Persistent lymphadenopathy in patients at risk of contracting acquired immune deficiency syndrome.
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Biomedical subjects
Publications and source records attributed to J C Brouet.
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We have studied the alterations of vimentin intermediate filaments in uninduced or differentiated HL60 and U937 human leukemic cell lines. Whereas uninduced lines exhibited only a discrete reseau of vimentin, TPA treated cells acquire a very rich vimentin network similar to that of normal monocytes. On the other hand, DMSO treated HL60 cells differentiate to polymorphonuclears without modification of the IF network. These findings indicate that leukemic cells retain the expression of vimentin and exhibit an IF network similar to that of their normal counterpart.
We present here the immunologic, morphologic and clinical features of 16 T-derived adult non-Hodgkin lymphomas (NHL) (lymphoblastic and cutaneous lymphomas being excluded) observed in an unselected series of 260 NHL. Malignant cells bore T cell antigens (16 cases) but formed E rosettes in 14 cases only. In nine cases studied with monoclonal antibodies to T cell antigenic subsets, the phenotype of malignant cells was homogeneous; in seven cases the cells had a clear-cut helper or suppressor/cytotoxic phenotype; in one case cells had a cortical thymocyte phenotype. No T-cell subset antigens were detected on malignant cells from the last patient. Prominent morphologic features were a striking variation in tumour cell sizes, vascular proliferation and admixture of a large number of macrophages; most often, those lymphomas with a diffuse growth pattern could not be easily assigned to a given NHL subtype. The course of the disease was aggressive in most patients, only four having experienced a sustained complete remission. Waldeyer's ring involvement, waxing and waning nodes, polyclonal hypergammaglobulinaemia and skin infiltrates may be distinctive clinical features in some patients.
The mechanism of cryoprecipitation of a monoclonal IgM kappa cryoglobulin (Mou) with a cold agglutinin activity of Pr2 specificity has been studied. By immunodiffusion this cryoglobulin reacted (by its Fab' fragment) with micellar GM3, a ganglioside bearing the Pr2 antigenic determinant. In contrast to previous reports that indicated a possible temperature dependent self-association of IgM molecules via an immunological interaction leading to cold precipitation, we could not detect any affinity of this cryoglobulin for IgM when we used passive hemagglutination or an indirect enzyme-linked immunosorbent assay (ELISA). However, a GM3-like ganglioside could be extracted, by drastic methods, from the cryoglobulin studied at 22 degrees C, whereas no GM3 was extracted from two control cryoglobulins. Some minor gangliosides (representing less than 25% of total amount of bound gangliosides) were also extracted from Mou cryoglobulin and these gangliosides were shown to crossreact with GM3, as they specifically bind to Mou cryoglobulin by ELISA. After cryoprecipitation the serum still contained a monoclonal anti-Pr2 IgM kappa. A GM3-like ganglioside could be extracted from this purified IgM, and cryoprecipitability could be induced by the addition of a minute amount of micellar GM3. These results suggest that Mou cryoglobulin circulates as an immune complex and that cryoprecipitation may depend on unique IgM-GM3 (or IgM-GM3 cross-reacting gangliosides) complexes.
The expression of vimentin, the major polypeptide of the intermediate filament (IFM) cytoskeleton of lymphoid cells, was studied in normal and malignant human lymphoid cell lines. Cells from 24 of 27 Burkitt's lymphoma cell lines (BLCL) were found to have an absent (16 lines) or decreased (8 lines) expression of vimentin IFM. In contrast, non-Burkitt's malignant lymphoid cell lines (5 lines) and lymphoblastoid cell lines (LCL) derived from normal B-cells (45 lines) exhibited a well-developed vimentin IFM network. However, low expression of vimentin was also found in 3 LCL derived from patients with the Langer-Giedion syndrome, which is characterized by a deletion of the distal end of chromosome 8. Treatment of vimentin-negative BLCL and Langer-Giedion LCL with azacytidine led to a transient reexpression of vimentin.
Cryoglobulins are serum proteins which precipitate at 4 degrees C and redissolve during warming. When purified, they can be divided by immunochemical analysis into three main groups: monoclonal cryoglobulin, mixed cryoglobulin containing a monoclonal immunoglobulin, and polyclonal mixed cryoglobulins. There is a close correlation between the immunochemical composition of cryoglobulins and the symptoms or diseases associated with their presence.
