Myeloid cells

1. physical barrier (skin, prevents infection)

2. innate immunity (tissue-resident immune cells activated after entering, recruiting of other immune cells by secretion of chemokines from the blood)

3. adaptive immunity (switch by transport of antigen to draining lymph node & massive clonal expansion)

1. pluripotent hematopoetic stem cells

2. common lymphoid progenitor (lymphopoiesis to T-/B-/NK-cells & ILC) or common myeloid progenitor

   CMP to granulocyte/ macrophage progenitor and to megakaryocytes/platelets (thrombopoiesis) or erythroblast/erythrocyte (erythropoiesis)

   or to immature DC, neutrophil, eosinophil, basophil, mast cell precursor & monocyte in the blood

3. mature DC, mast cell & macrophage in the tissues

also tissue-resident cells

infiltrate tissue early in life before birth

microglia in brain from Yolk Sac

Langerhans Cells in the skin from fetal liver

Kuppfer cells in the liver from fetal liver and bone marrow

common feature: constitutive MHCII expression

macrophages

Dendritic cells

B-cells

both antigen-presenting cells form the myeloid lineage

macrophage: phagocytosis and activation of bactericidal mechanism & antigen presentation

DC: antigen uptake in peripheral sites, antigen presentation

Phagocytic receptors

Pathogen recognition receptors

bound material internalized in phagosomes

broken down in phagolysosome

1. C-type lectins with carbohydrate-recognition domain CRD

   —>Dectin-1: ß-glucan (glucose polymer) on fungi

   —>Mannose receptor: mannosylated ligands (fungi, viruses, bacteria)

2. Scavenger receports

   —>class A: SR-A-1,-2, MARCO (anionic polymers, low density lipoproteins)

   —>class B: CD36 (high density lipoproteins

3. complement receptors (opsonization of pathogen, mark it for easier destruction)

4. Fc receptors (immunoglobulins, antibodies)

Toll-like receptors TLR

NOD-like receptors (NLR)

RIG-1 like helicase RLH

in innate immune cells

at cell surface but also in cytoplasm & intracellular vesicles

first immune cell actor

secretion of cytokines:

1. systemic & local effect

• IL-1ß: activates vascular endothelium

• TNFα: activates vascular endothelium —>permeability higher

• IL-6: lymphocyte activation

  
  

  1. local effect

     • CXL8: chemotactic factor recruits neutrophils

     • IL-12: activates NK cells

  
  

liver: acute-phase proteins (C-reactive protein Mannose-binding lectin)—>activation of complement, opsonization (acts antibody-like but faster production)

DC: TNFα stimulates migration to lymph nodes and maturation —>initiation of adaptive immune response

• cytokines produced by macrophages cause dilation of local small blood vessels

• leukocytes move to periphery of blood vessels as a result of increased expression of adhesion molecules by endothelium

• leukocytes extravasate at site of infection

effector cell recruitment

CXC: CXCL8/IL-8—>binds CXCR1 and 2 on neutrophils

CC: CCL2—>binds CCR2B on monocytes

CCL4/RANTES—> binds CCR1,3,5 on T-cells

CXXXC minor subfamily

C chemokines

C chemokine

CC chemokine

CXC chemokine

CXXXC chemokine

—>grouped based on their first 2C from the N terminus

1. rolling adhesion: few opportunities to bind to adhesion molecules (E-selectin on endothelial cells)

2. tight binding: after activation of endothelium expression of other adhesion molecules (ICAM-1, LFA-1) leads to tight binding, inside-out signaling (changes conformation of LFA-1 for tight interaction)

3. Diapedesis: pass through 2 endothelial cells

4. migration: to chemokine producing cell

same function mediated by several proteins

1. Selectins: bind carbohydrates

   —> P-selectin

   —>E-selectin

2. Integrins: bind cell-adhesion molecules & ECM, strong adhesion

   —>LFA-1

3. Immunoglobulin superfamily

   —>ICAM-1

   —>ICAM-2

   
   

• M1: proinflammatory /cytotoxic —>TH1 cells produce IFNγ and CD40L activating M1 macrophages at beginning of inflammation

