostic chromosome translocations, and substantial strides have been made in determining the specific oncogenes targetted by those translocations. We report the cloning of a novel fusion oncogene associated with a unique leukaemia/lymphoma syndrome. Patients afflicted with this syndrome present with lymphoblastic lymphoma and a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow, which generally progress to full-blown acute myelogenous leukaemia within a year of diagnosis. A specific chromosome translocation, t(8;13)(p11;q11-12), is found in both lymphoma and myeloid leukaemia cells from these patients, supporting bi-lineage differentiation from a transformed stem cell. We find that the 8p11 translocation breakpoints, in each of four patients, interrupt intron 8 of the fibroblast growth factor receptor 1 gene (FGFR1). These translocations are associated with aberrant transcripts in which four predicted zinc-finger domains, contributed by a novel and widely expressed chromosome-13 gene (ZNF198), are fused to the FGFR1 tyrosine-kinase domain. Transient expression studies show that the ZNF198-FGFR1 fusion transcript directs the synthesis of an approximately 87-kD polypeptide, localizing predominantly to the cytoplasm. Our studies demonstrate an FGFR1 oncogenic role and suggest a tumorigenic mechanism in which ZNF198-FGFR1 activation results from ZNF198 zinc-finger-mediated homodimerization.

Amino Acid Sequence↗
PubMed1998

Hepatobiliary lymphoepithelioma-like carcinoma associated with Epstein-Barr virus.

We describe the clinical and pathologic features of a lymphoepithelioma-like carcinoma (LELC) that originated in the hepatobiliary system. A woman, aged 71 years, was first seen with a noncholangiolar adenocarcinoma with lymphoid stroma, which was discovered by open liver biopsy in 1993. In 1995, retroperitoneal and peripancreatic lymph nodes were involved by LELC. There currently is no evidence of distant metastasis outside the hepatobiliary peripancreatic region. Review of the biopsy material revealed a well-differentiated adenocarcinoma with transition into LELC. Epstein-Barr virus (EBV) transcripts were expressed in all histologic phases of the tumor by in situ hybridization using immunoalkaline phosphatase-labeled oligonucleotide probes for EBV-encoded RNA 1 on formalin-fixed, paraffin-embedded sections. Polymerase chain reaction analysis for EBV nuclear antigen 2 was consistent with EBV strain type A. The LMP-1 gene was found to be wild type by polymerase chain reaction analysis. To our knowledge, this is the first report of a primary hepatobiliary adenocarcinoma associated with EBV infection that transformed into an undifferentiated LELC.

Adenocarcinoma↗
PubMed1998

World Health Organization Classification of lymphomas: a work in progress.

The World Health Organization (WHO) publishes classification handbooks for all neoplastic diseases. The last WHO Classification of leukemias and lymphomas was published in 1976. Since that time, through cytogenetics and molecular biology, it has been shown that many hematopoietic neoplasms are associated with a unique genetic profile. Similarly, the development of widely available and routinely applied monoclonal antibodies has allowed the identification of a unique immunophenotypic profile for most leukemias and lymphomas. These techniques have permitted the recognition of a number of distinct disease entities, and also enhance both diagnostic accuracy and reproducibility. The WHO Classification has been developed under the joint auspices of the European Association for Hematopathology (EAHP) and the Society for Hematopathology (SH). First organized in 1995, the Steering Committee appointed 10 committees covering T-cell and B-cell lymphomas and leukemias, myeloid and histiocytic tumors. The committees were asked to develop a list of diseases within their topic area, and to establish definitions of each disease according to established criteria. The WHO Classification uses the principles of the R.E.A.L. Classification, which defines each disease according to its morphology, immunophenotype, genetic features, postulated normal counterpart, and clinical features. Morphologic and clinical variants of individual diseases are discussed in the text, and their use is optional. The proposed classification was presented at the USCAP meeting in 1997, the site of the first joint meeting of the EAHP and SH. The presentation was followed by an open forum attended by EAHP and SH members. The Steering Committee also appointed a Clinical Advisory Committee to ensure that the classification meets clinical needs, and to resolve questions of clinical significance. The proposed WHO Classification for lymphomas is similar to the R.E.A.L. Classification for lymphomas, with minor modifications and reassessment of provisional categories based on new data since 1994.

