Acquired (or Adaptive) Immunity Monday, October 6, 2003

1. Acquired (or Adaptive) ImmunityMonday, October 6, 2003 • Reading- Anatomy and Physiology- Lymphocytes and Spleen (pp 8-11) La Persistance de la Memoire by Salvador Dali

2. Blood vessels Lymphatics Peripheral Lymphoid Tissues Pre-T Thymus Y T Y T NK Lymphoid Stem Cell NK Y B Y Pre-B B Bone marrow APC PPSC monocyte Platelets, RBCs, WBCs Myeloid Stem Cell Immune System Development and Distribution

3. Acquired Immunity Protection by the crude mechanism of innate immunity is augmented by "acquired" or "adaptive" immunity: •Prior exposure- acquired immunity requires prior exposure to the inducing agent for full expression; contact with the immunogen is immunization. •Specificity- the mechanisms of acquired immunity are always highly specific to the immunogen.

4. Acquired Immunity (cont’d) •Memory- primary response to immunization is short-lived with generation of specific memory lymphocytes. Secondary exposure leads to a rapid substantial response. --memory is the rationale for the practice of vaccination. •Discrimination between 'self' and 'non-self'- most important feature of acquired immunity is the ability to distinguish between host and foreign molecules.

5. Binding Antigens by B-Lymphocytes •Bind antigens by means of specialized antigen receptors, and they do collaborate in the immune response. •B-cell antigen receptor is an immunoglobulin (Ig) molecule. •B-cells can use their Ig receptors to recognize native antigenic molecules.

6. Binding Antigens by T-Lymphocytes •T-cell antigen receptoris a related molecule of different structure called the T-cell receptor (TcR). •T-cells recognize only peptide fragments of antigens prepared by antigen-presenting cells (macrophage-monocyte lineages and the B-cells themselves).

7. Binding Antigens by B- and T-Lymphocytes Common features that characterize mode of antigen recognition: •Cell surface receptors (thousands of them per cell) expressed by an individual T- or B-cell are identical; --confers specificity to respond to a single antigen, and to have limited cross-reactivity. •Antigen receptors are synthesized and expressedprior to encounters with antigens. --immune systems pre-arms itself with a vast array of antigen receptor specificity's.

8. Binding Antigens by B- and T-Lymphocytes (cont’d) •On encounter with an antigen, a T- or B-cellproliferates and differentiates into mature effector cells. --leads to expansion of clones and an effective immune response. •Alternatively, antigen encounter can lead to cell inactivation or immune cell death. --result is specific immune tolerance (that is, "self"). --formulated on theoretical grounds as the clonal selection theory, now supported by experimental evidence.

9. The Antigen-Presenting Cell (APC) •Many short fragments (peptides, carbohydrates) from these antigens are then bound to major histocompatibility complex (MHC) molecules and incorporated into the cell membrane. •If the antigen is of endogenous origin, that is, it was produced from inside the infected cell, it will bind readily to class I MHC molecules and move to the cell membrane of the infected cell. --MHC class I are found in virtually all nucleated cells.

10. Antigen Recognition by T-Cells •If the antigen is of exogenous origin, that is, it came from outside the body, it will bind to class II MHC molecules: --MHC class II are found in APC's. •T-cells do not recognize intact proteins as antigens. --T-cell receptor on T-cells recognizes foreign particle in the groove of MHC class I and II molecules.

11. Presentation of Antigen in Class I MHC There are several differences in the mode of antigen presentation by MHC class I restricted CD8+ T-cells: •Any nucleated cell is a potential APC. •Class I restricted CD8+ T-cells exert primarily a cytotoxic function against virally infected or neoplastic cells. •Antigenic peptide associated with the class I molecule is produced by the antigen presenting cell itself.

12. Presentation of Antigen in Class II MHC •In contrast, class II MHC molecules are constitutively expressed on a limited number of cell types. --T-cells that express CD4 interact with class II MHC. •Class II MHC-containing cells have a well-developed lysosomal apparatus, and cause phagocytosis of antigens: -macrophage-monocytes; -Langerhans cells; -dendritic cells; and -B-cells are antigen-presenting cells.

13. Relationships between APC and Other Immune Cells •An efficient humoral response does not occur in the absence of T-cell because they provide the help needed to promote B-cell proliferation and differentiation into plasma cells. •B-cell growth factors from T-cells: interferon-g, IL-2, IL-4.

14. Kill Pathogens Limit Damage Repair Tissue Inflammatory Response Inflammation Injury

15. Innate Immunity Acquired Immunity General Overview of the Immune Responses Immune Response Rapid General Slow Specific

16. Acquired vs. Innate Immunity- A Comparison • Innate Immunity Acquired Immunity • PhylogeneticMulti-Cell Organisms Jawed Vertebrates • SpeedRapid Slow • SpecificityGeneral Specific • RecognitionMolecular Patterns Structural Details • ReceptorsEncoded in germline Rearranged in development

17. Innate and Acquired Immunity- A “Bug’s Life” •Immunity is a race between pathogen and host! •Immunity and Anthrax: --Bacillus anthracis, Gram positive aerobic bacillus/spore --5th and 6th plagues of Egypt (Exodus); --Disease primarily of animals, also of humans; --Ideal weapon for bioterrorism. X

18. Anthrax- Disease in Man • •Cutaneous anthrax (skin): • --Most (about 95%) anthrax bacteria infections occur when the bacterium enters a cut/abrasion on the skin; • --Red macule papule  ulcer with black border; • --Not treated: ~80% spontaneous healing, ~20% death. •Inhalation anthrax: --Initial anthrax symptoms may resemble a common cold; --Inhaled spores germinate; --Outcome good if treated by day 4; 80% mortality if not!

19. Anthrax- Disease in Man (cont’d) •Gastrointestinal anthrax: --From eating poorly cooked meat, occurs very rarely; --Initial signs of nausea, loss of appetite, vomiting, and fever are followed by abdominal pain, vomiting of blood, and severe diarrhea.

20. Anthrax- Pathogenesis and Immunity •B. anthracisspores require phagocytosis to germinate. •B. anthracisbacteriaevade phagocytosis: --Anti-phagocytic capsule made of poly-D-glutamic acid •Toxins: --Protective antigen (PA) --Edema factor (EF) --Lethal factor (LF)

21. Anthrax Toxins • •Protective antigen (PA): • --Binds to cellular receptor Anthrax Toxin Receptor • --Forms pore • --Delivers EF and LF into cells via endosomal pathway • •Edema factor (EF): • --Adenylate cyclase • --Elevated cAMP blocks neutrophil bactericidal activity • --Edema • •Lethal factor (LF): • --Zn2+ metalloprotease • --Destroys macrophages, leads to shock and death

22. Anthrax Treatment •Antibiotics In intentional anthrax bacteria exposure, strains may be resistant to many commonly used antibiotics, so use Cipro and Doxycycline antibiotics. •Vaccine The main ingredient in vaccine is against “protective antigen”. •Anti-Toxin Drugs Soluble receptor works as a decoy to absorb the lethal factor toxin (LF) before it could attach to cells.