1. Lecture 10: Adaptive Immunity Edith Porter, M.D. 1

2.  Concept of immunity ▪ Innate immunity ▪ Adaptive immunity  Humoral and cellular adaptive immunity  Antigens and antibodies  B cells and humoral immunity  Effects of antigen-antibody binding  T cells and cellular immunity  Antigen presenting cells  Cytokines  Immunological memory 2

3. First Line of DefenseSecond Line of Defense NK cells 3

4. INNATE IMMUNITY  Functional at birth  Rapid responses: preformed or available within hours after infection  Limited specificity: pattern recognition via toll like receptors  Widely present in nature including in plants, invertebrates and vertebrates ADAPTIVE IMMUNITY Acquired, available within days High specificity Memory In higher vertebrates 4

5.  Humoral immunity  Transferable with serum  Highly specific  Mediated by antibodies and lymphocytes who produce these antibodies  These types of lymphocyte mature in the bone marrow and are called B lymphocytes (B cells)  Cellular immunity  Mediated by lymphocytes that mature in the thymus and are called T lymphocytes (T cells)  T cells orchestrate the immune response The thymus is located in mediastinum 5

6. http://www.aamdsglossary.co.uk/i/c/1_2_lymphocytes.jpg 6

7. B for Bone marrow T for Thymus 7

8. PRIMARY LYMPHATIC TISSUE  Lymphocyte formation and maturation  Bone marrow  Thymus SECONDARY LYMPHATIC TISSUE  Antigen contact  Spleen  Lymph nodes  Peyer’s patches  Mucosa associated lymphatic tissue (MALT) 8

9.  Recognize foreign agents (antigen)  Lymphocytes carry specific antigen receptors on their surface  B-cell receptor, T-cell receptor  Block and eliminate foreign agents  Through antibodies  By activating host defense cells via cytokines  By destroying infected host cells that have been taken over by infectious agents 9

10.  Substances that causes the body to produce specific antibodies  Any molecule that can be recognized by and bound to an antibody (“antibody generating”) or a T cell  Typically proteins and carbohydrates  Epitop (or antigenic determinant) is part of the antigen and is the specific region with which an antibody interacts 10

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12. Example: Penicillin  A molecule too small to stimulate antibody formation by itself  When combined with a larger carrier molecule it can initiate antibody production  Once antibodies are generated, hapten can be recognized by itself 12

13.  Globulin proteins (immunoglobulins or Ig)  Made in response to an antigen  A bacterium or virus has many antigenic determinants against which antibodies can be made  Bi-functional  One portion binds specifically to particular structures called antigen  The other part interacts with host cells 13

14.  2 heavy chains  2 light chains  Connected with disulfide bridges  Variable regions in heavy and light chains: bivalent antigen binding sites, mediate specificity  Constant regions on heavy chain mediate effector function 14

15.  Each class shares the constant region of the antibody molecule but has many different variable regions  Each class interacts with different types of host cells  Differ in their effector function  5 classes:  IgG  IgM  IgA  IgD  IgE 15

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17.  Monomer  80% of serum antibodies  Fix and activate complement (classical pathway)  In blood, lymph, intestine  Cross placenta  Opsonin (enhance phagocytosis); neutralize toxins & viruses; protect fetus & newborn 17

18.  Pentamer  5-10% of serum antibodies  First Ig of an immune response  Fix and activate complement (classical pathway)  In blood, lymph, on B cells  Agglutinates microbes 18

19.  Dimer  10-15% of serum antibodies  In secretions (milk!!)  Protection of mucosa  Mucosal pathogens like Haemophilus or Neisseria secrete IgA proteases 19

20.  Monomer  0.2% of serum antibodies  Mainly on B cells  Maturation sign 20

21.  Monomer  ~0.002% of serum antibodies  Mainly on mast cells, basophils, and activated eosinophils  Allergic reactions; defense against parasitic worms 21

22.  Bone marrow gives rise to B cells (B-lymphocytes)  Naïve but mature B cells migrate to secondary lymphatic tissue and become exposed to antigen  B cells recognizes epitopes with antigen specific B cell receptor  Each B-cell expresses a unique B cell receptor on its surface  B-cell receptor is actually the antibody produced by a particular B cell 22

23.  Clonal selection and expansion  Increased antibody production  Plasma cell or memory cell development 23

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25.  Begin after antigen-antibody complex has been formed  Aggluntination  Opsonization  Enhanced phagocytosis  Complement activation  Opsonization and enhanced opsonophagocytosis via c3b  Microbial lysis through C5b-C9n  Inflammation through C5a, C3a, C4a  Neutralization  Toxins  Viruses  Antibody dependent cytotoxicity  Eosinophils: secrete toxic granules onto helminths  NK cells: induce apoptosis of virus infected cells 25

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28.  Large granular lymphocyte-like cells  Part of first line of defense (innate immunity)  Activated by interferons (produced by virus infected cells) and other cytokines  Target altered host cells  Virus infected  Infected with intracellular organism  Tumor cells  Induce cell suicide (apoptosis)  Cells covered with antibodies (antibody dependent cytotoxicity)  Direct sensing of altered cells 28