B-Lymphocytes↗
PubMed1998

Workshop report on Hodgkin's disease and related diseases ('grey zone' lymphoma).

Despite advances in immunohistochemistry and molecular biology, the distinction between classical Hodgkin's lymphoma and related diseases such as nodular lymphocyte-predominant Hodgkin's disease, T-cell rich large B-cell lymphoma or anaplastic large cell lymphoma has remained difficult in rare cases. Lack of clear-cut diagnostic criteria represents a problem for both the pathologist and the clinician. To delineate this 'grey zone' between classical Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL) and to develop criteria for classification of such cases, 12 expert hematopathologists each submitted one to five borderline cases to a workshop. Cases were reviewed and classified at a multiheaded microscope and criteria were established for the diagnosis of questionable cases. Well established entities such as classical Hodgkin's lymphoma, anaplastic large-cell lymphoma and TCRBCL were defined more strictly and cases with unusual morphology or antigen expression could be identified. A distinctive subset of cases representing mediastinal large B-cell lymphomas with features of Hodgkin's lymphoma was identified.

Diagnosis, Differential↗
PubMed1998

Precursor B-Lymphoblastic lymphoma presenting as a solitary bone tumor and mimicking Ewing's sarcoma: a report of four cases and review of the literature.

Precursor B-lymphoblastic lymphoma (B-LBL) may present as a solitary bone tumor. Fewer than 10 cases with a proven precursor B-cell phenotype have been reported in the English literature. In this report, we describe four cases of B-lymphoblastic lymphoma presenting as a localized intraosseous mass, which clinically and histologically mimicked Ewing's sarcoma. Three tumors occurred in the tibia and one in the humerus. In all four cases, the initial diagnosis was either "Ewing's sarcoma" or "consistent with Ewing's sarcoma." All four patients were female. Three were children and one was an adult; mean age was 12.5 years (range, 4 to 31 years). All had extremity pain without significant constitutional symptoms. In three cases, the tumors were osteolytic on radiographic evaluation, and in one case, osteosclerotic. Immunohistochemical stains on paraffin-embedded tissue showed that the neoplastic cells expressed terminal deoxynucleotidyl transferase, CD43, vimentin, and CD99 (MIC2 gene product) in all cases. Three cases were negative for CD45. CD79a was positive in all four cases studied; however, CD20 (L26) was positive in only two of four cases. CD3 was negative in all cases. Two cases showed focal granular cytoplasmic staining for keratin. Two cases analyzed by polymerase chain reaction (PCR) revealed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene. Follow-up revealed that the three pediatric patients, who received a high-dose multiagent chemotherapy regime for LBL, are disease free at follow-up intervals of more than 1, 11, and 12 years, respectively. The adult patient died two years after diagnosis with disseminated disease. Although rare, B-lymphoblastic lymphoma should be considered in the differential diagnosis of small round cell tumors of bone. A diagnosis of Ewing's sarcoma should be made only after complete immunophenotyping and, if necessary, molecular diagnostic tests to exclude lymphoblastic lymphoma. A limited panel of antibodies can lead to an erroneous diagnosis; B-lymphoblastic lymphoma may be negative for CD45 and CD20 but positive for CD99 and even for keratin, mimicking Ewing's sarcoma. Correct diagnosis is extremely important because LBL usually is curable in the pediatric age group with appropriate therapy.

Adult↗
PubMed1998

Reticulum cell neoplasms of lymph nodes: a clinicopathologic study of 11 cases with recognition of a new subtype derived from fibroblastic reticular cells.

