The Immune System

1. The Immune System • The body’s defense • 1. Nonspecific • 2. Specific • Cell mediated • Antibody mediated

2. Three cooperative lines of defense have evolved to counter these threats. • Two of these are nonspecific - that is, they do not distinguish one infectious agent from another.

3. Nonspecific defenses • “Nonspecific” = don’t have to recognize an invader to fight it • Skin: physical barrier • Sweat glands: chemical defense • Mucous membranes: • Line body openings- physical barrier • Secretions: • Antimicrobial proteins present in secretions • Mucous traps particles • Acid in stomach-destroy most except hept.A

4. Besides being a physical barrier, the skin and mucous membranes chemically destroy pathogens. • Secretions from oil and sweat glands give the skin a pH ranging from 3 to 5, acidic enough to kill most microbes. • Growth is also inhibited by saliva, tears, and mucous secretions that continually bathe the exposed epithelium. • All these secretions contain antimicrobial proteins. • One of these, the enzyme lysozyme, digests the cell walls of many bacteria, destroying them.

5. 2ND LINE-Internal • Microbes that penetrate the first line of defense face the second line of defense, which depends mainly on phagocytosis, the ingestion of invading organisms by certain types of white cells. • Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins.

6. Second line of defense cells function like roaming patrols • 1. Nonspecific defenses of chemicals and cells-Stimulated by cytokinnins • 2. Act rapidly with infection • 3. Employ negative test that cannot be foiled by copycat foreign cells

7. 4. All cells possess major histocompatibility complex (MHC) proteins • 5. Different in each individual. Distinguish self from non self. Due to MHC proteins-before birth • 1. MHC 1-nucleated cells-body cells • 2. MHC II- Nucleated cells-macrophages-B cells-some t cells • a. 50 alleles-20 genes • b. In autoimmune diseases defensive cells attack body's own tissues • c.Autoimmune diseases like arthritis have inflammation without infection

8. Major Histocompatibility Complex • The basis of “self” • Genes for cell surface glycoproteins • In humans: human leukocyte antigens (HLA) • ENORMOUS variation (polymorphic) • 2 Types: • Class 1: found on all nucleated cells • Class 2 : found on macrophages, B cells, CD4 T cells

10. Phagocytic and Natural Killer Cells • Neutrophils: • Most abundant WBC’s • Chemotaxic • Engulf invaders, then self-destruct • Monocytes: • Less abundant, but more effective than neutrophils • Form macrophages • Reach pathogen with pseudopodia • Engulf pathogen, fuse it with a lysosome • Kill pathogen with toxic oxygen or enzymes

12. More WBC’s • Eosinophils: • Fight large invaders (ex: parasites) • Natural Killer (NK) cells: destroy “self” cells infected with viruses, cancer cells

14. The Inflammatory Response • Histamine is released by circulating leucocytes called basophils and by mast cells in connective tissue. • Histamine triggers both dilation and increased permeability of nearby capillaries. • Also discharge prostaglandins and other substances that promote blood flow to the site of injury. • Greater clotting capacity, faster repair • Initiated by chemical signals • From microbe- Chemotactic factor • From damaged ‘self’ cells (ex: histamine) • Chemokines from damaged cells attract phagocytes • Pus = dead phagocytes + fluids • Extreme = septic shock

15. The Complement System • Antimicrobial proteins • ~ 20 serum proteins • Function: microbe lysis

17. Another set of proteins that provide nonspecific defenses are the interferons, which are secreted by virus-infected cells. • While they do not seem to benefit the infected cell, these proteins diffuse to neighboring cells and induce them to produce other chemicals that inhibit viral reproduction. • Interferon limits cell-to-cell spread of viruses, helping to control viral infection. • Because they are nonspecific, interferons produced in response to one virus may confer short-term resistance to unrelated viruses. • One type of interferon activates phagocytes.

