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Biomedical subjects

N Talal

Publications and source records attributed to N Talal.

At least 127 records · Page 7Linked to original sources
PubMed1987

Overview of Sjögren's syndrome.

Sjögren's syndrome, a chronic inflammatory and autoimmune disorder (Shoenfeld and Schwartz, 1984; Smith and Steinberg, 1983), is characterized by diminished lacrimal and salivary gland secretion (sicca complex), resulting in keratoconjunctivitis sicca (KCS) and xerostomia. As originally described, the syndrome consisted of a triad of dry eyes, dry mouth, and rheumatoid arthritis. We now know that other connective tissue diseases (e.g., systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis) may be present in place of rheumatoid arthritis, and that the sicca complex can exist as a primary pathologic entity with no associated disorder (Strand and Talal, 1980; Talal, 1985). Moreover, generalized lymphoproliferation, pseudolymphoma, or even lymphoid malignancy may appear in some patients (Talal and Bunim, 1964; Talal et al., 1967). More than 90% of patients are women, with a mean age of 50 years at diagnosis. The disease occurs in all races and all ages.

Humans↗
PubMed1987

Autoimmune mechanisms in patients and animal models.

Autoimmune diseases in patients and animal models are reviewed from the standpoint of immunoregulatory defects which predispose to autoimmunity. New information is provided about autoantibodies which indicates, on the basis of idiotypic cross-reactivity, that they may be closer to normal antibodies than previously thought. The importance of estrogens as a predisposing factor and androgens as a protective factor is discussed in relation to modulation of immune response by sex hormones. Similarities between autoimmune diseases and Acquired Immunodeficiency Syndrome (AIDS) are presented and new therapeutic approaches are discussed.

Animals↗
PubMed1987

Interleukin 2, T cell receptor and sex hormone studies in autoimmune mice.

Systemic lupus erythematosus (SLE) is a disease of immune dysregulation in which B cell hyperactivity and T cell deficiency are important characteristics. Sex factors also play a major role in the pathogenesis based on the physiologic effects of estrogen in promoting immunologic hyperactivity. Our findings suggest that a posttranscriptional mechanism is responsible for the functional interleukin 2 (IL-2) defect since transcription of the IL-2 message occurs after mitogenic stimulation. The proliferating cell in the MRL/lpr mouse model of lupus may be an immature T cell. The T cell receptor in these mice has a lower molecular weight than normal. This aberrant T cell receptor might be explained by a defect in glycosylation. The administration of estrogen to pregnant mice late in gestation results in offspring with a permanently altered immune system. These mice develop features of autoimmunity similar to those that occur spontaneously in genetically susceptible autoimmune mice. This phenomenon may have etiopathological significance for familial SLE.

Animals↗
PubMed1987

A common idiotype expressed on a murine anti-Sm monoclonal antibody and antibodies in SLE sera.

A rabbit anti-idiotypic antiserum made against a murine monoclonal anti-Sm autoantibody (Y2) was used in a solid-phase radioimmunoassay to investigate idiotypic cross-reactivity among anti-Sm antibodies present in sera from patients with systemic lupus erythematosus. Sera from 25 of 51 SLE patients (49%) containing anti-Sm antibodies were positive for this Y2 idiotype compared to only one of 22 normal human sera. Nine of 28 SLE patients (32%) whose sera were anti-Sm negative were also positive for the Y2 idiotype in low titre. Binding was not due to rheumatoid factor-like activity but was specific for the Y2 determinant and could be eliminated by absorption with Y2 monoclonal antibodies. The anti-idiotypic antibody blocked the ability of 12 of 25 anti-Sm positive lupus sera to bind Sm. Conversely, Sm antigen inhibited the binding of anti-idiotypic antibody in nine of 12 lupus sera.

Animals↗
PubMed1986

Immune response gene control of lymphocyte proliferation induced by acetylcholine receptor-specific helper factor derived from lymphocytes of myasthenic mice.

