Immunity, Immune System and Immune Response

1. Immunity, Immune System and Immune Response Envr 421 Mark D. Sobsey

2. Antigens Any foreign substance that elicits an immune response when introduced into the tissues of a susceptible animal and capable of combining with the specific antibodies formed. Generally high molecular weight Typically, proteins or polysaccharides. Polypeptides, lipids, nucleic acids and many other materials also can also function as antigens Microbes are antigenic and they contain and produce many antigens Antigens have specific sites that bind to antibodies called “epitopes”

3. Immunity and Immune Response Made up of two cellular systems: • Humoral or circulating antibody system • B cells • Cell mediated immunity • T cells

4. Immunity and Immune Response • Immune system identifies antigens (foreign proteins or polysaccharides) • Components of microbes or their partially degraded byproducts and • Other foreign proteins and polysaccharides (including nucleic acids) • Host (human or animal) antigens not made by the individual are also antigens • Result: in graft, transplant rejection

5. The Immune System: Origin and Development • Human immune system begins to develop in the embryo. • Starts with hematopoietic (from Greek, "blood-making") stem cells. • Stem cells differentiate into major cells in the immune system • granulocytes, monocytes, and lymphocytes • Stems cells also differentiate into cells in the blood that are not involved in immune function, such as erythrocytes (red blood cells) and megakaryocytes (for blood clotting). • Stem cells continue to be produced and differentiate throughout ones lifetime.

6. Biological Components of Human Immune System

7. The Immune System (Cell-mediated immunity) (Antibody-mediated immunity) (Red blood cell) (Non-specific cells responding to antgens and allergens) • (AKA: polymorphonuclear leucocytes) • (neutrophils, eosinophils and basophils)

8. Immunity and the Immune Response System

9. Immunity and the Immune Response System

10. Clonal Selection of B Cells is Due to Antigenic Stimulation

11. Classes of Antibodies (Immunoghlobulins)

12. Humoral (Antibody-mediated) Immune Responseto Antigen • First-time Antigen Exposure: 1o Response • Several day lag, then antibody becomes detectable. • Antibody is IgM class • After a short time, antibody level declines • Later Re-exposure to Same Antigen: 2o (anamnestic) response • more rapid Ab appearance and in greater amount. • IgG class of antibody • Remains detectable for months, years or lifetime.

13. Humoral Immune Responseto Different Antigens • First exposure to antigen "A”: • Begin to make low levels of antibody after several days • Second exposure to antigen "A”: • produces a much faster response, and • Several orders of magnitude higher levels of antibody. • Ability of antibody to bind antigen also increases dramatically in the secondary response. • Injecting a new antigen "B” + "A" • Elicits only a primary response • Shows that a memory or prior exposure is required for the accelerated response.

14. Humoral or B-Cell Mediated Immune Response Produces secreted antibodies (proteins) • Bind to antigens and identify the antigen complex for destruction. • Antibodies act on antigens in the serum and lymph • B-cell produced antibodies may be • attached to B-cell membranes or • Free in the serum and lymph. • Each B lymphocyte makes a unique antibody molecule (immunoglobulin or Ig) • Over a million different B lymphocytes are produced in each individual • So, each individual can recognize more than a million different antigens

15. Immunoglobulin G (IgG) and Reaction with Antigen IgG antibody molecule • Composed of 2 copies of 2 different proteins • Two copies of a heavy chain • >400 amino acids long • Two copies of a light chain - • >200 amino acids long • Each IgG antibody molecule can bind 2 antigens at one time • A single antibody molecule can bind to 2 antigens (e.g., viruses, bacateria or other particle), which leads to clumping

16. Effect of Antigen Size on Humoral Immunity

17. Fate of Antigen-Antibody Complexes • Ag-Ab complexes engulfed into the B-cell and partially digested • Antigen is displayed on the B-cell surface by a special receptor protein (MHC II) fo recognition by helper T-cells • B-cell is activated by the helper T-cell to divide and produce secreted antibodies • Abs circulate in the serum and lymph • Some B-cells become memory cells to produce antibody at a low rate for a long time (long term immunity) • They respond quickly when the antigen is encountered again • the response is regulated by a class of T-cells called suppressor T-cells

