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What does the immune system do?
Protects the body from pathogens
Helps repair damage from physical injury
What is a pathogen?
An organism that can cause sufficient damage to result in disease
What is virulence?
Ability of a pathogen to cause disease
(higher = almost always causes disease)
(lower = usually goes away quicker)
What is a primary pathogen?
Organism that frequently causes significant damage when invading a healthy individual
What is an opportunistic pathogen?
Low virulence organism that causes damage in an immune-impaired host
What are some pathogen examples?
Bacteria, viruses, prions, fungi, protozoa, other parasites (worms)
What is the microbiome?
Has over 100 trillion microbes (10x the cells of host origin)
It should be considered as an organ clinically!
What is the microbiome required for?
Development, nutrition, immune regulation
What are the different factors that affect the mircrobiome?
Genetics, environment, diet, lifestyle, hormones, industry
Nose, mouth, lungs, stomach, colon, sexual organs, skin
What are the levels of defense against pathogens (increasing in specificity order)?
Anatomic barriers
Complement/antimicrobial proteins
Innate immune cells
Adaptive immunity
What are examples of anatomic barriers?
Skin, oral mucosa, respiratory epithelium, intestine
What are examples of complement/antimicrobial proteins?
C3, defensins, RegIIIgamma
What are examples of innate immune cells?
Macrophages, granulocytes, natural killer cells
What are examples of adaptive immunity cells?
B cells/antibodies, T cells
What are are examples of the structure/functions of barrier tissues?
Epidermis of skin
Bronchial ciliated epithelium
Gut epithelium
What is innate immunity?
It is non-specific, immediate action, short-lived, has no memory, has conserved microbe-associated molecular patterns (MAMPs) as antigens, and has germ-line encoded receptors
What is adaptive immunity?
It is antigen specific, has a delayed action time about 2-6 days after the innate response, long-lived, has memory, has diverse proteins, peptides, carbohydrates as antigens; has gene segments that rearrange to create diversity
What role do dendritic cells play with innate and adaptive immunity?
They bridge innate & adaptive immune responses
They will sit in the cell looking at the environment until they recognize something that’s not supposed to be there and then will rush to the nearest lymph node to activate the B cells!
What are the steps of adaptive immunity?
Virus affects and replicates within epithelium
Dendritic cell activation (pattern recognition receptors) - take infection to the lymph node
T & B cell priming in the lymph node (kick off the activation)
Which type of immunity helps make vaccines effective?
Adaptive immunity!
The first vaccine dose is the primary immune response, is slow to develop, and has low magnitude
With a booster vaccine, it will produce an amplified response that is rapid and helps to develop memory cells, and ensures protection improves over time
What does a macrophage do?
“Eats” up bacteria
What is a mast cell?
Sits ready to produce soluble mediators that affect vascularization; increases vessel leakiness
What do B cells do?
They express antibodies on the surface (through a B cell receptor)
What do antibodies do?
They are soluble they are able to move through the circulation and go into tissues to neutralize microbes & toxins - binds the pathogen and then can’t access the target cell (blocks it!)
There are different types of things that produce ABs - Phagocytes & NK cells
Can also combine with complement to enhance function
What are phagocytes responsible for?
Opsonization & phagocytosis of microbes - part of the AB can bind to microbe & enhance the efficiency of the process
The macrophages will eat bacteria faster when covered with ABs
What are natural killer cells (NK) responsible for?
Antibody-dependent cellular cytotoxicity - requires antibodies so that it can signal that the cell is infected & needs to be killed
What does complement activation result in?
Lysis of microbes (MHC complexes that are pore-forming protein units that punch holes in the pathogen)
Phagocytosis of microbes opsonized with complement fragments (e.g. C3b)
Complement stimulates other immune cells to produce inflammation
Commensal vs. Pathogenic Organisms
Commensal = the microbiome
Pathogenic = bacteria, viruses, prions, fungi, protozoa, other parasites (worms)
What cell types & functions does cytotoxicity have?
NK cells, CD8 cells
Elimination of virally infected & metabolically stressed cells
What cell types & functions does intracellular immunity (Type 1) have?
