Specific Immunity—3 rd line of defense

1. Specific Immunity—3rd line of defense • Who are the players? • Antigens • Antibodies and B-cells • Antibody editing and clonal selection • Cytotoxic T-cells • Helper T-cells • MHC and antigen processing

2. Who are the players? • Antigens: foreign proteins, usually part of virus or bacteria • Antibodies: Proteins made by immune cells that “recognize” or bind with particular antigens. Original diversity of antibody-producing cells depends on recombination of genetic sequences during cell development • Macrophages: phagocytic cells in blood) • Cytotoxic T-cells: “killer” white blood cells • Helper T-cells: present antigens so that good “match” can be found among antibody-making cells • B-cells: recognize antigens and make antibodies • MHC: Major Histocompatiblity Complex—allows body to recognize own cells so that their proteins don’t trigger immune response, also important in clonal selection • Clonal selection: process by which B and T-cells that make antibodies that recognize body’s own antigens (“autoantigen”) are eliminated during development.

3. Antigens • Proteins (or sometimes carbs) that are recognized (glom onto) specific antibody • Exogenous antigens: On outside or free of pathogen • Endogenous antigens: From pathogens that live and reproduce inside host cell. Immune cells can only see these antigens when they are “presented” on surface of host cell surface, incorporated into cell membrane • Auto-antigens: Body’s own antigens. Immune cells that recognize these antigens are eliminated during immune system development (by antibody editing or clonal selection/deletion—more below)

4. Antibodies • Each antibody has specific antigen binding site formed by variable regions of heavy and light amino acid chains. Variation among antibodies in these binding sites comes from random recombination from billions of possible DNA/gene combinations. • Rest of heavy and light chains are constant giving antibodies their characteristic shape and function

5. What do antibodies do? • Disable pathogens by glomming (agglutinating) them together • Neutralize toxins by glomming onto them on the surface of pathogens • Stick to surface of pathogen so it can be recognized by phagocytic cells • Immunoglobulins are classes of antibodies—each class has more specific immune function

6. Where do antibodies come from? • Made by B-cell lymphocytes • 1011 B-cells in body, each with specific antibody, present for life • Each B-cell has 100,000’s of copies of its antibody embedded in cell membrane, called B-Cell Receptors (BCR) • When a BCR reacts or gloms onto an antigen that it recognizes, that cell is stimulated to produce free antibodies that are secreted into blood as immunoglobulin (Ig)

7. How can each cell have its own different antibody if they all have the same DNA? • Nobel Price for Susumu Tonegawa • DNA is processed and can change as new cells are formed • Recombining regions of DNA that make the antibody recognition site produces all the billions of different combinations of antibodies (and BCRs, TCRs) that recognize any possible invader by the proteins it has on its surface (so we hope!)

8. Antibody editing by clonal selection or deletion • Variety of B-cells produced by random recombination of genes for variable regions of antibody • During B-cell development, certain clonal lines are eliminated because their antibodies glom onto the bodys own antigens • B-cell production and clonal selection occurs in bone marrow during early years of life

9. B-cells and antibodies—end result is macrophage ingestion • Each B-cell make specific antibody which is present on cell surface as BCR (B cell receptor) • When that cell “recognizes” an antigen (the antigen sticks to the BCR), then it begins producing free antibody (immunoglobulins or Ig’s) to secrete into the blood • Those Ig’s work to eliminate the source and possible damage caused by this antigen via agglutination, neutralization and opsonization • End result is generally macrophage ingestion or lysis of invading micro-organism…

10. Antibody action… …Result— Macrophage on the attack!!

11. B-cells and antibodies—end result is macrophage ingestion • Each B-cell make specific antibody which is present on cell surface as BCR (B cell receptor) • When that cell “recognizes” an antigen (the antigen sticks to the BCR), then it begins producing free antibody (immunoglobulins or Ig’s) to secrete into the blood • Those Ig’s work to eliminate the source and possible damage caused by this antigen via agglutination, neutralization and opsonization • End result is generally macrophage ingestion or lysis of invading micro-organism… BUT…usually B-cells cannot recognize antigens on their own…and the simple antibody response is usually not sufficient to fight an infection. THUS…T-cells (oh, no)….

12. T-cell lymphocytes • Also made in bone marrow, but mature in thymus (thus “T”) • Have TCR (T-cell receptor), much like BCR), but don’t produce Ig’s • Also about 1011 T-cells, each with its own specific antigen recognition site, produced by random recombination of genetic sequence and edited via clonal selection in thymus • 90% of lymphocytes in blood are T-cells. Also in lymph nodes, spleen, Peyer’s patches of intestines • Three types of T-cells:

13. Cytotoxic T-cells (CD8) • Recognize and kill other cells of the body—why? • Those cells are infected by virus or other intra-cellular pathogen • Cells “process” antigen from virus and “present” it on cell surface embedded in cell membrane so that TCR’s or antibodies can “recognize” that non-self antigen

14. Helper T-cells (CD4)—two types • Type 1—stimulate cytotoxic T-cells • Type 2—stimulate B-cells • Helper T-cells recognize antigens, but can do nothing about it on their own. They secrete cytokines (such as interleukin) to direct what kind of immune response should be activated. • For most infections, Helper T’s are crucial for a robust response. • Thus, in AIDS, these cells are killed, as they themselves present HIV viral antigens and invite cytotoxic T-cells or macrophages to ingest them. • Without the helper T-cells, good response to most infections cannot be mounted.

15. Antigen processing and MHC • Phagocytes that have ingested pathogens, as well as cells infected with virus can “process” and “present” antigens on their cell membrane • MHC molecules aid in this process • By presenting antigens, the immune response is greatly accelerated • Especially important in stimulating early response to previous pathogens (immunological memory—coming next!)

16. Antigen processing and MHC

17. Nice one-page summary review of specific immune response • From the molecules of HIV text • http://www.mcld.co.uk/hiv/?q=helper%20T%20cells

18. This animation has everything you need to know about the specific immune response… http://www.apchute.com/lymphatic/inflam.swf