Infection and Defects in Mechanisms of Defense

1. Infection and Defects in Mechanisms of Defense Chapter 7

3. Immune System “protects against foreign antigens” • Inappropriate • Exaggerated – allergy • Misdirected – autoimmunity • Against beneficial foreign tissue – alloimmunity • Insufficient – immune deficiency

4. Hypersensitivity • Allergy: exaggerated • Deleterious effects of hypersensitivity to environmental (exogenous) antigens • Autoimmunity: misdirected • Disturbance in the immunologic tolerance of self-antigens (autoantibodies) • Alloimmunity: beneficial tissue • Immune reaction to tissue of another individual

5. Hypersensitivity • Characterized by the immune mechanism • Type I IgE mediated • Type IITissue-specific reaction • Type IIIImmune-complex mediate • Type IVCell mediated • Tables:7-1, 7-2, 7-3

6. Mechanisms of Hypersensitivity “require sensitization against Ag from a 1° immune response” “disease symptoms after 2°immune response” • Immediate – minutes to hours • Anaphylaxis – rapid & severe • Delayed – hours to days

7. Type I Hypersensitivity • IgEmediated • Environmental antigens (allergens) • IgE binds to Fc receptor on a mast cell • Histamine release • H1 receptors • antihistamines

9. Type I • Genetic predisposition • Tests • Food • Skin • Lab (IqE) • Desensitization • IgG – blocking antibodies

10. Type I Hypersensitivity

11. Type II Hypersensitivity - autoimmune • Tissue specific • Cells or tissue (tissue-specific Ag) – target of an immune response

12. Type II • Five mechanisms • Cellular destruction – Ab + Complement • Phagocytosis • Neutrophil-mediated damage to tissue • Antibody dependent cell mediated cytotoxicity (NK cells) • Target cell malfunction

14. Type III Hypersensitivity • Immune complexes (Ag – Ab cplx) • Formed in the circulation → vessel walls or extravascular tissue → C3b + neutrophils → tissue damage • SLE, serum sickness, Raynaud phenomenon

16. Type IV Hypersensitivity • Cytotic T-lymphocytes – lymphokine • Direct killing or phagocytosis • Examples • Acute graft rejection TB skin test, contact allergic reactions (poison ivy) • Type II collagen → rheumatoid arthritis thyroid cell surface → Hashimoto disease • Pancreas → diabetes Type I

19. Allergy • Environmental antigens that cause atypical immunologic response – genetically predisposed individuals • Pollens, molds, fungi, foods, animals, dust • Allergen is contained within a particle too large to be phagocytosed or is protected by a nonallagenic coat

20. Autoimmunity • Loss of Tolerance • Views self as foreign • Examples • Acute rheumatic fever– group A streptococcal sore throat – M protein – capsule mimics normal heart Ag → antibodies to valve (Type II) • Glomerulonephritis – bacterial Ag into blood: immune cplx → kidney (Type III)

21. Autoimmunity :Example • Systemic lupus erythematosus (SLE) • “Chronic multisystem disease” • Autoantibodies against • Nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, etc. • Deposition of immune complexes • Kidneys, brain, heart, spleen, lung, GI tract, peritoneum and skin

23. Alloimmunity • Immune system reacts with antigens on the tissue of other genetically dissimilar members of the same species • ABO blood group • Rh antigen

25. Alloimmune Disease • Major histocompatibility complex(HLA) • Antigen – presenting molecules • Chromosome #6 (A, B, C, DR, DQ & DP) • 6 genetic loci • Class I CD8 on Tc cells • Class II CD4 on Th cells • Class III Complement • More than 300 different HLA-A antigens • Closer match with sibling

27. Graft Rejection • Classified according to time • Hyperacute • Immediate and rare → white graft • Preexisting antibody to the graft Ag (Type II reaction) • Acute • Cell-mediated against unmatched HLA antigens (days to months → Type IV reaction) • Chronic • Months to years, slow organ failure • Weak cell mediated (Type IV reaction) – endothelial cells of organ’s vessels

28. Infection • Number 1 cause of death world wide – 26% 2005 • Africa – 62% deaths • Developing countries – population & poor sanitation • Plague, cholera, malaria, tuberculosis, leprosy & schistosomiasis • New disease • West Nile virus, severe acute respiratory syndrome (SARS), Lyme disease, Hantavirus and drug resistant tuberculosis

