Understand 1st year medicine

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Overview of Immunity

 

Immunity

    • Innate: Non-specific, present at birth, does not become more efficient on subsequent exposure
      • Prevention of entry: Stomach acid, mucus, skin, lactic acid in vagina
      • Non-specific elimination:
        1. Enzymes: e.g. lysozyme in tears: Hydrolyzes NAM-NAG subunits of peptidoglycan cell wall in bacteria
        2. Phagocytosis in phagocytes: dendritic cell, monocyte, macrophage, B cell, basophil (mast cell), neutrophil
        3. Complement system:
          1. Opsonization (opsonin: complement plasma protein that binds to bacteria, promoting adhesion between the opsonized bacteria and the phagocyte, thus, phagocytosis)
        4. IFN-gamma (interferon): Secreted by Th1, NK and CD8+ (+APC presentation of macrophage, suppress Th2 activity)
        5. Inflammation

         

      Adaptive/acquired: T cells (mature in thymus) and B cells (mature in bone marrow), becomes more efficient with exposure
      • RECOGNITION
      • SELF/NON-SELF DISCRIMINATION.
      • SPECIFICITY.
      • MEMORY

    Previous classification system
    • Cell-mediated: Cell activation (e.g. macrophage, T cells etc.)
    • Humoral: Antibodies

    -------------

    Lymphatic System


    Functions
    1. Removes excess tissue fluid
    2. Absorb lipids and transport them back to circulatory system
    3. Transport immune cells
    4. Transport APCs (antigen presenting cells) to lymph nodes - initiating immune response

    • Cisterni chyli at L1/2
    • K veins (| azygous, /accessory hemiazygous, \ azygous)
    • Subclavian/bronchomediastinal/jugular trunk -> Right lymphatic duct / thoracic duct (left lymphatic duct) -> Right/left subclavian vein


    Primary lymphoid organs: Bone marrow, thymus, liver (fetus)
    • Lymphocytes produced from progeneitor cells
    Secondary lymphoid organs: Lymph node, spleen, follicles on mucous membrane (MALT - Peyer’s patch, tonsil, appendix)
    • Sites of lymphocyte activation, maturation


    Spleen


    Location: 9th to 11th rib
    Blood: Splenic artery →  Central artery (in PALS: T lymphocyte surround central artery) →  Trabecular vein → Splenic vein


    Visceral surface: Colic, renal and stomach

    Mainly red pulp: Hematopoetic function
    1. Store RBC, platelet
    2. Destroy old RBC (120 days) by macrophage
    3. Hematopoesis (produce blood cells) as a fetus
    4. Splenic cord: Macrophage
    5. Splenis sinus: RBC

    Marginal zone: Made of APCs antigen presenting cells
    1. Antigens from splenic artery (no afferent lymphatics) enter marginal zone trapped by APCs
    2. which carry it to the PALS
    3. The CD4+T from PALs migrate to primary lymphoid follicle (B cells) they develop into secondary follicles containing GC.

    Minor white pulp (PALS: Periarterial lymphatic sheath): Germinal Center
    1. Clonal expansion
    2. B cell differentiation into plasma cell/memory cells
    3. Antigenic differentiation
      • combo diversity of vdj + constant region
      • jxnal diversity (changes at junctions)
      • somatic hypermutation (V gene)
      • isotope/class switching at switch sequences of each C gene
        1. Switch antibody class (change the constant region of heavy chain) production from IgM/D to Ig A/G/E
    . Antigens from splenic artery (no afferent lymphatics) enter marginal zone of primary follicle, trapped by APCs
    2. which carry it to the PALS.

    3. The CD4+T from PALs migrate to primary lymphoid follicle (B cells) they develop into secondary follicles containing GC.
    --------------

    T cell differentiation

    T cell precursor in bone marrow to later differentiation in thymus (thymic education)
    1. Double positive: CD4, CD8, TcR in cortex
    2. Single positive: NAIVE CD4 OR CD8 + TcR in medulla
    All TcRs are complexed with CD3

