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  1. Innate immunity
    • nonspecific, responding within 24 hours
    • limited diversity responding to core structural components
    • usually phagocytose or lyse
    • alerts adaptive immunity (dependent on the innate)
    • no memory (responds same way each time)
    • without innate you would die pretty fast
    • physical barriers, bladder, cilia in lungs
    • definsins, stomach acid, flora, lysozymes (saliva, sweat, tears, blood)
    • complement (circulating and assisting proteins), effector cells
  2. Innate immunity effector cells
    • neutrophils phagocytose kill, increase vascular permeability, secrete cytokines
    • monocytes/macrophages phagocytose kill, secrete cytokines, present antigens
    • natural killer cells kill virally infected cells, secrete cytokines
    • mast cells/basophils release antimicrobial substances and increase vascular permeability
    • dendritic cels present antigens, secrete cytokines, transfer antigens to lymph
    • responsible for allergic reactions
  3. Adaptive immunity
    • highly specific, responds within 96 hours
    • this is what finally rids the infection
    • memory
  4. Adaptive immunity effector cells
    • must expand based on pathogen
    • T lymphocytes are cell mediated immunity
    • they do antigen specific production of cytokines (CD4) to tell macrophage to kill phagoyctosed microbe aka helper T lymphocte
    • antigen specific cytotoxic cells (CD8) kill infected cells aka cytotoxic T lymphocyte
    • recognize the polypeptide sequence of antigens when presented
    • B lymphocytes are humoral immunity
    • they do antigen specific production of antibodies and antigen presenting cells
    • recognize the 3D structure of antigens
    • differentiate into plasma cells
    • antibodies cannot cross plasma membrane of cell (only humoral)
  5. Stem cell origin of immune cells
    • common hematopoietic stem cell can become lymphoid or myeloid
    • common lymphoid progenitor becomes B, T or natural killer cell
    • common myeloid progeniror becomes granuolcyte/macrophage progenetor or megakaryocyte/erythrocyte progenator
    • megakryocyte becomes platelets
    • granulocyte/macrophage progenitor becomes all white blood cells except for lymphocytes
    • then go from naive to effector cells by maturation
    • or those that don’t differentiate can become memory cells
  6. Naive cells
    • B cells have low Ig affinity
    • only membrane associated IgM and IgD
    • T cells when naive just go to lymph nodes
    • once activated effector, T cells change surface molecules to leave lymph node
  7. Innate immune system receptors
    • recognize broad classes aka PAMPs, unique to bacteria invariant structures that are immunostimulatory
    • coded in germline instead of through genetic recombination
    • nonclonal
    • descriminate self
  8. Patter recognition receptors (PRRs)
    • surface, endosomal, cytoplasmic
    • toll like receptors (TLRs) can be surface or endosomal and recognize cell wall, flagellin, fungal mannans, lipoprotein etc
    • PAMPs endosomally can be ssRNA
    • activate NFkappaB or IRF-3 transcription factors cause more cytokines, chemokines, selectin which do inflammation, vascular permeability, activation of immune response
  9. Cytokines
    • some allow T and B to talk, some activate CD4 T and CD8 T lymphocytes
    • lymphokines (interleukin is subset), monokines, chemokines (B and T lymphocyte talk), interferons
    • low molecular weight
    • transient
    • paracrine or autocrine
    • extremely potent
    • act in network, multiple can have same effect and different receptors can recognize same cytokine (redundant and pleiotropic)
    • synergistic, additive, antagonistic
    • few like IL-1 endocrine to hypothalmus in brain, yay fever!
