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 Ryan Douglas Turnewitsch Brandon Joseph Stewart December 2, 2014 Biology 430.

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Presentation on theme: " Ryan Douglas Turnewitsch Brandon Joseph Stewart December 2, 2014 Biology 430."— Presentation transcript:

1  Ryan Douglas Turnewitsch Brandon Joseph Stewart December 2, 2014 Biology 430

2 Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies resulting from the dysfunction of T cells, B cells, and dendritic cells. These antibodies are principally anti-nuclear and induce an inflammatory response throughout the body. - Sang et al. 2013; Perl A. 2009; Dorner et al. 2011

3  5 million people with SLE o of every 100,000 o 1.5 million Americans o 16,000 new US cases annually  90% of cases occur in women o 10X more susceptible  Contributions from ethnicity o Incidence compared to Caucasians 3X higher for Asians 4X higher for African Americans (women) o Mortality compared to Caucasians 2X higher for Asians 3X higher for African Americans (women)  Survival Rates o ~90-95% in Western world (Lau et al. 2006; Ahmadpoor et al. 2014; “What is Lupus?”)

4  Wide range of symptoms o Affects many systems o Symptoms wax and wane  Most common symptoms o Mouth Sores o Hair Loss o Chest Pain o Extreme Fatigue o General Discomfort o Fever o Sunlight Sensitivity o Difficulty Breathing o Swollen Lymph Nodes o Skin Rashes (Butterfly Rash) (Bartels et al. 2014; “What is Lupus?”; Shiel et al. 2014) (http://www.lupusimages.com/browser/detail/129/mucocutaneous-sle-malar-rash)

5  Nervous System o Headaches, numbness, tingling, seizures, psychosis  Digestive System o Nausea, vomiting, dyspepsia  Cardiovascular System o Arrhythmias, pericarditis, myocarditis  Respiratory System o Pleurisy, pleural effusion, pneumonitis, pulmonary hypertension  Integumentary system o Raynaud’s phenomenon, malar rash  Excretory system o Edema, weight gain, acute renal failure (Bartels et al. 2014)

6  HLA genes most studied o HLA Class II gene polymorphisms o HLA DR2 and DR3  Associated with autoantibodies: o Anti-Sm, anti-Ro, anti-La, anti-nRNP, anti-dsDNA, anti-PL  Other Associated Genes o BANK1, BLK, IL-21-R, CD40, Lyn, PTPN22, TNFAIP3, Fc γ Rs, Blimp-1  Klinefelter Syndrome o Contributes to female susceptibility o Hypogonadotrophic hypogonadism (Dorner et al. 2011; Mok and Lau. 2003; Hu and Deng 2014)

7  Two Stage Disease o Loss of self-tolerance/Auto-Abs generation o Immune complex formation, causes inflammation/disease  Stage One: Loss of Self-tolerance o Involves self-antigen presentation by DCs  Role of Apoptosis o Impaired clearance of apoptotic cells o Results from defective complement system C2, C4, C1q defects Reduced CR1 receptors o Cells serve as immunogens o Induce auto-reactive T/B cells (Ahmadpoor et al. 2014; Dorner et al. 2011; Mok and Lau. 2003)

8  Aberrant DC activity o DC’s present self antigens from apoptotic cells Mostly nucleosomes, apoptotic blebs o DCs present to CD4 cells  Aberrant Lymphocyte Activity o Unregulated T-cell dependent B-cell activation  Aberrant Germinal Center Activity o Ligation between certain CD pairings o Somatic Hypermutation  Autoantibody Production o 95% are antinuclear Abs (anti-Sm, Anti-DNA) (Ahmadpoor et al. 2014; Dorner et al. 2011; Mok and Lau. 2003)

9 (Dorner et al. 2011)

10  Stage Two: Immune Complex Formation o Auto-Abs bind to: Pieces of DNA Nucleosomes Proteoglycans o Immune complex formation Accumulate in organ basement membranes  Results of Immune Complexes o Local inflammation o Local complement activation o Local apoptosis o Positive feedback loop (Ahmadpoor et al. 2014; Dorner et al. 2011; Mok and Lau. 2003)

