1. Overview of the Immune System Zoran Galic Ph.D. Division of Hematology/Oncology David Geffen School of Medicine UCLA zgalic@ucla.edu August 18, 2014

2. The Immune Response Outline:  Introduction to Immune Response Innate Vs Acquired Immunity  Cells and Organs of the Immune Response  How Does it Work?  Closing Comments

3. Introduction to the Immune Response  The central problem that the immune system deals with is invasion by microbial pathogens  The task of the immune system is to distinguish self from non-self.  It must not attack and destroy self, but it has to eliminate microbial threats: 1. Whole organisms (bacteria, fungi, parasites,etc); 2. Intracellular pathogens (viruses).  Immune responses are tailored to the type of organism involved.

4. In response to pathogens, vertebrate immune systems use two interconnected systems: Innate immunity Adaptive immunity Innate vs adaptive immunity

5. Overview of Innate Immune Response There are multiple barriers to infection: 1. Mechanical: Tight junctions of epithelial cells form a physical barrier. 2.(Bio)Chemical: Antibacterial peptides, enzymes, and low pH environment. 3.Cellular: Macrophages, Neutrophils, Natural Killer cells (NK), Dendritic cells

6. Skin and other epithelial barriers to infection

7. The major cells of innate immunity Antigen presentationPhagocytosis Big eaters/Always hungry Antigen Presenting Cells (APCs) Proteins eaten by APCs are broken down to small pieces (peptides), which are loaded on special receptors (MHCs) and transported to the cell surface. Peptide+MHC complex can be recognized by a T cell and that interaction can lead to an adaptive immune response.

8. Acquired Immunity (Adaptive, Specific) Characterized by more rapid, stronger memory response First appears in evolution in cartilaginous fishes (sharks, sting rays, etc) Can detect subtle changes in proteins, carbohydrates (sugars), and lipids This response is specific It must detect self versus non-self It must differentiate different forms of non-self (flu virus looks different than HIV) Antigen (Ag)- the molecule or structure against which the immune response is directed The immune response only sees bio-organic molecules (proteins, sugars, fats, etc) The antigenic universe is incredibly diverse This diversity must be overcome by the immune response

9. Adaptive immunity: humoral and cellular responses CD4 (helper) T cell CD8 (killer) T cell T cell receptors only recognize antigens presented on MHC molecules

10. B cells see soluble (free) Ag Antibody (Ab) is released, binds Ag, removes it How do B and T cells work? T cells need to see Ag on the surface of cells Pieces of Ag are “presented” in molecules called MHC molecules APC take up (eat/engulf) Ag Ag is digested (processed) Pieces of Ag get caught in MHC molecules, these go to the cell surface CD4 T cells see Ag in MHC-II molecules. They proliferate They secrete “helper factors” which help B cells and CD8 cells CD8 T cells see Ag in MHC-I molecules on infected cells They get help from CD4 T cells They proliferate They kill infected cells

12. Organs of the Immune System Immune cells localize in secondary lymphoid organs, such as the spleen, lymph nodes, etc. T cells are generated in the thymus The bone marrow contains blood-forming Stem cells, and makes B cells, innate cells, and all other blood cell types, except T cells. Red-primary lymphoid organs Blue-secondary lymphoid organs

13. Lymphatic System Fluid in blood leaks out of capillaries must be returned to circulation pressure in vessels too great to diffuse back Lymphoid system recovers fluid picked up in capillary sinuses, which coalesce into larger lymphatic vessels and ducts. Fluid returned to subclavian vein Pumped by action of adjacent muscles Drains every part of body Lymph nodes screen for pathogens Nodes packed with leukocytes (lymphocytes, APCs, no granulocytes)

14. Initiation of an immune response

15. Innate Immune Response: The Cellular Response Steps in phagocytosis of a bacterium Macrophage activation leads to: - Cytokine secretion - Induction of co-stimulatory molecules - Antigen processing and presentation (MHCII) ….hence…. Adaptive Response Can Be Activated Too!

16. Adaptive immune response

17. Memory is the hallmark of adaptive immunity – Primary response is initiated upon first exposure to an antigen Memory lymphocytes are left behind after antigen is cleared – A second exposure to the same antigen re-stimulates memory lymphocytes Reactivation yields faster, more significant, better response – Memory is NOT present in innate immunity Important concepts for understanding the mammalian immune response

18. Closing Comments  APCs, B cells, CD4 and CD8 T cells work together to fight infection  HIV perturbs APC function, and kills CD4 T cells  This allows secondary “opportunistic” infections to occur, leading to disease/death  Vaccines have the potential to halt HIV infection, but thus far an efficacious vaccine strategy has proven elusive  A vaccine approach that takes into account all aspects of the immune response will likely have the best chance of success