Immunologie (Fach) / MD PhD (Lektion)

Oxenius & Kopf

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• Passive immunization - Botulism - Cytomegalovirus - Diphtheria  - Hepatitis A and B - Measles - Rabies - Respiratory disease - Tetanus - Varizella zoster
• Live attenuated - Measles - Mumps - Polio - Rotavirus - Rubella - Tuberculosis - Varizella - Yellow fever
• Inactivated or killed - Cholera - Influenza - Hepatitis A - Plague - Rabies
• Toxoid - Diphtheria - Tetanus
• Subunit (inactivated exotoxin) - Hepatitis B - Pertussis - Streptococcal pneumonia
• Conjugate - Haemophilus influenza B - Streptococcal pneumonia
• Pattern recognition receptors (PRRs) - TLRs (toll-like receptors) are expressed on the cell surface or in the membrane of endosomal compartments - NODs (nucleotide-binding oligomerization domain) are present in the cytosol Outer membrane:TLR2: PeptidoglycanTLR4: Lipopolysaccharid In Endosomes:TLR3: dsRNA (intermediate in viral replication) TLR7/8: ssRNA (certain viruses)TLR9: CpG-containing bacterial DNA  NOD1/2: bacterial peptidoglycan structures  Scavenger receptors (SR)
• Acute-phase proteins e.g. C-reactive protein (CRP) produced in liver - Binding of CRP (to C-polysaccharide cell wall components of bacteria and fungi) leads to activation of complement system 
• MHC I/II formation MHC I:- Endogenous antigens- degraded to peptides in the cytosol- transported into the ER where they bind to MHC class I molecules and are further transported to the cell surface.  MHC II: - Exogenous antigens - taken up by APCs via endocytosis or phagocytosis- Peptide fragments of the antigens are generated in the endocytic pathway
• Oxidative burst Increased O2 consumption O2 – NADPH oxidase-- > O2.- Superoxide O2.- Hydrogen peroxide H2O2 Hypochlorous acid HOCl Nitric oxide NO - begins before phagocytosis is complete - generation of ROS: continues in phagosome - localizes to the interior of the phagosome 
• hematopoietic stem cell (HSC) markers: Sca-1, CD34 Location during development - yolk sac- liver/spleen- long bones- cranium, pelvis, sternum, ribs, vertebra
• CD16 - receptor for Fc region of IgG - located on NK cells
• CD3 signal transduction element of T-cell receptor (cytoplasmic tail is too short)
• Mononuclear phagocytes •Intestinal macrophages in the gut •Alveolar macrophages in the lung •Histiocytes in connective tissue •Kupffer cells in the liver•Mesangial cells in the kidney •Microglial cells in the brain •Osteoclasts in the bone •Macrophages are activated by „pathogen-associated molecular patterns“ (PAMPs) 
• Follicular dendritic cells (FDCs)  - Do not arise in BM (precursor is a stromal cell) - Are MHC class II negative - Are found in follicles of LNs (B cell zone) - Capture antigen/antibody complexes and present them to B cells 
• CD3 complex - associated with the TCR - Required to bring TCR to surface - Transduces activating signals to T cell when TCR recognizes MHC-peptide 
• T cell development 1. β-chain rearrangement (forms pre-TCR) 2. Proliferation 3. a-chain recombination –> αβ TCR on cell surface 4. Selection (positive and negative)5. T cells move to periphery During this process 95% T cells die due to unproductive TCR rearrangement or failure of positive or negative 
• T cell stimulation 1. TCR-antigen contact 2. Co-stimulationPositive signals:- CD28- ICOSNegative signals:- PD-1- CTLA-4 3. Cytokine production (IL-2, IL-2R)
• T-cell types Peptide + MHC class I:CD8: kills virus-infected cells Peptide + MHC class II:TH1: recognizes bacterial antigens on the surface of infected macrophages --> stimulates the macrophag'es microbidal acitivity to nable it to kill them TH1 and TH2: activates naive B-cells and induces class switchingTH17: induce epithelial/stromal cells to produce chemokines that recruit neutrophilsTreg: supress T-cell responses
• B-cell activation 1. B cell activation by antigen mediated crosslinking of the B Cell Receptor 2. Antigen presentation to the T cell (MHC II) 3. T cell activation, upregulates CD40L, produces cytokines 4. CD40 and cytokine-mediated activation of the B cell  - Cytokines determine the isotope-switch- allows somatic hypermutation within germinal centers - allows the development of memory B cells 
• Superantigens - eg Toxic shock syndrome toxin I (TSST-1) - Do not induce adaptive responses, but trigger a massive burst of cytokines that may cause fever, systemic toxicity & immune suppression  - Not processed - Only TcR β chain involved in recognition - 2-20% of T cells recognise a superantigen - Presented by almost any MHC class II molecule
• Peripheral tolerance - Anergy (no co-stimulation) - Ignorance (antigen sequestration in immunologically privileged sites) - expression of ligands for death receptors on T-cells (FasL, TRAIL) - supression by Treg
• Regulatory T cells (Treg) - express the surface markers CD4+ and CD25+ and the transcription factor Foxp3 - Can be of thymic origin (natural nTreg) or generated in the periphery (inducted iTreg) - stimulated in an antigen-specific manner - Inhibit proliferation and cytokine production of other T cells - Inhibitory signals mediated by cytokine secretion (IL-10, TGF-β) and/or receptors (i.e. CTLA-4) or indirectly through APCs (by decreasing CD86) - In vivo the cells can limit disease development and pathology 
• Treg development - in the thymus (natural nTregs) - in the periphery (iTregs) Differential signals:- TGFß- IL-2- Retinoic acid
• Molecular Mimicry - causes autoimmune disease - molecular structures of microorganisms have similarities to self molecule (mimicry) - The immune system (cross-reactive T cells or antibodies) then mistakenly attacks self molecules  Eg Antibodies against antigens from Streptococcus A bacteria cross react with human cardiac muscle. 