11  No permanent cure for SLE: treatment relieves symptoms  NSAIDs (nonsteroidal anti-inflammatory drugs) o Aspirin (Bayer), ibuprofen (Advil, Motrin), naproxen (Aleve) o Reduce inflammation and pain  Corticosteroids o Reduce inflammation o Used after significant organ damage  Antimalarial Drugs o Hydroxychloroquine (Plaquenil), chloroquinone (Aralen) o Reduces inflammation, protects against organ damage o Used for skin symptoms, joint pain  DMARDs (disease-modifying antirhematic drugs) o Belimumab (Benlysta), rituximab (Rituxan) o Suppress B cell development, block B cell stimulation (Bartels et al. 2014; Schur et al. 2014; Shiel et al. 2014)

12  Ahmadpoor P, Dalili N, Rostami M An update on pathogenesis of systemic lupus erythematosus. Iranian Journal of Kidney Diseases. 8(3):  Bartels CM, Muller D, Diamond HS, Farina GA, Goldberg E, Hildebrant J, Krause RS, Lakdawala VS, Leber MJ, Lozada CJ, Talavera F Systemic Lupus Erythematosus (SLE). “Practice Essentials.” Medscape. Web..  Dorner T, Giesecke C, Lipsky PE Mechanisms of B cell autoimmunity in SLE. Arthritis Research and Therapy. 13(243):  Hu, ZD, Deng AM Autoantibodies in pre-clinical autoimmune disease. Clinical Chimica Acta. 435:  Lau CS, Yin G, Mok MY Ethnic and geographical differences in systemic lupus erthematosus: an overview. Lupus. 15:  Mok CC, Lau CS Pathogenesis of systemic lupus erythematosus. Journal of Clinical Pathology. 56(7):  Perl A Overview of signal processing by the immune system in systemic lupus erythmatosus. Autoimmunity Reviews. 8:  Sang A, Zheng YY, Morel L Contributions of B cells to lupus pathogenesis. Molecular Immunology. 62:  Schur P, Shmerling R, Ramirez M "Patient Information: Systemic Lupus Erythematosus (SLE) (Beyond the Basics)." Systemic Lupus Erythematosus (SLE). UpToDate Health. Web..  Shiel W, Stoppler MC, Driver CB "Lupus Symptoms, Causes, Treatment - What Is the Treatment for Systemic Lupus?" MedicineNet. Web..  "What Is Lupus?" Lupus.org. Lupus Foundation of America, Web.. .

13 Multiple Choice Questions: 1) What immunological aberration is the principle cause for SLE? o Overproduction of T-helper cells o Inhibition of complement activity o Production of self-reactive antibodies o Stimulation of perforin and granzyme activity in facial tissue 2) What are the two stages of SLE pathogenesis? o Loss of immune-tolerance and degradation of secondary lymphoid organs o Overabundance of immune-tolerance and generation of immune complexes causing inflammation o Overabundance of immune-tolerance and manifestation of SLE causing bacteria o Loss of immune-tolerance and generation of immune complexes causing inflammation

14 Multiple Choice Questions Continued: 3) What type of immune of cells are least effected by SLE? o Neutrophils o T cells o B cells o Dendritic cells 4) What reason listed below accounts for impaired clearance of immune complexes in SLE? o Insufficient CTL activity o Serum viscosity is too high for complexes to fall out of solution o Insufficient quantities of macrophages to snarf up complexes o Defective complement system

15  Essay Response: Explain how a self antigen found in an apoptotic bleb can cause inflammation in the nephron (nephritis). In your explanation of this process, be sure to describe the roles the following cells: o Dendritic cells o CD4 cells o B cells

16  Study Questions Answers o 1: C2: D3: A4: D  Essay Response o Key points to mention: o Clearance of apoptotic cells/cell fragments is impaired because of defective complement system. o DC cells encounter and present portions, particularly nuclear portions, of apoptotic cells as self-antigens to CD4 cells. o T cell dependent B cell activation is unregulated and B cells that have self- antigen specificity are not eliminated as they should be. o B cells are activated into plasma cells. These cells secrete auto-reactive antibodies that can migrate anywhere in body. Some will migrate to kidney. o In kidney, antibodies will encounter self antigens, bind, and form immune complexes. These immune complexes will lead to an inflammatory response by immune system. Inflammation is local and will occur in portions of the kidney, such as the nephron, causing nephritis.


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