ILC1, TH1 cells
Elimination of intracellular pathogens; activation of macrophages
What cell types & functions does the mucosal barrier & barrier immunity have?
ILC2, TH2 cells
Elimination & expulsion of parasites; recruitements of eosinophils, basophils, & mast cells
What cell types & functions does extracellular immunity (Type 3) have?
ILC3, TH17 cells
Elimination of extracellular bacteria & fungi; recruitment & activation of neutrophils
What is Major Histocompatibility Complex (MHC) 1?
Nearly all cells express it
“I live in this organism passcard” and if not, then it’s killed
What is Major Histocompatibility Complex (MHC) 2?
On antigen presenting cells
Take up the antigen and present it to B & T cells
What do dendritic cells have higher levels of?
MHC 2 when activated, but still have MHC 1
How does MHC1 work?
Presents antigen from inside the cell:
Virus infects cell
Viral proteins synthesized in cytosol
Peptide fragments of viral proteins bound by MHC class 1 in ER
Bound peptides transported by MHC class 1 to the cell surface
What is antibody-mediated immunity?
Protection against a disease such as tetanus is mediated by antibodies found in blood serum!
This can be demonstrated by injecting this serum into a non-immune animal & confer immunity
This is “passive immunity”
What is cell-mediated immunity?
Rejection of foreign organ grafts (example of a cell-mediated adaptive immune response)
The body rejects the graft b/c it can sense that its cells are different from those of the recipient
The time course of the graft rejection process is similar to that of an antibody-mediated response
*Why we use immunosuppressants for transplant patients to avoid getting rejection
What is the function of the central (primary) lymphoid organs?
Production of vertebrate immune cells
Bone marrow
Thymus
What is the function of the peripheral (secondary) lymphoid organs?
Maintain naive lymphocytes
Initiate adaptive immune response
Lymph nodes
Spleen
Mucosal lymphoid tissues (Peyer’s Patches)
What is bone marrow?
The origin of vertebrate immune cells
Can take on the characteristics of the cells that they create
What are hematopoietic stem cells (HSCs)?
They self-renew, proliferate, & differentiate into HPCs
What are hematopoietic progenitor cells (HPCs)?
CD34 surface maker, do NOT self-renew (unidirectional), proliferate, & differentiate into varied colony forming units
What is the thymus?
Origin of T lymphocytes
It’s near the thoracic inlet & into the chest
What is the germinal center in the lymph node?
It has B cells proliferating in response to antigen, T cells & dendritic cells
What is the spleen?
Sets up structures for B & T cell interactions
What are the mucose-associated lymphoid tissue?
AKA M cells
Peyer’s patches are an example! - They are covered by an epithelial layer containing specialized cells (M cells) that have characteristic membrane ruffles
Have a T cell-dependent region
What is basic cell signaling?
Chemical messengers relay the signal from the ligand and receptor which creates a response (could be proliferation or tell it to die)
Cell signaling leads to the production of signals that serve as inputs for other cells
What are PAMPs?
Pathogen associated molecular patterns - could be part of the cell wall - nucleic acid (virus), peptidoglycan (bacteria)
STRANGERS - pathogens
What are DAMPs?
Danger-associated molecular patterns
Released when there are stressed cells (burn, trauma, etc.)
DANGERS - destruction/stress of a tissue What
Where are pattern recognition receptors (PRR)?
They are on the antigen presenting cells
What are the results of the PAMPs, DAMPs, & PRR?
Cytokines/chemokines immune cell recruitment
Inflammation
Adaptive immunity
Tissue repair (outcome!)
What are the different types of cellular locations for pattern recognition receptors?
Extracellular recognition
Cytosolic recognition - Live inside the cell
Endosomal recognition - (Endosome - intracellular vesicles) Where cells go through phagocytosis
What are soluble pattern-recognition receptors?
Collectins
Ficolins
Complement
Pentraxins
What pattern-recognition receptors are with vesicles?
TLR 3, 7, 8, 9
What are cytoplasmic pattern-recognition receptors?
Rig-1, NOD-like, Peptidoglycan receptors, DNA receptors
What pattern-recognition receptors are membrane-bound?
