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Biomedical subjects

I J Forbes

Publications and source records attributed to I J Forbes.

At least 19 recordsLinked to original sources

Ca2+/Mg(2+)-dependent nuclease: tissue distribution, relationship to inter-nucleosomal DNA fragmentation and inhibition by Zn2+.

Ca2+/Mg(2+)-dependent endonuclease has been implicated in the extensive internucleosomal DNA fragmentation that accompanies apoptosis (gene-directed cell death). We present further evidence that this enzyme is involved in apoptosis. Ca2+/Mg2+ nuclease activity was increased about 6-fold during colchicine-induced apoptosis in human chronic lymphocytic leukaemia cells. The increase in activity coincided with onset of DNA fragmentation. Spleen, liver, kidney and thymus expressed high levels of this enzyme while lung, brain, heart and testis contained little activity. Cells from tissues with high Ca2+/Mg2+ nuclease activity underwent rapid DNA fragmentation in response to a Ca2+ flux. Physiological concentrations of Zn2+ known to inhibit both apoptosis and DNA fragmentation also inhibited Ca2+/Mg2+ nuclease activity.

Animals

Null cell chronic lymphocytic leukaemia.

Lymphocytes lacking receptors for sheep erythrocytes and surface immunoglobulin were present in the blood in large numbers at some stage in four cases of chronic lymphocytic leukaemia (which included a mother and son), and formed a substantial proportion of the circulating lymphocytes in other cases. These null cells possessed receptors for mouse erythrocytes. Other B-cell markers were also found on these cells. Serial studies showed a great variation in the number of null cells during the course of the disease (which may be associated with treatment), suggesting variation in the the maturation of leukaemic cells, and indicating that the surface marker complement may not reflect the constitution of the cell undergoing the original malignant change.

Aged

Immunosuppression in bancroftian filariasis.

Immunological function in Filipino patients with bancroftian filariasis, manifested as either asymptomatic microfilaraemia or chronic obstructive disease, was compared with that found in healthy control subjects living in the same area. As a group, patients with filariasis had raised serum IgG levels, impairment of antibody responses to tetanus and typhoid vaccines, and suppression of delayed hypersensitivity skin reactions to heterologous antigens. This immunosuppression in filariasis may result from antigenic competition and may contribute to the development of secondary infections.

Antibody Formation

Radiation-related coronary artery disease in Hodgkin's disease.

Coronary artery disease is a rare and only recently recognised complication of mediastinal irradiation. A 34-year-old man died suddenly eight years after mediastinal irradiation for Hodgkin's disease. Autopsy disclosed severe narrowing of all major extramural coronary arteries by atherosclerotic plaques whereas all other systemic and visceral arteries were virtually free of atheroma. Autopsy findings in the five reported cases of radiation-related coronary artery disease are reviewed.

Adult

Surface marker studies in chronic lymphocytic leukaemia and non-Hodgkin's lymphoma.

Immunological surface marker techniques were applied in a study of 29 cases of chronic lymphocytic leumaemia and 22 of non-Hodgkin's lymphoma. Surface marker characteristics distinguished 2 subtypes of B lymphocytes. Chronic lymphocytic leukaemia was a monoclonal proliferation of B lymphocytes which produced spontaneous rosettes with mouse erythrocytes and had faintly immunofluorescent surface immunoglobulin. The majority of non-Hodgkin's lymphomas also had their origin from B lymphocytes but in contrast, this subtype did not show receptors for mouse erythrocytes and their surface immunoglobulin was brightly staining and demonstrated "capping". The clonal origin of nodular lymphomas could also be demonstrated on frozen sections stained for surface immunoglobulin. Two cases of true histiocytic lymphoma were identified. The current information available on surface marker characteristics of the leukaemias and lymphomas is reviewed.

Adult

Studies of the human lymphocyte-mouse erythrocyte bond.

