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Biomedical subjects

N Talal

Publications and source records attributed to N Talal.

At least 163 records · Page 9Linked to original sources
PubMed1984

Increased Ia expression, T lymphocyte subset abnormalities and autoimmunity in murine strains bearing the lpr gene.

Defects in cellular communication are fundamental to the development of autoimmune disease. Modulation of immunoregulatory events can be mediated by cellular expression of Ia antigens. We have analysed, by flow cytometry, the Ia antigenic levels on cells from mice expressing the lpr gene and their congenic counterparts. Surface Ia expression is dramatically increased on bone marrow, thymus, lymph node and spleen cells from lpr mice even prior to characteristic lymph node and spleen enlargement. In addition, IL-2 production abnormalities occur in the low density Lyt 1 subset of Thy 1.2 positive cells of normal mice which may be the counterpart of the majority cell type of lpr lymphocytes. Treatment of lpr mice with low dose whole body irradiation (300 rad) decreases lymphadenopathy, autoantibodies, proteinuria and the resident Ia positive cell population while increasing survival. We conclude that lymphoid alterations induced by irradiation reflect a recovery of immunological control associated with suppression of autoimmune manifestations.

Aging↗
PubMed1984

Defective LN cell proliferative response to Sm antigen in mice bearing the lpr gene.

Several normal and lpr/lpr congenic mouse strains were immunized with an autoantigen (Sm) and a conventional antigen (PPD) and tested for their respective in vitro proliferative responses. All normal strains of mice demonstrated a brisk proliferative response to Sm and PPD on days 3 and 5 of culture. Two month old mice bearing the lpr gene demonstrated a proliferative response to the two antigens only on day 3, while by day 5 of culture, the proliferative response was markedly diminished. Mixing experiments between +/+ and lpr/lpr Sm primed lymph node cells ruled out the influence of a suppressor cell within the lpr/lpr population at day 5. The inability to sustain an in vitro proliferative response to antigen in young lpr/lpr mice was not due to an overall T cell defect nor to in vitro cell death since Con A stimulation and viability were the same in cultures containing lpr/lpr and +/+ LN, cells, respectively. The primary defect may be partly attributed to a defect in interleukin-2 (IL-2) production and response. By day 5 of culture, lpr/lpr supernatants contained much lower levels of IL-2 activity compared to supernatants from +/+ cultures. The addition of exogenous IL-2 was only moderately successful in improving the response falling far below that seen when IL-2 was added to +/+ cultures. This study demonstrates a decrease in autoantigen-induced T cell proliferation in mice that spontaneously produce autoantibodies to that antigen.

Animals↗
PubMed1983

Cellular immune response to acetylcholine receptors in murine experimental autoimmune myasthenia gravis: inhibition with monoclonal anti-I-A antibodies.

Gene(s) at the I-A subregion of the murine major histocompatibility complex influence susceptibility to experimental autoimmune myasthenia gravis. C57Bl/6 mice immunized with acetylcholine receptors (AChR) in complete Freund's adjuvant demonstrated cellular and humoral immune responses to AChR. They developed muscle weakness characteristic of myasthenia gravis and demonstrated a reduction in the muscle AChR content. The kinetics of AChR-specific lymphocyte proliferation generally correlate with anti-AChR antibody response. AChR-specific lymphocyte proliferation was also observed in C57Bl/6 splenocytes after secondary immunization with AChR. The in vitro cellular reactivity to AChR in experimental autoimmune myasthenia gravis (EAMG) mice (C57Bl/6) was suppressed by monoclonal anti-I-Ab antibodies directed against private (Ia20) or public (Ia8) specificities, suggesting a critical role for these Ia determinants in the cellular immune response to AChR in murine EAMG.

Animals↗
PubMed1983

Deficient T-cell mitogen response in murine experimental autoimmune myasthenia gravis: a defect in the adherent cell population.

