IMMUNITY

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

            Anotações:

            • 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

               Anotações:

               • 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

            Anotações:

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

               Anotações:

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

                  Anotações:

                  • 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

      Anotações:

      • 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

Anotações:

• 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

      Anotações:

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

            Anotações:

            • 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

                     Anotações:

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

            Anotações:

            • Ag trapping, blood equivalent of lymphnodes
         3. MALT

            Anotações:

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

            Anotações:

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

         Anotações:

         • 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)

      Anotações:

      • Immunoglobulins
      1. Clonal selection hypothesis

         Anotações:

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

         Anotações:

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

         Anotações:

         • protein identification mucosa
      4. IgE

         Anotações:

         • Protein identification Helminths
3. Cellular (intracellular)

   Anotações:

   • 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

      Anotações:

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

            Anotações:

            • 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

                  Anotações:

                  • 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

         Anotações:

         • 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

                  Anotações:

                  • 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

               Anotações:

               • 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

                        Anotações:

                        • 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

      Anotações:

      • Difficultly breathing Oedema Shock
      1. Anaphylactoid

         Anotações:

         • 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

         Anotações:

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

            Anotações:

            • Blood based
            1. Eosinophils

               Anotações:

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

               Anotações:

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

               Anotações:

               • 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

                     Anotações:

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

                     Anotações:

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

                     Anotações:

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

                  Anotações:

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

                                 Anotações:

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

                        Anotações:

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

            Anotações:

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

   Anotações:

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

               Anotações:

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

               Anotações:

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

            Anotações:

            • 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

            Anotações:

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

      Anotações:

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

                  Anotações:

                  • PML, monocytes
                  1. pro-inflammatory substances

                     Anotações:

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

         Anotações:

         • 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

            Anotações:

            • ACh-R = Myasthenia Gravis
         2. Stimulates

            Anotações:

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

         Anotações:

         • 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

               Anotações:

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

                  Anotações:

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

               Anotações:

               • autocrine feedback, differentiate Th cells
         3. Morphology

            Anotações:

            • 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

                     Anotações:

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

         Anotações:

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

               Anotações:

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

            Anotações:

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

            Anotações:

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

      Anotações:

      • 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

   Anotações:

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

         Anotações:

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

            Anotações:

            • 1/52 after injection, 
         2. Tissue deposition

            Anotações:

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

            Anotações:

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

         Anotações:

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

      Anotações:

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

         Anotações:

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

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

         Anotações:

         • 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

         Anotações:

         • 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

         Anotações:

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

         Anotações:

         • not previously exposed
2. Morphology

   Anotações:

   • Kidney transplant - prototypic example
   1. Hyperacute

      Anotações:

      • 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

      Anotações:

      • Days
      1. Cellular

         Anotações:

         •  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

         Anotações:

         • (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

      Anotações:

      • 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

      Anotações:

      • Kidney's only
   2. Drugs
      1. Cyclosporine

         Anotações:

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

         Anotações:

         • inhibits leukocyte development from bone marrow precursors
      3. Steroids

         Anotações:

         • block inflammation
      4. rapamycin and mycophenolate mofetil

         Anotações:

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

      Anotações:

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

      Anotações:

      •     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

         Anotações:

         •     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

      Anotações:

      • CMV can be fatal