A subpopulation of human B lymphocytes forms rosettes with mouse erythrocytes through a glycoprotein-dependent bond. Further studies of this bond show that the lymphocyte receptor is not immunoglobulin, although the binding of antisera or staphylococci to surface immunoglobulin inhibits the formation of mouse rosettes. Rosette formation could not be induced in thymocytes by enzymatic modification of the surface, or in T cells by lectin-induced transformation. The capacity to bind mouse erythrocytes was lost after incubation in a serum-free medium of lymphcytes from most patients with chronic lymphocytic leukaemia (CLL) and normal subjects. This loss could be prevented by the addition of a variety of sera and glycoprotein-containing substances to the medium, including fetuin. Conditions conductive to the subsequent restoration of rosetting capacity could not be found, indicating that the loss of this capacity was not due to the shedding of a cell-surface receptor which could be re-synthesized. It is suggested that the functional receptors in B1 lymphocytes are held in aggregates by cross-linking peripheral glycoprotein molecules; disaggregation and consequent loss of the capacity to form rosettes with mouse erythrocytes occurs during incubation in serum-free media, and during maturation of lymphocytes to the B2 stage.

Animals

Maturation in B lymphocytic leukaemia.

Surface markers were studied serially in two cases presenting as acute B cell lymphocytic leukaemia. The leukaemic lymphocytes in both cases had the mouse erythrocyte receptor (MER) and surface immunoglobulin (SIg) with lambda light chain. Changes interpreted as an increase in immunological differentiation were observed in both, during the course of the disease and its treatment. These changes were loss of MER, increase in density of SIg, and the acquisition of SIgA. Selection of therapy to influence differentiation may ultimately afford better control of the lymphocytic leukaemias.

Adult

Erythroderma, an unusual manifestation of B cell lymphoma.

A case is described in which the initial manifestation of a malignant lymphoma was an erythematous skin rash over the face, scalp and trunk. Immunological surface marker analysis showed the malignant cells to be of B lymphocyte origin with a homogeneous secretion of IgM-K. Repeated skin and lymph node biopsies and finally post mortem documented the progression of the lymphoma from that of a mixed lymphocytic-histiocytic type with a nodular pattern of growth to a diffuse histiocytic lymphoma with frequently bizarre cells. The theory of ecotaxis or homing of lymphocytes to the skin and other non-lymphoid organs of the body is discussed in an attempt to explain the occurrence of cutaneous involvement as a primary manifestation of lymphoma.

Adult

B cell leukaemia distinguished from chronic lymphocytic leukaemia by surface markers.

Four cases of lymphocytic leukaemia were distinguished from CLL by surface marker analysis. CLL cells have relatively little SIg and have the mouse erythrocyte receptor. Cells in these cases had denser Slg and lacked the mouse erythrocyte receptor. The group presented a fairly uniform picture with onset in sixth or seventh decade, very high lymphocyte counts, splenomegaly (gross in three), heavy infiltration of marrow, relative resistance to chemotherapy and response to splenectomy. The lymphocytes were somewhat larger than those usually found in CLL and histological examination showed a quasi-nodular pattern in lymph nodes with diffuse infiltration of the spleen. Difficulties of classification are discussed. The addition of surface marker analysis to clinical and morphological parameters allows these cases of B-lymphocytic leukaemia (mouse erythrocyte-negative B leukaemia) to be distinguished clearly from chronic lymphocytic leukaemia. The mouse erythrocyte receptor is particularly useful in making this distinction.

Aged

Immunologic abnormalities in an animal model of chronic hypoplastic marrow failure induced by busulfan.

The immunology of chronic hypoplastic marrow failure (CHMF, aplastic anemia) was studied in an experimental murine model of the disease induced by busulfan. B lymphocytes of peripheral blood, spleen, and bone marrow were reduced to 30%-40% and T lymphocytes of thymus, spleen, marrow, and blood were decreased to 20%-70% of control values. IgG and IgM antibody titer to sheep red blood cells were reduced to one-third of control levels, and splenic IgG, but not IgM, plaque-forming cells were fewer on day 7 after antigen stimulation. The proliferative responses to phytohemagglutinin or concanavalin A were reduced in cultures of peripheral blood lymphocytes, splenic lymphocytes, and thymocytes, and cutaneous delayed-type hypersensitivity induced by dinitrofluorobenze was not detected in mice with CHMF. The results demonstrate disturbance of a variety of cellular and humoral functions and suggest that the disturbance was due to quantitative and possibly qualitative abnormalities of the cell types subserving these functions. The results suggest that residual cell injury, the lesion underlying experimental CHMF, is not confined to the myeloid stem cell but also involved cells of the lymphoid series.

Anemia, Aplastic

Changes in lymphocyte function during pregnancy.

