Specific Immunity

1. Specific Immunity Talaro Chapter 15 Dendritic cell (blue) communicates with four T lymphocytes (yellow). Talaro (5th ed.) page 445 Elvis receives his polio vaccination during a 1956 March of Dimes campaign. www.marchofdimes.com

2. Specific Immune Reaction Overview • Specific Immune Reaction Overview • Characteristics of Specific Immunity • Humoral & Cellular Immune Response • Lymphocyte Development & Differentiation • Cytokines • Major Histocompatibility Groups • Presenting of Antigens • Antibodies • Immunoglobins (Igs) • Two Scenarios • Humoral • Cellular • Immunological Memory

3. Four Characteristics of the Immune System • Specificity • Antigens are organisms or molecules that are specifically recognized as foreign by the immune system • The sites on antigens that the immune system recognizes are the antigenic determinants or epitopes • Each antigen typically has several different antigenic determinants. • The host creates T cells and/or antibodies that are specific to the antigenic determinants • T cells & Abs aid in the removal of the antigen

4. Foreign molecules less than 1,000 MW are not antigenic unless attached to a larger carrier molecule Proteins produced by the immune system that specifically binds to an epitope and initiates its removal of the antigen from the body Epitope Ab recognize and bind to a specific epitope Proteins (enzymes, exotoxins, Abs, hormones) Lipoproteins Glycoproteins Nucleoproteins (pure DNA isn’t antigenic) Polysaccharides (bacterial capsules) & LPS

5. Antigens Whole cells, viruses and complex molecules elicit the immune response. Viruses present various antigenic determinants. Each determinant will stimulate a unique lymphocyte and Ab response. Small molecules, simple molecules, and large but repetitive molecules can evade the immune system.

6. Characteristics of the Immune System • Diversity • The human immune system can distinguish and respond to  10 million different antigenic determinants • Distinguishing Self from Non-self • Major Histocompatibility Complex • Proteins on the surface of every cell • Immunological Memory • Once exposed to a pathogen, the immune system “remembers” and mounts future responses more rapidly

7. The Immune System • Humoral Immune Response • Defense against extracellular pathogens • Abs bind to antigens • Makes antigens easy targets for phagocytes • Cellular Immune Response • Intracellular pathogens & cancer • Bind & lyse abnormal cells • The two responses operate in concert and share mechanisms

8. LymphocytesWBC (leukocytes) involved in the immune response. Two types: B cells & T cells. Lymphocytes secrete cytokines that regulate the activities of many other types of cells and are often present at sites of inflammation. • B Lymphocytes(B-Cells) • - Lymphocytes that mature in bone marrow • Responsible for the production of antibodies and humoral • (fluid) immunity • T Lymphocytes (T-Cells) • - Lymphocytes that mature in thymus gland • Responsible for the cell-mediated immunity • Directed against a factor, such as a virus or mutation, that • changes a normal cell into an abnormal cell

9. Lymphocytes develop from the same stem cell but undergo a sequential development that begins in the embryonic yolk sac and shifts to the liver and bone marrow. Diverge into two distinct types: B cells & T cells.

10. Immature lymphocytes cannot react with antigens. Lymphocyte differentiation & immunocompetence are completed by late fetal or early neonatal period. Mature B cells are found in the lymph nodes, spleen, gut associated lymphoid tissue. Have immunoglobin receptors & numerous microvillus projections. Mature T cells are found in the lymphoid organs but pass between lymphatic & general circulation. 7 clusters of differentiation (CD) or receptors that recognize antigens bound on cells, MHC receptors, B cells, T cells and macrophages.

11. Brief Explanation of B Cells Specificity between the antigen & Ab Each B cell makes a unique Ab on its surface B cell divides Production of Clones “clonal selection” A few develop into memory cells that divide at a low rate Some develop into effector or plasma cells

12. Brief Explanation of T Cells Cytotoxic T cells destroy foreign or abnormal cells by secreting perforins that lyse cells (CD8 or TC) Helper T cells activate other T & B cells (CD4 or TH)

13. Cytokines • Soluble proteins • Regulate immune system activities • Cytokine network • A complex web of signals among all the cell types of the immune system • Cytokines have been named after their cells of origin, their function, and / or the order in which they were discovered

14. Common Examples of Cytokines • Interleukins (ILs) • Signal among leukocytes • 27 different ILs • Interferons (IFNs) • Antiviral proteins that may also acts as cytokines • IFN-g secreted by TH cells • Growth Factors • Stimulate stem cells to divide • Sufficient quantity of leukocytes • Tumor Necrosis Factor (TNF) • Kill tumor cells & regulate immune response to inflammation • Macrophages & T cells • Chemokines • Signal leukocytes to migrate to site of inflammation or infection • Activate other leukocytes