29. Classes of Human Infectious Organisms

30. Bacterial Disease • Exotoxin: protrin released during bacterial growth • Specific effects :cytotoxins, neurotoxins, hemolysins… • Immunogenic : antibodies(antitoxins) • Tetanus, diphtheria, pertussis • Endotoxin: contained within the cell walls of gram negative bacteria lysis/destruction • LPS: pyrogenic bacteria inflammation + fever, DIC, shock

31. Mechanism of Tissue Damage

32. Mechanism of Tissue Damage

33. Microorganisms and Human Relationships • Mutual relationships • Normal flora – Table 7-1 • Provided – nutrients • Produce • Enzymes to facilitate digestion • Produce antibacterial factors # colonization by pathogenic microorganisms • Useable metabolites (Vitamin K, B) • Opportunistic organisms – immune deficiency

34. Normal Indigenous Flora of the Human Body Table 7-1

35. Gram Stain & Bacteria

36. Pathogenic Defense Mechanisms • Surface coats • Inhibit phagocytosis • Toxins • Kill neutrophils & pyrogenic effect • Proliferation • Rapid > immune response • Antigenic variation • Mutation – antigenic drift • Recombination – antigenic shift • Gene switching

37. Bacteremia – Septicemia • Presence of bacteria in the blood • Usually gram-negative bacteria • Septic shock caused by endotoxins • Evaluation – blood culture “bugs in da blood”

38. Bacteria in Blood

39. Medical Uniforms & Bacterial Colonization(Am J Infection Control Sept 2011) Institution:Zedek Medical Center, Jerusalem Participants: 75 nurses, 60 physicians Evaluation: Cultures of 3 spots on uniforms Findings: Potential pathogens on 63% of uniforms. Antibiotic resistant strains on 14% nurses & 6% physicians. Eight cultures grew MRSA Suggestion: “infrequent hand washing”

40. Viral Disease “most common affliction humans” - colds → # cancers → AIDS • Obligate intracellular parasites • Dependent on the host cell • No metabolism – incapable of independent reproduction • Permissive host cell • Usually a self-limiting infection • Spreads cell to cell

41. Viral Replication • DNA or RNA • Single or double stranded • Protein receptor – binding site • Virus uncoats • Most RNA viruses directly produce mRNA • DNA “provirus” enters nucleus and is transcribed into mRNA

42. Viral Replication • Translation of mRNA results in the production of viral proteins • New viruses are released through budding • Viral DNA, integrated into host cell DNA is transmitted to daughter cells by mitosis.

43. Cellular Effects of Viruses- • Inhibition of host cell DNA, RNA or protein synthesis • Disruption of lysosomal membranes • Promotion of apoptosis • Fusion of infected, adjacent host cells • Alteration of antigenic properties

44. Cellular Effects of Viruses • Transformation of host cell into cancerous cells • Promotion of secondary bacterial infections

45. Clinical Manifestations of Infection • Variable depending on the pathogen Direct cause → pathogen Indirect cause → products • Fever – “reset hypothalamus” • Exogenous – cell walls - “LPS” → inflammation • Endogenous IL-1, IL -6, interferon, TNF-a

46. Countermeasures • Vaccines • “Induction of long-lasting protective immune response – no disease in a healthy recipient → memory cells (T or B):” • Attenuated viruses (MMR, varicella) • Killed organisms (hepatitis A) • Recombinant viral protein (hepatitis B) • Bacterial antigens – capsular polysaccharides 10 strains S. pneumoniae • Toxins – diphtheria, cholera, tetanus → toxoid (IgG) “chemical detoxified”

47. Countermeasures • Antimicrobials: • Inhibit synthesis of cell walls • Damage cytoplasmic membranes • Alter metabolism of nucleic acids • Inhibit protein synthesis • Modify energy metabolism

48. Pathogenic Adaptations • Immune system suppression • HIV • Multiple drug resistance • Streptococcal pneumonia, tuberculosis, MRSA, VRE, E. coli, Klebsiella • Genetic mutation → selection • “Overuse and compliance”

49. Immune Deficiencies :Lab Evaluation Table 7-12 • Hallmark • Unusual or recurrent, severe infections • Primary(congenital) immunodeficiency • Genetic anomaly – single gene • Secondary (acquired) immunodeficiency • 2° to another illness • More common

50. Secondary (Acquired) Deficiencies • Causes • Normal physiologic condition • Psychological stress • Dietary insufficiencies • Malignancy • Physical trauma • Medical treatment • Infection • AIDS