Mechanism of SLE
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Mais de Chulalongkorn Allergy and Clinical Immunology Research Group
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Mechanism of SLE
- 1. MECHANISM OF DISEASE(SLE) นพ . สุรสฤษดิ์ ขาวละออ 11/11/2009
- 5. GENETIC Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
- 6. GENETIC Abul K. Abbas. Cellular and molecular immunology 6th edition 2007
- 7. GENETIC Mary K Crow.Developments in the clinical understading of lupus. Arthritis Research & Therapy 2009;11:245
- 8. GENETIC Mary K Crow.Developments in the clinical understading of lupus. Arthritis Research & Therapy 2009;11:245
- 11. Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
- 14. Autoantibodies in lupus การติดสี fluorescein จากการตรวจ indirect immunofluorescent assay & specific autoantibodies ที่เกี่ยวข้อง
- 15. Autoantibodies in lupus การติดสี fluorescein จากการตรวจ indirect immunofluorescent assay & specific autoantibodies ที่เกี่ยวข้อง
- 30. Source of autoantigens in lupus Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
- 39. The role of T cells Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
- 40. The role of T cells Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
- 50. Cytokines in lupus Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939 Treatment of patients who had elevated serum BLyS levels with intensive courses of high - dose corticosteroids resulted in marked reductions in serum BLyS levels
- 54. Implications for treatment Leandro MJ et al.Arthritis Rheum.2002 Oct;46(10):2673-7
- 55. Implications for treatment Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24
- 69. Implications for treatment Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
- 70. Implications for treatment Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
- 79. Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
- 83. TNANK YOU
Notas do Editor
- -randomized controlled trial ; menopausal women with lupus who received hormone-replacement tx had risk of dz flare 1.34 times risk among woman who received placebo(P=0.01)
- P = แขนสั้นของ chromosome , q = แขนยาว
- - suggest stimulation of these peptide-specific helper T cells help B cell respond to antigenic epitopes derived from nucleosomes - Kang et al รายงานไว้ใน journal of immunology 2005 พบว่า some histone peptides promotes development of Treg And delayed development of nephritis
- Figure 1. Interaction between a T Cell and an Antigen-Presenting Cell (APC). -The APC binds antigen in a complex with a molecule from the major histocompatibility complex (MHC) on its surface. -This complex interacts with the T-cell receptor (TCR). The effect on the T cell depends on the interaction between other molecules on the surfaces of the two cells. Two alternative interactions are shown: B7 with CD28, which is stimulatory, and B7 with cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), which is inhibitory. -If the positive signal caused by the CD28–B7 interaction dominates, the T cell is activated, leading to cytokine release, B-cell help, and inflammation. If the negative signal caused by the CTLA-4–B7 interaction dominates, activation is suppressed.
- Figure 2. T Cell–B Cell Interaction. -The B cell acts as an APC, with costimulation being obtained through the interaction between CD40 and the CD40 ligand -This interaction stimulates the T cell to produce a number of cytokines, some of which act on the B cell to promote antibody formation. MHC denotes major histocompatability complex, TCR T-cell receptor, and TNF tumor necrosis factor.
- -cytokines ที่ได้จากการกระตุ้น T cell หลักๆจะประกอบด้วย 1. TNF- 2.interferon 3.IL-10
- -CD20 พบบนผิวของ mature B cells
- Fig. 1. A prolonged clinical remission of a child treated with rituximab. The patient is a 15-year-old Caucasian female with lupus nephritis,arthritis, pericarditis, pancytopenia, cutaneous vasculitis, who received 4 weekly doses of rituximab (375mg/m2) after failed treatment with cyclophosphamide, and pulse methyprednisolone. The anti-double-stranded DNA, Complement C3 and C4 levels in the upper panel and CD19- positive B cells numbers and prednisone dose in lower panel are shown. Her symptomatic improvement was consistent with her laboratory improvement. She experienced a prolonged remission and was able to completely discontinue prednisone after one course of rituximab. She wa ห started on MMF as a maintenance therapy on week 52 post-rituximab and remains in remission at 24 months of follow-up.
- -CD20 พบบนผิวของ mature B cells
- -CD20 พบบนผิวของ mature B cells
- IL-10 ผลิตโดย macrophage & helper T cell -function = inhibit activated macrophage & maintain homeostatic control of innate and Cell-mediated immune reaction -excess production of IL-10 ass with impaired CMIR
- -Mex-SLEDAI = mexican SLE disease activity index Active disease when score >= 2
- -Mex-SLEDAI = mexican SLE disease activity index Active disease when score >= 2
- Pleiotropic = cytokine 1 ชนิดออกฤทธิ์ทางชีวภาพได้มากกว่า 1 อย่าง หรือมีผลต่อ cell อื่นได้มากกว่า 1 cell Redundancy = cytokine หลายชนิดมีฤทธิ์ทางชีวภาพเหมือนกัน synergy antagonism
- New Zealand Black/New Zealand White (NZB/NZW) F1 mice spontaneously develop a systemic autoimmune disease that closely resembles human systemic lupus erythematosus (SLE).
- Chimeric Ab = Genetically engineered combination of a human and mouse antibody - By replacing constant regions of a mouse antibody with those of a human antibody an antibody that binds to an antigen like the original monoclonal antibody , but which is recognised by the human immune system like a human protein
- Phase I - first stage of testing in human subjects - Normally, a small ( 20-50 ) group of healthy volunteers will be selected - This phase includes trials designed to assess the safety ( pharmacovigilance ) , tolerability, pharmacokinetics , and pharmacodynamics of a drug . --These trials are often conducted in an inpatient clinic, where the subject can be observed by full - time staff Phase II -Once the initial safety of the study drug has been confirmed in Phase I trials, -Phase II trials are performed on larger groups ( 20-300 ) -designed to assess how well the drug works -as well as to continue Phase I safety assessments in a larger group of volunteers and patients -divided into Phase IIA and Phase IIB . Phase IIA : to assess dosing requirements ( how much drug should be given ) Phase IIB : to study efficacy (how well the drug works at the prescribed dose Some trials combine Phase I and Phase II, and test both efficacy and toxicity Phase III - randomized controlled multicenter trials on large patient groups ( 300–3,000 or more depending upon the disease / medical condition studied ) -aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment Phase IV - known as Post Marketing Surveillance Trial - Phase IV trials involve the safety surveillance ( pharmacovigilance ) and ongoing technical support of a drug after it receives permission to be sold
- Figure 4. Targeted Therapeutic Approaches in Systemic Lupus Erythematosus. -This simplified diagram, which is based on our increased understanding of the immunologic events thought to occur in lupus, indicates the targets of current therapeutic interventions -APC denotes antigen-presenting cell, BLyS B-lymphocyte stimulator, CTLA-4–Ig cytotoxic T-lymphocyte–associated protein 4 IgG1, TACI-Ig transmembrane activator and CAML interactor immunoglobulin (CAML denotes calcium modulator and cyclophilin ligand).