15. Major Histocompatibility ComplexCellular surface glycoproteinsSelf identifying labelsCoordinate interactions among lymphocytes & macrophages • These molecules are called human leukocyte antigens (HLA)

16. Class I MHC proteins are present on the surface of every nucleated animal cell • Not present on RBC • Class II MHC proteins are found mostly on the surface of B cells, macrophages, and other antigen-presenting cells • When an antigen is ingested by an antigen-presenting cell, it is broken down and fragments are presented at the cell surface by class II MHC proteins • Class III MHC proteins include some of the proteins of the complement system that interact with antigen–antibody complexes to cause lysis of foreign cells • Not surface proteins

17. Antigen Presenting Cell Macrophage takes up an antigen by phagocytosis Macrophage processes the antigen by breaking it into fragments A class II MCH protein binds the processed antigen A closer look at this interaction The MHC “presents” the antigen to a helper T cell

18. Interleukin-2 is produced by TH to activate B & T cells IL-1 Interleukin-1 is secreted by APC to activate TH cells

19. Antibodies / Immunoglobins Bivalent Variable regions differ in the a.a. sequences at the antigen-binding site & are responsible for the diversity of Ab specificity Fc

20. Antibodies interact with the epitope of the antigen by • shape/shape recognition (lock and key mechanism) • - Recognition depends on multiple noncovalent bonds • between the antigen-binding site and epitope • Antibodies work to eliminate antigens by either • enhancing phagocytosis or inducing the complement • protein cascade

21. The variable regions differ in the amino acid sequences at the antigen-binding site and are responsible for the diversity of antibody specificity • The enormous range of antibody specificities is made possible by the recombination of numerous versions of coding regions for the variable regions

22. The Genetic Basis of Antibody Diversity • As B cells develop, their genomes become modified until the cell can produce only one specific type of antibody • If we had a different gene for each antibody our immune systems are capable of producing, our entire genome would be taken up by antibody genes • Instead, just a small number of genes that can recombine to generate multitudes of possibilities are responsible for the vast diversity of antibodies

23. The Genetic Basis of Antibody Diversity • Each gene encoding an immunoglobin is in reality a “supergene” assembled from several clusters of smaller genes located along part of a chromosome • During B cell development, these variable regions rearrange and join • Pieces of DNA are deleted, and DNA segments formerly distant from one another are joined together • Immunoglobulin genes are assembled from randomly selected pieces of DNA random process

24. Another pool of segments is used for the constant region Variable region for heavy chain Constant Region Encoded by one V segment, one D segment & one J segment Figure 18.18 Heavy-Chain Genes

25. The Genetic Basis of Antibody Diversity • There are multiple genes coding for each of the four kinds of segments in the polypeptide chain for the heavy chain in mice: 100 V, 30 D, 6 J, and 8 C regions • Each B cell randomly selects one gene for each of the V, D, J, and C regions • A similar process occurs for the light chain • Theoretically, there are 144,000 x 144,000 possible combinations of light and heavy chains • 21 billion possibilities

26. Immunoglobin • There are five immunoglobulin classes are based on differences in the constant regions of the heavy chain • Table 15.2 • IgG • Classic Y shape • Compose 85% of the total immunoglobulin content of the bloodstream • Complementation activation • Neutralize toxins • Opsonization • FC binds to phagocytes • Cross the placenta • Leave blood vessels and enter tissues • IgM • Pentamer • More efficient at complement activation, neutralization and agglutination • Produced as a first response by plasma cells • FC binds to B cells

28. Macrophage has receptors for constant region of Ab Binding of Ab to receptor initiates phagocytosis Opsonization Covered by complement proteins or Ab

29. Some Review Before Moving On… Two General parts of Immune Response… • Cell mediated immunity – deals with destruction of cells… infected or tumor or injured cells • Humoral or Ab-mediated immunity – deals with production of Ab

30. Some Review Before Moving On… Lymphoid Tissue…characterized by two types Primary: Bone Marrow Thymus Gland Secondary: Lymph Nodes, Spleen, Tonsils, Appendix (?)

31. Review of Cells of Immune System Ag-Presenting Cells- APCs Include macrophages and some other lymphocytes

32. T-Cells 5 Types 1) TD cells: D = Delayed-type hypersensitivity, involved in allergic reactions and inflammation 2) Natural Killer Cells (NK Cells): Responsible for cell killing (many consider these not T cells and are sometimes called null cells)

33. T-Cells 3) TC cells: Cytotoxic T cells – Responsible for cell killing 4) TH cells: Helper T cells – two types a) TH1 Cells: Stimulate TC cells and so part of Cell-mediated immune response; Stimulate macrophages, Involved in inflammation b) TH2 Cells: Stimulate B cells – leading to Ab production so part of humoral immune response