29.  After NK cell have recognized their target they release their large granules containing  Pore-forming toxins  Enzymes that induce suicide of target cell Tumor Cell NK-Cell t0 t60’ 29

30.  After differentiating in the thymus, T cells migrate to lymphoid tissue  T cells become activated effector T cells when stimulated by an antigen  T cells respond to digested antigens via T-cell receptor  T cells recognize antigen only when presented by other cells on special molecules  Major histocompatibility complex (MHC)  Some effector T cells become memory cells 30

31.  Short contiguous amino acid (aa) sequence  Processed antigens  Antigen must have been unfolded and degraded  Primary aa structure  Only when bound to a specialized antigen presenting molecule (MHC) APC MHC T-Ly 31

32.  Major Histocompatibility Complex  Same as HLA (human leukocyte antigen)  Determine compatibility of donor and recipient in transplantation  Every individual as a unique set of MHC molecules  Within an individual all cells are equipped with the same set  Have a peptide binding groove onto which antigen can be loaded  MHC I: peptides newly synthesized and degraded in cytoplasma (endogenous)  MHC II: peptide fragments generated in phagolysosome (exogenous) 32

33.  Depends on surface molecules on T cells that determine the interaction with MHC molecules and their type of response  Cytokine release  Sending trigger to target cell to commit cell suicide  T helper cells  Cytotoxic T cells (“T killer cells”)  Regulatory T cells 33

34.  Express the surface molecule CD4  Recognizes exogenous digested antigen presented on MHC type II molecule  Interact with antigen presenting cells  Macrophages  Dendritic cells  B-cells  Respond with secretion of cytokines and activate immune cells 34

35.  Express MHC II  Highly specialized in uptake of foreign antigen, degradation and presentation to T helper cells via MHC II  Macrophages and dendritic cells  Take up antigen via phagocytosis  B cells  Bind antigen with surface antibody and internalize the complex 35

36. Ag Presenting Cell MHC II Digested Ag Microbe CD4 TCR TH Cell Cytokines 36

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38.  TH1  Secrete the cytokine IFN  ▪ Activates macrophages ▪ Promotes IgG antibody production in B cells  TH2  Secrete the cytokine IL4 ▪ Promotes IgE production in B cells ▪ Pro-allergic 38

39.  Express the surface molecule CD8  Recognizes endogenous antigen presented on MHC type I molecule  Can interact with any nucleated cell  Respond with secretion of perforin and granzyme  Kill target cells via apoptosis in a highly specific manner 39

40. Any Nucleated Cell MHC I Endogenous Ag Endogenous Ag CD8 TCR CTL 40

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42.  Treg and TH3  Differentiate from T helper cells  Turn off immune response when Ag no longer present  Use inhibitory cytokines (IL10) 42

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46.  Activate simultaneously up to 20% of all TH cells  Cause an intense immune response due to release of cytokines from host cells (“cytokine storm”)  Fever, nausea, vomiting, diarrhea, sunburn-like rash, shock, death  Examples : Toxic Shock Syndrome Toxin 46

47.  Once lymphocytes have encountered their specific antigen they undergo clonal expansion  Some of these cells develop further into memory cells  Can circulate for many years  Upon re-contact with the same antigen they quickly proliferate and resume effector function ▪ B cells: antibody production ▪ T cells: cytokine production (TH, Treg) and cytotoxicity (CTL) 47

48. 48  IgM is always the first antibody  IgG follows IgM  IgG level does not go back to baseline  Re-exposure to the same antigen will lead to an augmented and accelerated immune response with higher residual antibody levels

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50.  Key players in adaptive immunity  Antibodies  B-cells  T-cells  Lock- key principle: Ag-Ab  B cells make antibodies  5 Types of antibodies : IgM (first), IgG (placenta), IgD (maturation), IgA (mucosa), IgE (allergies)  Antibodies can agglutinate, activate complement, promote phagocytosis, neutralize and initiate cell lysis by NK cells  T cells recognize digested antigen when presented to them on MHC molecules  Main effector T-cells  Helper T-cells: strengthen defense cells  Cytotoxic T-cells: kill infected cells  Regulatory T cells: down regulate immune response  Cytokines serve cell-to-cell communication 50

51.  1) What type of immunity results from vaccination?  A) Innate immunity  B) Naturally acquired active immunity  C) Naturally acquired passive immunity  D) Artificially acquired active immunity  E) Artificially acquired passive immunity  3) What type of immunity results from recovery from mumps?  A) Innate immunity  B) Naturally acquired active immunity  C) Naturally acquired passive immunity  D) Artificially acquired active immunity  E) Artificially acquired passive immunity  15) The antibodies found in mucus, saliva, and tears are  A) IgG.  B) IgM.  C) IgA.  D) IgD.  E) IgE.  26) The best definition antibody is  A) A serum protein.  B) A protein that inactivates or kills an antigen.  C) A protein made in response to an antigen that can combine with that antigen.  D) An immunoglobulin.  E) A protein that combines with a protein or carbohydrate. 51