The role of lymphokines secreted by acetylcholine receptor (AChR)-reactive lymphocytes in the regulation of an autoimmune response to AChR has not been studied in the human or murine model of myasthenia gravis. We investigated whether AChR-immune lymphocytes derived from mice with experimental autoimmune myasthenia gravis (EAMG) can produce an AChR-specific, genetically controlled soluble factor with biologic activity. AChR-reactive lymphocytes of mice with EAMG secreted an AChR-specific helper factor in vitro, which induced proliferation of AChR-immune but not Mycobacterium tuberculosis-immune lymphocytes. Recombinant, I-A mutant, and monoclonal anti-I-A antibody analyses suggest that AChR-specific helper factor-induced lymphocyte proliferation is controlled by an immune response gene at the I-A subregion of the murine major histocompatibility complex, and is mediated by the I-A molecule.

Animals↗
PubMed1986

Altered K+ channel expression in abnormal T lymphocytes from mice with the lpr gene mutation.

The observation that voltage-dependent K+ channels are required for activation of human T lymphocytes suggests that pathological conditions involving abnormal mitogen responses might be reflected in ion channel abnormalities. Gigaohm seal techniques were used to study T cells from MRL/MpJ-lpr/lpr mice; these mice develop generalized lymphoproliferation of functionally and phenotypically abnormal T cells and a disease resembling human systemic lupus erythematosus. The number and predominant type of K+ channels in T cells from these mice differ dramatically from those in T cells from control strains and a congenic strain lacking the lpr gene locus. Thus an abnormal pattern of ion channel expression has now been associated with a genetic defect in cells of the immune system.

Animals↗
PubMed1986

Modulation of spontaneous immunoglobulin production by natural killer cells in rheumatoid arthritis.

Synovial fluid (SF) mononuclear cells obtained from patients with rheumatoid arthritis (RA) spontaneously produce large amounts of immunoglobulin. In the rheumatoid joint, natural killer (NK) cell activity is reduced in comparison with that in the peripheral blood (PB). We examined the ability of SF NK cells to modulate the spontaneous production of Ig in RA SF, and we contrasted this with the activity in PB from RA patients and from normal subjects. We found that the spontaneous production of IgG was greater in RA SF than in RA or normal PB. The baseline NK activity was significantly lower in RA SF than in RA or normal PB (P less than 0.005). Incubation with anti-Leu-11b and complement reduced NK activity in PB, but not in SF, and it significantly (P less than or equal to 0.021) increased IgG production in both RA SF and RA PB. Lysis of NK cells in this manner also resulted in a significant increase (P less than 0.02) in IgM production in RA SF. These results suggest that NK cells with a Leu-11b phenotype down-regulate the ongoing synthesis of IgG and IgM in the rheumatoid joint.

Adult↗
PubMed1986

Altered natural killer and natural cytotoxic cellular activities in lpr mice.

Three strains of mice bearing the autosomal recessive lpr gene (MRL, C57BL/6, and C3H) that had spontaneously developed a lupus-like disease were studied sequentially for functional natural killer (NK) and natural cytotoxic (NC) cell activity. Natural killing was impaired in spleen and bone marrow cells from all the lpr strains, as well as from the congenic strain MRL--+/+, which develops a late onset lupus-like disease. The NK cell activity was found to be depleted as early as 2 months of age in all lpr strains, and decreased further with age. NK activity was augmentable by Poly I:C and interleukin 2 (IL-2), suggesting that the residual cells can respond to NK modulators. In contrast with NK cell activity, NC activity was not decreased in lpr mice but could be augmented by IL-3-rich supernatants. The spontaneous decrease in NK cell activity was associated with an increased autologous plaque-forming cell (APFC) response to bromelin-treated mouse red blood cells, which is produced primarily by B cells possessing the Ly-1 phenotype (Lyt-1+ B). When NK cell activity was increased by exogenous administration of Poly I:C, the APFC response diminished. Treatment of spleen cells with anti-asialo GM1 prior to Poly I:C treatment resulted in a decreased NK response but increased both APFC and Lyt-1+ B cells. The possible regulation of autoreactivity by NK cells is discussed.

Animals↗
PubMed1986

Shared idiotypes and restricted immunoglobulin variable region heavy chain genes characterize murine autoantibodies of various specificities.