Lymph nodes contain nonlymphoid accessory cells including follicular dendritic cells (FDCs), interdigitating dendritic cells (IDCs) and fibroblastic reticular cells (FBRCs). Neoplasms derived from FDCs are uncommon, and those of IDC origin are even more rare. We report the clinicopathologic features of 11 reticulum cell neoplasms, including 2 of FBRC origin. There were seven male patients and four female patients ranging in age from 13 to 73 years. All cases involved lymph nodes (cervical or supraclavicular-6 cases), (abdominal--2 cases), epitrochlear (1 case); two had more than one site of involvement (cervical lymph node and mediastinum--1 case, cervical and abdominal lymph nodes--1 case). One case of FDC tumor had concomitant Castleman's disease, plasma cell variant. Each neoplasm showed similar histology with oval-to-spindle-shaped cells in a storiform or fascicular pattern. Based on immunophenotypic findings, the neoplasms were classified as FDC (five cases), IDC (two cases), FBRC (three cases), and reticulum cell neoplasm, not otherwise specified (one case). The FDC tumors showed immunoreactivity for CD21 or CD35, vimentin, and CD68. The IDC tumors showed strong positivity for S-100 protein and variable positivity for CD68 and CD1a. The cases derived from FBRCs were positive for vimentin, desmin, and smooth-muscle actin. The neoplasm classified as reticulum cell neoplasm, not otherwise specified had similar morphologic features but showed only equivocal positivity for CD68 and vimentin. Follow-up was available for 9 of 11 (82%) cases with a mean of 3.5 years. Four of five patients with FDC tumors were alive with disease when last seen; the fifth is alive and well with no evidence of disease at 4-year follow-up. One patient with IDC tumor had a recurrence in a different nodal site. Two patients with FBRC tumor were disease free at follow-up of 2 years and 8 years, respectively. The patient with reticulum cell neoplasm, not otherwise specified, was alive and disease free 8 years after diagnosis.

Adolescent↗
PubMed1998

Phase II and dose-escalation with or without granulocyte colony-stimulating factor study of 9-aminocamptothecin in relapsed and refractory lymphomas.

PURPOSE: To assess the efficacy and maximum dose-intensity of a new topoisomerase I (topo I)-targeting agent, 9-aminocamptothecin (9-AC), in patients with relapsed or refractory lymphomas. PATIENTS AND METHODS: Eligible patients had measurable disease and were considered incurable. 9-AC was infused over 72 hours at an initial dose rate of 40 microg/m2/h every 3 weeks with subsequent intrapatient escalations or reductions in 10-microg/m2/h increments based on toxicity. To assess the impact of granulocyte-colony stimulating factor (G-CSF) on dose-intensity, the first 16 patients received no G-CSF and the subsequent 29 patients received G-CSF on all cycles. RESULTS: Forty-five patients received a total of 142 cycles of 9-AC. The patients' median age was 55 years, 73% had stage IV disease, and histologies included indolent and aggressive non-Hodgkin's lymphoma (NHL) in 33% and 58% of patients, respectively, and Hodgkin's lymphoma in 9%. Patients had received a median of two prior chemotherapy regimens, and 67% of patients had chemotherapy-sensitive disease. Of 40 assessable patients, 10 (25%) achieved a partial response (PR). Chemotherapy-sensitive patients had a 32% response rate compared with 8% in chemotherapy-resistant patients. With a median follow-up duration of 35 months, the median event-free survival (EFS) and overall survival times were 1.5 and 12.5 months, respectively, and the median duration of response was 5 months (range, 1 to 10). G-CSF significantly reduced the incidence of neutropenia and diarrhea, but did not permit a significant increase in dose-intensity. CONCLUSION: 9-AC had a reasonable response rate of 25% in heavily pretreated patients. The low response rate in patients with chemotherapy-resistant disease suggests that there is cross-resistance between 9-AC and standard chemotherapy. However, there was no association between 9-AC response and the number of prior regimens. Due to dose-limiting thrombocytopenia, G-CSF support did not increase dose-intensity, although individual patients benefited from the use of G-CSF.

Adult↗
PubMed1998

Cytotoxic granular protein expression, Epstein-Barr virus strain type, and latent membrane protein-1 oncogene deletions in nasal T-lymphocyte/natural killer cell lymphomas from Mexico.

