IMMUNOLOGY: Part 1: Introduction to immunobiology and innate immunity (p1-36)
1. Chapter 1: Basic concepts in immunology
• Zie extra papieren
• In plant & animal kingdom: looked at NOD like receptors (NLR) (innate immunity) (zie extra)
o = sense presence of pathogens in terms of biomolecules => then immune respons that react to a
CLASS of pathogens (vb funga, virus) (not to specific pathogen)
• Summary of molecules of the immune system & innate and adaptive immune characteristics
o Adaptive immunity = responds to specific pathogen & adapts when organism encounters that
specific pathogen during lifetime
▪ Vb: antibody production against particular pathogen as defense
o Innate immunity = immunity inherited from parents = basic level of immunity (always present) =
fixed genes that respond to pathogens, but independent of pathogen you encounter (nonspecific) +
no adaptation (ppt: from Classical down)
▪ Vb: macrophages engulf many MO as defense (nonspecific; always present)
o => Innate & adaptive immune system integrate to give immune respons
• Edward Jenner
o Invention: vaccination = inoculation of healthy people with weakened or attenuated strains of
disease-causing agents in order to provide protection from disease
o Process: Cows have pox virus that gives lesions to uiers/tiets => milk maids exposed & infected by
pox virus (not lethal) did also not get sick by variola virus (lethal)
▪ => isolates from pox virus became vaccination for variola virus
o Gevolg: Eradication of small pox (variola) by vaccination (small pox vaccination)
• Origin of vertebrate immune cells
o Immune system = effector cells that protect body from infectious agents & their toxins (immune
cells reside in blood stream, lymphatic system, peripheral tissues)
o Both innate & adaptive immune respons ~ activity of leukocytes or white blood cells
o 1) All cellular elements of bloods, including immune cells, derive from the hematopoietic stem cells
(HSCs) of the bone marrow = pluripotent (give rise to different types of cells)
o 2) HSCs divide to produce two types of stem cells
▪ 1) Common lymphoid progenitor (CLP): gives rise to lymphoid lineage (blue) of white blood
cells or leukocytes – innate lymphoid cells (ILCs), natural killer (nK) cells & T & B lymphocytes
• T & B lymphocytes have antigen receptors ILCs & NK cells lack antigen specificity
• T & B lymphocytes have different site of differentiation: thymus (T) & bone marrow
(B)
o After encounter with antigen: B cell differentiate into antibody secreting
plasmacells & T cells differentiate into effector T cells
▪ 2) Common myeloid progenitor (CMP): gives rise to myeloid lineage (pink & yellow), which
compromise the rest of the leukocytes (monocytes, dendritic cells, neutrophils, eosinophils,
basophils), erythrocytes (red blood cells) & megakaryocytes that produce platelets
• Neutrophils, eosinophils, basophils = circulate in blood = granulocytes (cytoplasmic
granules)
• Immature dendritic cells = phagocytic cells that enter tissues; maturation after
encountering a pathogen; majority from myeloid, some from lymphoid progenitor
• Monocytes = enter tissues and differentiate then into macrophages or dendritic cells
• Mast cells (allergies) = also enter tissues & complete their maturation there
▪ Opm: 2 categories leukocytes: lymphoid (adaptive: T,B,NK) & myeloid (innate: neutrophils..)
▪ Opm : erythrocytes (carrier O2): not immune cells, but role in immune respons via receptors
Principles of innate immunity
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,• Classification of immune cells = based on surface markers & signaling molecules
o Surface markers = called cluster of differentiation, used for immunophenotyping of lymphocytes
▪ Vb: CD4 (helper) & CD8 (killer) markers for T cells (they allow to differentiate in T effectors)
B cell has antibody on its surface (both for antigen detection????)