• M2: anti-inflammatory/pro-angiogenic/tissue repair: TH2 recruits and activates M2 macrophages via IL-4 and IL-13 at the end of inflammation

polymorphonuclear—>PMN leukocytes (all besides mast cells)

• neutrophils: phagocytosis and activation of bactericidal mechanisms (60% of peripheral blood leukocytes)

• eosinophil: killing of antibody-coated parasite

• basophil: promotion of allergic responses and augmentation of anti-parasitic immunity

• mast cell: release of granules containing histamine and active agents

not polymorphonuclear

derived form hematopoietic precursors

blood precursor not identified

tissue-resident granulocytes in mucosa and connective tissue surrounding blood vessels

• enzymes: tryptase, chymase (remodel connective tissue)

• (toxic) mediator: histamine, heparin (increase vascular permeability, smooth muscle contraction)

• cytokine: TNFα (promotes inflammation, stimulates cytokine production & activates endothelium), IL-4/13/33 (stimulates & amplifies TH2 cell response), IL3/5 (promote eosinophil production and activation)

• chemokine: CCL3 (attracts monocytes, macrophages & neutrophils)

• lipid mediator: prostaglandins & leukotrienes (smooth muscle contraction, chemotaxis of eosinophils, basophils, and TH2 cells, increase vascular permeability & stimulate mucus production), platelet-activating factor (attracts leukocytes, amplifies production of lipid mediator, activates neutrophils, eosinophils, and platelets)

preformed/immediate action upon mast cell activation

4G protein-coupled receptors (H1-H4)

H1 expressed on endothelial cells & muscles

act after histamine because have to be synthesized after mast cell activation

some similar functions but much more potent

also G-protein-coupled receptors

derive from membrane phospholipids

via phospholipase A2 to arachidonic acid

then with lipoxygenase to leukotrienes or with cyclooxygenase to prostaglandins (inhibited by aspirin/acetylsalicylic acid)

degranulation

secretion of granules

mediated by multivalent antigen cross-linking IgE antibody

IgE binds FcεRI

IgE receptor

FcγRI- FcγRIII: bind IgG1

FcεRI & FcεRII bind IgE

FcαRI binds IgA1/2

have different cytosolic domains: ITAM/ITIM motif

similar to mast cells: tissue remodelling enzymes, cytokines, chemokines, lipid mediators

+microbe toxic products (intracellular killing after phagocytosis of neutrophils)

+extracellular killing of large microbes after degranulation (eosinophils/basophils)

acidification in the phagolysosome

respiratory burst in the phagolysosome

anti-microbial peptides

enzymes

Rac2 assembles functional NADPH oxidase from cytochrome components

senses fMLF (methionine from start codon in bacteria formylated)

GPCR mediated, Rac2 is a GTPase

• before ligand binding, GPCR not associated with a G protein (inactive G protein has GDP)

• ligand binding causes conformational change in receptor and association with G protein (release GDP and binding GTP)

• G protein dissociates into α and ßγ subunits activating other proteins

• α subunit cleaves GTP to GDP & reassociation

creation of reactive oxygen species—>consumption of oxygen

hydrogen peroxide eakly toxic —>microbe catalase

hypochlorite HOCl highly toxic

main target ROS: DNA mutations and breaks

or reactive nitrogen species

iNOS= inducible nitric oxide synthase by fMLP cleaves arginine into NO and citruline

2 families with distinct specificity for Gram+/-

proproteins contain amphiphilic domain, released after enzymatic processing

inserts into the membrane and forms a pore

—>disruption of the membrane

active of Gram+

cleaves disaccharide unit of peptidoglycan (in Gram- hidden by lipopolysaccharide)

active on Gram-

binds to lipid part of LPS (lipid A) and destabilizes outer membrane

neutrophil specific, not in macrophages

active on Gram-

cleaves OmpA (outer membrane protein A)

major basic protein

eosinophil cationic protein

binds to parasite after degranulation (kill large microbes outside of the cell)

in vitro killing

no mechanism known

costly —>huge cell proliferation

when possible avoided by the host