Fundamentals of Acquired Immunity

1. Fundamentals of Acquired Immunity

2. I. Definitions

3. Immunology – the study of all aspects of host defense against infection and of adverse consequences of immune response • Immunity – the state of protection fro infectious diseases utilizing both innate and acquired mechanisms

4. Immune response - a specific and complex series of events throughout the animal’s body that helps it defend against disease-causing organisms or substances • Antigen – particular foreign molecules that stimulate and immune response • Often immunogenic on its own, otherwise requires a carrier molecule) • Non-self substances to which lymphocytes can respond

5. Innate Immunity:non-specific protective mechanisms conferring basic resistance to disease

6. general, physical, chemical, and biological barriers against disease • discussed in previous unit • also referred to as innate or natural immunity

7. II. Different Types of Acquired Immunity

8. Acquired Immunity:specific protective mechanisms displaying specificity, diversity, memory and self/non-self discrimination • Often dependent on innate immunity for full activation • Can be acquired actively or passively

9. Naturally acquired active immunity - An individual comes in contact with an antigen (Ag) and produces sensitized lymphocytes and/or antibodies that inactivate the antigen • Ag is encountered naturally • Immune responses are activated • Antibodies made • Lymphocytes sensitized • Result: Ag inactivated or destroyed • Memory generated (long-lasting immunity)

10. Naturally acquired passive immunity - transfer of antibodies (Abs) from one individual to another • Abs transferred from a donor to a recipient (adoptive transfer) • Maternal transfer of IgG Abs to fetus across the placenta • Maternal transfer of IgA Abs to newborn in colostrom and breast milk • Newborn has immunity to infections encountered by mother previously • Short-lived (weeks to months)

11. Artificially acquired active immunity - deliberate exposure of an individual to a vaccine with subsequent development of an immune response • Vaccine = preparation of attenuated or killed microbes or inactivated toxins (toxoids)

12. Artificially acquired passive immunity - deliberate introduction of antibodies into an individual • Abs made deliberately in another animal or synthesized using in vitro methods • Antiserum • Antitoxins • Antivenom • Monoclonal antibodies (in vitro)

13. III. Origin, Maturation and Function of Lymphocytes

14. B Lymphocytes • Birds: Bursa of fabricius • Part of the chicken cloaca where B cells mature • Absent in mammals • Humans: • Fetal liver • Bone marrow stem cells • Two types • T-dependent B cells (require T cell help) • T-independent B cells (do not require T cell help)

15. T Lymphocytes • Originate in the thymus • DiGeorge Syndrome: athymic – no T cells • Specialized anatomicl locations responsible for educating T cells • Cortex • Medulla • Education involves two main processes • Positive selection • Negative selection

16. Three types: • TH1 = Inflammatory T cells • Help macrophages (and B cells) • TH2 = Helper T cells • Help B cells • Tcyt = Cytotoxic T cells (killer T cells) • Kill target cells using perforin and granzyme

17. Natural Killer Cells (NK cells) • Probably derived from prethymic lymphocytes • Do not have the characteristics of either B-cells or T-cells • AKA Large Granular Lymphocytes (LGL) • AKA Null cells • Not equivalent to killer T cells but kill their target cells using same mechanism (perforin and granzyme) • Participate in ADCC

18. Humoral Immunity

19. B Cells and Their Role in Humoral Immunity • Involvement of Ab in immune responses • T-dependent • T-independent • Protects against pathogens that exist in fluid spaces • Bacteria and their toxins • Viruses • Protozoans • Helminths • When B cells begin to produce antibody upon activation by antigen, they differentiate into plasma cells

20. Cell-Mediated Immunity

21. T Cells and Their Role in Cell-Mediated Immunity • Involvement of T cells subsets • TH1 • TH2 • Tcyt • Requirement for direct interaction with infected cell or foreign cells • Involves complex of T cell receptor (TCR), Major Histocompatibility Complex molecule (MHC) and Antigenic peptide fragment

22. Functions • Lysis of host cells infected by viruses • Elimination of cancer cells • Productin of cytokines to assist other cells in eradicating foreign Ags • Cytokines: Molecules secreted by one cell and affecting a different cell type  specific regulatory interactions • Trasplantation rejection • Due to differences in MHC class I and class II molecules (alloantigens)

23. NK Cells and Their Role in Cell-Mediated Immunity • Nonspecifically kill tumor cells, virus-infected cells, and other parasite-infected cells • Play a role in regulating the immune response • Exhibit antibody dependent cell-mediated cytotoxicity (ADCC)