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A 31-year-old Frenchman had an acquired immunodeficiency syndrome (AIDS) with profound depression of cellular immunity and relative sparing of humoral immunity. The clinical picture included intractable secretory diarrhoea, vomiting, abdominal pain, and weight loss. Gastrointestinal cryptosporidiosis was present and a perfusion technique showed profuse secretion of fluid in the proximal small bowel. The patient also had recurrent Salmonella typhimurium septicaemia, cytomegalovirus infection, and cerebral toxoplasmosis and he died within 13 months. This patient did not belong to any of the groups known to be affected by this type of acquired immunodeficiency (homosexuals, drug addicts, haemophiliacs, Haitians) but had been transfused with Haitian blood 4 years before onset of symptoms. This case supports the notion that some forms of AIDS may be transmitted by blood, with a long incubation period.
The Tn (or polyagglutinability) syndrome corresponds to a human nonmalignant acquired condition which results from a somatic mutation occurring at the level of bone marrow stem cells. This model offers therefore a unique opportunity to study the contribution of multipotential stem cells to the maintenance of cells from the lymphoid lineage. We found that the Tn mutation is expressed by both myeloid and lymphoid mature blood cells. Whereas a large proportion of surface IgM-bearing B cells carry the Tn mutation, only a small percentage of T cells and IgA- or IgG-bearing B cells are defective, showing that under physiological conditions the penetration of stem cells into the various myeloid and lymphoid compartments is variable.
Erythrocyte (E) rosette-forming cells have been investigated in three patients with B chronic lymphocytic leukemia whose leukemic lymphocytes were easily identifiable. A small percentage of fresh neoplastic cells formed E rosettes in two patients. In every patient, most unstimulated, cultured leukemic lymphocytes became E+ and this was further enhanced by phytohemagglutinin and pokeweed mitogen stimulation or neuraminidase treatment. These E+ B cells lacked detectable T cell antigens (except for a weak expression of an antigen associated with the helper T cell subpopulation in one case). They were unreactive or weakly reactive by immunofluorescence with a monoclonal antibody to the E receptor. However, this antibody completely inhibited E-rosette formation. The enhanced expression of E-rosette receptors by in vitro cultured cells appeared to be dependent upon the presence of a small number of E-rosetting cells at the beginning of the culture. E-rosette receptor expression by leukemic lymphocytes was most likely in a fourth case (out of 9 patients studied). This finding may account for some of the discrepancies in the study of so-called T cells in B chronic lymphocytic leukemia.
This study examines the target cell and the mode of action of a factor (TsF), produced by a human T-T hybridoma, which suppresses pokeweed mitogen-induced B cell differentiation as previously reported (J. Immunol. 1982. 129: 1008.). The suppressive effect still exists when peripheral blood leukocytes are depleted of T8+ cells or when TsF is added to a mixture of purified T4+ and B cells. This suppressive effect disappears when the T4 cells are irradiated. The suppression, however, is restored when a large number of T8 cells are added to the irradiated T4 cells. Lastly, a 24 h preincubation of T4 but not T8 cells, with TsF is able to generate suppressive effectors. These results suggest that the target cell for TsF is a radioresistant T4 cell which, upon activation, is able to induce radiosensitive T4 or T8 cells to suppress B cell differentiation.
We describe the alterations of vimentin intermediate filament (IF) expression in human hemopoietic committed precursors as they differentiate into mature cells of the erythroid, granulomonocytic, megacaryocytic and lymphoid lineages. A double labelling fluorescence procedure was used to identify hemopoietic cells expressing lineage-specific antigens and to decorate the vimentin IF network. Whereas very early progenitors from each lineage expressed vimentin, the density and organization of the network differed strikingly as the cells matured on a given pathway. T lymphocytes, monocytes and granulocytes retained vimentin expression at all stages of maturation. In contrast, megakaryoblasts lose vimentin expression at a very early stage of differentiation, erythroblasts at variable steps between the committed erythroid cell and the red cell. Finally, B lymphocytes tend to lose vimentin expression later when they mature into plasma cells.
Renal biopsy and autopsy specimens were studied in 43 patients with renal complications of multiple myeloma and correlated with immunoelectrophoresis (IEP) and other clinical data at the time of biopsy. Lesions specifically related to multiple myeloma fell into two categories, with different patterns of protein excretion. (1) Myeloma Cast Formation: When other lesions which might contribute to renal insufficiency (RI) were excluded, there was a good correlation between the extent of myeloma cast formation and severity of RI. Sixteen of 19 patients excreted free light chains (LCs) in the urine, in seven as the predominant or sole urinary protein. (2) Tissue Deposition of Paraproteins: Nine cases had generalized glomerular, tubular basement membrane and vascular deposits of presumed kappa-chains (one with associated alpha-heavy chains). Four patients, all with myelomas secreting lambda LCs, had diffuse amyloid deposits in similar distribution. All patients (save two who were anuric) had diffuse, nonselective proteinuria by IEP, most within the nephrotic range. Four patients had free LCs in the urine, but in none was this the predominant component. Cast nephropathy and LC tissue deposition tended to occur in mutually exclusive fashion. Cases with diffuse tissue deposits of LCs showed few or no myeloma casts. Cases with cast nephropathy had only occasional mild mesangial lesions and focal interstitial and vascular deposits of amyloid. Evidence indicates that these lesions represent incidental LC deposition in cases whose basic lesion is longstanding and/or severe cast nephropathy, and that their contribution to RI is minor in comparison to that of the myeloma casts.