o Signaling molecules = effector molecules (cytokinines & chemokines) expressed by lymphocytes
▪ Vb: IL17 (cytokinine?) associated with specific set of T lymphocytes
• Density gradient centrifugation to isolate vb: lymphocytes (isolate a specific celltype) in blood
o = separation according to celltype: cells with large volume = lower relative density compact
o Gevolg: based on density some cells will float, others will sink
• Evaluation of the cellular components (T,B,monocytes,…) of the human immune system
o => if you have immune response, amount of cells in blood & amount of antibodies will change
o 1) Blood values can indicate an normal or a pathological condition
▪ Vb: increase in neutrophiles, show early infection
o 2) Antibody/immunoglobin measurement can also indicate normal or a pathological condition
▪ Vb: increase in IgE, you have an allergy or a parasite
▪ Vb: measure type of heavy chain: igM represents early stage of immune respons igG
represents older stage of immune respons => see if exposure to parasite was recent or later
• FACS analysis: cytometrie to zoom in in population (sorted out via gradient density) to a certain subtype
o = uses antibodies, labeled with fluorofoor, to detect a specific antigen
o 1) Navigate these as single cells via narrow channel
o 2) Different lasers to excite the fluorofoor & a detector
o => like this figure out which antigens are on the surface (& thus which surface markers)
• Magnetic-activated cell sorting (MACS) to isolate cells in heterogenous population of lymphocytes (ipv
identify)
o = uses same technology as FACs, but now antibodies coupled to paramagnetic particles/beads
o 1) Use magnetic field to capture these cells & unlabeled cells are washed out
o 2) Magnetic field is removed, releasing the coupled cells (& see thus which surface markers)
• Thin film (old school)
o = technique to find out if there is inflammation
o 1) Drip of blood & pull one microscope slide over the other slide => result: thin film of blood
o 2) Fix cells & color cells with GEIMSA vb: basophilic dye colors DNA & acidic one colors cytoplasma
o 3) Count nr of cell: if neutrophiles nr is much higher = early stage of inflammation
• Commensal organisms cause little host damage while pathogens damage host tissues by a variety of
mechanisms
o Pathogens vary in size & lifestyle vb viruses small parasites larger
o But same immune cells (cells of innate & adaptive immune system with diff surface markers & signal
molecules) defend against these pathogens
• Protection against pathogens relies on several levels of defense
o Anatomical and chemical barriers are the first defense against pathogens
o 1) Anatomical barriers: provided by body’s epithelial surfaces: skin, oral mucosa, respiratory
epithelium, intestine (prevent exposure to microbes
o 2) Complement/antimicrobial proteins: chemical and enzymatic systems: C3, defensines, Regilly
▪ = act as antimicrobial barrier near these epithelia (mucosa produce antimicrobial proteins)
▪ Complement = acts with antibodies to lyse bacteria
• Blood: serum, proteins, unhabitable for pathogen => part of this is because of
complement system (effectors in serum)
• Complement system needs to differentiate between pathogens & host cells (both
made up by biomolecules DNA, proteins,..) => regulation done by C3, defensins,
Regilly => complement acts against pathogens & leaves host cells alone (??)
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, o 3) If anatomical barriers are breached or evaded, other components of the innate immune system
can act: macrophages, granulocytes, natural killer cells (in antigen independent way kill host cells)
o 4) If pathogen overcomes barriers, slower acting defenses of adaptive immune system act: B
cells/antibodies, T cells
• Cell-mediated immunity proceeds in a series of steps
o A pathogen that breaches host barriers (1): encounters cellular defenses of innate immunity
o 1) The immune system is activated by inflammatory inducers that indicate the presence of
pathogens or tissue damage: bacterial lipopolysaccharides, ATP, urate crystals
o 2) Sensor cells (macrophages, neutrophils, dendritic cells) detect these inducers by expressing innate
recognition receptors:
▪ & in response produce mediators (cytokinines, cytotoxicity: can kill cells) that act directly in
defense or further propagate the immune respons
▪ & they act on various target tissues vb endothelial tissue for production of antimicrobial
proteins & induction of intracellular antiviral proteins ; killing of infected cells (cytotoxins); or
vb other immune cells (NK cells, ILCs)
• Summary innate vs adaptive immune system (tekening S45)
o Innate (macrophages, monocytes,..) (zie verder)
▪ 1) Have Toll like receptors
▪ 2) Nod receptors in cytoplasma
o Adaptive (B cell (secrete antibodies) (plasmacell special one), T cell (CD4+/Helper, CD8+/Killer)
(parallel with CD8% u have NK cells in innate immunity)
▪ Helpercells produce cytokines (effectors) & killer cells produce toxins (effectors)
o Exam: see extra paper (can copy paste in front of book; or make these at paper question)
• Phases of the immune respons (time)
o Innate immune respons: occur rapidly on exposure to infectious agent (min) ; first fast responders
o Adaptive immune respons : take days rather than hours to develop; slow responders
▪ Adaptive immunity recalls pathogens they encountered (memory) => so next time they
encounter same pathogen, you can respond quicker
▪ but adaptive respons eliminate infections more efficient because of specificity of antigen
recognition by lymphocytes innate
o Immunological memory = adaptive immune system can generate this = if you have been exposed
