Cell-Mediated Immunity and T Lymphocytes

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1 Cell-Mediated Immunity and T Lymphocytes

2 T helper (Th) Cells

3 Peripheral lymhoid tissue thymus Lymphoid stem cell CD8+ CD4+ CD4+ Treg CD8+ CTL + antigen Cytotoxic T lymphocyte CD4+ Th Helper T cell CD4+ Treg Regulatory T cell

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5 T cell sees antigen as a peptide presented on an APC Antigen Antigen-Presenting Cell T cell

6 Antigen presented on antigen-presenting cell (APC) selects T cell with correct receptor. APC

7 Activated Naïve T Cell Undergoes Clonal Proliferation and Maturation Naïve CD4+ T cell Effector Th1 cell Memory Th1 Cell

8 T and B Lymphocytes Become Activated by Antigen in Lymph Nodes that Drain the Site of Infection

9 Videos

10 Most Pathogens Are Cleared by the Immune System, with the Development of Memory

11 Tuberculosis A Disease in Which The Pathogen is not Always Cleared and CD4 Th Cells May Contribute to Disease

12 Mycobacterium tuberculosis

13 Robert Koch, who discovered tuberculosis

14 Tuberculosis (TB) Facts TB can be active or latent Latent: no symptoms and not contagious, but the bacteria can become active if immune system is stressed (like HIV) Active: symptoms include cough, fever, weight loss, fatigue, night sweats Overall, one-third of world population is infected with TB (5% to 10% of people not infected with HIV will become sick or infectious) In the U.S., prevalence was 4.2% latent TB in the year

15 History of TB In the mid-19 th century, TB was the cause of 1 in 7 deaths Known as the white plague Many famous people died of TB: The three Bronte sisters and their brother Frederic Chopin John Keats Thoreau Voltaire Anton Chekhov Eleanor Roosevelt

16 A Major Function of Th1 Cells is to Activate Macrophages

17 When the immune system cannot complete eliminate the mycobacteria, a granuloma forms. Cells in the center are macrophages with ingested bacteria. T cells (CD4+) surround this central core.

18 CD4 Th1 Cells are Both Protective and Pathogenic in TB TB bacilli infect macrophages. Resting macrophages cannot kill the bacteria. So bacteria replicate, infect new macrophages. CD4 Th1 cells specific for TB antigen activate infected macrophages to stimulate their killing ability. In many cases, the immune response stops bacterial replication, and bacteria are cleared. But, if the immune response fails to clear the bacteria, both CD4 Th1 and CD8 CTL mount a huge attack to kill the infected cells. Results in serious damage to lung tissue.

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20 Rheumatoid Arthritis

21 CD4 Th1 Cells are Pathogenic in Rheumatoid Arthritis (RA) Osteoarthritis: Much more prevalent than RA; 27 million in U.S. Not autoimmune Rheumatoid Arthritis: Chronic autoimmune disease Age of onset usually 30 to 50 years old Affects 3 times more women than men Prevalence estimates vary from 1.3 to 2 million persons in U.S. (0.5% to 1.0% of population)

22 Rheumatoid Arthritis Characterized by inflammation of the synovial tissue and bone damage in the joints Inflammation is initiated by CD4 Th1 cells that recognize an auto-antigen in synovial tissue, and trigger an inflammatory response. Diagnosis based on: Rheumatoid factor Symptoms (symmetric arthritis), morning stiffness, X-ray findings of joint involvement, etc.

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24 Genetics of Rheumatoid Arthritis RA does not aggregate in families with very high frequency. Arthritis Research 1:37, If one identical twin has RA, the chance of the other twin developing RA is relatively low (12-15%). Prevalence in siblings of person with RA is between 2% and 4%.

25 Possible Environmental Effects on Development of RA Infection (Epstein-Barr virus most consistently associated) Oral contraceptive pill may be protective. Cigarette smoking associated with increased risk: Men who smoke are almost 3 times more likely to develop RA if they smoke Heavy smokers of both sexes have 13-fold more risk People who stop smoking reduce their risk

26 Dietary effects Risk may increase for people who have a diet low in fruits and vitamin C, or high in red meat. Mediterranean diet may reduce risk of inflammatory arthritis Cooked vegetables and olive oil are beneficial High daily intake of oily fish reduced risk by almost half.

27 Treatment of RA Fortunately, in the last few years, a shift in strategy toward the earlier institution of disease modifying drugs and the availability of new classes of medications have greatly improved the outcomes that can be expected by most patients.

28 Drugs Used to Treat RA Non-steroidal anti-inflammatory drugs (NSAIDs) Corticosteroids Disease-Modifying Anti-Rheumatic Drugs (DMARDs) Can alter the disease course and improve bone appearance on X-ray Include methotrexate, hydroxychloroquine (Plaquenil), Sulfasalazine, Leflunomide

29 Antibodies & Related Proteins Approved as DMARDS in Treatment of RA Antibodies against TNF: Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira/Trudexa), Certolizumab (Cimzia), Golimumab (Simponi) Antibody against receptor for another inflammatory cytokine: Tocilizumab (Actemra/RoActemra) Antibody blocking activation of T cells: Abatacept (Orencia)

30 TNF INHIBITORS AS DRUGS: Approved for Rheumatoid Arthritis, Crohn s disease, plaque psoriasis, ankylosing spondilitis TNF receptor

31 What Happens if TNF is Removed? [Answer: Inflammation, Bone Destruction Are Prevented.] Normal Endothelium TNF TNF Inflamed Endothelial Cells Express Selectins