Innate immunity

“ unspecific” immunity against infections

-> present and fully effective after birth

-> recognition of evolutionary conserved pathogen-derived strucutres, not of single AG

-> no increased response upon repeated exposure to the same pathogen

-> no immunologic memory -> does not remeber infection with the same pathogen

-> consists of cellular & humoral components -> humoral - all body fluids

immune system

innate immunity adaptive immunity

humoral cellular humoral cellular

complement macrophages Dendritic cells ABs lymphocye cells

cytokines granulocytes cytokines DCs

NK Cells

innate immunity

• immediate - 0-4hrs: infection -> recognition by performed, nonspecific effectors -> removal of infectious agent

early induced response

• early - 4-98hrs: infection -> recruitment of effector cells (Chemokines, inflammatory cells into wound) -> recognition, activation of effector cells

  -> removal of infectious agent

adaptive immune response

• late >96hrs: infection -> transort of AG to lymphoid organs -> recognition by naive B&T cells -> clonal expansion % differentation to effecotr cells -> removal of infection

• -> 3-7d until AIS takes fully place

route of entry mode of transmission

Mucosal surfaces: (dt. schleimhaut)

• airway - inhaled droplet - nasal

• gastrointestinal tract - contaminated water or food - oral

• reproductive tract - physical contact - sexual

external epithelia (skin)

• external surface - physical contact

• wound & abrasions - minor skin abrasions etc.

• insect bites - mosquito bites

infection

innate immunity (0-4h)

infection -> recognition by performed, non-specfic effectors -> removal of the pathogen

routes of entry :

• on mucosal (Respiratory/gastrointestinal, urogential tract)

• outer epithelia (wound, insect bites)

mechanical: epithelia cells joined by tight junctions. longitudinal flow of air or fluid across epithelium. movement of mucus by cilia.

chemical: FA

• enzymes : lysozomes (Salvia, sweat, tears), pepsin

• low pH: stomach

• antibacterial peptides, defensins (skin, gut), cryptidins (intestine)

mircobiological: normal flora compete for nutrient and attachment to epithelium and can produce anitbacterial substances

pathogen recognition - through to pathogen recognition receptores (PRRs)

infection -> recognition by performed, non-specific effectors -> removal of the pathogens

receptor mediated recognition

macrophages -> receptor dock on

bacti -> phagocytosis

• a class of PRRs that inititate the innate immune response by sending conserved molecular patterns of early immune recognition

• TLR 1, 2, 6 -> peptidoglycan (Gram+ bacti)

• TLR 3 -> ds RNA (RNA virues, ds bc viruses have to replicate

• TLR 4 -> LPS & lipoteinchoic acid (gram + bacti)

• TLR 9 -> non-methylated CpG DNA (present in procaryotes)

1. lipid A / LPS ——————————————--> TLR 4 (gram - bacti)

1. Lipopeptides, Peptidoglycan, Teicho acid —> TLR2 (gram + bacti)

2. ds RNA ——————————————————> TLR 3

3. Flaggelin ————————————————-->TLR 5 (Bacti flagella)

4. Procaryotic DNA —————————————-> TLR 9 (CpG DNA, non-meht.)

improtant where are they expressed? -> body fluids

plants - kind of basicc TLRs

dropsophila - nüsslein-vollhard called it Toll bc of german Toll - she was so excited

mammals and drosophila - same signal pathway

S13 abbildung einfügen

Lipid A Core Polysaccharides

lipid a Lectins- recognise sugars

LPS receptors complemt

mediators Opsonization - marking of a pathogen

cytokines (TNF-a, IL1, IL-6, IL-8) phagocytosis

Inflammation chemotaxis

Shock lysis

1. soluble lectins (humoral): collection (C-Type lectin family) - e.g. mannose binding proetin (MBP)/ surfactant proteins

collagen structure lectin domain sugar

• binding to receptors (CR1/CD35) -> mediated phagocytosis

• complemt activation

1. transmembrane receptors (cellular): Lectin receptors on phagocytes

   • e.g. macrophage mannose receptor / “Scavenger” receptor

innate immunity: infection -> recognition by preformed, non-specific effectors -> removal of pathogen

1. acidification - pH3.5 - 4.0 - bacteriostatic, bactericidal

2. reactive oxygen species - superoxide, hydrogen peroxide, signlet oxygen, hydroxyl radical, hypochlorite -> if they are reactive everytime kills also our cells

3. reactie nitrogen species - nitrite oxide

4. antimicrobial peptides - defensis cationic proteins

5. enzymes - lysozyme - damages cell walls of some pram+ bacti. acidic hydrolyses -furhter digest bacterial proteins

