(I) Lecture 4: Innate Immunity Part III Flashcards
Immune Proteins
Cytokines
Complement Proteins (C3a and C3b)
Antibodies (Adaptive Immunity)
Types of Cytokines
Interleukins
Interferons
Tumor Necrosis Factors
Chemokines
Cytokines
Chemical messages (proteins that communicate w/ cells)
- target cells can only respond if they have a receptor for it
- cytokine receptors have HIGH AFFINITY = powerful biological responses
- regulates hematopoiesis
- have a role in BOTH innate and adaptive immunity
Responses induced from interaction btwn cytokines and their receptors
- changes in expression
- increase/decrease enzyme activity
- induce differentiation
- modulate effector functions
- cell survival/death
Mode of action of cytokines
secreted cytokine binds SPECIFIC receptors
signal transduction pathway
- stimulus triggers cell to translate stimulus into expression of cytokine –> cytokine binds receptor –> biological response
Pleiotropy, redundancy, cascade induction
Pleiotropy
SAME cytokine act on DIFFERENT cells to evoke different responses
Redundancy
DIFFERENT cytokines evoke SAME response in cells
Cascade induction
action of a cytokine INDUCES PRODUCTION of one or more additional cytokines
Pro-inflammatory cytokines
Their presence triggers inflammation
Interleukins (IL): IL-1 and IL-6
Tumor Necrosis Factor (TNF): TNF alpha
Chemoattractant cytokines
Chemokines
cell recruitment to site of infection
Antiviral response cytokines
Interferons (IFN): Type I IFN
Homeostasis and cytokines
Cytokine networks moderate the cross-talk btwn epithelial cells w/ innate and adaptive immune cells to maintain homeostasis
Disruption of cytokine-guided cross-talk
Leads to initiation of inflammation (mostly by innate derived pro-inflammatory cytokines)
leads to IBD (inflammatory bowel disease)
If unresolved, it can lead to chronic inflammation since immune cells attack epithelia
Phagocytosis and inflammation
Phagocytosis results in inflammation
- Sensing PAMP/PRR (PAMP binding to PRR also triggers production of cytokines = inflammation)
- Phagocytosis
- Starvation/Intoxication
- Killing
- Signaling
Chemokines
chemoattractant cytokine
attracts immune cells to infected tissues
BOTH immune and epithelial cells secrete chemokines
immune cells w/ chemokine receptors are recruited from blood into specific tissue
inflammatory trigger causes release of chemokines = neutrophils go to site of infection
PAMP-PRR binding
Leads to phagocytosis and cytokine secretion
Signs of Inflammation
DOLOR: pain
RUBOR: redness
CALOR: heat
TUMOR: swelling
FUNCTIO LAESA: loss of function
Inflammation
dilation and increased permeability of endothelial cells
- increased local blood flow
- leakage of fluids and blood proteins into tissues
- extravasation (leakage) of immune cells into tissues
- results in heat, redness, and swelling
leads to increase in immune cells and enhanced clearance of pathogens
Neutrophils in the immune system
- Neutrophil sense bacteria
- Neutrophil slows and squeezes through blood vessel
- Neutrophil moves towards bacteria which have been marked by antibodies for ingestion
- Neutrophil engulfs and destroys marked bacteria
Pathogens and inflammation
- bacteria/viruses trigger macrophages to release cytokines and chemokines
- vasodilation and increased vascular permeability cause redness, heat and swelling
- inflammatory cells migrate into tissue and release inflammatory mediators that cause pain
Why is inflammation a good thing?
inflammation quickly recruits circulating immune cells into infected tissue to enhance immune defenses
- cytokines produced by macrophages cause dilation of local small blood vessels
- leukocytes move to periphery of blood vessel as a result of higher expression of adhesion molecules
- WBCs extravasate at site of infection
Fever
an early response to infection
pathogens activate phagocytes
phagocytes release cytokines
cytokines stimulate hypothalamus
hypothalamus produces prostaglandins
prostaglandins trigger fever
may help to combat infection by reducing growth rate of microbes (highly debated)
Liver and infection
Cytokines can act on liver to promote release of acute phase proteins like CRP and Complement 3 protein
CRP
C-reactive protein
used clinically to quantify inflammation
Complement System
50-plus serum proteins that cooperates w/ both innate and adaptive immune systems to ELIMINATE PATHOGENS
Complement proteins
- directly kill microbes by forming the MAC (Membrane Attack Complex) = target pathogens for cell lysis and activation
- decorate pathogens to promote phagocytosis (opsonization)
- recruit immune cells/inflammation
Complement Protein 3
Cleaved into C3a and C3b
C3a
Maintains inflammation
- recruits phagocytes to site
- acts a cytokine
C3b
helps w/ opsonization (coating of a surface of a pathogen with antibodies and complement proteins to promote PHAGOCYTOSIS)
- bacterium is coated w/ C3b
- when only C3b binds to CR1, bacteria are not phagocytosed
- C5a can activate macrophages to phagocytose via CR1
- helps phagocytes recognize pathogen faster and better
Interferons
type of cytokine that are important in directing ANTIVIRAL responses
Type I Interferon: IFN alpha and IFN beta
- critical to antiviral immune response
- rapidly secreted by virus-infected cells
Cytokine release and IFNs
Type I IFN is RAPIDLY secreted after a viral infection
after cytokine release, a wave of NKC follows
they control viral replication together
Virus-infected cells and PRRs
Have PRRs expressed on the surface and inside of cells
Viruses have BOTH extracellular and intracellular phases
Endosomal PRRs recognize components released during intracellular viral replication/degradation (ex. nucleic acids)
Surface PRRs recognize components on the outside of the virus
Viral particles bind PRR and triggers rapid expression of IFN by infected cell
IFNs and NKCs
Type I IFNs promote NK cell killing of virus-infected cell
Virus-infected cell secretes chemokines (attracts NKCs) and Type I IFN (activates NKCs)
NKCs release toxic enzymes (perforin and granzye) to target infected cell for apoptosis
Viral Survival
some viruses can block IFN secretion and signaling
- express effectors that act to suppress IFN expression (ex. hepatitis, polio, SARS-CoV2)
- Need To cell immunity to fight them off
Type I IFN are used to treat SOME viral infections (ex. herpes and hep B)
Cytokine Therapy
Cytokine inhibitor industry continues to grow
used for asthma, rheumatoid arthritis and some cancers to reduce inflammation
IFNs are used as therapy for MS
Effector Function of Cytokines
- phagocytosis (extracellular)
- NK-mediated apoptosis (intracellular viruses)
- inflammation
Innate immunity response time
Rapid (seconds, minutes, hours)
Innate immunity specificity
Broad (conserved molecular patterns only found in pathogens)
Innate immunity diversity
Limited diversity
Germline-encoded receptors
Innate immunity main cells
Phagocytes, NK cells, epithelial cells
Innate immunity proteins
Proinflammatory cytokines, type I IFNs, tumor necrosis factors, chemokines
Innate immunity mechanism of pathogen destruction/inactivation
- Phagocytosis
- Apoptosis
- Chemical attack by antimicrobial peptides
Innate immunity immune response
Non-adaptive = same response for every exposure to identical pathogen
Innate immunity memory
NO memory is formed
Innate immunity efficiency
Rarely malfunctions
Innate immunity intracellular viruses
