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CDAC 2018 Mishra immune system part b

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Presentation at the CDAC 2018 Workshop and School on Cancer Development and Complexity
http://cdac2018.lakecomoschool.org

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CDAC 2018 Mishra immune system part b

  1. 1. Types and Signals Immunologic Systems Biology Conventions Immune Systems Part B: Genomics & Systems Biology Bud Mishra & James Bannon (No Relation) Courant, NYU Como, May 2018
  2. 2. Types and Signals Immunologic Systems Biology Conventions Outline 1 Types and Signals Innovation and Interpretation Symbolic Recommender/Verifier World 2 Immunologic Systems Biology Basics The Primary Response Cancer 3 Conventions
  3. 3. Types and Signals Immunologic Systems Biology Conventions Self & Self-Reference What contains what? Self, Encoding of Self and Recognition of Self What cells know that they belong to a multi-cellular organism?
  4. 4. Types and Signals Immunologic Systems Biology Conventions Genomics Antibody Signal Repertoire Random rearrangements of variable (V), joining (J), and in some cases, diversity (D) gene segments. Select “good” (Stable) Separating Nash Equilibria: (Self vs. Non-self)
  5. 5. Types and Signals Immunologic Systems Biology Conventions Possible Signals 2 Constant (Cµ and Cδ) gene segments (in Heavy & Light Chains 44 Variable (V) gene segments in Heavy Chains 27 Diversity (D) gene segments in Heavy Chains 6 Joining (J) gene segments in Heavy Chains. - The light chains have 2 C gene segments and numerous V and J gene segments, but do not have D gene segments. 3 × 1011 combinations of antibodies! DNA rearrangement causes one copy of each type of gene segment to go in any given lymphocyte, generating an enormous antibody repertoire. CAN THEIR NASH EQ BE MEASURED (QUICKLY) USING SHORT-READ NGS (NEXT-GEN. SEQUENCING) METHODS?? HINT: NO! – nanomapping & nanzam!
  6. 6. Types and Signals Immunologic Systems Biology Conventions Mechanisms V(D)J recombination is mediated by VDJ recombinase – a diverse collection of enzymes recombination activating genes 1 and 2 (RAG) terminal deoxynucleotidyl transferase (TdT), and Artemis nuclease, a member of the ubiquitous non-homologous end joining (NHEJ) pathway for DNA repair. Plus others: DNA-PK, XRCC4, DNA ligase IV, NHEJ1, their paralogs, DNA polymerase λ and µ. . Maintaining specificity of recombination: V(D)J recombinase recognizes and binds to Recombination Signal Sequences (RSSs) flanking the variable (V), diversity (D), and joining (J) genes segments. 12/23 Rule: gene segments to be recombined are usually adjacent to RSSs of different spacer lengths (i.e., one has a ”12RSS” and one has a ”23RSS”).
  7. 7. Types and Signals Immunologic Systems Biology Conventions ImmunoGlobulin 1 Fab region 2 Fc region 3 Heavy chain (blue) with 1 variable (VH) followed by 1 constant (CH1), 1 hinge, & 2 more constant (CH2 and CH3) regions 4 Light chain (green) with 1 variable (VL) and 1 constant (CL) domain 5 Antigen binding site (paratope) 6 Hinge regions
  8. 8. Types and Signals Immunologic Systems Biology Conventions Replicator Dynamics and Nash Equilibria Utility Maximization: The B lymphocyte cell’s utility depends on antigen matching its signals/receptors. A match triggers activities inside the B cell. Differential Replication: Once activated, the B cell starts to divide to produce clones of itself. During this, two new cell types are created, plasma cells and B memory cells. The plasma cell specializes in producing an antibody, that responds to the same antigen that matched the B cell receptor. Antibodies are released (∼ 104 /sec from the plasma cell to seek out intruders. When the Y-shaped antibody matches antigen, it attaches to it – signaling macrophage to “act” on it (Phagocytosis). Pathogens covered with antibodies are more likely attacked by the proteins from the complement system. The Memory Cells, also produced by the division of B cells, have a prolonged life span to “remember” a good NE, associated with specific intruders.
  9. 9. Types and Signals Immunologic Systems Biology Conventions Outline 1 Types and Signals Innovation and Interpretation Symbolic Recommender/Verifier World 2 Immunologic Systems Biology Basics The Primary Response Cancer 3 Conventions
  10. 10. Types and Signals Immunologic Systems Biology Conventions Immune System Basics Immune system has two necessary abilities: Recognize self vs. non-self. Remove, neutralize, kill dangerous non-self. Has two key arms: 1 Inate immune system (iIS) 2 Adaptive immune system (aIS) These operate with two broad mechanisms of action: Humoral immunity. Cell-mediated immunity.
