Mapa mental

IMMUNITY

Joey Ellston Pathology Inglés

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IMMUNITY

Innate
- Components
  - Epithelia
  - Cells
    - Phagocytes
      - Neutrophils
      - Macrophages
        Monocytes migrated to tissue
        process Ag
        present to T cells
        kill opsonised cells
        IgG
        C3b
    - Anti-viral
      - Dendritic
        (Interdigitating) dendritic Cells
        Primary response - antigen presenting cells
        Located under epithelia/interstitium
        Langerhans cells
        Many receptors
        Mannose R
        TLRs
        Recruited to T-cell zones of lymphoid
        Increases number of molecules to present to CD4+
        Follicular dendritic cells
        Germinal centres of lymphoid follicles
        Fc-R for IgG and C3b-R
        Trap bound antigens to present to B-cells
        improve Ig quality
      - NK cells
        10-15% lymphocytes
        "large granular lymphocytes"
        dense azurophilic granules
        Kill without prior exposure
        viruses
        some tumours
        Antibody dependent cell-mediated cytotoxicity (ADCC)
        CD16
        Fc-R for IgG
        CD56
        Balance
        Activating-R
        NKG2D
        DNA damage
        Infection
        Inhibiting-R
        self class I MHC (healthy cells)
        Killer cell Ig-like-R
        CD94 lectins
  - Plasma proteins
    - includes complement
  - Cytokines
    - TNF
    - IL-
      - 1
      - 12
    - IFN
      - Type 1
      - γ
    - Chemokines
- Recognition
  - TLRs
    - Pathogen associated molecular patterns
    - Danger associated molecular patterns
    - Transcription
      - Cytokines
        Phagocytes
- Alternative & lectin pathway
Adaptive
- http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4377-0792-2..50011-0--f1&sectionEid=4-u1.0-B978-1-4377-0792-2..50011-0&isbn=978-1-4377-0792-2&uniqId=415924964-5
- Classical pathway
- Humoral (extracellular)
  - B lymphocytes
    - 'Bone-marrow derived' 10-20% circulating lymphocytes recognise Ag by Ag-specific cell surface-R
    - Lymphoid tissues
      - Lymph nodes
        nodular aggregates of lymphoid tissue located along lymphatic channels that concentrate microbes/antigens http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4377-0792-2..50011-0--f7&sectionEid=4-u1.0-B978-1-4377-0792-2..50011-0&isbn=978-1-4377-0792-2&uniqId=415896009-14
        Lymphocyte recirculation
        Naive T cell
        Ag in lymphnodes
        High endothelial venules (HEV)
        effector T cells
        Tissues
      - Spleen
        Ag trapping, blood equivalent of lymphnodes
      - MALT
        Mucosa Associated Lymphoid Tissue Contains 50% of lymphocytes e.g. tonsils, Peyer's patches
    - Membrane bound
      - IgM
        Mainly responsible for polysaccharide and lipid identification, activates complement (classical pathway)
      - IgD
    - Stimulate Plasma cells
      - Secrete Ig
    - Ig alpha & beta
      - invariant, analogous to CD3 and zeta proteins, involved in signal transduction
    - +
      - Complement
        CR2/CD2
        receptor for EBV
      - Fc Receptors
      - CD40
  - Antibodies (Ig)
    - Immunoglobulins
    - Clonal selection hypothesis
      - Ig specific clones of lymphocytes develop before and independent of exposure
      - 10^7-10^9 specificities
    - IgG
      - Protein identification, activates complement (classical pathway), crosses placenta, t1/2=3 weeks
    - IgA
      - protein identification mucosa
    - IgE
      - Protein identification Helminths
- Cellular (intracellular)
  - http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4377-0792-2..50011-0--f11&sectionEid=4-u1.0-B978-1-4377-0792-2..50011-0&isbn=978-1-4377-0792-2&uniqId=416004816-7
  - T lymphocytes
    - Thymus derived 60-70% of lymphocytes in blood
    - Specific receptors (TCRs)
      - RAG1 & RAG2 genes
        genes in all cells, only T-cells are they rearranged
      - lymphoid tumour detection
        Monoclonal (neoplastic)
        Polyclonal (non-neoplastic)
      - Non-covalently linked to 5 polypeptide chains
        CD3
        identical in all T-cells
        signal transduction
        zeta chain dimer
        Others
        CD4
        CD8
        CD2
        Integrins
        CD28
      - Types
        alpha & beta chains
