Chapter 24 THE IMMUNE SYSTEM

1. Chapter 24 THE IMMUNE SYSTEM

2. Introduction Resistance: Ability to ward off disease. • Nonspecific Resistance: Defenses that protect against all pathogens. • Specific Resistance: Protection against specific pathogens. Susceptibility: Vulnerability or lack of resistance.

3. Protection Against Invading Pathogens 1. First Line of Defense: Non-specific natural barriers which restrictentry of pathogen. Examples: Skin and mucous membranes. 2. Second Line of Defense: Non-specific defenses that provide rapid local response to pathogen after it has entered body. Examples: Fever, phagocytes (macrophages and neutrophils), inflammation, and interferon. 3. Third lineof defense: Antigen-specific immune responses, specifically target and attack invaders that get past first two lines of defense. Examples: Antibodies and lymphocytes.

4. Defenses Against Infection

5. First Line of Defense: Skin is an Effective Barrier Against Infection by Most Pathogens

6. Second Line of Defense: Interferon is Nonspecific Inhibitor of Viral Infection

7. Inflammation is a Nonspecific Defense 1. Damaged cells release chemical signals: Histamine and other molecules. 2. Local response to chemical signals: • Increase in local blood flow and vascular permeability • Redness • Heat • Swelling • Pain 3. Phagocytic white blood cells come into area: Engulf bacteria, dead cell parts, and other microbes. 4. Tissue heals

8. Inflammatory Response: Nonspecific Defenses

9. Third Line of Defense: The Immune Response Immunity: “Free from burden”. Ability of an organism to recognize and defend itself against specific pathogens or antigens. Immune Response: Involves production of antibodies and generation of specialized lymphocytes against specific antigens. Antigen: Molecules from a pathogen or foreign organism that provoke a specific immune response.

10. Lymphatic and Immune System Components: Lymph, lymphatic vessels, bone marrow, thymus, spleen, and lymph nodes. Functions: • Defends against infection: bacteria, fungi, viruses, etc. • Destruction of cancer and foreign cells. • Synthesis of antibodies and other immune molecules. • Synthesis of white blood cells. Homeostatic Role: • Returns fluid and proteins that have leaked from blood capillaries into tissues. • Up to 4 liters of fluid every day. • Fluid returned near heart/venae cavae.

11. Lymphatic System

12. The Immune Response Destroys Specific Invaders Antigen: Molecule that elicits an immune response. “Antibody generating”. • Microbial antigens: Viral capsid, bacterial call wall, etc. • Nonmicrobial antigens: Pollen, latex, food, etc. Antibody: Protein found in blood plasma that attaches to antigen and helps counteract its effects. Vaccination or Immunization: Process in which harmless forms of antigen or pathogen are introduced into body to provoke an immune response.

13. Lymphocytes Mount a Dual Immune Defense 1. Cell Mediated Immunity • Immunity that requires cell to cell contact. • Carried out by T cells: • Develop in the thymus. • Only recognize antigen associated with self-protein. • T cytotoxic cells: Important in defense against: • Cancer cells • Self cells infected with fungi, viruses, protozoans, and bacteria. • T helper cells: Play a central role in immunity. Act indirectly by controlling the immune functions of other cells: • Increased antibody production by B cells. • Increased phagocytosis by macrophages. • Increased killing of foreign and cancer cells.

14. Development of T and B Lymphocytes

15. T helper cells play a central role in immunity

16. Lymphocytes Mount a Dual Immune Defense 2. Humor al (Antibody Mediated) Immunity • Antibodies are found in our body fluids: • Blood • Lymph • Interstitial fluid • Antibodies are produced by B cells. • B cells develop in bone marrow. • Antibodies are specific molecules that circulate through out our body and attach to foreign antigens, marking them for destruction. • Foreign antigen does not have to be associated with a self antigen to be recognized. • Antibodies can be passed from one individual to another: • Mother-child: Mother’s antibodies cross placenta. Also found in breast milk. • Serum: Snake bite antivenom.

17. Antibodies are Protein Molecules that Recognize Specific Foreign Antigens

18. Antibodies Help Eliminate Foreign Antigens

19. Acquired Immunodeficiency Syndrome (AIDS) History • 1950s: Blood samples from Africa have HIV antibodies. • 1976: First known AIDS patient died. • 1981: First reports of “Acquired Immuno-deficiency Syndrome” at UCLA. • 1983: Virus first isolated in France. • 1984: Virus isolated in the U.S. • 1985: Development and implementation of antibody test to screen blood donors.

20. History (Continued) • 1986: Virus named Human Immunodeficiency Virus (HIV-1). Related virus (HIV-2) identified. • 1992: AIDS becomes the leading cause of death among adults ages 25-44 in the U.S. • 1998: AIDS death rates start to decline in U.S. due to the introduction of new drug cocktails. • 1999: Over 33 million HIV infected individuals. Another 16 million have already died from AIDS. • 2000: World Health Organization predicts up to 40 million infected individuals.

21. AIDS Becomes a Leading Cause of Death Among People Aged 25-44 years in U.S. Deaths per 100,000 people aged 25-44 years

22. People Living with HIV/AIDS by End of 1999 North America 920,000 Western Europe 520,000 East Europe & Central Asia 360,000 East Asia & Pacific 530,000 North Africa & Middle East 220,000 South/South East Asia 6.0 million Latin America 1.3 million Sub-Saharan Africa 23.3 million Australia & New Zealand 12,000 Total: 33.6 million people

23. Transmission of HIV (Worldwide) 1.Sexual contact with infected individual: All forms of sexual intercourse (homosexual and heterosexual). 75% of transmission. 2. Sharing of unsterilized needles by intravenous drug users and unsafe medical practices: 5-10% of transmission. 3. Transfusions and Blood Products: Hemophiliac population was decimated in 1980s. Risk is low today. 3-5% of transmission. 4. Mother to Infant (Perinatal): 25% of children become infected in utero, during delivery, or by breast-feeding (with AZT only 3%). 5-10% of transmission.