  11. 11. Types and Signals Immunologic Systems Biology Conventions Branches of The Immune System Inate Immune System Fast and Non-specific Includes organs (skin), materials (mucous, acids), cells (Dendritic Cells, Macrophages (Mφ)) Adaptive Immune System Slower, extremely specific. Except for secondary response. Mostly cells (B & T) but some serum (antibodies). We’ll focus on adaptive for now.
  12. 12. Types and Signals Immunologic Systems Biology Conventions
  13. 13. Types and Signals Immunologic Systems Biology Conventions Development of aIS Cells
  14. 14. Types and Signals Immunologic Systems Biology Conventions Primary Response 1 Antigen/pathogen enters body 2 Antigen/pathogen is eaten by DC, macrophage (endocytosis), or infects. 3 DC → Lymph node to perform antigent presentation. 4 In Lymph node DC activates B & T cells. these circulate in and out of lymph nodes in SEPARATE compartments!
  15. 15. Types and Signals Immunologic Systems Biology Conventions Primary Response 1 Activated B-cell → barrier of compartment 2 Same for activated T. 3 T-Cell, B-Cell handhake: T-cell differentiation based on DC cytokine signaling (depends on the nature of the pathogen) Some helper T form germinal centers 4 Some B-cells become plasma cells . 5 B-cells also form gernimal centers.
  16. 16. Types and Signals Immunologic Systems Biology Conventions Germinal Centers
  17. 17. Types and Signals Immunologic Systems Biology Conventions Cancer & The Immune System Is cancer self? Non-self? Both? Why aren’t tumors immediately destroyed? They do have antigens. One hypothesis: the three E’s Eradication - Tumor Destroyed Equillibrium - Standoff Escape - Tumor evolves ability to Equillibrium ∼ decades. Makes things worse. Might be an opportunity! (CHA automata).
  18. 18. Types and Signals Immunologic Systems Biology Conventions Tumor Antigens Tumor Associated Antigen (TAA) is not the same as Tumor Specific Antigen (TSA).
  19. 19. Types and Signals Immunologic Systems Biology Conventions One Escape Mechanism
  20. 20. Types and Signals Immunologic Systems Biology Conventions Basic B cell function: bind to an antigen, receive help from a cognate helper T cell, and differentiate into a plasma cell that secretes large amounts of antibodies
  21. 21. Types and Signals Immunologic Systems Biology Conventions Information Asymmetry The DC and B Cell systems work by surveying the extracellular environment – and can be deceived! Mtb and other pathogens can cause Macrophage pyroptosis to evade innate immune system. Safety will require augmenting the system with a verifier that can 1 Maintain safety of the self 2 Modulate the immune response as infection subsides 3 Survey the internal environment of a cell TCR (T cell receptor) made of α-β chain (with genes similar to Ig Heavy and Light - V(D)J regions.
  22. 22. Types and Signals Immunologic Systems Biology Conventions
  23. 23. Types and Signals Immunologic Systems Biology Conventions CAR T-cell therapy uses genetically engineered T cells, deploys the immune system to kill cells with surface antigens that can be specifically recognized by the engineered CAR T cells. The therapy requires drawing blood from patients and separating out the T cells. Next, the T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptor, or CARs, which is tethered to T cell-activating modules.
  24. 24. Types and Signals Immunologic Systems Biology Conventions Evolution: Jawed vs Jawless Fish
  25. 25. Types and Signals Immunologic Systems Biology Conventions
  26. 26. Types and Signals Immunologic Systems Biology Conventions
  27. 27. Types and Signals Immunologic Systems Biology Conventions
  28. 28. Types and Signals Immunologic Systems Biology Conventions
  29. 29. Types and Signals Immunologic Systems Biology Conventions
  30. 30. Types and Signals Immunologic Systems Biology Conventions Outline 1 Types and Signals Innovation and Interpretation Symbolic Recommender/Verifier World 2 Immunologic Systems Biology Basics The Primary Response Cancer 3 Conventions
  31. 31. Types and Signals Immunologic Systems Biology Conventions Another Earth Kepler-22b An extrasolar planet orbiting G-type star Kepler-22. It is located about 600 light years away from Earth in the constellation of Cygnus.
  32. 32. Types and Signals Immunologic Systems Biology Conventions “Klaatu Barada Nikto” Will they have RNA, DNA and Protein? Crick’s dogma? Genetic Codes? Can we find multi-cellular alien life-forms somewhere else? Will they look anything like us? In their body plan, will they have mouth in the front (ventral) and anus in the back (dorsal)? Will they have feelings? Will they have a central nervous system (CNS)? Will they have limbs? Will they have fingers? How many? Will they say, “Klaatu Barada Nikto?” Will they trade gold kryptonite? In Elohim will they trust? Will they have a theory that multi-cellular life could have evolved on earth about 1 bya?
  33. 33. Types and Signals Immunologic Systems Biology Conventions End La fin Die Ende Shuryou Slutten Wakas Sfarsit Samapta El fin Son Ukuphela

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