        T-helper
        help B lymphocytes and macrophages
        CD4+
        MHC II
        60%
        T-killer
        CD8+
        MHC I
        30%
        disulphide bond
        95%
        recognise peptide antigens presented by MHC
        gamma & delta chains
        No MHC
        recognise lipid/peptides/small molecules
        sentinels, gather at epithelia
        NK-Tcells
        glycolipid recognition (CD1)
    - MHC
      - Peptide Display System - for recognition by Ag specific T cells. MHC/HLA complex
      - Chromosome 6
        polymorphic: many alleles of each gene
        barrier to transplant
      - Class I
        all nucleated cells & platelets
        HLA -
        A
        B
        C
        heterodimer
        α/heavy chain
        44kD
        polymorphic
        CD8-R
        extracellular region
        α1
        α2
        α3
        peptide binds in cleft
        β2 microglobulin
        non-polymorphic
        not encoded with MHC
        Display protein peptides
        e.g. viral Ag
      - Class II
        Ag presenting cells
        HLA-D
        loci also encodes: complement TNF lymphotoxin
        P
        Q
        R
        heterodimer
        α
        polymorphic
        α1
        α2
        β
        polymorphic
        β1
        β2
        CD4-R
        T helpers Allow affinity maturation
        Th1
        IFN-γ
        Macrophage activation
        Th2
        IL-5
        IL-4
        Activate B cells
        Th17
        IL-17
        Neutrophils/monocytes
      - HLA disease
        Inflammatory (B27)
        Ankylosing spondylitis
        Post-infective arthritis
        Anterior Uveitis
        Autoimmune (DR)
        T1 DM (3/4)
        Chronic hepatitis (3)
        Primary Sjogren's (3)
        Inborn Errors of Metabolism
        Hereditary Haemochromatosis (A)
        21-hydroxylase deficiency (BW47)
    - Cytokines
      - IL-
        2
        4
        5
        17
      - IFN-γ
      - B7 proteins
        CD80
        CD86
Disease
- Type I (Immediate) Hypersensitivity
  - Systemic Anaphylaxis
    - Difficultly breathing Oedema Shock
    - Anaphylactoid
      - Non-immune anaphylaxis, no antigen, but mast call degranulation
  - Local Immediate
    - Urticaria
    - Angioedema
    - Allergic Rhinitis (Hayfever)
    - Bronchial asthma
  - Th2
    - IgE
      - receptor for Fc portion is on ast cells and basophils, bridging causes mast cell degranulation
      - Mast cells
        Blood based
        Eosinophils
        IL-5 is potent stimulator Release: Proteolytic enzymes Major basic protein Eosinophil cationic proteinAll of which are toxic to epithelia
        cytokines
        leukocyte recruitment in late phase
        TNF
        IL-1
        chemokines
        IL-4
        increase Th2
        Mediators
        see table 6.3 http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-0792-2..50011-0--cesec23&isbn=978-1-4377-0792-2&uniqId=416320572-3#4-u1.0-B978-1-4377-0792-2..50011-0--cesec25
        Preformed (granules)
        Histamine
        vasoactive amines increase vasc perm, sm contraction, increase mucous
        Enzymes
        tissue damage
        hydrolase
        proteases
        tryptase
        chymase
        Proteoglycans
        package and store amines in granule
        heparin
        chondroitin
        Lipid (membrane)
        formed in mast cell membrane
        phospholipase A2
        arachidonic acid
        Leukotrienes
        vasoactive/spasmogenic
        C4
        activates mast cells
        D4
        inflammatory cell recruitment
        B4
        PGD2
        PAF
        Platelet aggregation Histamine release Bronchospasm, increase permeability, vasodilation
      - Basophils
        Tissue based
  - 2 phases
    - 1 hour
    - 1-20 hour
- Type II (Antibody mediated) Hypersensitivity
  - Antigen + Ig on cell surface or ECM (endogenous or exogenous)
  - Opsonisation & Phagocytosis
    - IgG
      - Complement (classical)
        C3b & C4b
        Allows recognition by phagocytes
        Membrane Attack Complex (MAC)
        drills holes in membrane of thin walled cells (such as Neisseria) --> lysis
      - ADCC
        Antibody dependent cellular cytotoxicity Effector cells (neutrophils, monocytes, eosinophils, NK cells) bind to Fc region of Ig.