6. competitors - lactoferrin, binda FE, and Vitamin B12 binding protein

pathogen associated molecular patterns (PAMPs) (recognise PRRs)

• evolutionary conservedmolecular patterns of pathogens

• including: bacterial LPS, peptidoglycan, zymosam (Polysaccharides of fungi), Flaggelin (major protein in Flagella), non-methylated cpG DNA (mostly to differentiate host DNA from pathogen DNA, CpG - Cytosind & guanin)

pattern recognition receptors (PRRs)

• including: TLRs, Receptors of apoptotic cells (Lectin receptor), receptors of opsonin (Recognized sugars), complement receptors (from pathogen)

1. adherence to epithelium -> 2. local infection, penetration of epithelium -> 3. local infection of tissues (bacti start to replicate) -> 4. adaptive immunity

protection against infection

1. normal flora, local chemical factors, phagocytes (especially in lung)

2. wound heling induced, antimicrobial proteins and peptides, phagocytes and complemet destroy invading mircoorganisms (activation of y o T cells?)

3. complement phagocytes, cytokines, NK cells, activation of macrophages, dendritic cells migrate to lymph nodes to initiate adaptive immunity.

4. infection cleared by specific AB T-cell dependent macrophage activation and cytotoxic Tcells. (swelling of lymph knot e.g)

   
   

• PRRs ( TLR, c-type receptors) recognize evolutionarily conserved strucutres on pathogens

• release of cytokines, chemokines and other inflammatory mediators

• recruitment of neutrophils, monocytes, and lymphoctes to the site of nfection

immature = innate immuntiy

mature = adaptive immunity

maturation of DCs: (adaptive immunity)

• initially increased phagocytosis of pathogens upon activation of pattern recognition receptors

• reduced phagocytic capacity after pathogen digestion

time course

1. pathogen uptake

2. migration into draining lymph nodes

3. AG presenting presentation to T cells in combination with co-stimulatory molecules (B/ molecules: CD80, CD86)

-> maturing DCs migrate to the draining lymph nodes!

-> bc DC are immature before they go to lymph node. on the way from DC to draining lymph node they get “activated”

AG uptake by Langerhans’ cells (DCs in expidermis) in the skin -> Langerhans’ cells leave the skin and enter the lymphatic system (migration) ->Langerhans’ cells enter the lymph node to become DCs expressing B7 -> B7-pos. DCs stimulate naive T-cells

1. basic components of immune system

2. Key apell of pathogen invasion pattern recognition

3. main clases of PRR- (TLR,..) (macrophages, DCs..)

classical pathway:

After adaptation, by then the ABs are there.

AG:AB complexes -> complement activation -> recruitment of inflamatory cells, opsonization of pathogens, killing of pathogens

MB-Lectin pathway:

act undependent - MB membrane binding

Lectin binds to AG surfaces -> complemt activation -> recruitment of inflammatory cells

alternative pathway:

spontaniously activated by pathogen surfaces

pathogen surfaces -> complemt activation -> recruitment of inflammatory cells, opsonisation of pathogens, killing of pathogens

why is it only activated by pathogen surface? - marking the pathogen& the host cells -> block the cascade of hostcells

only with innate immunity you can use complemt cascade

complemt cascade active in fluid system. viruses connected to cells -> mainly lifecycle in the cell

classical pathway, MB-lectin pathway & Alternative pathway -> C3 convertase -> (C4a)* C3a, C5a -> Peptide mediators in inflammatory phagocyte recruitment. -> if C3 c. broken - most severe bc connects all 3

-> C3b -> 1. Binds to complemt receptors of phagocytes -> 1.b. opsonization pf pathogens, removal of immune complexes.

-> 1. terminal complement compinents C5b, C6, C7, C8, C9 -> membrane attack complec, lysis of certain pathogens and cells

C5b binds C6 and C7 -> C5b,6,7 complexes bind to membrane via C7 -> C8 binds to the complex and inserts into the cell membrane -> C9 molecules bind to the complec and polymerize -> 10-16 molecules of C9 bind to form a pore in the membrane

activated macrophages secrete a range of cytokines ->

IL1 -> activates vascular endothelium; activates lymphocytes; local tissue destruction; increases access of effector cells -> systemic effects are fever, production of IL6 and Crosstalk for reaction.

TNF-a -> activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complemtn, and cells to tissues and increases fluid drainage to lymph nodes -> systemic effects are fever, mobilization of metabolites and shock

IL-6 -> lmyphocyte activation; increased AB production -> systemic effects are fever, induces acute phase and protein production

IL-8 -> chemotactic factor recruits neutrophils, basophils and Tcells to site of infection.