  10. Epithelium innate response
    • physical barrier
    • local peptide antibiotics
    • intraepithelial lymphocytes kill
  11. Mononuclear phagocytes
    • monocytes differentiate to macrophages upon leaving
    • then to microglial in CNS
    • to kupffer in liver
    • to alveolar macrophages
    • to osteoclasts in bone
    • phagocytose and destroy by release of granule contents
    • recruited to infection site by microbial signals
  12. Natural killer cell
    • innate response
    • kill by recognition of MHC
    • or downregulation of MHC
    • respond to IL-12 produced by macrophages with phagocytosed microbe respond with interferon gamma (IFN) gamma telling macrophage to produce mediators that kill phagocytosed members (feed forward by further activation)
    • Fc receptors on natural killer bind antibodies on infected cell or tumor cell and kill it
  13. Costimulation by innate
    • stimulation of T and B lymphocytes by antigens is necessary but not sufficient for activation, proliferation, differentiation
    • additional signals come from innate immune cells are required
  14. Immunoglobin
    • aka antibody
    • recognize proteins, polysaccharides, lipids, nucleic acids, small molecules, conformational shapes
    • found on B cells, thus BCR
    • heavy chain light chain, hinged (IgG)
    • variable N termini called complementary region lock and key to epitope
    • rest is constant
    • divalent
  15. Epitopes
    • regions of an antigen that are recognized by immune system
    • can be multiple epitopes on any given macromolecule
  16. Special immunoglobins
    • IgG dominating and in placenta (g for gestation)
    • does everything, neutralizes, opsonizes, activates complement, antibody dependent cytotoxicity by natural killer cells, feedback inhibition of B cell activation
    • IgM forms pentamers with J chain, first synthesized, activates complement, also predominates plasma and blood stream with IgG
    • IgA forms dimers with J chain mucosal immunity (transport across mucosal membrane requires dimerization so that it can bind Poly-Ig receptor to transcytose), breast milk, neutralization
    • IgE mast cell degranulation, thus epithelial, helminths
    • modify C terminus by polyadenylation alternate splicing, class switching, membrane to secreted if signaled (absence of signal makes the membrane)
  17. T cell receptor
    • basically just snap off a branch from the Y shape of an antibody
    • alpha and beta chains (or gamma and delta)
    • variable and constant
    • requires MHC presentation to bind
    • only bind 1-3 aa of polypeptide and MHC
    • do not bind non proteins, these are thymus independent antigens
  18. Genetic recombination
    • heavy chain has VJD, light VJ
    • beta chain has VJD, alpha VJ
    • first somatic recombination D and J, then somatic of V and JD
    • V is variable, thus codes most of the variability
    • transcribe and splice
    • also can remove or add nucleotides at the V-J or J-D junctions for more diversity
  19. Heavy chain isotype switching
    • B cells signaled by T lymphocytes
    • absence of signal keeps making IgM
    • CD40 ligand, cytokines tell it to make different classes IgG etc
    • S genes are after VDJ and are points between which activation induced deaminase occurs
    • this deletes the C (and S) genes between these two points
    • the next C gene will be used for the stop codon and after splicing out the remaining combined S genes and junk, you get the new isotype protein
    • irreversible
  20. MHC variability
    • lots of variability
    • reason for tissue rejection
    • many different alleles at different sites of variability
    • most allelic variation at peptide cleft domain
    • gives people different affinities
    • codominant and most people are heterozygous, thus 4 possibilities
    • polygeny with three different genes
  21. MHC class 1
    • all cells of body except for RBC (even T cells!)
    • present antigens to effector cytotoxic T cells
    • around 10 amino acids presented
    • alpha 1 and 2 are peptide cleft domain
    • alpha 3 is transmembrane, beta 2 is just there
    • CD8 receptor binds to alpha 3
    • cytosolic peptides proteasomed and transported into ER by TAP (transporter associated with antigen processing)
    • can work on viral expressed proteins
  22. MHC class 2
    • B cells, macrophages, dendritic cells, thymic epithelium (maybe T cells)
    • present antigens to helper T cells
    • around 20 amino acids presented
    • beta 1 and alpha 1 are peptide cleft domain
    • beta 2 and alpha 2 are transmembrane
    • CD4 domain binds to beta 2
    • peptides degraded in endocytotic vesicle
    • MHC class 2 escorted from golgi to endosome by binding Ii (invariant chain)
    • binding portion of Ii is CLIP and DM in endosome proteolyses this
  23. MHC peptide binding features
    • broad specificity
    • only can bind peptides
    • degraded if not binding peptide
    • peptide bound for as long as required (days)
  24. Dendritic cells
    • Langerhans in epidermis
    • presentation often via MHC class 2 pathway
    • when activated express CCR7 (chemokine receptor)
    • chemotaxis to T cell zone of lymph node via CCR7
    • can do cross presentation where it phagocytoses a virally infected cell, gets antigen into cytosol, and epresses its antigen on MHC class 1 and presents to naive cytotoxic T cells (think cross presentation like it uses endosome but does MHC class 1)
  25. Thymic selection
    • positive selection for T cells that have any affinity, those without die of neglect