        Lysis without phagocytosis
    - Examples
      - Transfusion reactions
        Commonest blood transfusion reaction
      - Erythroblastosis fetalis
      - Autoimmune haemolytic anaemia/granulocytosis/thrombocytopenia
      - Various drug reactions
  - Inflammation
    - Complement and Fc mediated reactions at BM/ECM
    - Ig
      - Complement
        C5a
        attract cells
        PML, monocytes
        pro-inflammatory substances
        enzymes/ROS
        C3a
        C3b
    - Examples
      - Table 6.4 http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-0792-2..50011-0--cesec23&isbn=978-1-4377-0792-2&uniqId=416320572-3#4-u1.0-B978-1-4377-0792-2..50011-0--cesec25
  - Cellular dysfunction
    - Ig
      - Blocks R
        ACh-R = Myasthenia Gravis
      - Stimulates
        e.g. TSH-R = Graves disease
- Type IV (Cell mediated) Hypersensitivity
  - T cells
    - CD4+ DTH
      - Delayed type hypersensitivity aka 'immune inflammation' 1st stage - diferentiation of Th cell. 2nd stage -repeat exposure to differentiated cells.
      - Th-17
        Neutrophils
        cytokines
        IL-1, 6, 23 TGF-B LI-17, 22, chemokines - inflammationIL-21 - amplify Th-17
      - Th-1
        Macrophages
        cytokines
        Inflammation: TNF IL-1 Chemokines IL-2 - amplifies Th1
        IFN/IL-2
        autocrine feedback, differentiate Th cells
      - Morphology
        predominantly CD4 & macrophages 'perivascular cuffing' --> endothelial hypertrophy. See: http://www.mdconsult.com/books/figure.do?figure=true&eid=4-u1.0-B978-1-4377-0792-2..50011-0--f23&sectionEid=4-u1.0-B978-1-4377-0792-2..50011-0--cesec23&isbn=978-1-4377-0792-2&uniqId=416389836-5
        macrophage
        epitheloid
        granuloma
        epitheloid cells surrounded by lymphocytes (also formed by foreign bodies)
    - CD8+
      - Cell mediated cytotoxicity Graft rejection/viruses/Type 1 DM
      - Complex
        Perforins
        Granzymes
        proteases that cleave and activates capsases
        Serglycin
      - Fas ligand
        binds to target cells Fas and casues APOPTOSIS
      - cytokines
        IFN --> inflammation less important.
  - Examples
    - Table 6.6 http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-0792-2..50011-0--cesec23&isbn=978-1-4377-0792-2&uniqId=416913232-3#4-u1.0-B978-1-4377-0792-2..50011-0--cesec23
    - Poison Ivy
    - MANTOUX
- Type III (Immune-complex) Hypersensitivity
  - Ag + Ig = inflammation & Damage Jarison-herxheimer - reaction to endotoxins released by harmful organisms. Penicillin and syphillis.
  - Systemic
    - Phases
      - C3 levels decrease as consumed (measure of activity)
      - Complex formation in circulation
        1/52 after injection, 
      - Tissue deposition
        medium sized, Ag excess
        Glomeruli
        Joints
      - Inflammation
        10 days Symptomatic -vasculitis -arthritis -GN
    - Prototypic = Acute Serum Sickness
      - -previously when horse diptheria injected in large amounts
    - Morphology
      - 'Fibrinoid"necrotising vascullitis
        necrosis
        Infiltration
  - Localised
    - local tissue necrosis secondary to local immune vasculitis.