    In the lymph nodes.. from naive to immunocompetent.. IL2 is the cytokines for both CD8 and CD4T cells
    • Cytotoxic T cell:
      • CD8+ T cells become cytotoxic T cells - kill virus-infected/neoplastic/donor-graft cell
    • T helper cell
      • CD4+ T cells under the influence of cytokines differentiate to either effector Th1 (Th1 and 2... IL12) (cell-mediated) or Th2 (humoral)... 2 different and opposing IL4 and IL10s!
        • IL12 promotes Th1; Th1 activates macrophage by making IFN-gamma
        • IL4, 10 (anti-inflammatory - downregulates IL2 production, expression of costimuli and MHCII) promotes Th2;
          • CD40 on B cell x CD40L on Th2
          • Th2 help B cells make antibody by making InterLeukens IL4, 5, 6


    Other T cell subtypes (stimulated by TGF-b- transforming growth factor)
    - Treg aka Tsupressor: Stimulated by TGF-B, Only responsive to cell-cell interaction (NOT cytokine), secrete IL10 (immunoesuppressor) and TGF-B (immunosupressive  - converts T cells into Treg)
    IL10
    - Th17: Stimulated by TGF-B, Secrete IL17 involved in autoimmune

    And via positive feedback, the Th’s make the same cytokines too (i.e. for Th1: IL12, for Th2: IL4 and 10)!

    4 x 2 = 8 or 8 x 1 = 8
    Helper T cells (CD4+T) have CD4 which binds to MHC2 on APCs (macrophage, B cell, DC)
    Cytotoxic T cells (CD8+T) have CD8 which binds to MHC1 on viral-infected cells.

    MHC 1: HLA- A, -B and -C; are expressed on ALL nucleated cells (one letter only)
    MHC2: HLADP, DQ, DR; expressed on APCs only (two letters!)

    MHC is expressed codominantly
    ------------

    Lymph node


    Secondary lymphoid organ

    Afferent lymphatics: APC (e.g. dendritic cell) with antigen enters and stimulate/interact with

    • Cortex (B cell)
    • Paracortex (T cell)
    • Medulla (Plasma cell)

    B cell either

    1. Stays in cortex and form germinal center in cortex
    2. Move to medullary cord and differentiate into plasma cell to secrete Ig

    Cortex

    Follicle: Site of B cell proliferation etc.

    - Primary: Dense and dormant

    - Secondary: Pale germinal center, active


    ParacorTex

    Contain T cells

    Sandwiched between cortex and medulla

    Contain HEV (postcapillary venule) where lymphocytes enter blood


    Medulla

    Medullary cord: Plasma cells

    Medullary sinus: Macrophage


    PMN (Polymorphonuclear cell: Segmented nuclei)
    • Granlocytes contain granules in cytoplasm

    Mononucleated (Single nuclei cell)
    • Agranulocyte


    Function of B cells
    Make antibodies: IgE (allergy - type I hypersensitivity), IgG (type II - cytotoxic and III - immune complex)
    Cause hyperacute organ rejection - preformed Ab vs antigen on blood vessels of graft

    Function of T cells
    CD4+: Th1 - activate macrophage, Th2 - Activate B cells
    CD8+: Kill virus infected cells
    DTH (Type IV hypersensitivity): Involves Th1
    Organ rejection (acute and chronic NOT hyperacute - preformed B cell)

    Th
    - Th1: CD4+CD8-, involved in DTH and cell mediated immunity, responsive to MHC2
    - Th2: CD4+CD8-, involved in humoral response, responsive to MHC2

    Tc: CD4-CD8+, involved in viral infected cells, responsive to MHC1
    Ts/Treg: CD4-CD8+CD25+, involved in immunosupression, responsive to MHC1

    T cell activation

    CD4+ activation
    1. APC phagocytose foreign body presented on MHCII
    2. MHCII recognized by TcR on Th
    3. Costimuli B7.1/.2 (CD80/86) on APC and CD28 on CD4+
    4. Th produce cytokine

    CD8+ activation
    1. Endogenous protein presented on MHC1
    2. MHC recognized by TcR on cytotoxic T cell
    3. Autocrine production of IL2 by Tc
    4. Tc activated and kills the viral infected cell

    NK cell (innate) have activating and inhibitory receptors
    • Kill cells via performin, granzyme,  (not fas L - CTL only!) cell does not have a MHCI that the inhibitory receptor recognizes
    • Lymphocyte subset
    • Activated by TNF-alpha, IFN alpha and beta, IL12 (from Th1)


    TNF-alpha, IL1 and IL6 act together!

