Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary alveolar proteinosis (PAP) is an idiopathic disease characterized by the accumulation of surfactant in the pulmonary airspaces. The development of a PAP-like syndrome in the GM-CSF knockout mouse and resolution of disease by local GM-CSF expression strongly implicates GM-CSF in surfactant homeostasis and disease pathogenesis. Based on murine data, GM-CSF therapy was administered to PAP patients, with a subset responding to therapy. The lack of response to GM-CSF therapy in some patients is unexplained. In adult idiopathic PAP there appears to be no intrinsic cellular defect in synthesizing or secreting GM-CSF and/or function in the GM-CSF receptor. Subsequent studies have shown the presence of circulating, neutralizing anti-GM-CSF antibodies in all adult PAP patients studied to date. Whether the anti-GM-CSF is causally related to the PAP disease and whether it should be the target of manipulation remains to be determined. The present study quantified the anti-GM-CSF levels sequentially in PAP patients receiving GM-CSF therapy. The data indicate that titers of circulating anti-GM-CSF predict response to GM-CSF therapy. In addition, we present data from a patient undergoing plasmapheresis in which anti-GM-CSF titer decreased with improvement in the lung disease. Together, these data support the hypothesis that PAP is an anti-GM-CSF autoimmune disease due to the development of antibodies, which results in the deactivation or neutralization of GM-CSF.
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PMID:Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. 1249 16

IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12Rbeta1/IL-12Rbeta2), whose beta2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12Rbeta2 would protect from EAE, we found that IL-12Rbeta2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4(+) T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12Rbeta2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-alpha, GM-CSF, IL-17, IL-18/IL-18Ralpha, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12Rbeta2(-/-) mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12Rbeta2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
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PMID:Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. 1257 88

In autoimmune Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) and cause hyperthyroidism. We studied the effects of fms-like tyrosine kinase receptor 3 ligand (Flt3-L) or GM-CSF treatment on the development of experimental autoimmune GD (EAGD) in mice, a slowly progressing Ab-mediated organ-specific autoimmune disease of the thyroid induced by immunization with syngeneic cells expressing TSHR. Flt3-L and GM-CSF treatment resulted in up-regulation of CD8a(+) and CD8a(-) dendritic cells, and skewing of cytokine and immune responses to TSHR in favor of Th1 and Th2, respectively. However, this skewing did not persist until the later stages, and thus failed to affect the course or severity of the disease. To determine whether the total absence of either IL-4 or IFN-gamma could affect the development of EAGD, we immunized wild-type, IFN-gamma(-/-) and IL-4(-/-) BALB/c mice with TSHR. Nearly 100% of the wild-type and IFN-gamma(-/-) mice developed EAGD with optimal TSHR-specific immune responses, while IL-4(-/-) mice completely resisted disease and showed delayed and suboptimal pathogenic Ab response. These data demonstrated that skewing immune responses to TSHR, using either Flt3-L or GM-CSF, in favor of Th1 or Th2, respectively, may not be sufficient to alter the course of the disease, while the complete absence of IL-4, but not IFN-gamma, can prevent the development of EAGD.
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PMID:Absence of IL-4, and not suppression of the Th2 response, prevents development of experimental autoimmune Graves' disease. 1257 93

Human mast cells (huMC) increase surface expression of FcgammaRI (CD64) in response to IFNgamma. Subsequent receptor aggregation of FcgammaR1 using CD64-specific F(ab')(2) or antibody directed against FcgammaR1-bound IgG results in cell activation. Human mast cells may be observed degranulating in inflammation associated with autoimmune disease and where IFNgamma is produced. We sought to determine if human mast cells cultured in IFNgamma would degranulate in response to aggregated IgG, what mediators might be generated (i.e., cytokines and eicosanoids), and whether C3a might enhance such activation. Activation of IFNgamma-treated huMC sensitized with 1 microg/ml aggregated IgG(1) resulted in 15-30% degranulation (beta-hexosaminidase release), which was half-maximal by 7.5 min; no degranulation was observed using heat-generated aggregates of IgG(2), IgG(3), or IgG(4). Activation using aggregated IgG(1) led to PGD(2) and LTC(4) generation as well as enhanced IL-3, IL-13, GM-CSF, and TNFalpha production. Preincubation of cells with F(ab')(2) from CD64-specific clone 10.1 reduced aggregated IgG(1)-mediated beta-hexosaminidase release by 38% while degranulation was unaffected by blocking FcgammaRII with F(ab')(2)-specific antibody (clone 7.3). Simultaneous activation of huMC via aggregated IgG and C3a led to additive degranulation. These data support a mechanism by which mast cells may contribute to the inflammatory component in fibrosis, vasculitis, and arthritis.
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PMID:Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a. 1500 14

Type 1 diabetes is an autoimmune disease that results from the destruction of the insulin-producing pancreatic beta islet cells, probably via the influence of cytokines. However, direct correlation between the expression of selected cytokines by various immune cells at different time points during the progression of the disease has not yet been clearly demonstrated. In this study, we showed that the mRNA expression of the pro-inflammatory cytokines, TNF-alpha, IL-1 beta, IL-6, and GM-CSF, were increased while the anti-inflammatory cytokine, TGF-beta, decreased in the peritoneal macrophages of nonobese diabetic (NOD) mice. IL-6 expression however decreased when the mice became diabetic. Surprisingly the expression of IFN-gamma and IL-2 by splenic CD4+ cells were lower in 5-week-old NOD mice as compared to the nonobese diabetic resistant (NOR) control mice, but their expression was higher in older NOD mice. The expression of IL-4 and IL-10 decreased in splenic CD4-positive lymphocytes. Splenic CD8-positive lymphocytes expressed increased levels of IFN-gamma and IL-10 but the latter decreased sharply when diabetes occurred. The relevance of these findings to the pathogenesis of type 1 diabetes is discussed.
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PMID:The expression of cytokine genes in the peritoneal macrophages and splenic CD4- and CD8-positive lymphocytes of the nonobese diabetic mice. 1502 85

Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 x CBA)F(1) mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3(+) mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves' hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.
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PMID:Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice. 1532 Aug 99

The CD1 family of cell surface glycoprotein has been demonstrated to be a third lineage of antigen-presenting molecules for specific T cell responses. They present lipidic, glycolipidic antigen and hydrophobic peptide to T cells. CD1d restricted T cells play a role in autoimmune disease and in tumor immunity. Transforming growth factor beta (TGFbeta), a member of the family of polypeptide growth factors synthetized by human keratinocytes, has inhibitory effects on proliferation and differentiation of immune cells, especially on CD1d-restricted natural killer T cells. These properties led us to investigate the role of TGFbeta in CD1d expression on dendritic cells (DC), which are known to play a key role in initiation of the immune response. Here, we observed CD1d molecules on DC developed from PBMC with GM-CSF and IL4 but not with GM-CSF, IL4 and TGFbeta for 7 d. RT-PCR and FACS analysis (mAb 42.1) performed at various stages of differentiation on CD34+ HPC show that CD1d mRNA levels and CD1d molecule expression at the cell surface decreased progressively during the differentiation process. Thus, while committing DC-precursors differentiation toward the Langerhans cell (LC) pathway, TGFbeta likely inhibits CD1d transcription. Therefore, LC freshly recovered from epidermal sheet were evaluated by flow cytometry. In accordance with in vitro observation, they did not expressed measurable levels of CD1d molecules at the cell membrane. Thus, TGFbeta produced by keratinocytes contribute to selectively downregulate CD1d expression on intraepidermal-resident LC.
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PMID:TGFbeta inhibits CD1d expression on dendritic cells. 1565 63

Autoimmune regulator (AIRE) gene is a responsible gene for the rare autosomal recessive autoimmune disease: autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). Although it has been reported that AIRE is expressed in the thymic epithelial cells and monocyte-dendritic cell lineage, the regulatory mechanisms of AIRE gene expression have as yet been poorly understood. Here we show that the expression of AIRE gene was induced in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells. In GM-CSF-stimulated OTC-4 cells, stat5 was not phosphorylated, while mitogen-activated protein kinases (MAPKs), including MAPK kinase (MEK) 1/2 and p38 MAPK, were phosphorylated, indicating activation of MAPK pathway. In addition, the expression of AIRE gene was inhibited by specific p38 MAPK inhibitor (SB203580), whereas the expression was rather enhanced by the MEK1/2 inhibitor (U0126), suggesting that AIRE gene expression is regulated by mitogen-activated protein kinase pathway.
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PMID:Mitogen-activated protein kinase pathway controls autoimmune regulator (AIRE) gene expression in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells. 1589 21

Recent studies provide valid criteria that help differentiate idiopathic narcolepsy from other disorders of excessive daytime somnolence [3]. Research to date suggests that idiopathic narcolepsy might properly be considered a disorder of excessive sleepiness with dysfunctional REM-sleep mechanisms, clinically evidenced as cataplexy and electrophysiologically recognized as SOREMPs. Given these criteria, a diagnosis can generally be made using a combination of history, PSG, and MSLT. Traditionally, the medical treatment of idiopathic narcolepsy has centered on a two-drug regimen (stimulants for sleepiness and TCAs for cataplexy and auxiliary symptoms). Some newer medications are proving efficacious for sleepiness with minimal adverse effects, whereas others may provide a single-drug regimen that simultaneously addresses sleepiness and cataplexy [18]. New research has allowed some experts to hypothesize that idiopathic narcolepsy may be the result of a genetic predisposition to autoimmune disease [176]. It is possible that aberrant genetic coding of elements in the hypocretin/orexin systems allows a sensitivity to inducible and possibly virally mediated changes, which leave cells in the lateral hypothalamus susceptible to autoimmune attack [96]. As such, genetic screening of high-risk individuals might eventually rationalize the prophylactic use of immunosuppressants in some instances. In the future, for atypical cases(poorly responsive to therapy), genetic, CSF, and brain imaging studies, and possibly even neuronal transplantation may prove beneficial in the assessment and treatment of idiopathic narcolepsy.
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PMID:Narcolepsy and disorders of excessive somnolence. 1593 92

Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of lipoproteinaceous material within the lung alveoli. Recent studies indicate that PAP is an autoimmune disease characterized by a neutralizing anti-granulocyte macrophage colony stimulating factor (GM-CSF) antibody. At present the only definitive diagnostic test for PAP is open lung biopsy. We have previously published that anti-GM-CSF is diagnostic for PAP and correlates with disease pathogenesis using a traditional serial anti-GM-CSF antibody titer format (T. L. Bonfield, M. S. Kavuru, and M. J. Thomassen, Clin. Immunol. 105:342-350, 2002). Titer analysis is a semiquantitative method, and often subtle changes in antibody titer are not detectable. In this report we present data to support anti-GM-CSF detection by a quantitative highly sensitive multiplexed particle-based assay which has the potential to be a clinical diagnostic test.
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PMID:Multiplexed particle-based anti-granulocyte macrophage colony stimulating factor assay used as pulmonary diagnostic test. 1600 29


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