Nasal T-lymphocyte/natural killer cell lymphomas (nT/NKLs) are a distinct group of neoplasms highly associated with Epstein-Barr virus (EBV), with a high prevalence in Asia but rare in Western countries. Recent studies indicate that these neoplasms are of cytotoxic T- or NK-cell derivation. Previous studies identifying a characteristic 30-base pair deletion within the 3' end of latent membrane protein-1 (del-LMP-1) in other EBV-associated lymphomas suggested a pathogenetic role for del-LMP-1 in those neoplasms. We examined 23 cases of nT/NKL from Mexico for expression of the cytolytic granular proteins TIA-1 and perforin (PRF), and for the presence of EBV by in situ hybridization (ISH). Polymerase chain reaction was performed to identify the EBV (EBNA-2) strain type and the status of the LMP-1 gene (del-LMP-1). Controls consisted of 11 sinonasal B-cell lymphomas (nBLs) and 30 reactive tonsils (RTs) from healthy Mexican individuals. The nT/NKLs expressed TIA-1 in 21 (91%) of 23 cases and PRF in 15 (65%) of 23 cases. In contrast, all of the nBLs were negative for TIA-1 and PRF. Twenty-two (96%) of 23 nT/NKLs were positive for EBV by ISH. In contrast, only 2 (18%) of 11 nBLs were positive for EBV by ISH. EBV strain Type A was identified in 21 (91%) of 23 cases, whereas strain Type B was present in 2 (9%) of the 23 nT/NKLs. A similar percentage (80%) of Type A was noted in 12 of the 15 RTs. del-LMP-1 was detected in 6 (26%) of 23 nT/NKLs, comprising 4 cases of Type A and 2 of Type B. del-LMP-1 was detected in 9 (45%) of 20 RTs. Our results indicated that TIA-1 and PRF were sensitive markers of nT/NKL. The presence of del-LMP-1 in comparable frequencies in the RTs and nT/NKLs suggested to us that this genotype was common in the Mexican population and argued against a definite pathogenetic role for del-LMP-1 in nT/NKL.

Adolescent↗
PubMed1998

Expression of human herpesvirus-8 oncogene and cytokine homologues in an HIV-seronegative patient with multicentric Castleman's disease and primary effusion lymphoma.

Human herpesvirus-8 (HHV-8) has been described in association with two lymphoproliferative disorders: one benign, multicentric Castleman's disease (MCD), and one malignant, primary effusion lymphoma (PEL). The factors that lead to malignant transformation of lymphoid cells are unknown, although most cases of PEL also are positive for EBV, suggesting a role for EBV as a cofactor in malignant transformation. We encountered a rare case of an HHV-8-associated MCD, followed by the development of an HHV-8-positive pleural PEL and a gastric large cell lymphoma in an HIV-seronegative male patient. The lesions were negative for Epstein-Barr virus (EBV). The combination of these diverse HHV-8-associated lymphoproliferative disorders in a single patient afforded us the ability to study potential differences in gene expression in these conditions. HHV-8 DNA was demonstrated by PCR in lymphoid tissues involved by MCD and PEL. By reverse transcriptase-PCR, HHV-8-related transcripts, including vG-coupled protein receptor, vbcl2, vcyclin D, vIL-6, vMIPI, and vMIPII, were detected in the PEL from the pleural cavity and the gastric lymphoma, whereas these transcripts, except for vIL-6, were not detected in a lymph node biopsy with MCD. Expression of hIL-10 was weak in the PEL from the pleural cavity, and expression of hIL-6 was undetectable in all three lesions. These data suggest that vIL-6 may be integral to the pathogenesis of MCD, whereas other viral transcripts that encode oncogene and chemokine homologues are important for HHV-8 tumorigenicity.

Antigens, CD↗
PubMed1997

The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein-Barr virus-positive lymphoproliferative disease.