The study of the Ig variable region heavy chain (VH) genes used to encode antibodies specific for self-epitopes from murine hybridomas showed that three VH families are primarily utilized: VH J558, the largest family, and VH QPC52 and VH 7183, the families most proximal to the Ig joining region heavy chain genes. These monoclonal autoantibodies express cross-reactive idiotopes shared by rheumatoid factors and antibodies specific for Sm. The expression of these idiotypes is independent of major histocompatibility complex and Ig constant region heavy chain haplotypes, self-antigen specificity, and even the VH gene family utilized. Though the experiments described here are limited to murine autoantibodies, similarities exist between murine and human autoimmune diseases. Studies that aim to investigate the relationship between VH gene expression and the presence of cross-reactive idiotypes among human autoantibodies should enable us to better understand the mechanisms of autoimmunity and self-tolerance.

Animals↗
PubMed1986

Shared idiotypes and restricted VH genes among murine autoantibodies of various specificities.

The autoantibodies studied here express cross-reactive idiotypes despite the fact that they are heterogeneous with respect to combining site. Furthermore, the presence of cross-reactive idiotypes is independent of the major histocompatibility complex, VH gene usage, and isotype. Similarly, VH gene usage shows that autoantibodies are derived from a restricted number of VH gene families. This restriction is independent of antigen specificity as well as the method of induction (i.e., spontaneous vs. induction). The observation that the VH 7183 gene is predominantly used suggests that certain autoantibodies may be derived from a unique set of B cells such as the Ly1+ B cells. It has been reported that these B cells secrete a high percentage of IgM autoantibodies. The studies reported here may provide greater insight into the genetic and immunoregulatory mechanisms by which autoantibodies arise. The precise mechanisms are not known but may involve both molecular (i.e., VH gene usage) and extracellular (i.e., idiotypic recognition) events.

Animals↗
PubMed1985

Mutation at I-A beta chain prevents experimental autoimmune myasthenia gravis.

Immune response (Ir) gene(s) at the I-A subregion of the mouse H-2 complex influence susceptibility to experimental autoimmune myasthenia gravis (EAMG). To determine the importance of the Ir gene product, the Ia antigens, in EAMG pathogenesis, we studied the degree of EAMG susceptibility of an I-A mutant strain, the B6.C-H-2bm12 (bm12), and its parent B6/Kh. According to the cellular, humoral, biochemical, and clinical manifestations of EAMG, the I-A mutation converted an EAMG susceptible strain (B6/Kh) into a relatively resistant strain (bm12). The relative resistance to EAMG induction in bm12 may be due to the lack of Ia.8 and/or Ia.39 determinants and/or quantitative expression of Ia antigens.

Animals↗
PubMed1985

Muscle acetylcholine receptor loss in murine experimental autoimmune myasthenia gravis: correlated with cellular, humoral and clinical responses.

An extensive analysis of the relationship between immunological parameters and clinical responses and biochemical loss of muscle acetylcholine receptors (AChR) was performed in murine experimental autoimmune myasthenia gravis. The onset of clinical muscle weakness correlated strongly with the onset of significant muscle AChR loss. Mice with clinical muscle weakness had greater amount of muscle AChR loss. There was no correlation between the concentration of anti-AChR antibodies and the presence of clinical muscle weakness or amount of muscle AChR loss. However, the kinetics of autoantibody response correlated well with that of muscle AChR loss.

Autoantibodies↗
PubMed1985

Phorbol ester induction of Ia and a shared B-cell/T-cell phenotype in normal but not autoimmune (lpr) mice.

Tumour-promoting phorbol diesters are mitogenic for lymphocytes and induce differentiation of B and T cell lines as well as promyelocytic leukaemia cells. This paper demonstrates that 12-O-tetradecanoyl-13-acetate (PMA), when cocultured with normal murine bone marrow cells (BMC), significantly augments an antigenic cell-surface determinant called 14D10. This antigen is present constitutively in the majority of bone-marrow lymphocytes of autoimmune lpr mice. PMA has little enhancing effect when cocultured with lpr BMC. In addition, Ia antigenic determinants are increased by PMA in normal but not lpr BMC. Retinoic acid (RA) and PMA act synergistically both to increase 14D10 and to enhance the stimulatory ability of target lymphocytes as measured by proliferation in an autologous mixed lymphocyte reaction (AMLR). We suggest that lpr mice have persistent expression of gene products like 14D10 that are usually repressed in normal adult mice. These gene products can be activated in normal mouse bone marrow by PMA which acts through a Ca2+-dependent phospholipid-dependent C protein kinase. The in vivo enhanced expression of 14D10 in lpr mice suggests activation by some mechanism or factors yet to be described.

Animals↗