T-Lymphocyte number and functions are often reduced, while B-lymphocyte function is often increased in patients with autoimmune disorders. To study the mechanisms responsible for these T-cell malfunctions in autoimmunity we adapted the murine experimental autoimmune myasthenia gravis (EAMG) model. Splenocytes from C57BL/6 mice immunized with acetylcholine receptors (AChR) in complete Freund's adjuvant (CFA) produced approximately half the amount of concanavalin A (Con A)-induced interleukin 2 (IL-2) as did splenocytes of CFA-inoculated controls. Further, AChR plus CFA-immunized splenocytes showed a marked reduction in T-cell proliferative responses induced by Con A or phytohemagglutinin when compared with CFA-inoculated controls. By contrast, lipopolysaccharide-induced B-cell function is preserved. Deficient Con A splenic T-cell response is seen early after secondary inoculation with CFA or AChR in CFA. T-Cell recovery occurs in CFA-inoculated mice but not in AChR plus CFA-inoculated mice. Defective Con A splenic T-cell response seen early after secondary immunization with CFA or AChR in CFA is due to the presence of a defective splenic adherent cell population. Moreover, defective Con A splenic T-cell response seen after established autoimmunity to AChR in EAMG is also due to the presence of a defective splenic adherent cell population.

Animals↗
PubMed1983

Natural killing activity in Sjögren's syndrome. An analysis of defective mechanisms.

Natural killing (NK) by peripheral blood mononuclear cells (PBMC) against K562 cells was examined in 27 patients with Sjögren's syndrome and 17 normal controls. NK activity in the patients was significantly reduced compared with normal controls (34.6 +/- 3.4% versus 52.2 +/- 3.4%, P less than 0.001). Patients with secondary Sjögren's had lower cytotoxicity compared with those who had primary Sjögren's (28.5 +/- 5.5% versus 37.3 +/- 4.2%, P less than 0.01). The proportion of PBMC with characteristics of NK cells was not decreased in the patients. NK by normal PBMC was diminished both in the presence of sera from patients with reduced NK and when the effector cells were pretreated with the sera. Pretreatment of target K562 cells did not alter NK activity. Suppression of NK by sera from patients did not correlate with levels of immune complexes or with antilymphocyte antibodies. Some patients had adherent cells which inhibited NK function. Addition of either indomethacin or catalase partially restored NK activity in such patients, indicating that both prostaglandins and hydrogen peroxide play a role in suppression. These data suggest that multiple mechanisms are involved in the defective NK activity seen in patients with Sjögren's syndrome. The reduction of NK activity in Sjögren's syndrome may contribute to the increased incidence of lymphoid malignancy.

Adult↗
PubMed1983

Interleukins in experimental autoimmune disease.

New mouse models of SLE have been developed recently including strains bearing the lpr gene. The presence of this gene results in antibodies to nucleoproteins and DNA, immune complex glomerulonephritis, and proliferation of Lyt 1+23- T cells. A defect in Interleukin-2 (IL-2) production is a common abnormality in these autoimmune mice. We have utilized an antigen presentation system to study T cell proliferation in MRL/lpr, C57B16/lpr and C3H/He/lpr mice and their normal congenic counterparts. The normal mice proliferate well whereas there is little proliferation in the lpr variants. Mixing experiments demonstrate that the defect resides with the lpr responding T cells and not with the lpr macrophages. This abnormality could be due to defective IL-2 production by Lyt 1+23- T cells.

Animals↗
PubMed1983

T-cell macrophage subset interactions and decreased autologous mixed lymphocyte reaction in Sjögren's syndrome.

T-cell macrophage subset interactions were studied in relation to the decreased autologous mixed lymphocyte reaction (AMLR) in 15 patients with Sjögren's syndrome (SS). Monoclonal antibodies against a macrophage (M theta) subset (Mac-120) stimulatory in the AMLR and against nonpolymorphic determinants of Ia antigen were used to identify adherent M theta. Four patients with decreased AMLR had a reduced percentage of Mac-120+ cells, suggesting that a defect in stimulatory M theta may account for their decreased AMLR. No correlation was found between the magnitude of the AMLR and the percentage of Ia+ M theta. Another six patients with diminished AMLR had a normal to high percentage of Mac-120+ M theta. However, this group of SS patients showed a decreased response to Concanavalin A, suggesting that they may have a defect in the responding T cells. Patients with normal AMLR had normal percentages of Mac-120+ M theta and showed normal responses to T-cell mitogens and alloantigens. These results suggest that a defective AMLR may have multiple causes. SS patients are heterogeneous in this regard and can be sorted into three groups using the AMLR and monoclonal antibodies.

Adult↗
PubMed1983

Effects of castration and sex hormones on immune clearance and autoimmune disease in MRL/Mp-lpr/lpr and MRL/Mp-+/+ mice.