• Induction of autoimmunity - by molecular mimicry (eg Strep A) - Modification of self antigens (eg haemolytic anemia in susceptible people when penicillin binds to erythrocytes) - Release of antigen from immunoprivileged sites (viral infection, trauma, surgery) - Bystander activation of Dendritic cells (by inflammatory cytokines or microbial products)
• Th1 cells - promoted by IL-12  - associated with intracellular infection including protozoa, bacteria, and viruses - IFN-γ is the key cytokine produced by Th1 cells, which is absolutely essential for activation of macrophages  - eg tuberculosis, leishmania, hepatitis
• Th2 cells - promoted by IL-4 - associated with Helminth infection and allergies  - promote clearance of infection with gastrointestinal nematodes by production of IL-4 and IL-13 
• Th17 cells - promoted by IL-6, TGFß - promote clearance of bacterial infection at mucosal surfaces (i.e. intestines and lung) and the skin - IL-17A promotes recruitments of Neutrophils, which are essential for killing of bacteria  - can also cause autoimmunity
• The cytokine environment directs Th subset development - IL-12 promotes Th1 and inhibits Th2 development - IL-4 promotes Th2 development - IL-6 and TGFβ promote Th17 development 
• Cytokines Key Features - pleiotropic: a single cytokine that has multiple biological activities - redundant: two or more cytokines that mediate similar functions - synergic: combined effects of two cytokines on cellular activity is greater than the additive effects of the individual cytokines Pro-inflammatory: IL-1, IL-6, IL-12, TNF-aAnti-inflammatory: IL-10, TGF-ßLymphokines: IL-2, IL-4, IL-10, IL-21Growth factors: GM-CSF
• Cytokines Structure - Hematopoietin family: IL-2, IL-4, IL-7, IL-13, IL-15, IL-21  - Structure: 4 alpha helical bundles  Bind to:- Hematopoietin receptor family (class I cytokine receptors) - Interferon receptor family (class II cytokine receptor) - TNF receptor family - Immunoglobulin superfamily- Chemokine receptor superfamily 
• Type I hypersensitivity 1. Sensitization: Development of a Th2-dependent IgE response following encounter with an environmental antigen (allergen) 2. Activation of B cells and IL-4-mediated switching to IgE producing B cells 3. Differentiation to IgE producing plasma cells 4. IgE binding to Fcε (IgE) receptor cn mast cells and basophils 5. Re-exposure: Mast cells or basophils release pharmacologically active mediators
• Type II hypersensitivity Step One: Sensitization towards a cellular bound antigen (self or foreign) and production of IgM and/or IgG antibodies specific for that antigen. Step Two: Subsequent exposure to the same cell-bound antigen results in coating of the cell with specific antibody. Step Three: Cellular-bound antibody causes cell lysis by activating antibody dependent cellular cytotoxicity (ADCC) (which is mediated by NK cells) or formation of the complement membrane attack complex.  Examples:- Blood transfusion reactions (ABO incompatibility)- Hemolytic disease of the newborn (erythoblastosis fetalis)- Penicillin (alters self-antigens on RBCs)- Goodpasture's syndrome- Myasthenia gravis- Pemphigus
• Complement Functions - Lysis of bacteria, viruses, and cells by MAC (Membrane-Attack Complex)- Opsonization (promotes phagocytosis of pathogens)- Enhancement of antibody responses- Activation of inflammatory responses by attraction and activation of phagocytes - Clearance of immune complexes - Clearance of apoptotic cells
• Type III Hypersensitivity - also called arthus reaction Step One: Sensitization towards a soluble antigen (self or foreign) and production of IgM and/or IgG antibodies specific for that antigen. Step Two: Subsequent or continued exposure to the same soluble antigen results in the formation of Immune complexes (antigen-antibody complexes). Step Three: Immune complexes located within the tissue containing the antigen (i.e. joints) or deposited in organs from the blood then activate complement causing a localized influx of inflammatory cells and resulting in tissue damage.  Examples:- Rheumatoid arthritis- Systemic lupus erythematosus (SLE)- serum sickness- EAA- Polyarteritis nodosa
• Type IV Hypersensitivity Step One: Sensitization towards a pathogen or contact antigen and generation of specific Th1 cells. Step Two: Subsequent exposure to the pathogenic or contact antigen resulting in recruitment and activation of effector Th1 cells at the site of exposure. Step Three: Massive cytokine production by recruited Th1 cells followed by additional recruitment and activation of macrophages (and to a lesser extent granulocytes) resulting in tissue damage and possible granuloma formation. Note: this takes 24-72 hours to occur. Examples:- Nickel allergy- Poison ivy 
