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Immunology Lecture 2

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How is the immune system classified?
"1. Primary Lymphoid Organs - Development and maturation of lymphocytes"

The central or primary lymphoid organs generate lymphocytes from immature progenitor cells.

The thymus and the bone marrow constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes.

"2. Secondary Lymphoid Organs - Trap Antigens, Allow lymphocytes to interact and react"

Secondary or peripheral lymphoid organs maintain mature naive lymphocytes and initiate an adaptive immune response. The peripheral lymphoid organs are the sites of lymphocyte activation by antigen. Activation leads to clonal expansion and affinity maturation. Mature lymphocytes recirculate between the blood and the peripheral lymphoid organs until they encounter their specific antigen.

Secondary lymphoid tissue provides the environment for the foreign or altered native molecules (antigens) to interact with the lymphocytes. It is exemplified by the lymph nodes, and the lymphoid follicles in tonsils, Peyer's patches, spleen, adenoids, skin, etc. that are associated with the mucosa-associated lymphoid tissue (MALT).
How does the primary and the secondary lymphoid organs connect to one another?
Blood and lymphatic system join the two organ types

Allows transfer of lymphocytes from point of origin to point of action
What constitutes the primary lymphoid organs?
"1. Primary Lymphoid Organs - Development and maturation of lymphocytes"

The central or primary lymphoid organs generate lymphocytes from immature progenitor cells.

The thymus and the bone marrow constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes.
The immune system involves single organs only T/F

Explain answer
Immune system is extremely complex - Involves multiple organs and tissues
Conceptually explain what a leukocyte is
White blood cells, or leukocytes are cells of the immune system involved in defending the body against both infectious disease and foreign materials.

Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a hematopoietic stem cell.

They live for about three to four days in the average human body. Leukocytes are found throughout the body, including the blood and lymphatic system.

Participate in the immune response
What are the only leukocytes that directly participate in the immune response?
Lymphocytes (Directly interact with antigens; Specific antigen receptors)

Exhibit all characteristics required for the immune response

Diversity, specificity, memory and self/non-self recognition
What are the 4 characteristics required for the immune response?

What cells directly participate in this?
1. Diversity
2. Specificity
3. Memory
4. Self/non-self recognition

Lymphocytes (Sub-class of leukocytes)
Many cells in the immune response system execute what role in the immune response system?
1. Accessory role, often involved in activation
2. May enhance phagocytosis
3. May induce production / secretion of signaling molecules

Only lymphocytes involved in:
1. Diversity
2. Specificity
3. Memory
4. Self/non-self recognition
How are all blood cells created?

What does this involve?
Hematopoiesis - formation of blood cellular components.

Involves differentiation of hematopoietic stem cells (HSC; Notice this in the figure where this is the beginning portion)
What are the characteristics of HSC? What does HSC stand for?
HSC = Hematopoietic stem cells

1. Capable of differentiating into all types of blood cells
2. Self renewing capability - maintain population by cell division
Where does hematopoiesis begin?
Embryonic yolk sac for mammals
Initially, what do HSCs differentiate into exclusively?
Red Blood Cells
When do HSCs migrate to the spleen and liver?
3rd month
In month three, where do HSCs migrate to?
Spleen and Liver
In month seven, where do HSCs migrate to?
Bone marrow
When do HSCs migrate to bone marrow?
Month seven
What does the term pluripotent mean?
Nika - Capable of differentiating into any or all cell types

Immortal?
During differentiation of hematopoiesis, what are the two types of progenitors that are capable of differentiating into?
LYMPHOID PROGENITOR CELL
Gives rise to:
1. T cells
2. B cells
3. Dendritic cells
4. Natural killer cells (NK)

MYELOID PROGENITOR CELL
Gives rise to:
1. Macrophages
2. Neutrophils
3. Eosinophils
4. Basophils
5. Mast cells
6. RBC
7. Megakaryocytes that give rise to platelets
What do lymphoid progenitor cells give rise to?
LYMPHOID PROGENITOR CELL
Gives rise to:
1. T cells
2. B cells
3. Dendritic cells
4. Natural killer cells (NK)
What do myeloid progenitor cells give rise to?
MYELOID PROGENITOR CELL
Gives rise to:
1. Macrophages
2. Neutrophils
3. Eosinophils
4. Basophils
5. Mast cells
6. RBC
7. Megakaryocytes that give rise to platelets
What is the term of the step that is performed when a cell differentiates into either the lymphoid or the myeloid cell?

What are the consequences of this?
Committal step

Consequence:
1. Can no longer differentiate into any cell type
2. No longer have capacity for self renewal
HSCs have many possible fates (Outcomes), how is this made possible in the cell? What needs to happen?
Cells need instructions due to having many possible fates
What molecule functions as a signaling molecules for HSC stem cell differentiation?
Cytokines

Cytokines (Greek cyto-, cell; and -kinos, movement) are small cell-signaling protein molecules that are secreted by numerous cells and are a category of signaling molecules used extensively in intercellular communication.

Cytokines can be classified as proteins, peptides, or glycoproteins; the term "cytokine" encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin
What are the consequences for the different cytokines that are stimulated?
Type of cytokine that stimulates HSC to proliferate dictates fate
How many different cytokines are possible?

What is the role of each cytokine?
Over 60 different cytokines

Cytokines are small polypeptide (Proteins) molecules

Role:
Each activates transcription of different subset of genes

Type of cytokine that stimulates HSC to proliferate dictates fate
Where does differentiation of stem cells occur?
Network of bone marrow STROMAL CELLS
Conceptualize what stromal cells are
In cell biology, stromal cells are connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, and the ovary.

They are cells that support the function of the parenchymal cells of that organ.

Fibroblasts, immune cells, pericytes, and inflammatory cells are the most common types of stromal cells.