IL-12 -> activates NK cells; induces the differentiation of CD4 cells into TH1 cells.

Liver: acute-pahse proteins (C-reactive protein, mannan-binding lectin) -> activation of complemt opsonization

Bone marrow endothelium: Neutrophil mobilisation -> phagocytosis

Hypothalamus: increased body temp. -> decreased viral and bacterial replication, increased AG processing and increased specific immune response

Fat, muscle: protein and energy mobilization to allow increased Body temp. -> decreased viral and bacterial replication, invreased AG proc. and increased specific immune response

DCs: TNF-a stimulates, migration to Lymph nodes and maturation -> initation of adaptive immune response

• heterogeneous family of soluble proteins and peptides

• trigger chemotaxis already at extremely low concentrations (pM-mM) - much faster

• Comparable to the mode of activation of hormones

• may act locally, but also systemically

• high pleiotropic activitiy (induce a variety pf biological effects)

• partially redundant functions of several chemokines

sepsis: overload of bacteria - ABs just make sence in early cells -> bc bloodpressure is very low.

cytokines, particularly TNF-a and IL-1 augment the adhesive capacity of endothelia and increase the permeabiliyt of the endothelium

generally, endotheia are impermeable for cells and plasma.

pathogens: epithelia -> Epithelial activation -> epithelial cytokines -> increased permeability of endothelia (IL-1, TNF-a, IL6) -> extravasation of cells and plasma (get out of capilarry into tissue) -> opsonisation -> phagocytosis -> activation of adaptive immunity

• in case of a systemic infection (sepsis) macrophages in spleen and liver release TNF-a into the circulation

• TNF-a augments endophelial permeability for cells, plasma and proteins

• TNF-a increases the adhesive capacites of leukocytes and platelets

• result: septic shock!

• Local- protecive, systemic death - may caused by sepsis

macrophages ativated to secrete TNF-a in the tissue-> increased release of plasma proteins into tissue. increased phagocyte and lymphocyte migration into tissue. increased platelet adhesion to blood vessel wall -> phagocytosis of bacteria. local vessel occlusion. plasma and cells drain to local lymph node -> removal of infection

Adaptive immunity

macrophages activated in liver and spleen secrete TNF-a into the bloodstream -> systemic edema causing decreased blood volume, hypoproteinemia, and neutropenia, followed by neutrophilia. decreased blood volume causes collapse of vessels ->disseminated intravascular coagulation leading to wasting and multiple organ failure -> death

virus-infected host cell -> IFN-a, IFN-ß -> induce resistance to viral replication in all cells, increase MHC class1 expression and AG presentation in all cells, Activate NK cells to kill virus-infected cell.

IFN-ß released by all cells

• different from T & b cells

• no classical AG receptor - unspecific

• cellular component of innate immune system

• recognition and elimination of abnormal cells such as virus-infected cells and tumor cells

• iduction of apoptosis in target cells (by perforn/ granzyme-dependent mechanism)

• involved in AB-dependent cell-mediated cytotoxicity (ADCC)

How do NKc kill virus-infected cells? virus within the infected cell most of the time. -> expressed type 1 interferon

what does a virus enjected cell do -> enter cells, replicates -> cell destroid, only production of viral proteins

missing self! - NK dont recognize virus infection. KIR & KAR regulate

MHC class 1 on normal recognized by killer inhibitory receptors (KIRs) or by lectinlike CD94:NKG2 heterodimers on NKcs which inhibit signals from activating receptors -> NKc doesnt kill the normal cell -> ‘Altered’ or absent MHC class 1 cant stimulate a negative signal. NKc is triggered by signals from activating receptors -> activated NKcell releases granule contents inducing apoptosis in target cell

difference - resting and activated mast cell - resting many round blobs around nucleus, activated - looks destroid but nucleus intact

released mediators: Leukotrienes C4 & D4, prostaglandin D2, PAF chymase, trypase, heparin, histamine, cytokines (IL4,5,6,8, TNF-a)

effector functions: increased endothelial permeability; concentration of smooth muscles; bronchoconstriction; activation of neutrophils, eosinophils and monocytes, inhibition of blood coagulation

epithelial barriers -> seconds

epithelial activation -> minutes

complement -> minutes

cytokines/chemokines -> minutes to days

neutrophils -> hours

monocytes/macrophages -> hours to days

NK cells - hours to days

barriers -infection-> innate immunity -inflammation-> adaptive immunity

skin& mucosa cellular &humoral components. cellular and humoral compoents

innate: lysozyme; secretion of mucus; complemt; cytokines/chemokines; Phagocytes; NKcells

adaptive: ABs; Cytokines, CD4+ t cells, CD8+ Tcells