Innate immunity Flashcards
How do pathogens cause infection?
they enter the body by breaching an epithelial or mucosal barrier
name 4 epithelial surfaces providing first barrier of defence against infection
skin, gut epithelium, respiratory epithelium, mucosal membranes
name 2 protective substances that epithelial layers produce?
acidic pH, antimicrobial peptides
name the 4 major categories of innate immunity cellular elements
granulocytes (neutrophils)
monocytes & macrophages
dendritic cells
NK and ILCs (innate lymphoid cells)
name the 4 main stages of an infection and its response
- pathogens adhere to epithelium
- local infection, penetration of epithelium
- local infection of tissues
- adaptive immunity
name the 3 types of cells mediated by phagocytes
macrophages, neutrophils, immature dendritic cells
what can dendritic cells and macrophages do through phagocytosis (other than removing pathogens)?
generation of antigenic peptides for presentation to T cells
what are called soluble proteins bound to microbial surfaces for pathogen recognition? what do they do?
opsonins or soluble pattern-recognition proteins
enhance phagocytosis (opsonization)
give an example of opsonins
antibodies
what are called membrane protrusions that extend from phagocytes?
pseudopodia
what are called large membrane-enclosed endocytic vesicles?
phagosomes
what do phagosomes fuse with? what does that form?
they fuse with lysosomes to form phagolysosomes
what happens in phagolysosomes to kill microbe?
acidification and acquiring of antimicrobial peptides and enzyme
what 4 things are contained in phagolysosomes that kill microbes?
antimicrobial proteins and peptides, low pH, hydrolytic enzymes, oxidative attack
What’s an oxidative attack?
phagocytes generate ROS with their NADPH oxidase enzyme complex. ROS increase oxygen consumption causing a respiratory burst
what does DAMPs stand for and what does it signal
damage-associated molecular patterns -> signal dying cell
what does CD47 signal? what type of cells express a LOT of CD47?
healthy erythrocytes (inhibits phagocytosis)
tumour cells
what type of innate immune cells are neutrophils?
where do they reside?
what can they produce?
phagocytes
reside in the circulation
produce extracellular matrix NETs
what are microglia also called?
what are they responsible for?
what do they recognize?
macrophages of the brain: important for establishing proper neuronal connections
recognize DAMPs
what are the 4 main stages of phagocytosis?
- PRRs recognize DAMPs and pseudopodia appear
- bacterium injested in phagosome
- fusion with lysosome = phagolysosome
- bacterium is killed and digested by enzymes
describe complement system
soluble proteins that cooperate with the innate and adaptive immune system to eliminate pathogens.
mainly proteases
what are the 3 main functions of complements?
increase vascular permeability and chemotaxis, destroy pathogen cell membrane, opsonization
what do complements start as?
inactive pro-proteases
what does proteolytic cleavage of pro-proteases generate?
small fragment: a; specific function
large: b; proteolytic activity (cascade)
name the 2 C3 convertases
C4b2a and C3bBb
what are lectins? what PRRs trigger the lectin activation pathway?
lectins: circulating PRRs
Mannose-binding lectin MBLs or Ficolins
lectin pathway and classical pathway activation
C4b2a (C3 convertase) cleaves C3 into C3a and C3b. happen on pathogen surface
what does C1q binds to? what does it trigger?
C1q binds to pathogen or to antibodies on pathogen
Triggers signalling cascade of classical pathway or links to adaptive immunity
what are C3a and C3b functions?
C3a = inflammation
C3b = opsonization; is a C5 convertase
describe the alternative pathway
factor B and protease factor D:
amplification loop of C3b (C3bBb)
C3 spontaneous hydrolysis
what factor stabilizes C3 convertase C3bBb from the alternative pathway?
properdin (factor P) secreted by neutrophils
stabilizes by binding to microbial surfaces
what’s C3 convertase’s role?
cleave C3
which complements trigger inflammation? and what else do they do?
C3a and C5a recruit phagocytes
what happens if there is too much C3a and C5a?
anaphylactic shock
how do C3a and C5a promote inflammation?
bind to C3aR and C5aR on granulocytes to stimulate proinflammatory cytokines and granule release from basophils, eosinophils, neutrophils and mast cells
which complements are involved in membrane attack?
C5b (directly involved) and C3b (indirectly involved)
negative regulation of complement
complement-regulatory proteins prevent appearance and promote disappearance of C3 convertase
what complement-regulatory protein inhibits MAC formation?
protectin (CD59)
what does PAMPs stand for
Pathogen-Associated Molecular Patterns
what cells express PRRs?
myeloid white blood cells (neutrophils, basophils, eosinophils, granulocytes, mast cells, macrophages)
T cells, B cells, NK cells
name groups of PRRs
toll-like r, NOD-like r, RIG-like r, C-type lectin r, ficolins, MBL, ..
how do TLRs work?
