VM 606 Exam #1

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?

1. Virus affects and replicates within epithelium

2. Dendritic cell activation (pattern recognition receptors) - take infection to the lymph node

3. 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:

1. Virus infects cell

2. Viral proteins synthesized in cytosol

3. Peptide fragments of viral proteins bound by MHC class 1 in ER

   1. 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?

1. Rejection of foreign organ grafts (example of a cell-mediated adaptive immune response)

2. The body rejects the graft b/c it can sense that its cells are different from those of the recipient

3. 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

1. Neutrophils - granules pale azue or pale pink with neutral stains

2. Eosinophils - granules take up eosins to stain bright red or orange

3. 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

1. Neutrophils ~75% of total WBCs in blood

2. Eosinophils less common: 1-10%

3. 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!

1. Most abundant in the GI tract

2. 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

1. Makes them different from adaptive