    • negative selection for T cells that have too strong of affinity, eliminated
    • there is a sample of antigens from all tissues at some level of concentration
    • problems in this or with macrophages and dendritic cells (required for presentation) can cause problems
    • CD4 T cell is the one effected by macrophage and dendritic issue
  26. T cell receptor associated polypeptides
    • alpha associated with CD3 delta and beta asociated with CD3 gamma and each with a CD3 epsilon
    • all transmembrane external
    • two transmembrane internal zeta chains
    • these help transport T cell receptor to the membrane and transduce signals to interior (electrostatic except zeta)
  27. Bone marrow selection
    • check for specificity with self using IgM
    • no self reaction migrates it to periphery
    • recognizes too well can be modified by trying new downstream J agent or is deleted
    • if recognizes a soluble self molecule it is changed to not recognize the molecule as well and it migrates to periphery as anergic B cell
  28. Antigen receptor mediated signaling in B cells
    • binding causes phosphorylation of Ig alpha and Ig beta, which activates cascades that can change transcription by PLC or MAP (Ras G protein)
    • uses Myc, NFAT, NFkappaB, AP-1
    • causes clonal expansion, increased cytokine receptor expression (better response to cytokines), migration to edge of follicle for T cell interaction, secretion from of IgM
    • also upon binding it can stimulate CR2 copmlement
  29. B cells to T helper cells interaction
    • B cell has Ig that can bind epitope
    • receptor mediated endocytosis of antigen
    • presentation of epitope for T helper cell (not necessarily the same epitope)
    • B cell expresses costimulators for T cell activation like B7
    • T cell recognizes antigen
    • B cell has CD40 that binds to CD40 ligand on T cell when they come together, CD40 ligand is only expressed when the T cell becomes activated by binding the antigen
    • in response T cell secretes cytokines to B cell to induce B cell proliferation and differentiation (promotes isotype switching) and becomes plasma cell
  30. Higher affinity B cells
    • via heavy and light chain mutations associated with long time of exposure to antigen
    • follicular dendritic cells trap antigens so that they cannot circulate
    • high affinity B cells can pull these away to the germinal center
  31. Termination of B cell activation
    • Fc receptors block activating signals from antigen receptor when it binds antigen
    • the bound antigen probably has secreted IgG bound as well
    • Fc receptor activates a phosphatase to kill the kinase activity and inhibit pathway via immunoreceptor tyrosine-based inhibition motif (ITIM)
  32. B cell subsets
    • Follicular B cell in germinal center specifically do isotype switching, high affinity, and live long plasma cells
    • marginal zone B cells in lymph organs recognize polysaccharides, lipids etc, mainly IgM and short lived plasma cells
    • B-1 B cells same as marginal but live in mucosal tissues and peritoneal cavity
  33. Secondary antibody response
    • memory B cells set higher antibody baseline
    • faster expansion and a higher antibody concentration at peak
    • followed by even higher antibody baseline and more memory B cells
    • more maturation so higher affinity
  34. Functions of antibodies
    • neutralize microbe and toxin
    • opsonization and phagocytosis of microbes
    • cytotoxicity via Fc receptors on natural killer cells
    • activate complement cascade causing lysis of microbes, phagocytosis of microbes, inflammation
  35. Opsonization
    • Fc receptors on macrophage or neutrophil (or eosinophil)
    • bind to antibodies on microbe
    • Fc signals phagocytosis
    • CR1 can bind complement C3b or C4b to cause phagocytosis
    • (this is opsonization)
  36. Fc receptors
    • bind antibodies
    • specific to certain antibodies
    • example Fc gamma RI and Fc gamma RIIA bind certain IgG
  37. Complement system basic mechanism
    • activation by 3 different pathways
    • steps are proteolysis of complement protein with larger chunk remaining bound to complex at surface of microorganism and small peptide diffusing away to do things
  38. Classical pathway complement activation
    • antigen antibody complex binds C1 complex (C1q, C1r, C1s), which were there to begin with, to form a protease
    • protease cleaves C2 and C4
    • cleaved C2 and C4 larger chunks become C3 convertase
    • C3 convertase cleaves C3 to kick off the cascade
  39. MB lectin pathway complement activation
    • mannose binding lectin binds mannose on pathogen
    • this causes C4 and C2 cleavage
    • cleaved C2 and C4 larger chunks become C3 convertase
    • C3 convertase cleaves C3 to kick off the cascade
  40. Alternative pathway complement activation
    • C3 binds to microbe surface
    • C3 spontaneously cleaves to C3b and associates with Bb to form C3 convertase
    • C3 convertase cleaves C3 to kick off the cascade
  41. Complement activation pathway
    • early steps
    • C3 convertase recruits and cleaves C3 to form C3b (binding) and C3a (small and leaves to do chemotaxis)
    • C3b and the other two are now a C5 convertase
    • C5 convertase recruits and cleaves C5 to form C5b and C5a
    • C5a goes off to do inflammation
    • C3 steps could also be C4
    • late steps
    • C5b recruits and associates with C6 C7 and C8
    • C7 and C8 are membrane bound so it no longer needs the C5 convertase