    ILs

    Hot T Bone stEAk
    IL1: Heat
    IL2: T cell activation
    IL3: B cell
    IL4: IgE
    IL5: IgA and eosinophil


    Complement cascade (MAC)
    - Mannose-binding leectin (MBL): innate
    - Alternative pathway: innate … endotoxin
    - Classical pathway - humoral (involves antibody)

    Classical pathway
    c1q portion of c1 becomes activated when it binds to Fc portion of IgG/M
    Activated c1 cleaves c2 and c4 into c2a and c4b -> combine to form c3 convertase
    c3 convertase cleaves c3 into c3b
    c2a+c3b+c4b forms c5 convertase
    c5 convertase cleaves c5 into c5b
    c5b - 9 make up the MAC

    Opsonin: C3b and C4b
    Phagocytes have c3b receptor (cr1) and FcR for IgG - eat up immune complex
    RBC also have c3b receptors. So when complement+/-immune complex binds to it, it is rid of once the RBC enters RES (think hemolytic anemia)

    Chemotactic: Anaphylatoxin (c3a, c4a, c5a) and anaphylatoxin receptor on WBC (3 complements... 3 functions)
    • SM contraction (c3a induce mast cell degranulation via gpcr -> th2 cytokines generated from mast cell), + BV permeability, chemotactic

    Lysis: MAC (c5b-c9)
    Clearance of immune complex or apoptotic cell: c1q, c3 and c4

    Mannose-binding lectin pathway
    MBL on microbial surface forms c3 convertase

    Alternative pathway
    Endotoxin on microbial surface form c3 convertase



    Kinin system
    http://www.jci.org/articles/view/15490/files/JCI0215490.f2/medium
    Note that ACE breaks down bradykinin so no vasodilation!

    HK - High molecular weight kininogen
    PK - prekallikrein

    Shock: Reduced tissue perfusion -> thus - tissue perfusion

    Types of shock
    • Hypovolemic shock: (e.g. severe hemorrhage, cholera, skin burn) -> baroreceptor reflex -> vasoCONSTRICTION and symp -> cold and clammy
    • Cardiogenic shock: Pump failure (arrthymia, post-MI): -> low CO -> baroreceptor reflex -> vasoCONSTRICTION and symp -> cold and clammy
    • Anaphylactic shock: Type 1 hypersensitivity (ACID) - vasoDILATION (laryngeal edema -> suffocate!) and hypotension
    • Neurogenic: Damaged spinal cord Damaged symp. outflow from hypothalamus? (HR decrease and vasodilation for artery ->  TPR falls too)
    • Septic: Endotoxin from LPS portion of Gram -’ve bacteria -> alternative pathway of comp system (C3b x LPS) -> Vasodilation (warm skin)






    Inflammation for Module 2

    Genes and Immune cells
    Foxp3 - Treg
    STAT - Other cells
    ------
    Proteins

    3 types of serum proteins
    - Fibrinogen
    - Albumin
    - Globulins
    alpha: highly mobile and some has the activity of inhibiting protease (e.g. alpha1-trypsin)
    beta: less mobile
    gamma: least mobile (Ig’s)
    http://upload.wikimedia.org/wikipedia/commons/2/26/Electrophoresis.png

    Immunoglobulin

    Types:
    D: Found on surface of cells
    M: Found on surface of cells, pentamer joined by J chain(10 antigen binding sites) -> trap antigens, the FIRST Ig made in primary response to antigen (MGGM), fix complement; type 2 hypersensitivity
    G: Fix complement, main antibody in secondary response to antigen, most common, opsonin; the ONLY isotype that can cross placenta (Rh disease!!!) type 2 and 3 hypersensitivity
    A: Found in secretions (e.g. breast milk - colostrum), dimer joined by J chain
    E: Anti-parasites, Binds to mast cell and basophil. When cross-linked with antigen on second exposure, release inflammatory mediators e.g. histamine, MBP (major basic protein), eosinophilic cationic protein, eosinophil peroxidase; type 1 hypersensitivity

    MGGM
    http://old.lf3.cuni.cz/mikrobiologie/teozak/imun/fig1_18.jpg

    Antibody structure

    Components:
    - Heavy chain: Variable and constant
    • Variable: combination of 3 genes, called VH, DH, and JH
    • Constant: mu for IgM, delta for IgD etc...