We have studied the structure of a crystallizable gamma 1 heavy-chain disease protein that lacks the entire VH and C gamma 1 domains. The protein starts within the hinge region at aspartic acid 221 (Eu numbering). The native protein is a disulphide-linked dimer with an apparent molecular weight of 52,000, consistent with the biochemical data obtained on the whole protein and its cyanogen bromide fragments. The carbohydrate content of this protein was 6.8%. As shown by biosynthesis experiments intracytoplasmic gamma chains synthesized by neoplastic cells had an apparent molecular weight similar to that of the serum heavy-chain disease protein. These data are compared with those obtained for other gamma 1 heavy-chain disease proteins beginning in the hinge region, and the mechanisms leading to those abnormal Ig products are discussed.
We investigated, by indirect immunofluorescence, the binding of monoclonal IgM to human peripheral nerve in 25 patients with Waldenström's macroglobulinemia and peripheral neuropathy. In 10 cases (40%), an antibody activity against the myelin sheaths was demonstrated. The reactivity was mediated by the F(ab')2 fragments of the IgM. Prior delipidation of nervous tissue was needed to allow full expression of the target antigen(s). In nine cases, the IgM reacted with both peripheral and central myelin of primates, but not mouse or rabbit nervous tissue. In one case, the IgM reacted only with human peripheral nerve. The patients, whose IgM had an antibody activity to myelin antigen(s), had some distinct hematologic and neurologic features. The peripheral neuropathy always antedated the hematologic symptoms by several years. The serum level of the monoclonal IgM was low in all cases, and overt lymphoid malignancy was frequently absent. In other patients with neuropathy, the monoclonal IgM, which lacked antimyelin antibody activity, displayed either cross-idiotypic antigenic determinants or anti-intermediate filament antibody activity. These results taken together emphasize the heterogeneity of antibody activity of the monoclonal IgM from patients with Waldenström's macroglobulinemia and peripheral neuropathy.
To determine whether the human T-cell lymphoma-leukemia virus (HTLV) is associated with particular cancers, patient sera were surveyed for HTLV-specific antibodies. An association was seen with aggressive cancers of mature T-cells, specifically Japanese adult T-cell leukemia (ATL) and T-cell lymphosarcoma cell leukemia (TLCL), a similar cancer of Caribbean blacks. Ninety to 100% of these patients possessed HTLV-specific antibody. Forty-seven and 20% of relatives of ATL and TLCL patients, respectively, and 12 and 4% of healthy donors from ATL and TLCL endemic areas were also antibody positive. Visceral organ involvement, hypercalcemia, and skin manifestation, features of ATL and TLCL, were often seen in other antibody-positive patients. Childhood cancers, most cutaneous T-cell and all non-T-cell leukemias and lymphomas, myeloid leukemias, Hodgkin's disease, and solid tumors were not associated with HTLV. Healthy United States donors and European patients with non-malignant diseases were antibody negative. HTLV is thus associated with a subtype of adult T-cell leukemia-lymphoma, clustered in viral endemic areas, with apparent racial and geographic predilection.
The incidence of malignancies is strikingly high in patients with primary immunodeficiency diseases. Analysis of clinical data and the types of neoplastic proliferations raise several hypothesis. Occurrence of cancers does not seem to be favored by secondary immunodeficiencies related to lymphoma or immunosuppressive therapy.
Although recently identified, this disease is by no means exceptional. It is characterized by the deposition in various organs of an amorphous substance which differs from the amyloid substance and contains monoclonal immunoglobulin determinants: either a light kappa or lambda chain, or a light and a heavy chain. The severity of the disease is due to various organs being involved, notably the kidneys. There is in every case a monoclonal plasmocytic or lymphoplasmocytic proliferation which may appear as benign. In almost one-third of the cases no monoclonal immunoglobulin can be detected in the serum. In a study of immunoglobulin biosynthesis, 6 out of 8 patients showed striking structural abnormalities. The relationship between these very unusual lg's and tissue deposition is discussed in detail.