bind PAMPs with adaptor proteins -> signaling cascade -> phosphorylation -> activates TFs -> transcription of innate immune/pro-inflammatory genes
Name the key adaptor proteins and TFs that work with TLRs
adaptor proteins = MyD88 & TRIF
transcription factors = IRF3/7, NF-kB, AP-1
describe C-type Lectin receptors
membrane receptors that bind carbohydrates on pathogen and allergens
describe the CLRs signaling cascad
binding -> activates tyrosine kinase -> CARD adaptor protein -> IRF5 activation -> MAPK pathway -> AP-1 and NF-kB(TF) activation
describe RIG-I-like receptors RLRs
cytosolic PRRs that binds viral dsRNA -> activates mitochondrial signaling protein MAVS -> activates IRFs and NF-kB (TFs)
describe NOD-like receptors NLRs
(NOD = nucleotide oligomerization domain)
cytosolic PRRs that recognize peptidoglycan from bacteria cell wall & triggers NF-kB, AP-1, and IRF signaling and activates caspase-1 protease -> triggers pro-inflammatory cytokines release (post-translational modification)
name the cytokines produced from PRR signaling involved in inflammation
IL-1, IL-6, IL-18, TNF-alpha, IL-12
name the cytokines produced by PRR signaling that have antiviral effect
Type 1 IFN (IFN-alpha, IFN-beta)
what are 2 costimulatory molecules who’s expression is increased through PRR signaling and what do they do
B7.1 (CD80), B7.2 (CD86); do 2nd signal of t cell activation
how does PRR signaling help moving stuff around the cell
enhance migration to secondary lymphoid organs (targets DCs to lymphoid tissue) and upregulates adhesion molecules
how do type 1 interferon work
PRR signal = IFN secretion = triggers more signaling = more transcription of genes that help kill virus
name the transcription factors that get activated through PRR signaling
NF-kB, IRFs, AP-1
which interferon deficiency leads to severe Covid-19?
Type 1 IFN
summary what are the 6 effects of PRR signaling?
cytokine secretion, chemokine secretion, receptor expression, migration, costimulation, expression of other genes
where are adhesion molecules located?
different locations! some only on activated endothelium, some are everywhere
what are the adhesion molecules that slow down leukocytes on vascular epithelium?
selectin
what can severe or chronic inflammation cause?
arthritis or loss of function
what are the 4 steps of migration
rolling adhesion, tight binding, diapedesis, migration
what kind of molecules are cytokines?
small mostly soluble heterogeneous glycoproteins
what is cytokine’s main role?
cellular communication
in what 3 ways can cytokines act?
autocrine, paracrine, endocrine
name 4 examples of function of cytokines?
change adhesion molecules/chemokine receptors expression
increase/decrease enzyme activity
activate B and T cells
cascade induction
what are the 5 major cytokines groups?
interleukins, interferons, tumor necrosis factors TNF, growth factors, chemokines
what is pleiotropism?
what is redundancy?
Pleiotropism: one molecule (ex cytokine) may be produced by many different cell types and have effects on many different cell types
Redundancy: different molecules (ex cytokines) may have the same effect
what is synergy?
what is antagonism?
Synergy: many (cytokines) work togther to induce an effect
Antagonism: one (cytokine) can inactivate the effect of another
how are cytokines related to adaptive immune response?
they tell which adaptive immune response to use (cell-mediated or humoral)
describe cell-mediated immunity
mostly directed to viral infections and intracellular pathogens
is characterized by macrophage and cytotoxic T lymphocyte activation
describe humoral immunity
mostly directed to extracellular pathogens/bacteria
is characterized by B cell activation and antibody production
What is the main cytokine involved in inflammation? what secreted it? how does it work? what 2 diseases is it involved in?
TNF-alpha
- secreted by macrophages
- stimulates vasodilation, clotting, innate cells migration
- involved in Rheumatoid arthritis and Crohn’s disease
what is sepsis?
systemic infection and inflammation caused by TNFalpha
what happens with a systemic infection?
macrophages are activated in the liver and spleen -> TNF-alpha secreted in bloodstream -> decreased blood volume -> vessels collapse -> spreaded coagulation -> wasting, organ failure -> death
describe acute phase response
increased production and secretion of antimicrobial proteins from liver, such as MBL, complement, C-reactive protein
- induced by pro-inflammatory cytokines working synergically
what can C-reactive proteins do?
can opsonize bacteria and induce complement classical pathway activation
what is special about natural killer cells?
they share a common lymphoid progenitor with B and T cells but are innate lymphoid immune cells
what is unique to ILCs and NK cells compared to other lymphoid myelage cells?
they are not antigen specific
where are ILCs?
How do they get activated?
what do they do?
they reside in tissues (and lymphatic vessels lwk).
they are activated by cytokines (no PRRs) produced by other innate cells or DCs.
they contribute to defense against specific pathogens by secreting cytokines.
where are NK cells?
mainly in circulation, sometimes in tissue
what activates NK cells?
infection, malignant transformations, other stresses
what can NK cells do?
kill altered self cell, or produce cytokines that induce adaptive responses against altered self cell
describe NK cell’s receptors
Germline encoded
Inhibitory (prevent NK activation) or activating
Recognize MHC class 1
what binds to NK cell’s inhibitory receptor?
MHC class 1 (present on healthy cells)
what are the 2 ways how NK cells can kill altered self cell
via granules that trigger apoptosis, or express a TNF that gets recognized by target cell receptor and triggers apoptosis
what induces acute phase response?
proinflammatory cytokines (IL-1, IL-6, TNFalpha)