34. T-Cells 5) TS Cells: Supressor (or regulatory) T cells – Supresses immune response of other cells… very important. Two types… a) One with CD4 receptor b) One with CD8 and CD25 receptors Some are using these to combat autoimmune diseases

35. CD (Cell-Associated Differential) Receptors Two main types (for us) 1) CD4: On TH cells and TD cells and some TS cells 2) CD8: TC cells and some TS cells

36. Major Histocompatibility Complex Proteins Found in all vertebrate animals Collectively called Human Leukocyte Antigens (transplantation problems) Two Types: 1) Class I MHC – found on surfaces of all nucleated cells 2) Class II MHC – found on B lymphocytes macrophages, and dendritic cells (all of which are APCs)

37. B Cells B Cells Give rise to 2 to two types of cells… 1) Plasma Cells – cells that produce antibodies 2) Memory cells - slow growing cells that will produce antibodies when same Ag in reintroduced to host

38. Additional Information of Immunoglobulins 5 Classes: 1) IgG (80%): Found in extracellular fluid, blood and lymph, crosses placenta 2) IgM (6%): First Ab to appear after immunization, bind complement strongly; found in blood and lymph, and on the surfaces of B lymphocytes (as a monomer)

39. Additional Information of Immunoglobulins 3) IgA (dimer) (13%): Known as major secretory Ab, found in all kinds of secretions including saliva, colostrum, serum; is a monomer in serum and dimer in everything else 4) IgD (1%): Minor circulating Ab found in blood and lymph and lymphocyte surfaces; very heat labile; no known function but abundant of surface of memory B cells…

40. Additional Information of Immunoglobulins 5) IgE (0.002%): Involved in allergic reactions, binds to mast cells; found in blood and lymph only Know term valence… valence

41. Opsonization Definition: Enhancement of phagocytosis by antibody or complement binding When Ab binds to an Ag on surface of cell, the cell is more likely to be phagocytized… When complement binds this Ab-Ag complex, it is even more likely to be phagocytized

42. Superantigens –e.g., Staphylococcus aureus Toxins (TSS toxins) Proteins capable of eliciting a very strong immune response because they activate more T cells than that activated in a “normal” immune response…

43. Other Terms… • Natural Active Immunity- • Artificial Immunity – • Passive Immunity- • General passive immunity- advanatges and disadvantages • Maternal Passive Immunity- good for about 6 months

44. Two Scenarios

45. Phases of the Humoral Immune Responses (Part 1) TH cells bind to an antigen presented to it by an antigen-presenting macrophage IL-1 The activated TH cell produces and secretes IL-2 molecules,which attach to their own specific cell membrane receptor proteins IL-2 The TH celldivides to produce clones capable of interacting with B cells These steps, called the activation phase, occur in the lymphatic tissues

46. Phases of the Humoral Immune Responses (Part 2) In theeffector stage, an antigen of the same sort that was processed by the macrophage binds to a specific IgM receptor on the surface of a B cell IL-4 The B cell degrades the antigen and presents a piece of processed antigen in a class II MHC protein on its cell surface IgM One of the TH cells created in the activation stage recognizes the processed antigen and class II MHC protein on the surface of the B cell The TH cell releases growth factor, which activate B cell proliferation and differentiation into plasma cells and memory cells The plasma cells secrete Abs

47. Phases of the Cellular Immune Responses (Part 1) Like class II MHC molecules, class I MHC molecules also present processed antigen to T cells Foreign protein fragments are bound by class I MHC molecules and carried to the plasma membrane, where TC cells can check them If a cell has been infected by a virus, or has mutated, it may present protein fragments that are not normally found in the body IL-2 drives T cell division If a TC cell binds to the MHC I–antigen complex, the TC cell is activated to proliferate and differentiate

48. Phases of the Cellular Immune Responses (Part 2) In the effector stage, TC cells once again bind to the cells bearing MHC I–antigen complex and secrete perforin molecules create pores within the cell TC secrete granzymes that enter the pores and induce apoptosis Granzymes are stored in cytoplasmic granules This system helps rid the body of virus-infected cells. It also helps to destroy some cancer tumors

49. Memory (Fig 15.13) Specificity between the antigen & Ab Each B cell makes a unique Ab on its surface B cell divides Production of Clones clonal selection A few develop into memory cells that divide at a low rate Some develop into effector cells (plasma cells)

50. Augmented response related to a prior stimulation of the immune system by antigens. First exposure to the antigenPrimary response: IgM & IgGSecondary response: IgG & IgM Memory B cells survive in lymphoid tissue Latent Period Antigen concentrated in lymphoid tissue Memory B cells differentiate into plasma cells and produce IgG Persists 5 days Persists 23 days Produced by plasma cells Body produces memory B cells Memory cells will divide and differentiate into plasma cells without interaction with APC