The clearance of erythrocytes sensitized with IgG was studied in MRL/Mp-lpr/lpr (MRL-lpr) and MRL/Mp-+/+ (MRL-+/+) mice, which spontaneously develop autoimmune disease. In both strains, an age-dependent decline in clearance of IgG-sensitized erythrocytes was found. Impaired clearance occurred at an earlier age in MRL-lpr mice than in MRL-+/+ mice, correlating with the relative severity of autoimmune disease in these strains. Androgen treatment improved clearance in MRL-+/+ mice but not in MRL-lpr mice, even though autoantibody levels, renal function, and survival were improved. These results suggest that the beneficial effects of androgen on autoimmune disease are not due solely to improved clearance of immune complexes. Castration followed by estrogen administration did not influence immune clearance or autoimmune disease in MRL-lpr mice. These results indicate that impaired immune clearance is a common feature in several autoimmune mouse strains. However, the effects of sex hormones on immune clearance and autoimmune disease may be dissociated in some strains.

Animals↗
PubMed1983

Molecular and antigenic nature of isolated Sm.

The Sm antigen was isolated and purified from calf thymus nuclear extract by affinity chromatography. The affinity columns were made with serum antibodies from an SLE patient or an anti-Sm monoclonal antibody derived from a hybridoma cell line. Proteins eluted from these two columns had m.w. of 58,000 and 35,000 by SDS polyacrylamide gel electrophoresis. The natural conformation of this antigen appears to be 95,000 in m.w. with the 58,000 particle containing the Sm antigenic determinant. The affinity column-purified antigen detected by the human anti-Sm antibodies is also recognized by anti-Sm antibodies in murine lupus serum, as shown by solid-phase radioimmunoassay. This study 1) demonstrates the molecular and antigenic nature of the Sm antigen and 2) compares the anti-Sm binding capabilities of antibody populations present in sera from SLE patients and from MRL lpr/lpr mice.

Animals↗
PubMed1983

Immunomodulation by isoprinosine: effects on in vitro immune functions of lymphocytes from humans with autoimmune diseases.

Isoprinosine (IPS) is a new anti-viral agent which appears to have immunomodulatory activities which include its ability to enhance the in vitro blastogenic responses of normal lymphocytes to mitogens. The present study compares the effects of IPS on the in vitro immune functions of peripheral blood mononuclear cells (PBMC) from systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients with its effects on PBMC from normal controls. Each mitogen (Con A, PHA or PWM) was used at its optimal concentration with a range of IPS concentrations (0-25 micrograms/ml). PHA-induced blastogenesis by PBMC from all three groups was enhanced by IPS at or above 5 micrograms/ml. The Con A-induced responses of SLE lymphocytes were significantly enhanced over controls by IPS (P less than 0.02 at 5 micrograms/ml) while those of RA lymphocytes were not. IPS had little effect on PWM-induced blastogenesis by RA lymphocytes but did enhance the blastogenic responses of SLE lymphocytes (P less than 0.01 at 5 micrograms/ml). In contrast, the characteristically high immunoglobulin synthesis by SLE lymphocytes was decreased by IPS. The mechanism responsible for these effects is not known but IL-2 production by patient lymphocytes in vitro which was low for both RA (P less than 0.01) and SLE (P less than 0.02) increased significantly (P less than 0.05) when SLE lymphocytes were cultured with IPS. These data identify IPS as an agent for the study of aberrant immune regulation in autoimmune diseases and suggest that it may have potential therapeutic value in SLE.

Adult↗
PubMed1983

Effect of androgen therapy on survival and suppressor cell activity in aged NZB/NZW F1 hybrid mice.

Male NZB/NZW F1 hybrid (B/W) mice survive their first year of life and die of lupus nephritis or lymphoid malignancy during the second year. Androgen therapy, even if delayed until 9 months of age, improves survival considerably. We report here that androgen therapy in aged B/W mice is associated with improved cell-mediated immune function as well as increased survival. Androgen treated mice have significantly augmented spleen cell responses to phytohaemagglutinin (PHA) and a decreased incidence of abnormal splenic suppressor activity. These results suggest that androgen may prolong survival in B/W mice in part through an effect on abnormally suppressive regulatory cells that impair T lymphocyte function.

Aging↗
PubMed1983

Impaired AMLR in autoimmunity.