The mechanisms of tissue necrosis and vascular damage characteristics of certain Epstein-Barr virus (EBV)-associated lymphoproliferative disorders are unknown. The CXC chemokines interferon-gamma-inducible protein-10 (IP-10) and the monokine induced by interferon-gamma (Mig) caused tissue necrosis and vascular damage in Burkitt's lymphoma tumors established in nude mice. We report higher levels of IP-10 and Mig gene expression in tissues with necrosis and vascular damage from EBV-positive lymphomatoid granulomatosis and nasal or nasal-type T/natural killer (NK)-cell lymphomas compared with tissues with lymphoid hyperplasia, which lacked tissue necrosis and vascular damage. By immunohistochemistry, Mig and IP-10 proteins localized with similar patterns in viable tissue surrounding dead tissue, mostly within endothelial cells, monocyte/macrophages, and lymphocytes. Circulating levels of IP-10 were abnormally elevated in patients with EBV-positive lymphomatoid granulomatosis and nasal or nasal-type T/NK-cell lymphomas. These experiments provide the first description of the presence of Mig in any human normal or diseased tissue and the first description of IP-10 in certain lymphoproliferative lesions. These data suggest that Mig and IP-10 play an important role in the pathogenesis of tissue necrosis and vascular damage associated with certain EBV-positive lymphoproliferative processes.

Adult↗
PubMed1997

Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.

Anemia, Hemolytic, Autoimmune↗
PubMed1997

Cytotoxic cell antigen expression in anaplastic large cell lymphomas of T- and null-cell type and Hodgkin's disease: evidence for distinct cellular origin.

Anaplastic large cell lymphoma (ALCL) is composed of large, frequently bizarre, cells of T- or null-cell phenotype that show a preferential sinusoidal growth pattern and consistent CD30 positivity. Whether these tumors represent a single entity or several, and what the exact cell origin, is controversial. Recently, granzyme B, a cytotoxic granule component, was reported in a small percentage of ALCL, suggesting that some cases may originate from cytotoxic lymphocytes. To further investigate this possibility, we performed an immunohistochemical study of 33 ALCLs of T- and null-cell type, using monoclonal antibodies to cytotoxic cell-associated antigens, including CD8, CD56, CD57, and the cytotoxic granular proteins perforin and TIA-1. In addition, CD4 expression was also evaluated. ALCL cases included 27 classical systemic forms and variants, 3 primary cutaneous (PC) forms, and 3 acquired immunodeficiency syndrome-associated forms. Cytotoxic antigen expression was also studied in 51 cases of Hodgkin's disease (HD) and 17 large B-cell lymphomas (LBCLs) with anaplastic cytomorphology and/ or CD30 positivity. We found that 76% of ALCLs, representing all subtypes except the PC forms, expressed either TIA-1, perforin, or both proteins. Expression of TIA-1 and perforin were highly correlated (P < .001). On the basis of their immunophenotypic profiles, several subtypes of cytotoxic antigen positive and negative ALCL could be recognized. Fifty-five percent of ALCLs (18 of 33) displayed an immunophenotypic profile consistent with cytotoxic T cells. Six cases expressed cytotoxic granular proteins in the absence of lineage specific markers, and one case expressed both T-cell- and natural killer cell-like markers. These 7 cases (21%) were placed into a phenotypic category of cytotoxic lymphocytes of unspecified subtype. Twenty-four percent (8 cases) of ALCLs were cytotoxic granule protein negative. All but one of these displayed a T-cell phenotype. Cytotoxic granule protein expression did not correlate with the presence of the NPM-ALK fusion transcript. Only 10% of the 51 HD cases were found to be TIA-1+, and none expressed perforin. Cytotoxic antigen expression was absent in LBCL. The expression of cytotoxic granule proteins in the majority of ALCL implies a cytotoxic lymphocyte phenotype and suggests that most cases originate from lymphocytes with cytotoxic potential. Furthermore, the demonstration of cytotoxic cell related proteins may be a useful addition to the current panel of antibodies used to distinguish ALCL, HD, and anaplastic LBCL.

Adolescent↗