once to a pathogen, u will make a stronger & faster response against any subsequent exposure to it
▪ = memory that can last depending on the pathogen from days/weeks/months to lifelong
immunity (vb vaccin will protect you 4-6 months)
• Myeloid cells in innate & adaptive immunity and their activated function
o CMP = precursor of macrophages, granulocytes (white blood cels: neutrophils, eosinophils,
basophils), mast cells, and dendritic cells of the innate immune system
o 0) Monocyte = progenitor of macrophage, in blood => when monocyt leaves blood it can
differentiate into a macrophage (different phenotypes depending on tissue)
o 1) Neutrophils & Macrophages = phagocytic cells that engulf pathogens (clean up) and destroy them
in intracellular vesicles via bactericidal mechanisms (function in both A&I respons)
▪ => macrophages can also present antigens to T lymphocytes & activate T lymphocytes &
initiate A respons (=antigen presentation) neutrophils
▪ => neutrophils role in inflammation: typical adaptive immune responses in different
compartments, and one compartment recruit neutrophils
▪ => macrophages orchestrate immune response: help induce inflammation which is
prerequisite to succesful immune response & produce inflammatory mediators that activate
other immune system cells & recruit them into an immune respons (~ complement)
o 2) Dendritic cells = are phagocytic when they are immature & can take up pathogens
▪ => after maturing, they are specialized cells that present pathogen antigens to T
lymphocytes & activate T lymphocytes & initiate A respons (= antigen presentation)
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, ▪ => dendritic cells orchestrate immune respons also (“): emit cytokinines to
orchestrate/navigate immune respons
o 3) Eosinophil (lot of granules) = killing of antibody-coated parasites vb worms via granules
o 4) Basophil (lot of granules) = promotion of allergic responses & anti-parasitic immunity
o 5) Mast cell (even more granules) = release of granules containing histamine & active agents when
encountering antigen => content act on local blood vessels (vasoconstriction) => like this trigger local
inflammatory respons to antigens
o Opm: mast cells, eosinophils, basophils = important in allergic responses & are secretory cells that
release content of granules upon activation via antibody during an adaptive immune respons
• Sensor cells (macrophages, neutrophils, dendritic cells) express (innate) pattern recognition receptors (PRRs)
o 1) that provide an initial discrimination between self & nonself
o 2) that thus detect pathogens or the damage induced by them
o Via recognizing regular patterns of molecular structure = pathogen-associated molecular patterns
(PAMPs) that are part of many MO (nonself biomolecules), but NOT of the host body’s own cells (self
biomolecules) => necessary bec all organisms are made up by same biomolecules DNA, RNA,…
o Voorbeeld van PRR’s:
▪ 1) Toll like receptors (TLRs) = transmembrane proteins = detect PAMPs derived from
extracellular bacteria or bacteria taken into vesicular pathways by phagocytosis
▪ 2) NOD like receptors (NLRs) = cytoplasmic proteins = sense intracellular bacterial invasion
o But auto immune disease (see further): antibodies detect normally peptidic antigens, but there is
something wrong & they now detect host own antigens
• Infection triggers an inflammatory response:
o Activation of PRR on sensor cells can directly induce effector functions vb phagocytosis & destroying
bacteria => but sensor cells also amplify the immune respons by production of inflammatory
mediators (cytokines, chemokines) & like this induce inflammatory response
o 1) Bacteria trigger macrophages to release cytokines and chemokines (left)
o 2) Gevolg cytokines: vasodilatation and increased vascular permeability => allowing fluid and
proteins to pass into the tissues => this accumulation causes redness, heat and swelling (central)
o 3) Gevolg chemokines: direct the migration of neutrophils to site of infection (central)
o 4) Stickness of endothelial cells of blood vessel wall also changes => hereby immune cells
(inflammatory cells: neutrophils & monocytes/macrophages) enter tissue from a blood vessel
▪ Inflammatory cells in tissue, release inflammatory mediators that cause pain by triggering
pain receptors
o Accumulation of fluid + cells at site of infection => causes redness, heat and swelling and pain
▪ = inflammation
• Innate lymphocytes and natural killer cells are effector cells that share similarities with lymphoid lineages of
the adaptive immune system
o CLP give rise to antigen specific lymphocytes of the adaptive immune system (B, T cell) & to innate
lineages that lack antigen specific receptors (NK)
o Natural killer cells (NK) (innate immune equivalent of cytotoxic T cell)
▪ = large granular lymphoid like cells with functions in innate immunity (especially against
intracellular infections) & can kill other cells (via lytic granules similar to CD8+ T cells)
▪ Opm: they lack antigen-specific receptors & are additional layer of surveillance
Principles of adaptive immunity
• Interaction of antigens with antigen receptors induces lymphocytes to acquire effector & memory activity
o Lymphocytes = small & inactive cells (little cytoplasm, large nucleus), until they encounter a specific
antigen with their antigen receptor => become active or effector lymphocytes (cytoplasm increases)
o 1) B lymphocytes (plasmacell)
▪ B cell antigen receptor (BCR): made of genes that encode antibodies (igE; immunoglobulins)
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