TLR 1, 2, 4, 5, 6
Lectins
Mannose receptor
Langerin
Dectins
Integrins
Scavenger receptors
What is a phagocyte?
A cell type capable of ingesting small particles such as bacteria, cellular debris, foreign debris
Examples: neutrophils, macrophages, dendritic cells
What is an antigen presenting cell?
Cells that process and display antigen in the context of major histocompatibility complex (MHC - 2?) in order to initiate an adaptive immune response
Examples: macrophages, DCs - Dendritic Cells, B lymphocytes/cells
What is a Fc receptor (FcR)?
Receptors on the surface of cells that bind the constant region of the antibody molecule (can activate an effector response)
What movement of cells into an inflammatory region for an acute injury?
Mast cells - already present in tissues
Neutrophils - 20 minutes to hours (quick)
What movement of cells into an inflammatory region for a chronic injury?
Macrophages - Hours to days (cleaning crew, then migrate out of circulation to the problem)
Lymphocytes - Days (recirculate back to secondary lymph tissue (blood), adaptive response)
Fibroblasts - Days to weeks (live in tissue, number decreases when scar tissue is replaced with normal)
What cells are in between an acute & chronic injury?
Eosinophils - Hours to days (found in high numbers of tissues of GI tract, called into problem areas)
What are monocytes?
In the blood, it is 15 to 20 micrometers in diameter (bigger than neutrophils)
Oval or bean-shaped nucleus
Gray-blue cytoplasm with small vacuoles (pink) & occasional granules
What are patrolling monocytes?
Sensors for endothelial damage or infection
Only found patrolling the vasculature
What are macrophages?
Monocytes outside of the cell
In tissues, the macrophage morphology is variable (pleomorphic)
Sometimes swollen & filled with phagocytosed debris
Can have an “epitheloid” morphology
Can be multinuclear
What are resident macrophages?
Referred to as mononuclear phagocyte or reticuloethodothelial system
Heterogeneous population of immune cells that fulfill tissue-specific & nice-specific functions (clearance of cellular debris, iron processing, immune surveillance, response to infection, resolution of inflammation)
How does polarization of macrophage activation happen?
Activation: Acquisition of competence to execute a complex function
M1 - microbial, pro-inflammatory - Classically activated macrophage
M2 - Immunomodulatory, poorly microbicidal (not eating up bacteria) - Alternatively activated macrophages
What are features of macrophage activation?
Rapid
Reversible
Remarkable plasticity
What are inflammatory macrophages?
Unlike neutrophils, macrophages can divide leaving the circulation
Resident macrophages recruit macrophages - amplification of response
Neutrophils recruit additional macrophages from circulation
~ 1/3 are locally derived (already there)
~ 2/3 are recruited from the bloodstream
What kinds of effects can macrophages have?
Innate, adaptive, & systemic effects
What inflammatory cytokines do activated macrophages secrete?
IL-1beta, TNF-alpha, IL-6, CXCL8, IL-12
Which inflammatory cytokines have systemic effects?
IL-1beta: Fever, production of IL-6
TNF-alpha: Fever, mobilization of metabolites, shock
IL-6: Fever, induces acute-phase, protein production
What are mast cells?
Large, round nucleus
Contain intensely violet granules (metachromatic staining due to heparin in granules)
Long lived residents of vascularized tissue
Beneath epithelial surfaces exposed to external environment (skin, respiratory & GI tracts) - around vessels, close to peripheral nerves
What are mast cell receptors?
FcERI - Bind IgE
PRRs - TLRs, FMLP-R, complement receptors
What do mast cells do?
Degranulate to release histamine & serotonin (vasoactive amines)
Not killed by degranulation
Secretion is orderly & well-coordinated
What are mast cells regulated by?
By endothelial cells - ingest & degrade released granule contents (fast)
What do mast cells synthesize?
Prostaglandins & leukotrienes - Attract PMNC & macrophages
What are type 1 hypersensitivity reactions?
Most mast cells have IgE receptors (FcERI)
Some mast cells only respond to T-cell cytokines
What do mast cells regulate?