A defective AMLR and impaired production and response to Interleukin 2 (IL-2) occur as a common feature of disease in several autoimmune-susceptible strains of mice and in patients with various autoimmune and lymphoproliferative disorders. We have studied the functional significance of these abnormalities and the cellular mechanism responsible by measuring specific antigen-induced proliferation following in vivo immunization with TNP25-KLH in three autoimmune strains bearing the lpr gene. The lpr mice manifest a decreased response in this assay system. Mixing experiments, in which T cells and macrophages from lpr mice and their normal congenic partners are allowed to interact, demonstrate that the defect resides with the responding Lyt 1+ T cells and not with lpr antigen-presenting macrophages. Flow cytofluorometry analysis using monoclonal antibodies to Thy 1.2, Lyt 1 and Lyt 2 reveals an abnormal distribution of these T cells reflecting a low antigen density on the cell surface. The actual number of Lyt 1+ cells is not diminished, but the pattern is displaced. These results suggest that the decreased AMLR, decreased IL-2 production, and decreased antigen-induced proliferation are not due to deficient numbers of responding cells but rather to functional impairment.

Animals↗
PubMed1983

Interleukin-2 and autoimmune disease.

Interleukin-2 (IL-2) deficiency is a common feature of autoimmune disease in several inbred strains of mice genetically predisposed to a lupus-like illness, including four (MRL, C57Bl/6, AKR/J, and C3H/He) bearing the lpr gene. Defective production of IL-2 in response to concanavalin A can occur even when the proliferative response to mitogens is preserved. In C56Bl/6-lpr mice there is no apparent influence of the lpr gene and IL-2 deficiency on the induction of the experimental autoimmune myasthenia gravis that follows immunization with the acetylcholine receptor. The production of IL-2 by peripheral blood mononuclear cells stimulated with PHA is decreased in patients with systemic lupus erythematosus and rheumatoid arthritis.

Animals↗
PubMed1983

Lymphocyte subsets in Sjogren's syndrome: a quantitative analysis using monoclonal antibodies and the fluorescence-activated cell sorter.

Lymphocyte subsets in the peripheral blood of 18 patients with Sjogren's syndrome (SS) were studied using monoclonal antibodies and the fluorescence-activated cell sorter (FACS). The percentage of T cells was decreased when compared to normal controls. In primary SS, there was a proportional decrease in both suppressor/cytotoxic (anti-Leu-2a reactive) and helper/inducer (anti-Leu-3a reactive) T cells with an unchanged helper/suppressor ratio (1.8 vs. 1.7 for normals). In SS with an associated connective tissue disorder, there was a significant decrease only in the suppressor/cytotoxic subset. There was increase in B cells and null cells in primary SS compared to controls. Quantitative immunofluorescence allowed the calculation of determinant density per cell. Cells expressing low antigen density Leu-2a were increased in 8 patients (4 with primary SS and 4 with SS with an associated disorder). Thus, in addition to quantitative changes in lymphocyte subsets, we found changes in Leu-2a expression suggesting abnormal differentiation of the suppressor/cytotoxic subset. These changes may contribute to the immunoregulatory disturbance in Sjogren's syndrome.

Adult↗
PubMed1982

The 1982 revised criteria for the classification of systemic lupus erythematosus.

The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.

Arthritis↗
PubMed1982

Panhypogammaglobulinemia in systemic lupus erythematosus: in vitro demonstration of multiple cellular defects.

Classically, systemic lupus erythematosus (SLE) is a disease of antibody overproduction, whereas the hallmark of acquired immune deficiency is antibody underproduction. Two patients are presented in whom panhypogammaglobulinemia developed during the course of SLE. In both patients, the levels of the major immunoglobulin (Ig) classes did not fall simultaneously. Anti-DNA antibodies were present, and exacerbations of SLE nephritis occurred in both cases 6 to 8 yr after Ig levels became subnormal. One patient still requires immunosuppressive therapy for renal disease; both patients are experiencing recurrent sinopulmonary bacterial infections. In the pokeweed mitogen--stimulated Ig biosynthesis assay, both patients showed abnormal Ig production due to defective function of three cell types: hyporesponsive B cells, excessive T suppression, and subnormal T help. The latter defect is rare in common variable hypogammaglobulinemia. One patient also showed extreme suppression of Ig production by phagocytic mononuclear cells. Thus, despite the similarity in the histories, the cellular function of these two patients was not identical in vitro.

Adult↗