    - 'Arthus reaction'
      - max at 4-8 hours
    - deposition
      - fibrinoid necrosis & thrombosis
        ischaemic injury
Graft rejection
- Mechanisms
  - T cell mediated (Cellular)
    - Direct
      - probably the key factor in acute rejection T cells recognise MHC presented on DONOR APCs B7-1, B7-2 co-stimulators. Delayed type hypersenitivity.
    - Indirect
      - probably the key factor in chronic rejection donor MHC presented by HOST APCs --> peptides then presented with host MHC. Principle response is cytokine productionas cannot recognise or kill graft cells.
  - Antibody mediated (Humoral rejection)
    - Hyperacute rejection
      - preformed Ig present -previous transplant/transfusion -post-pregnancy
    - Rejection vasculitits
      - not previously exposed
- Morphology
  - Kidney transplant - prototypic example
  - Hyperacute
    - mins or hours cyanotic, mottled, and flaccid  Ig and complement deposition -> endothelial injury and fibrin-platelet thrombi Neuts accumulate -> thrombotic occlusion -> fibrinoid necrosis -> necrosis (infarction)
  - Acute
    - Days
    - Cellular
      -  months interstitial mononuclear cell infiltration and edema/hemorrhage CD4+ and CD8, IL-2 receptor focal tubular necrosis CD8+ - endothelitis  If no humoral rejection -> respond well to immunosuppressive Rx.     
    - Humoral
      - (rejection vasculitis) antidonor antibodies mediated necrotizing vasculitis with endothelial cell necrosis, neutrophilic infiltration, deposition of Ig, complement, and fibrin, thrombosis. necrosis of the renal parenchyma. In  many cases, the vasculitis is less acute and is characterized by marked thickening of the intima with proliferating fibroblasts, myocytes, and foamy macrophages narrowing of the arterioles -> infarction or renal cortical atrophy mimic arteriosclerotic thickening, caused by cytokines that cause proliferation of vascular smooth muscle cells.Deposition of C4d in allografts = strong indicator of humoral rejection (C4d is produced during activation of the complement system classical pathway).Rx B cell–depleting agents     
  - Chronic
    - Vascular changes (dense, obliterative intimal fibrosis, principally in the cortical arteries), interstitial fibrosis, and tubular atrophy with loss of renal parenchyma. Glomeruli - scarring, with duplication of basement membranes ‘chronic transplant glomerulopathy’.   Interstitial mononuclear cell infiltrates of plasma cells and numerous eosinophils.  
- Survival
  - HLA matchiing
    - Kidney's only
  - Drugs
    - Cyclosporine
      - blocks NFAT transcription factor - encode IL-2 and other cytokines
    - Azathioprine
      - inhibits leukocyte development from bone marrow precursors
    - Steroids
      - block inflammation
    - rapamycin and mycophenolate mofetil
      - inhibit lymphocyte proliferation
    - monoclonal anti–T-cell antibodies
    - proteins that bind to B7 costimulators
  - donor inoculum
    - mixed chimerism
- Bone Marrow Transplant
  - Graft vs Host
    -     Prevented by depletion of donor T cells before transfusion however: the incidence of graft failures and EBV-related B-cell lymphoma ‘graft-versus-leukemia effect’ -  used in the treatment of chronic myelogenous leukemia when patients relapse after bone marrow transplantation.     
    - Acute
      -     days to weeks skin (rash --> desquamation) liver (bile duct destruction à jaundice) intestines (bloody diarrhoea) tissues are usually not heavily infiltrated by lymphocytes  CD8+, cytokines released by the sensitized donor T cells     
    - Chronic
  - Immunodeficency
    - CMV can be fatal

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Descripción: Pathology Mapa Mental sobre IMMUNITY, creado por Joey Ellston el 03/07/2013.
Creado por: Joey Ellston · jul 2013
Actualizado: 8 jul 2017
Visitas: 103
Etiquetas: pathology
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IMMUNITY

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