    - Light chain: Variable and constant
    • Variable: VL and JL.
    • Constant: Kappa or lambda chain


    Receptor diversity on inflammatory cells

    -  Combinatorial diversity: Through chromosomal looping and recombinase enzymes, any genes can be cut out and joined with any other genes. Finally this VDJ combination is added to any of the constant region genes.  (e.g. μ - mu for IgM).


    - Junctional diversity: The cutting and splicing is conducted by an enzyme. Existing nucleotides may be lost or new added to junction of genes as this occurs.

    The amino acid sequence determines the shape of the Fab portion, therefore its function. This is irreversible.


    - Somatic hypermutation of B cells: IgM has low affinity binding. During B cell development this affinity is improved via somatic hypermutation (random mutation on V gene) and those giving better affinity are selected

    - Isotype/class switching: Occurs only during active immune response, and the result depends on the cytokines secreted (remember... hot t bone steak!)
    • C genes: Recombination
      • Switch sequences are in the 5’ side of each C gene. Recombination (enzyme: Activation-Induced Deaminase (AID)  between the switch regions with deletion of intervening DNA

    ----------------------

    Why are B cell cancers more common than T cells?
    B cells produce antibodies thus genetic switching is more common!
    Meanwhile, only certain amount of  switching occurs in T lymphocytes as thymus atrophies after puberty
    ------------------------------
Signs of inflammation

    Tumor - swelling (exudate formation)
    Rubot - redness (vasodilation)
    Calor - heat (vasodilation)
    Dolor - pain (histamine, serotonin, prostaglandin, substance P)
    Loss of function


Exudate formation (MAD8)
  1. Margination: Cells to periphery of blood vessel due to less fluid (higher vessel permeability)
  2. Adhere: ICAM expression from activated endothelium
  3. Diapedesis: Secrete protease to degrade vessel BM and rearrange cytoskeleton to squeeze through (forming pseudopods)
  4. Chemotaxic: IL8 gradient

 

    Macrophage phagocytose → Macrophage release IL1, TNF-alpha, IL8 → Activate endothelium to express ICAM
    Normal:
    Arteriole → Metaarteriole with precapillary sphincter → true capillaries.
    When precapillary sphincter contract, this increases TPR as afterload increases.

    Inflammation
    • Opening precapillary sphincters of metarterioles → Opened capillary bed → Hyperemia (red)
    • C5a, Histamine: Vasodilation and High vascular permeability (actin on endothelium contract) → Higher hydrostatic pressure and oncotic pressure (plasma proteins escape) → Edema
    -------------

    Transudate or exudate

    ExudateTransudate
    Due to inflammation - endothelial poresHigh hydrostatic, low oncotic
    CloudyClear
    Many proteinFew protein (endothelial pores are intact!)
    SAAG <1.1 (lots of fluid albumin!)SAAG >1.1

Serum albumin ascites gradient (SAAG)
SAAG = [Serum albumin] - [Fluid albumin]

    Fluid protein / Serum total protein

    If less than or equal to 0.5 → exudate

    If greater than 0.5 → transudate


    Types of exudate
    • Serous: Resemble exudate of blood serum; from blood or from mesothelium (peritoneum, pericardium, pleura)
    • Catarrhal: Mucus (throat infections..)
    • Fibrinous: Fibrinogen, fibrin (rheumatic carditis)
    • Purulent: Dead neutrophils - pus

    Exudate:
    • Neutrophil
    • Bacteria and associated toxin
    • Ig: Due to increased vascular permeability - complement activation (IgM/G), opsonin (IgG)
    • Coagulation factor: Due to increased vascular permeability - (e.g. fibrinogen - trap pathogen for phagocytosis, matrix for granulation)

    Rolling: Weak selectin on endothelium x carbohydrate (e.g. sLex) on WBC
    Adhesion: ICAM-1 on endothelium x LFA-1 (integrin) on WBC

    -----------------------
Metabolic hyperemia
exercise -> NS  -> alpha 1 (transient coronary vasoconstrict), but increased metabolic activity increases production of vasodilator metabolites (potassium ion, carbon dioxide, nitric oxide, and adenosine) .to increase blood flow

e.g. Coronary heart muscle, skeletal muscle