18. Temperature Response • Pyrogens • Ex: Interleukin-1 • Detected in blood by hypothalamus -- raise in body temp • How it works: • Speeds cellular reactions • Stimulates phagocytosis • Stimulates liver/spleen to store Fe • Endotherms - may regulate behaviorally

20. Immunity terms • Humoral vs Cell mediated • Acquired/active vs Passive • Lymphocytes: T and B cells, specific • Antigen: Foreign molecule (from pathogens, pollen, transplanted tissue, etc.) • Antibodies: made by B cells, specific • Antigen receptors: on membranes of T & B cells • B cells: membrane antibodies • T cells: similar, but never secreted

21. T cells • TI = inducer • TC = cytotoxic • killers • TH = helpers • Activate others • TS = suppressor • Causes B cells to ignore antigens

22. Antigen presentation • Antigen binds to MHC within cell • MHC molecules bring proteins to surface

25. Cell mediated response • TC cells kill cancer cells, viral infected cells • All cells have class 1 MHCs (all susceptible to viral infection) • Class 1 MHC captures viral protein • MHC + antigen move to cell surface • Present to T cytotoxic cell • Enhanced by CD8 • Active killer cell

27. Mechanism • T cytotoxic cell releases perforin • Forms pores in membrane of target cell • Cell lyses, pathogen inside is exposed to circulating antibodies • T cytotoxic cell moves on to other cells infected w/ same pathogen

31. Antibody mediated immunity • Aka Humoral immunity, B cells activated, antibody production • Ex: macrophage engulfs a bacterium • Class 2 MHC picks up bacterial peptide • MHC + antigen move to cell surface • Presents to T helper cell/releases Il-1 • Enhanced by CD4 receptor on T helper cell • T cell proliferates • Activated T helper cells: secrete cytokines to stimulate other lymphocytes

32. Humoral response in detail • B cell activation by IL-2, proliferate into plasma and memory cells • Plasma cells: secrete antibodies • Memory cells: long-lived • Some antigens are T-independent • Bind to membrane antibodies on B cells • Plasma cells made w/ out signal from T cells

36. Structure of antibodies • Globular protein, in plasma, • aka: immunoglobulins (Igs) • Structure: 4 chains: 2 heavy, 2 light • Constant region • Variable region • Epitope: part of the antigen where antibody binds • 5 classes • Made in vitro • Polyclonal: made from many B cell clones • Work on different epitopes of the same antigen • Monoclonal: made from one B cell clone • All work at the same epitope of the same antigen

39. How antibodies work • Neutralization: • Block antigen activity • Opsonization: • Enhance macrophage attachment/phagocytosis • Agglutination: • Clumping • Complement fixation: • can be activated by antibodies or by pathogens • Antibodies attach to antigens • Complement proteins activate, cause lysis

40. Active vs. Passive Immunity • Active immunity: your own response • Natural: from infection • Artificial: from vaccinations • Passive: antibodies from another individual • Ex: across placenta, through breast milk • Ex: antivenoms,Rhogam • Rhogam: injection given to Rh- mothers after birth of Rh+ child. • Destroy fetal cells before her immune system responds to them, develops antibodies • Anti Rh antibodies are class IgG - can cross placenta

41. Tissue transplantation • Blood types: ‘A’ and ‘B’ antigens • T-independent humoral response • Antibodies don’t cross the placenta • Organ transplants • Rejection due to MHCs that are too dissimilar • Suppress immune system to decrease rejection • Bone marrow: graft rejection

42. Overactive/under active Immune Systems • Allergies: antigen induces inflammatory response • Histamine released from mast cells • Anaphylactic shock: severe allergic reaction, may cause death (due to  BP) • Epinephrine may counteract • Autoimmune diseases: immune system attacks self tissue • Lupus, rheumatoid arthritis, MS, type 1 diabetes

43. Under active Immune System • Immunodeficiency diseases: • Severe combine immunodeficiency (SCID) • Genetic, need marrow transplant • May treat w/ gene therapy • Hodgkin’s: damages lymphatic system • AIDS • Susceptible to opportunistic infections • Caused by HIV, 2 strains • Infect CD4 cells: requires CD4 receptor and co-receptor • Implications for treatment: • Chemokines bind to coreceptor - may block entry • Defective CD4 receptors prevent infection

44. More on AIDS • High mutation rate • Test is actually for HIV antibodies • T cell count indicates disease progression • Drugs only slow the progression, are very expensive • 30-40 million (?) world wide cases • 70% in sub-saharan Africa