    • recruits C9 which polymerizes with other C9 to form a MAC pore
    • lyses cell
  42. Functions of complement
    • opsonization to enhance phagocytosis
    • lysis via MAC (C9)
    • C3a C4a C5a can recruit and activate leukocytes
  43. Regulation of complement
    • proteins regulate it
    • complement regulator (soluble protein) inhibits the protease
    • CR1 (complement regulator) on our cells and CDs on our cells prevent complement from attacking self
    • CR1 also DAF displaces Bb from C3b
    • CR1 also MCP cleaves C3b to prevent action (I mediated proteolytic cleavage producing iC3b)
    • many other ways
  44. T cell immune synapse
    • T helper cell activation
    • TCR antigen recognition of peptide and MHC class 2
    • PAMPs activate APC to upregulate CD80 and CD86
    • CD28 does signal transduction (along with CD3 and zeta chains) and binds upregulated CD80 and CD86 on antigen presenting cell
    • adhesion so that multiple antigens can be presented to T cell
    • adhesion through LFA-1 (beta2 integrin) on T cell binding ICAM-1 on antigen presenting cell
    • LFA-1 made high affinity by chemokines secreted by antigen presenting cell
    • cytokines released onto T cell to expand and differentiate it
    • expansion by IL-2 autocrine to IL-2R
  45. Cytotoxic T cell activation
    • requires T helper cell activation if interacting with dendritic cell MHC class 1
    • T helper cell nearby or on same dendritic cell releasing IL-2 to cause expansion
    • low levels of IL-2 are sufficient autocrine for expansion if interacting with MHC class 1 of infected cell (including infected dendritic cell)
  46. T cell activation gene expression
    • First increase c-Fos and c-Myc transcription
    • hours later make CD40 ligand and Fas ligand
    • then hours later IL-2 and IFN gamma
    • followed by IL-2 receptors
    • downregualtion of L selectin to get out of lymph node (binds to high endothelial cells)
    • upregulation of E and P selectins to get through endothelium in periphery
    • downregulation of CCR7 which binds CCL19 and 21 chemokines for integrin activation and chemotaxis
    • instead it upregulates other ones like CXCR3 for integrin activation and chemotaxis
  47. Interleukin 2 receptor regulation
    • naive T cell has low interleukin 2 receptor affinity
    • IL-2Rbeta and IL-2Rgamma c (common gamma chain), thus 2 chains
    • when activated it expresses IL-2R alpha that complexes to make a 3 chain complex
    • this has high affinity for IL-2
    • this is so that you do not cause spurious expansion of nearby T cells that are not specific to the antigen
  48. CD40 signalling
    • bidirectional
    • CD40 ligand expressed when activated
    • T helper cells have CD40 ligand (CD40L)
    • binds to CD40 signaling T cell to make cytokines
    • APC can express CD40 and when engaged with CD40L it tells APC to make more MHC
    • B cells can also express CD40 and they receive the cytokines that it produces (just mentioned) telling them to differentiate to plasma cells, isotype switch and secrete antibodies
  49. Different subtypes of T helper cells
    • Th1 from IL-12 transcription factor Tbet secretes interferon gamma IFN gamma and TNF alpha, which stimulates IgG switch and acts on macrophages and sort of neutrophils, killing what’s in their lysosomes
    • Th2 from IL-4 transcription factor GATA3 secretes IL-4, which stimulates IgG and IgE switch, and IL-5 which activates eosinophil to kill (helminth) and IL-13 which works with IL-4 to activate macrophage to do tissue repair and fibrosis (proinflammatory)
    • Th17 from IL-1, IL-6, IL-23 and TFG beta transcription factor RORgamma t secrete IL-17 and granular macropahge colony stimulating factor GM-CSF to act on endothelial cells and increase neutrophil response, also IL-17 induces antimicrobial peptides in epithelial cells
    • Tregg from TGF beta transcription factor FoxP3 secretes TGF beta and IL-10 regulatory cytokines
  50. Delayed type hypersensitivity
    • type IV hypersensitivity
    • antigen injected
    • recognized by memory T cells (Th1) which recruit and activate lymphocytes and macrophages
    • 1000s per Th1
    • lymphocytes and macrophages cause inflammation (non specific phagocytosis)
    • if you inject T cell sera into someone else and try and infect them, the macrophages are the most important part of the sera for seeing a immunizing effect in the other person
  51. CD8 killing of target cells
    • conjugation via MHC class 1 with TCR
    • release of granules or granzymes via exocytosis
    • enter target cell by perforin molecule (pore)
    • perforin made by cascade similar to complement cascade
    • granzymes cause apoptosis
    • alternate route by FasL on cytotoxic T cell that interacts with Fas on target cell to cause apoptosis
    • other ways like granulysin
  52. Viral evasion of immune system
    • herpes simplex virus interferes with TAP to inhibit MHC class 1 presentation
    • cytomegalovirus inhibits proteasome to inhibit MHC class 1 presentation
    • epstein-barr virus inhibits proteasome too and also make surrogates of IL-10 onto macrophage and dendritic cell to inhibit activation
    • pox virus makes surrogates of IL-1 and interferon gamma (INF-1) to block cytokine activation of effector cells
    • we use something similar to the pox pathway for rheumatoid arthritis
  53. Interferon gamma
    • IFN gamma
    • causes IgG switch
    • activates macrophages and neutrophils to a lesser extent
    • secreted by natural killer cell and Th1
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