24. Figure 31.20

25. IV. The Nature of Antigens

26. SELF VERSUS FOREIGN

27. Self • Prior to and after birth, the immune system develops and is able to differentiate between self proteins and foreign proteins • T cells that are responsive to self Ags are eliminated early in their developmental pathway • Negative selection • Apoptosis occurs in the thymus • Never enter periphery

28. B cells interacting with self Ags either apoptose or anergize • Apoptosis = programmed cell death • Anergy = induction of non-responsive state

29. Self-Tolerance • The process of elimination of self-reactive lymphocytes is called self tolerance • Leads to removal of what could initiate harmful autoreactive response = Autoimmunity • Is very efficient, but not complete

30. FOREIGN

31. Immunogenicity • The term immunogen is often used synonymously with the term antigen • Careful!!!! • All immunogens are antigens, but not all antigens are immunogens • An immunogen is any substance that can mediate an immune response

32. Types of Antigens (immunogens) • Antigens recognized by B cells • Proteins, peptides, glycoproteins, nucleoproteins, polysaccharides, lipids, glycolipids, and small chemical groups (haptens) • B cell receptor = Antibody (Ab) • Antigens recognized by T cells • Peptide in association with MHC molecule • T cell receptor = TCR

33. Epitopes • Epitopes (antigenic determinant sites) are areas of an antigen that can stimulate production of specific antibodies and that can combine with them • Some antigens have more than one site capable of interacting with Abs

34. Valence - the number of epitopes on an antigen; determines number of antibody molecules an antigen can combine with at one time • Generally the high the valency, the more immunogenic the substance • Epitopes (determinants) that are more easily accessible stimulate better immune response (projections or NH2/COOH ends)

35. Figure 32.3: The number of antigenic determinant sites (epitopes) on an antigen is its valence.

36. Hapten - a small organic molecule that is not itself antigenic but that may become antigenic when bound to a larger carrier molecule • Examples: • Dinitrophenol (DNP) • Penicillin

37. Figure 32.4: Effect of carrier on immunogenicity of hapten.

38. V. Structure and Function of Antibodies (Immunoglobulins)

39. What is an antibody?

40. Antibodies • A group of glycoproteins in the blood, serum, and tissue fluids of mammals; • Produced in response to an antigen and can combine specifically with that antigen • In the serum, four major classes can be measured electrophoretically, but there are actually five classes

41. Figure 32.6: Electrophoresis of human serum – showing distribution of serum proteins and four major classes of immunoglobulins.

42. Immunoglobulin structure • Multiple antigen-combining sites (usually two; some can form multimeric antibodies with up to ten combining sites) • Composed of four polypeptide chains (two heavy or long, and two light or short) that form a flexible Y with a hinge region • Heavy chain: ~440 aa, 50-70kDal (GAMED) • Light chain: ~220 aa, 25kDal (kappa or lambda)

43. The stalk of the Y (called the Fc) is constant in amino acid sequence (i.e., the amino acid sequences of antibodies of the same subclass do not vary significantly) • Constant regions are relatively invariable between Igs belonging to the same class (= isotype, IgG, IgA, IgM, IgE, IgD) • Constant regions confer different biological properties upon the Ig classes (in vivo half life, anatomical location, interactions with other molecules)

44. B cells can switch from production of one type of Ig to another type (isotype) by a mechanism known as ISOTYPE SWITCHING • Isotype switching is mediated by signals received during ongoing immune responses (e.g. T cell cytokines)

45. The arms of the Y have variable regions and constitute the antigen-binding domains (Fab) • Each Ab has 2 Ag-combining sites (bivalent) made up of H and L chain regions encoded by the variable portion of the Ig (VLVH) • Some Abs exist as dimers (IgA) or pentamers (IgM) and so have 4 or 10 Ag-binding sites, respectively

46. Intrachain disulfide bonds create “loops” on both heavy and light chain • Each loop contains ~25 aa making up a single “domain” • Interchain disulfide bonds hold the heavy and light chains together • H to H • H to L

47. Within the Fab segment are hypervariable (or complementarity determining) regions; • these regions are responsible for the diversity of antibodies

48. Figure 32.8: Constant and Variable Domains in Heavy and Light Chains Dark blue = hypervariable regions in the variable domains Hypervariable regions are also known as complementarity determining regions (CDRs).

49. Pockets Grooves Extended Surfaces Peptide Ag = Red HIV peptide = Orange HEL + F(ab) frag. 5 CDRs used Red = Ab contact sites Blue = Backbone Yellow = Ag

50. There are five types of heavy chains that determine the five classes (isotypes) of immunoglobulins (IgG, IgA, IgM, IgD, and IgE) • In IgG there are four subclasses, and in IgA there are two subclasses