• Cells with Fc receptors - Macrophages - NK - Neutrophils bind to antibody-coated pathogens for destruction 
• Comparison naive and effector cells Naive:- Require co-stimulatory molecules (CD28-B7)- low expression of adhesion molecules- transport pattern through HEVs, secondary lymphoid tissues Effector:- do not require co-stimulation- many adhesion molecules (LFA)- transport to tertiary lymphoid organs, inflammatory sites
• CFSE (Carboxy-fluorescein diacetate, succinimidyl ester) dilution assay - Measures T cell proliferation in cell-mediated response  - intracellular labeling with fluorophor CFSE  - daughter cells have 50% of fluorescence --> peak count in FACS
• 51Cr release assay - measures cytotoxicity (performance of effector cells) 1. Labeling of target cells with 51Cr and +/- peptide 2. Incubation of target cells with effector cytotoxic T cells 3. Quantification of 51Cr in supernatant 
• Molecules with cytotoxic potential CTL: Soluble: perforin, granzymes (granules), TNFa, TNFb (=LTa) Membrane-bound: fasL (granules, cell surface)  Th: Soluble: TNFa (Th1)Membrane-bound: fasL, TNFb (=LTa) in Th1 NK: Soluble: perforin/granzymes, TNFa, TNFb (=LTa) Membrane-bound: fasL, TNFa 
• Natural killer cells (NK cells) - Lymhpoid cells dervied from bone marrow - No expression of TCR or CD3, generation of NK cells is thymus-independent - Effector mechanisms include cell-mediated cytotoxicity and cytokine secretion - NK cells express fasL and have granules with perforin and granzymes - NK cells are constitutively cytotoxic (unlike CTLs which depend on TCR-triggered activation) --> have both activation and inhibition receptors  - NK cells can lyse/induce apoptosis in virus-infected cells or in tumor cells - NK cell activity does not increase after a second injection e.g. of tumor cells (no immunological memory) 
• KIR and CD94/NKG2 - "killer cell inhibitory receptor"- multiple KIRs can be expressed on one NK cell CD94/NKG2- recognizes HLA-E on target cells- HLA-E is only transported to the cell surface if it has bound a peptide from HLA class I- the amount of HLA-E serves as an indicator for the overall level of HLA class I biosynthesis 
• Antibody-dependent cellular cytotoxicity (ADCC) - Macrophages - NK - Neutrophils - Eosinophils
• Requirements for a successful vaccine 1. Safe 2. Protective 3. Gives sustained protection 4. Produces neutralizing antibodies (to prevent infection of cells that cannot be replaced eg neurons) 5. Practical considerations
• Vaccine types - Live attenuated pathogens - Inactivated pathogens - Subunit vaccines:--> Antigens expressed as soluble proteins/polysaccharides --> Antigens expressed within live vectors - DNA vaccination
• Ig diversity - multiple germ-line gene segments- combinatorial V(D)J joining (random)- junctional flexibility• RSSs (signal joint) are always joined precisely, coding joints are often joined imprecisely• Amino acid variation that is generated by coding joints falls within the CDR3 - P-region nucleotide additions• Complementary nucleotides are added by repair enzymes and generate a palindromic sequence  - N-region nucleotide additions (TdT)• Non-template driven addition of nucleotides is catalized by terminal deoxynucleotidyl transferase (TdT) • only in heavy chains!- somatic hypermutation (in germinal centers during B cell activation) - combinatorial association of light and heavy chains 
• Somatic hypermutation - Occurs during germinal center within 1 week of immunization - Somatic hypermuation is targeted to rearranged V regions- Mechanism: nucleotide substitutions (largely but not completely random fashion)- Activation-induced cytidine deaminase (AID) is an essential enzyme (also in class switch recombination)- Somatic hypermutations are clustered within the CDRs of VH and VL- Following exposure to antigen, B cells that have generated receptors with higher affinity will be preferentially selected for survival („affinity maturation“) 
• IPEX = immunodysregulation polyendocrinopathy enteropathy X-linked syndrome - dysfunction of the transcription factor FOXP3 (and regulatory T cells) --> Autoimmunity

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