A gradual increase in spontaneous lymphocyte DNA synthesis was demonstrated in each trimester of pregnancy. Autoradiographic studies indicated that lymphocytes were primarily responsible for this activity. PHA-induced lymphocyte transformation in both fetal calf serum and autologous serum was significantly reduced in the second and third trimesters of pregnancy. Spontaneous lymphocyte DNA synthesis was significantly reduced in patients with mild pre-eclampsia. However, no significant differences were seen in patients with severe pre-eclampsia in the third trimester of pregnancy compared with the normal control subjects. No evidence was adduced to implicate inhibitory humoral factors affecting the peripheral blood lymphocytes in pregnany patients in experiments in which washed lymphocytes were cultured in medium containing heterologous serum. In vitro experiments demonstrated that cortisol, progesterone and HPL caused a significant reduction in lymphocyte DNA synthesis, and HGH and HCG had a variable effect. However, only cortisol was regularly inhibitory at physiological concentrations. The progesterone effect was dose-related, producing 90 per cent inhibition of activity at a concentration of 10 mug/ml. No synergism could be shown between HPL and progesterone on lymphocyte transformation. The increase in activity of circulating immunoreactive cells during pregnancy and its depression with the onset of pre-eclampsia is discussed.

Chorionic Gonadotropin

A subpopulation of human B lymphocytes that rosette with mouse erythrocytes.

A proportion of human peripheral blood lymphocytes form rosettes with mouse erythrocytes (M-RFC). It is confirmed that the proportion of such rosette-forming cells is high in chronic lymphocytic leukaemia (CLL). Analysis of normal lymphocyte populations revealed that M-RFC belong to the B-lymphocyte subclass exclusively. Analysis of their surface markers showed: (a) complement receptors in 50% as compared to 71% of the total B-cell population; (b) a distribution of surface immunoglobulins G, A, M and E typical of the lymphocyte sources; (c) lack of sheep erythrocyte receptor. No differences in the ratio of M-RFC to total B cells was found between lymphocyte population from tonsils, bone marrow and peripheral blood although a significantly higher ratio was seen in cord blood and in chronic lymphocytic leukaemia. Investigation of the properties of mouse erythrocyte rosette formation revealed the following: (a) incubation of lymphocyte mouse erythrocyte mixtures at 37degreesC before centrifugation inhibited rosette formation when CLL lymphocytes were used; (b) treatment of mouse erythrocytes with neuraminidase or trypsin increased their adhesiveness to lymphocytes; (c) treatment of lymphocytes with neuraminidase promoted M-rosette formation but trypsin treatment had an inhibitory effect; (d) cyanide and fluoride at concentrations which strongly inhibited E-rosette formation had no inhibitory effect on M rosettes; (e) M-rosette formation was inhibited by anti-immunoglobulin serum but not by anti-lymphocyte serum; and (f) M-rosette formation was also inhibited by the presence of staphylococci. E-rosette formation was unaffected. The nature of the bond in mouse rosettes is discussed in the light of these findings. The evidence indicates that the lymphocyte receptor may be a part of an immunoglobulin molecule.

Animals

Increased resistance to helminth infestation in an atopic population.

Faecal egg counts were compared in three groups in an area of universal hookworm infestation. Egg counts were lower in asthmatic and atopic non-asthmatic subjects than in a non-atopic population. The atopic population was defined by skin testing for immediate hypersensitivity responses. It is suggested that the atopic state may confer increased resistance to helminth infestation.

Adolescent

Humoral and cellular immunity in asthma.

Parameters of humoral and cellular immunity have been measured in 91 asthmatic patients. Mean serum levels of IgG and IgE were raised. IgG levels were higher in those with a family history of asthma. IgE levels were higher in those with a past history of atopic eczema, but intrinsic and extrinsic asthma could not be differentiated on the basis of IgE levels. Thirteen of 74 patients failed to respond to tetanus immunization, while only 1 failed to respond to Salmonella typhi H antigen. Tetanus nonresponders had a raised mean serum IgA level, reduced spontaneous lymphocyte tritiated thymidine uptake, and reduced thymidine uptake in fetal calf serum. Eight of 87 patients failed to mount delayed hypersensitivity reactions to a battery of five intradermal antigens. The tritiated thymidine uptake of lymphocytes stimulated with phytohemagglutinin was normal in autologous serum, but reduced in fetal calf serum. The data support the hypothesis that asthma may be associated with immunodeficiency states.

Adolescent