18. Cell-Mediated Immunity and T Cells • T cell receptors are cell surface receptors that bind non-self substances on the surface of other cells •  Major histocompatibility complex (MHC) proteins protrude from the surfaces of most cells in mammals • They help to distinguish self from nonself • They coordinate interactions among lymphocytes and macrophages •  Cytokines are soluble signal proteins released by T cells • They bind and alter the behavior of their target cells

19. Cell Mediated Immune System: T lymphocytes • T-cells mature in the thymus (thus the name T-cell) • Act on antigens appearing on the surface of individual cells. • Over a million different kinds of T-cells • Each produces a different receptor in the cell membrane • Each receptor is composed of 1 molecule each of two different proteins • Each receptor binds a specific antigen but has only one binding site • Receptor only recognizes antigens which are "presented" to it within another membrane protein of the MHC type (major histocompatibility complex) • Recognizes specific antigens bound to the antigen- presenting structures on the surface of the presenting cell. • Recognizes antigens presented by B-cells, macrophages, or any other cell type

20. T Cells and their Functions • Have a specific receptor for a fragment of antigen • Cytotoxic T-cells: • Contain a surface protein called CD8 • Destroy pathogen infected cells, cancer cells, and foreign cells (transplanted organs) • Helper T-cells: • Contain a surface protein called CD4 • Regulate both cellular and humoral immune systems • This regulation reduces autoimmunity.

21. Autoimmune disease • Self immunity • Some examples: • rheumatic fever • rheumatoid arthritis • ulcerative colitis • myasthenia gravis • Lyme disease (microbial etiology) • Guillan-Barre syndrome (microbial etiology) • Reiter’s syndrome or reactive arthritis (microbial etiology) • Insulin dependent diabetes mellitus (IDDM) (microbial etiology?)

22. Interactions of the Components of The Immune Response • T-cells, B-cells, and macrophages use MHC-II receptors for presentation; • All other cells use MCH-I • (responsible for most of tissue graft rejection) • When a T-cell is presented with an antigen: • its receptor binds to the antigen and • it is stimulated to divide and produce helper T-cells • activate B-cells with bound antigen • suppressor T-cells • regulate the overall response • Cytotoxic "killer" T-cells • kill cells with antigen bound in MHC-I

23. Role of Immunity in InfectionsLocalized Infections: • Immunity to infection is usually short-term and transient • Mucosal (secretory or IgA) immunity in the gut or respiratory tract wanes over time • Proof of concept: live, oral rotavirus vaccine: • immunity declines over time and reinfection with “wild” type rotaviruses occurs • Repeated localized (e.g., gastrointestinal) re-infection is possible. Examples: • Viruses: rotaviruses, noroviruses, adenoviruses and some enteroviruses. • Salmonella spp, Shigella spp., Campylobacter spp, and E. coli spp. cause localized infections • Giardia lamblia and Cryptosporidium parvum

24. Role of Immunity in Infections:Generalized/Systemic/Disseminated Infections • Immunity against generalized/systemic/disseminated infection is usually lifelong, unless immune system is severely compromised • Localized (e.g., gastrointestinal) re-infection is possible • Hepatitis A and E and many enteroviruses are viruses causing systemic/generalized/disseminated infections • Salmonella typhi is a bacterium causing systemic infection • Typically, immunity against severe illness is long-term and probably lifelong • Proof of concept: live, oral poliovirus vaccine and poliomyelitis eradication; susceptibles are newborns and infants • Antigenic changes in microbes may overcome long-term immunity and increase risks of re-infection or illness

25. Antigenic Shift: Major change in virus genetic composition by gene substitution or replacement (e.g., reassortment) Antigenic Drift: Minor changes in virus genetic composition, often by mutation involving specific codons in existing genes (point mutations) But, a single point mutation can greatly alter microbial virulence! Role of Selection of New Microbial Strains in Susceptibility to Infection and Illness: Antigenic Shift and Drift • Antigenic changes in microbes overcome immunity, increasing risk of re-infection or illness • Antigenically different strains of microbes appear and are selected for over time and space • Constant selection of new strains (by antigenic shift and drift) • Partly driven by “herd” immunity and genetic recombination, reassortment , bacterial conjugation, bacteriophage infection and point mutations Drift=minor change Shift=major change