Genes and Immunity

1. Genes and Immunity Immune response system is remarkably adaptive defense system a. protects against pathogens and cancer b. immune recognition or specificityis the hallmark of IRS c. distinguishes between self versus non-self d. effect or response-calls in a variety of cells and proteins (B cells, T cells etc) e. exhibits memory--protection against second invasion                   eg polio vaccine Problems with immune system • Type I diabetes (B cells and insulin cells are killed by the immune system)

2. Pioneers:Discipline of immunology has its roots in the early observations and experiments by Edward Jenner and Louis Pasteur (human medicine and veterinary medicine) Edward Jenner, 1898---viral etiology • country physician • smallpox--40-50% fatality • observations for almost 20 years--milk maids no pock marks on their body from small pox • cowpox--blisters on their hands, did not get small pox • fluid from cowpox blister--inoculated 8 year old boy, waited and inoculated with smallpox--did not get small pox • established procedure for preventing smallpox throughout Europe Louis Pasteur--chance observation--1880, • experimenting with chicken cholera--major disease of chickens • left preparation of cholera bacteria on shelf 2 weeks • injected chickens--did not die--re-injected with live bacteria-did not die • 1881--injected sheep with attenuated anthrax--gave live anthrax-did not die

3. Duality of the IRS: Elie Metchnikoff, 1883 cellular immunity (T cells) Emil von Behring, 1890--humoral immunity (Ab's) Today's thinking is that IRS is combination of cellular and humoral Thymus-----------------------T cells (cellular) (T helper/killer) Bone Marrow ----- Bursa Equiv-------------------B cells (humoral) • T cells are present in all areas of the body and ask the question: self or non-self? • Without T helper cells there would be not B cell response. Take home lesson These two systems are not independent of each other, but are in constant communication..

4. Where do our immune cells come from? • Formation and development of RBC’s and WBC’s (leukocytes) • All blood cells arise from one type of cell called the hematopoieticstem cell • Stem cells have the ability to differentiate into a number of different cell types. • They are self renewing and maintain their populations via division.

5. The Major Players • B cells (Humoral) • produce antibodies which bind to pathogens and disable them or flag them for destruction T cells (Cellular) • kill infected cells • coordinate entire adaptive response

6. Humoral Branch • Antibodies are immune system-related proteins called immunoglobulins. • Antibody consists of four polypeptides– two heavy chains and two light chains joined to form a "Y" shaped molecule. • The amino acid sequence in the tips of the "Y“ varies greatly among different antibodies. • This variable region, give the antibody its specificity for binding antigen. The variable region includes the ends of the light and heavy chains. • The constant region (Fc) determines the mechanism used to destroy antigen (secondary biological function)

7. five major classes, IgM, IgG, Iga, IgD and IgE IgA about 15% of total antibody count. Found in mucous secretions and mother’s milk IgD less than 1%Appears to have a role in activating and suppressing lymphocyte activityFound in large quantities in the cell walls of many B-cells. IgD has a single binding site. IgE less than 1%Mediator in allergic responses. Most importantly activates histamine secreting cells. Also appears to play a role in parasitic infection. IgG- composes 75% of our immunoglobulin pool. IgG stimulates high immune response. Most importantly, it is the only antibody that can cross the placenta and confer immunity on the fetus. IgM - makes up 10% of our total antibodies. This is the predominant early antibody; the one that first activates in an initial attack of antigen. Because of its high number of antigen binding sites (5), it is an effective agglutinator of antigen . This is important in the initial activation of B-cells, macrophages, and the complement system.

8. Explaining Ab specificity. • ImmunoGlobulin (Ig) molecules • Thousands on surface of each B cell • Ig are essentially just bound antibodies What do Antibodies bind to? • An antigen is defined as "anything that can be bound by an antibody". This can be an enormous range of substances from simple chemicals, sugars, small peptides to complex protein complexes such as viruses. • In fact antibodies interact specifically with relatively small parts of molecules. These are known as antigenic determinants or epitopes.

9. Antibody diversity • How is this astonishing diversity generated? • This problem has been resolved over the past 20 years by the demonstration that Ig genes rearrange during B cell development. • light chains- two types k or λ • contain V J C gene segments • Rearranged V J segments encode the variable region of the light chain. • heavy chain family contains V D J C genes segments • Rearranged V D J segments encode the variable region of the heavy chain.

10. Pairing of different combinations of Ig heavy and light chains. Recombination of V, D and J segments (VJ for light chains) Together these potentially generate some 5x106 different antibodies.

11. Cellular Branch T cells • T lymphocytes constitute the "cellular" arm of immunity. • There are two major subsets of T lymphocytes that differ in function

12. Specificity of T cells • Each T cell has a unique surface molecule called a T cell receptor (TCR) • Specificity through similar process of DNA splicing... • Like Ig’s, each cell’s TCRs recognizes a unique pattern (10^7 TCR types)

13. TH cells are activated and proliferate only when presented with the antigen via self MHC. • MHC genes are organized into regions that encode 3 classes of molecules • Class I – present on the surface of nearly all nucleated cells. Major function is to present antigens to Tc cells • Class II – present on APC’s Major function to present antigens to TH cells • APC –Dendritic Cells (can present with either class I or class II). They are the major APC in our body • Macrophages

14. Establishing Self Tolerance • T cells originate in the bone marrow then migrate to the Thymus where they mature • Selection of T cells through binding to common MHC-self peptides in thymus • strong binders are killed (clonal deletion) • weak binders die from lack of stimulation (clonal selection) • They then go on to make either Tc or TH cells, but 95% of all cells entering the thymus undergo apoptosis. • Remaining T cells are not self-reactive

15. Bringing it all together Typical Immune Response • Ex. Polio • Initial response started out by IgM • IgG activated later

16. Low Response • IgM response. • T cell independent Taking a closer look at cell involvement. Clonal Expansion

17. High Response • T cell dependent • IgG now becomes involved • How do T cells get involved in the IRS? • In order for a T cell to get involved in the IRS, it needs to be presented the antigen in a very specific manner. • This is made possible via presentation of the antigen by an Antigen Presenting Cell (APC) • Macrophages • B cells • Dendritic cells

18. Sequence of Events • Ag recognized by Ab on B cell • Ingested by (APC), immunogen broken down • Select peptides of immunogen presented on surface of APC via MHC • Peptide is presented to T helper cell via TCR. • Cytokine release (chemical signals) • Cytokine release from T helper cell telling B cell to continue making Ab's that are specific to the immunogen.