They regulate eosinophils
Ingest eosinophilic major protein
Produce IL-5 (affects differentiation, activation & maintenance of eosinophils; primes eosinophils for effects of other cytokines)
Granules contain eosinophil chemotactic factor
What describes attributes of resident macrophages?
Tissue macrophages originate from monocytes that migrate from the circulation into tissues throughout the body
Resident macrophages can have radically different appearances depending on the tissue and the activation state of the cells
Resident macrophages in the liver are called Kupffer cells and play an important role in removing antigens from portal circulation
Resident macrophages in the red pulp of spleen remove aged red blood cells and play an important role in iron processing
What are characteristics of mast cells?
They produce eosinophil chemotactic factor and IL5 as part of the mast cell-eosinophil regulatory axis
They are long-lived residents of vascularized tissues
They express Fc receptors & pattern recognition receptors
They attract neutrophils and macrophages into sites of inflammation
What is a PMNC?
PolyMorphic Nucleic Cells:
Neutrophils, eosinophils, basophils
What is the morphology for PMNCs?
Lobed or segmented nuclei
Granules contain enzymes & mediators of inflammation
Neutrophils - granules pale azue or pale pink with neutral stains
Eosinophils - granules take up eosins to stain bright red or orange
Basophils - granules take up basophilic stains to stain dark blue (heparin)
What other features are there of PMNC?
Terminally differentiated: Non-dividing, short half life
Found circulating in the blood & in tissues
Neutrophils ~75% of total WBCs in blood
Eosinophils less common: 1-10%
Basophils rare
What are some characteristics of neutrophils?
Phagocytic but not Antigen Presenting Cells
Most prevalent blood leukocyte & in early phase of inflammation
Only live a few days & are the first line of defense
What’s opsonization?
The coating of the surface of a pathogen or antibody and/or complement that makes it more easily ingested by phagocytes
What can be created by opsonization?
Chemotaxis, adherence, ingestion, and destruction
What are Neutrophils Extracellular Traps (NETs)?
Like kamakazi cells - the neutrophils kill bacteria until they die
The highly activated neutrophils have special cell death that leads to NETosis
NETosis = Neutrophils will release de-condensed DNA (“fishing net”)
NETs - antimicrobial proteins; common in sites of inflammation (i.e. mastitic milk)
What are heterophils?
Have the same characteristic of neutrophils and also do the net trick!
In rabbits: Bright red granules, function just like neutrophils of other mammalian species
In birds & reptiles: Elongate red granules, aren’t as antibacterial as mammalian neutrophils
What are characteristics of eosinophils?
Parasite-mediated inflammatory reactions
Immune-mediated reactions
Found in all tissues!
Most abundant in the GI tract
May play a regulatory role
What’s the major function of eosinophils?
To kill parasites!
Degranulate onto the cuticle/surface (of large pathogens) - causes the cuticle to separate from the body wall
Especially attracted to antibody-coated proteins
What are the different parts of eosinophils?
Major basic protein (MBP)- Parasiticidal (pokes holes into cuticle like the C5-9 complex; tissue damage is prevented by ingestion of MBP by mast cells)
Eosinophil cationic protein (similar to MBP)
Eosinophil peroxidase
Eosinophil-derived neurotoxin
What are degradative enzymes within eosinophils?
Arylsulfatase B - neutralizes heparin
Histaminase - inactivates histamine
Phospholipase D - inactivates PAF (Platelet Activating Factor)
What do mast cells do?
Produce eosinophil, chemotactic factor & IL-5
Degrade major basic protein
What do eosinophils mainly do?
Degrade histamine, heparin, LTs, PAF, and others
What are basophils?
Associated with chronic inflammation, chronic (delayed) type hypersensitivity reactions, & type 1 hypersensitivity reactions
Synthesize PGs & LTs
What is the morphology of basophils?
They have a segmented nucleus and cytoplasm that contains dark blue granules
What do the granules of basophils contain?
Heparin, histamine, serotonin, eosinophil chemotactic factor, tryptase, and others
What are innate lymphoid cells (ILCs)?
Have classical lymphoid morphology
Cytotoxic and non-cytotoxic subpopulations
Lack somatically rearranged antigen receptors
Makes them different from adaptive
Note
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