24. Perinatal Transmission of AIDS Source: Tropical Medicine and Parasitology, 1997

25. Characteristics of all viruses • Acellular infectious agents • Obligate intracellular parasites • Possess either DNA or RNA, never both • Replication is directed by viral nucleic acid within a cell • Do not divide by binary fission or mitosis • Lack genes and enzymes necessary for energy production • Depend on host cell ribosomes, enzymes, and nutrients for protein production

26. Unique Characteristics of HIV • Retrovirus: Unique enzyme reverse transcriptase, converts viral RNA into DNA. • Genetic material: 2 strands of RNA. • Integrase: Inserts viral DNA into host DNA. • Protease: Processes viral proteins. Essential for maturation. • Envelope with glycoproteins: Viral capsid is covered by envelope derived from host cell membrane. Envelope contains a glycoprotein (gp120) which attaches to CD4 receptor on host cell membrane. • Coreceptors: Required for HIV infection. CXCR4 and CCR5.

27. Structure of the Human Immunodeficiency Virus HIV is a Retrovirus

28. Life Cycle of HIV 1. Attachment: Virus binds to surface molecule (CD4) of T cells and macrophages. • Coreceptors: Required for HIV infection. • CXCR4 and CCR5 mutants are resistant to infection. 2. Fusion: Viral envelope fuses with cell membrane, releasing contents into the cell. 3. Reverse Transcription: Viral RNA is converted into DNA by unique enzyme reverse transcriptase. Reverse transcriptase RNA ---------------------> DNA Reverse transcriptase is the target of several HIV drugs: AZT, ddI, and ddC.

29. HIV Life Cycle: Reverse Transcriptase Converts RNA into DNA

30. Life Cycle of HIV 4. Integration: Viral DNA is inserted into host cell chromosome by unique enzyme integrase. Integrated viral DNA may remain latent for years and is called a provirus. 5. Replication: Viral DNA is transcribed and RNA is translated, making viral proteins. Viral genome is replicated. 6. Assembly: New viruses are made. 7. Release: New viruses bud through the cell membrane.

31. Course of HIV Infection

32. Definition of AIDS AIDS is a syndrome: A collection of several diseases and symptoms that differ from one individual to another, but point to severe immunosuppression. HIV Antibody positive and one of the following (partial list): • Kaposi’s sarcoma • Pneumocystis carinii pneumonia • HIV dementia • non-Hodgkin’s B cell lymphoma • Yeast infection of esophagus, trachea, or lung • Multiple bacterial infections in children <13 years • Tuberculosis of the lung* • Recurrent pneumonia* • Invasive cervical carcinoma* • All HIV+ persons with <200 CD4+ cells/ul* *Added January 1, 1993.

33. AIDS Associated Disease Categories 1. Gastrointestinal: Cause most of illness and death of late AIDS. Symptoms: • Diarrhea • Wasting (extreme weight loss) • Abdominal pain • Infections of the mouth and esophagus. Pathogens: Candidaalbicans, cytomegalovirus, Microsporidia, and Cryptosporidia.

34. African AIDS patient with slim disease Source: Tropical Medicine and Parasitology, 1997

35. Opportunistic Oral Yeast Infection by Candida albicans in an AIDS Patient Source: Atlas of Clinical Oral Pathology, 1999

36. AIDS Associated Disease Categories 2. Respiratory: 70% of AIDS patients develop serious respiratory problems. Partial list of respiratory problems associated with AIDS: • Bronchitis • Pneumonia • Tuberculosis • Lung cancer • Sinusitis • Pneumonitis

37. Chest X-Ray of AIDS Patient with Tuberculosis

38. AIDS Associated Disease Categories 3. Neurological: Opportunistic diseases and tumors of central nervous system. Symptoms many include: Headaches, peripheral nerve problems, and AIDS dementia complex (Memory loss, motor problems, difficulty concentration, and paralysis).

39. AIDS Associated Disease Categories 4. Skin Disorders:90% of AIDS patients develop skin or mucous membrane disorders. • Kaposi’s sarcoma • 1/3 male AIDS patients develop KS • Most common type of cancer in AIDS patients • Herpes zoster (shingles) • Herpes simplex • Thrush • Invasive cervical carcinoma 5. Eye Infections: 50-75% patients develop eye conditions. • CMV retinitis • Conjunctivitis • Dry eye syndrome

40. Extensive tumor lesions of Kaposis’s sarcoma in AIDS patient. Source: AIDS, 1997

41. Chronic Herpes Simplex infection with lesions on tongue and lips. Source: Atlas of Clinical Oral Pathology, 1999.

42. Non-Hodgkin’s Lymphoma & ascites in AIDS patient Source: Tropical Medicine and Parasitology, 1997

43. Drugs Against HIV • Reverse Transcriptase Inhibitors: Competitive enzyme inhibitors. Example: AZT, ddI, ddC. • Protease Inhibitors: Inhibit the viral proteases. Prevent viral maturation. • Problem with individual drug treatments: Resistance. • Drug Cocktails: A combination of: • One or two reverse transcriptase inhibitors • One or two protease inhibitors. • Drug cocktails have been very effective in suppressing HIV replication and prolonging the life of HIV infected individuals, but long term effectiveness is not clear.