IMMUNITY

1. Components
   1. Epithelia
   2. Cells
      1. Phagocytes
         1. Neutrophils
         2. Macrophages

            Anmerkungen:

            • Monocytes migrated to tissue
            1. process Ag
               1. present to T cells
            2. kill opsonised cells
               1. IgG
               2. C3b
      2. Anti-viral
         1. Dendritic
            1. (Interdigitating) dendritic Cells

               Anmerkungen:

               • Primary response - antigen presenting cells
               1. Located under epithelia/interstitium
                  1. Langerhans cells
               2. Many receptors
                  1. Mannose R
                  2. TLRs
               3. Recruited to T-cell zones of lymphoid
               4. Increases number of molecules to present to CD4+
            2. Follicular dendritic cells
               1. Germinal centres of lymphoid follicles
               2. Fc-R for IgG and C3b-R
               3. Trap bound antigens to present to B-cells
                  1. improve Ig quality
         2. NK cells

            Anmerkungen:

            • 10-15% lymphocytes
            1. "large granular lymphocytes"

               Anmerkungen:

               • dense azurophilic granules
            2. Kill without prior exposure
               1. viruses
               2. some tumours
            3. Antibody dependent cell-mediated cytotoxicity (ADCC)
               1. CD16

                  Anmerkungen:

                  • Fc-R for IgG
               2. CD56
            4. Balance
               1. Activating-R
                  1. NKG2D
                     1. DNA damage
                     2. Infection
               2. Inhibiting-R
                  1. self class I MHC (healthy cells)
                     1. Killer cell Ig-like-R
                     2. CD94 lectins
   3. Plasma proteins

      Anmerkungen:

      • includes complement
   4. Cytokines
      1. TNF
      2. IL-
         1. 1
         2. 12
      3. IFN
         1. Type 1
         2. γ
      4. Chemokines
2. Recognition
   1. TLRs
      1. Pathogen associated molecular patterns
      2. Danger associated molecular patterns
      3. Transcription
         1. Cytokines
            1. Phagocytes
3. Alternative & lectin pathway

Anmerkungen:

• 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

1. Classical pathway
2. Humoral (extracellular)
   1. B lymphocytes

      Anmerkungen:

      • 'Bone-marrow derived' 10-20% circulating lymphocytes recognise Ag by Ag-specific cell surface-R
      1. Lymphoid tissues
         1. Lymph nodes

            Anmerkungen:

            • 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
            1. Lymphocyte recirculation
               1. Naive T cell
                  1. Ag in lymphnodes

                     Anmerkungen:

                     • High endothelial venules (HEV)
                     1. effector T cells
                        1. Tissues
         2. Spleen

            Anmerkungen:

            • Ag trapping, blood equivalent of lymphnodes
         3. MALT

            Anmerkungen:

            • Mucosa Associated Lymphoid Tissue Contains 50% of lymphocytes e.g. tonsils, Peyer's patches
      2. Membrane bound
         1. IgM

            Anmerkungen:

            • Mainly responsible for polysaccharide and lipid identification, activates complement (classical pathway)
         2. IgD
      3. Stimulate Plasma cells
         1. Secrete Ig
      4. Ig alpha & beta

         Anmerkungen:

         • invariant, analogous to CD3 and zeta proteins, involved in signal transduction
      5. +
         1. Complement
            1. CR2/CD2
               1. receptor for EBV
         2. Fc Receptors
         3. CD40
   2. Antibodies (Ig)

      Anmerkungen:

      • Immunoglobulins
      1. Clonal selection hypothesis

         Anmerkungen:

         • Ig specific clones of lymphocytes develop before and independent of exposure
         1. 10^7-10^9 specificities
      2. IgG

         Anmerkungen:

         • Protein identification, activates complement (classical pathway), crosses placenta, t1/2=3 weeks
      3. IgA

         Anmerkungen:

         • protein identification mucosa
      4. IgE

         Anmerkungen:

         • Protein identification Helminths
3. Cellular (intracellular)

   Anmerkungen:

   • 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
   1. T lymphocytes

      Anmerkungen:

      • Thymus derived 60-70% of lymphocytes in blood
      1. Specific receptors (TCRs)
         1. RAG1 & RAG2 genes

            Anmerkungen:

            • genes in all cells, only T-cells are they rearranged
         2. lymphoid tumour detection
            1. Monoclonal (neoplastic)
            2. Polyclonal (non-neoplastic)
         3. Non-covalently linked to 5 polypeptide chains
            1. CD3
               1. identical in all T-cells
               2. signal transduction
            2. zeta chain dimer
            3. Others
               1. CD4
               2. CD8
               3. CD2
               4. Integrins
               5. CD28
         4. Types
            1. alpha & beta chains
               1. T-helper

                  Anmerkungen:

                  • help B lymphocytes and macrophages
                  1. CD4+
                  2. MHC II
                  3. 60%
               2. T-killer
                  1. CD8+
                  2. MHC I
                  3. 30%
               3. disulphide bond
               4. 95%
               5. recognise peptide antigens presented by MHC
            2. gamma & delta chains
               1. No MHC
               2. recognise lipid/peptides/small molecules
               3. sentinels, gather at epithelia
            3. NK-Tcells
               1. glycolipid recognition (CD1)
      2. MHC

         Anmerkungen:

         • Peptide Display System - for recognition by Ag specific T cells. MHC/HLA complex
         1. Chromosome 6
            1. polymorphic: many alleles of each gene
               1. barrier to transplant
         2. Class I
            1. all nucleated cells & platelets
            2. HLA -
               1. A
               2. B
               3. C
            3. heterodimer
               1. α/heavy chain

                  Anmerkungen:

                  • 44kD
                  1. polymorphic
                  2. CD8-R
                  3. extracellular region
                     1. α1
                     2. α2
                     3. α3
                     4. peptide binds in cleft
               2. β2 microglobulin
                  1. non-polymorphic
                  2. not encoded with MHC
            4. Display protein peptides
               1. e.g. viral Ag
         3. Class II
            1. Ag presenting cells
            2. HLA-D

               Anmerkungen:

               • loci also encodes: complement TNF lymphotoxin
               1. P
               2. Q
               3. R
            3. heterodimer
               1. α
                  1. polymorphic
                  2. α1
                  3. α2
               2. β
                  1. polymorphic
                  2. β1
                  3. β2
                     1. CD4-R

                        Anmerkungen:

                        • T helpers Allow affinity maturation
                        1. Th1
                           1. IFN-γ
                              1. Macrophage activation
                        2. Th2
                           1. IL-5
                           2. IL-4
                              1. Activate B cells
                        3. Th17
                           1. IL-17
                              1. Neutrophils/monocytes
         4. HLA disease
            1. Inflammatory (B27)
               1. Ankylosing spondylitis
               2. Post-infective arthritis
               3. Anterior Uveitis
            2. Autoimmune (DR)
               1. T1 DM (3/4)
               2. Chronic hepatitis (3)
               3. Primary Sjogren's (3)
            3. Inborn Errors of Metabolism
               1. Hereditary Haemochromatosis (A)
               2. 21-hydroxylase deficiency (BW47)
      3. Cytokines
         1. IL-
            1. 2
            2. 4
            3. 5
            4. 17
         2. IFN-γ
         3. B7 proteins
            1. CD80
            2. CD86

1. Type I (Immediate) Hypersensitivity
   1. Systemic Anaphylaxis

      Anmerkungen:

      • Difficultly breathing Oedema Shock
      1. Anaphylactoid

         Anmerkungen:

         • Non-immune anaphylaxis, no antigen, but mast call degranulation
   2. Local Immediate
      1. Urticaria
      2. Angioedema
      3. Allergic Rhinitis (Hayfever)
      4. Bronchial asthma
   3. Th2
      1. IgE

         Anmerkungen:

         • receptor for Fc portion is on ast cells and basophils, bridging causes mast cell degranulation
         1. Mast cells

            Anmerkungen:

            • Blood based
            1. Eosinophils

               Anmerkungen:

               • IL-5 is potent stimulator Release: Proteolytic enzymes Major basic protein Eosinophil cationic proteinAll of which are toxic to epithelia
            2. cytokines

               Anmerkungen:

               • leukocyte recruitment in late phase
               1. TNF
               2. IL-1
               3. chemokines
               4. IL-4
                  1. increase Th2
            3. Mediators

               Anmerkungen:

               • 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
               1. Preformed (granules)
                  1. Histamine

                     Anmerkungen:

                     • vasoactive amines increase vasc perm, sm contraction, increase mucous
                  2. Enzymes

                     Anmerkungen:

                     • tissue damage
                     1. hydrolase
                     2. proteases
                        1. tryptase
                        2. chymase
                  3. Proteoglycans

                     Anmerkungen:

                     • package and store amines in granule
                     1. heparin
                     2. chondroitin
               2. Lipid (membrane)

                  Anmerkungen:

                  • formed in mast cell membrane
                  1. phospholipase A2
                     1. arachidonic acid
                        1. Leukotrienes
                           1. vasoactive/spasmogenic
                              1. C4

                                 Anmerkungen:

                                 • activates mast cells
                              2. D4
                           2. inflammatory cell recruitment
                              1. B4
                        2. PGD2
                     2. PAF

                        Anmerkungen:

                        • Platelet aggregation Histamine release Bronchospasm, increase permeability, vasodilation
         2. Basophils

            Anmerkungen:

            • Tissue based
   4. 2 phases
      1. 1 hour
      2. 1-20 hour
2. Type II (Antibody mediated) Hypersensitivity

   Anmerkungen:

   • Antigen + Ig on cell surface or ECM (endogenous or exogenous)
   1. Opsonisation & Phagocytosis
      1. IgG
         1. Complement (classical)
            1. C3b & C4b

               Anmerkungen:

               • Allows recognition by phagocytes
            2. Membrane Attack Complex (MAC)

               Anmerkungen:

               • drills holes in membrane of thin walled cells (such as Neisseria) --> lysis
         2. ADCC

            Anmerkungen:

            • Antibody dependent cellular cytotoxicity Effector cells (neutrophils, monocytes, eosinophils, NK cells) bind to Fc region of Ig.
            1. Lysis without phagocytosis
      2. Examples
         1. Transfusion reactions

            Anmerkungen:

            • Commonest blood transfusion reaction
         2. Erythroblastosis fetalis
         3. Autoimmune haemolytic anaemia/granulocytosis/thrombocytopenia
         4. Various drug reactions
   2. Inflammation

      Anmerkungen:

      • Complement and Fc mediated reactions at BM/ECM
      1. Ig
         1. Complement
            1. C5a
               1. attract cells

                  Anmerkungen:

                  • PML, monocytes
                  1. pro-inflammatory substances

                     Anmerkungen:

                     • enzymes/ROS
            2. C3a
            3. C3b
      2. Examples

         Anmerkungen:

         • 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
   3. Cellular dysfunction
      1. Ig
         1. Blocks R

            Anmerkungen:

            • ACh-R = Myasthenia Gravis
         2. Stimulates

            Anmerkungen:

            • e.g. TSH-R = Graves disease
3. Type IV (Cell mediated) Hypersensitivity
   1. T cells
      1. CD4+ DTH

         Anmerkungen:

         • Delayed type hypersensitivity aka 'immune inflammation' 1st stage - diferentiation of Th cell. 2nd stage -repeat exposure to differentiated cells.
         1. Th-17
            1. Neutrophils
            2. cytokines

               Anmerkungen:

               • IL-1, 6, 23 TGF-B LI-17, 22, chemokines - inflammationIL-21 - amplify Th-17
         2. Th-1
            1. Macrophages
               1. cytokines

                  Anmerkungen:

                  • Inflammation: TNF IL-1 Chemokines IL-2 - amplifies Th1
            2. IFN/IL-2

               Anmerkungen:

               • autocrine feedback, differentiate Th cells
         3. Morphology

            Anmerkungen:

            • 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
            1. macrophage
               1. epitheloid
                  1. granuloma

                     Anmerkungen:

                     • epitheloid cells surrounded by lymphocytes (also formed by foreign bodies)
      2. CD8+

         Anmerkungen:

         • Cell mediated cytotoxicity Graft rejection/viruses/Type 1 DM
         1. Complex
            1. Perforins
            2. Granzymes

               Anmerkungen:

               • proteases that cleave and activates capsases
            3. Serglycin
         2. Fas ligand

            Anmerkungen:

            • binds to target cells Fas and casues APOPTOSIS
         3. cytokines

            Anmerkungen:

            • IFN --> inflammation less important.
   2. Examples

      Anmerkungen:

      • 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
      1. Poison Ivy
      2. MANTOUX
4. Type III (Immune-complex) Hypersensitivity

   Anmerkungen:

   • Ag + Ig = inflammation & Damage Jarison-herxheimer - reaction to endotoxins released by harmful organisms. Penicillin and syphillis.
   1. Systemic
      1. Phases

         Anmerkungen:

         • C3 levels decrease as consumed (measure of activity)
         1. Complex formation in circulation

            Anmerkungen:

            • 1/52 after injection, 
         2. Tissue deposition

            Anmerkungen:

            • medium sized, Ag excess
            1. Glomeruli
            2. Joints
         3. Inflammation

            Anmerkungen:

            • 10 days Symptomatic -vasculitis -arthritis -GN
      2. Prototypic = Acute Serum Sickness

         Anmerkungen:

         • -previously when horse diptheria injected in large amounts
      3. Morphology
         1. 'Fibrinoid"necrotising vascullitis
            1. necrosis
            2. Infiltration
   2. Localised

      Anmerkungen:

      • local tissue necrosis secondary to local immune vasculitis.
      1. 'Arthus reaction'

         Anmerkungen:

         • max at 4-8 hours
      2. deposition
         1. fibrinoid necrosis & thrombosis
            1. ischaemic injury

1. Mechanisms
   1. T cell mediated (Cellular)
      1. Direct

         Anmerkungen:

         • probably the key factor in acute rejection T cells recognise MHC presented on DONOR APCs B7-1, B7-2 co-stimulators. Delayed type hypersenitivity.
      2. Indirect

         Anmerkungen:

         • 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.
   2. Antibody mediated (Humoral rejection)
      1. Hyperacute rejection

         Anmerkungen:

         • preformed Ig present -previous transplant/transfusion -post-pregnancy
      2. Rejection vasculitits

         Anmerkungen:

         • not previously exposed
2. Morphology

   Anmerkungen:

   • Kidney transplant - prototypic example
   1. Hyperacute

      Anmerkungen:

      • 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)
   2. Acute

      Anmerkungen:

      • Days
      1. Cellular

         Anmerkungen:

         •  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.     
      2. Humoral

         Anmerkungen:

         • (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     
   3. Chronic

      Anmerkungen:

      • 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.  
3. Survival
   1. HLA matchiing

      Anmerkungen:

      • Kidney's only
   2. Drugs
      1. Cyclosporine

         Anmerkungen:

         • blocks NFAT transcription factor - encode IL-2 and other cytokines
      2. Azathioprine

         Anmerkungen:

         • inhibits leukocyte development from bone marrow precursors
      3. Steroids

         Anmerkungen:

         • block inflammation
      4. rapamycin and mycophenolate mofetil

         Anmerkungen:

         • inhibit lymphocyte proliferation
      5. monoclonal anti–T-cell antibodies
      6. proteins that bind to B7 costimulators
   3. donor inoculum

      Anmerkungen:

      • mixed chimerism
4. Bone Marrow Transplant
   1. Graft vs Host

      Anmerkungen:

      •     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.     
      1. Acute

         Anmerkungen:

         •     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     
      2. Chronic
   2. Immunodeficency

      Anmerkungen:

      • CMV can be fatal