Stromal cells (in the dermis layer) adjacent to the epidermis (the very top layer of the skin) release growth factors that promote cell division.

This keeps the epidermis regenerating from the bottom while the top layer of cells on the epidermis are constantly being "sloughed" off of the body.
What does differentiation of stem cells within the network of bone marrow stromal cells generate?
Hematopoietic-inducing microenviornment

What's that mean?

Matrix with bound or diffusible growth factors (cytokines)
How were growth factors identified?
Found by practical evidence (empirical data)

Verifiable by observation or experience rather than theory or pure
What do growth factors have the capability of generating?
Stromal cell layer required for differentiation
What is the hypothetical outcome of progenitor cells that lack growth factors?
Progenitor cells will not grow unless media supplemented with growth factors
If progenitor cells are not growing, what is a plausible explanation?
Media has not been supplemented with growth factors
Where did colony stimulating factor (CSF) generate its name?
Growth factors allowed progenitor cells to form colony on stromal cells
There are many classes of CSF (Colony Stimulating Factors). What does each one do differently? What is the consequence of each CSF?
Each activates a different transcription factor

Types of CSF used to stimulate progenitor cell dictates fate
What are the 4 types of CSF (Colony Stimulating Factors)?
1. MULTILINEAGE CSF (IL-3)

2. MACROPHAGE CSF (M-CSF)

3. GRANULOCYTE CSF (G-CSF)

4. GRANULOCYTE-MACROPHAGE CSF (GM-CSF)
What do combinations of CSFs along with cytokines do?

How is this made possible?
"Instruct" HSCs as to what type of cell to differentiate into

Accomplishes by activating specific transcription factors at specific stages of differentiation
What is the life span of a RBC and a T cell?
RBC = 120 Days

T cell = 20-30 years (memory T cell)

Reason for vaccines lasting for a decade or too

Must get new vaccine so that you remain immune
What is the consequence if there is insufficient replenishment of blood cells?
Anemia or immune deficiencies
What is the consequence if there is over abundant replenishment of blood cells?
Cancer (Leukemia)
What is anemia a result of?
consequence if there is insufficient replenishment of blood cells
What is leukemia a result of?
Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts".

consequence if there is over abundant replenishment of blood cells
Conceptualize what leukemia is
Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts".

consequence if there is over abundant replenishment of blood cells
What are the 4 factors involved in regulation of hematopoiesis?
Four factors involved in regulation:

1. Control of types and amounts of cytokines produced by stromal cells in bone marrow

2. Production of cytokines by other cells (activated T cells)

3. Regulation of cytokine receptor expression in HSC and progenitor cells

4. Removal of cells by programmed cell death (apoptosis)
What are the "steps" and characteristics of apoptosis?
Cell decreases in volume

DNA degraded (Chromatin)

Nucleus fragments

Cell ultimately fragments into numerous membrane bound "blebs"
During apoptosis, what occurs when membrane "blebs"?
Macrophages will phagocytize all the intracellular components contained

Yellow cell is macrophage which will engulf the cell
What is the primary differences in apoptosis and necrosis?
Apoptosis Necrosis
Natural: Yes No

Effects: Beneficial Detrimental

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death.

Necrosis is the premature death of cells and living tissue. Necrosis is caused by external factors, such as infection, toxins or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death.

Seperate fingers in embryo development and prevent tumor (homeostatis between cell death rate and mitosis rate) these intercellular content damage neighbouring cells cause inflammation.
definition: programmed cell death the cell or tissue damage due to external factors.

process: membrane blebbing, shrinkage of cell, nuclear collapse (nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation), appoptopic body formation. Then, engulf by white blood cells

Dying cell swells and burst,releasing the intercellular content.
What does necrotic cell death have the consequence of?
Release of cytosolic components (cause inflammation; which may actually damage tissues)
What are some factors that activate apoptosis?
1. bax
2. bcl-XS
3. fas
4. caspase
What are some factors that inhibit apoptosis?
1. bcl-2
2. bcl-XL
How are factors regulated to allow proper production and removal of blood cells?
Temporally (of or relating to time)
What two things in combination, activate B cells promoting rapid proliferation in regards to apoptosis in the immune response?
Combination of:

1. Antigen interaction with receptor
2. Cytokine stimulation activates B cell, proliferates rapidly
As cytokine receptor expression increase in regards to apoptosis in the immune response, what is an effect?
Bcl - 2 expression decreases
Bcl - 2 expression with decrease when what occurs? (In respect to apoptosis in the immune response)
Cytokine receptor expression increases
In regards to antigen presence, when will occur with cytokine production and expression? (Think about apoptosis in the immune response)
As long as antigen is present cytokines continue prevent apoptosis

Once antigen is cleared, cytokine production ceases
If the Block to apoptosis is removed, what happens in reference to the B-cell?
Effector B cell gets depleted through apoptosis
What cell in the immune system is extremely critical?
Lymphocytes (Type of leukocyte)

(Directly interact with antigens; Specific antigen receptors)

Exhibit all characteristics required for the immune response

Diversity, specificity, memory and self/non-self recognition
What percentage of the total WBC % and lymph % constitute lymphocytes?
WBC = 20-40%

Lymph = 99%

Lymph = Lymph is the fluid that circulates throughout the lymphatic system. The lymph is formed when the interstitial fluid (the fluid which lies in the interstices of all body tissues) is collected through lymph capillaries.

As the blood and the surrounding cells continually add and remove substances from the interstitial fluid, its composition continually changes and it changes into lymph fluid.

It is then transported though lymph vessels to lymph nodes before emptying ultimately into the right or the left subclavian vein, where it mixes back with blood.
What are the three classes of lymphocytes?
1. T cells

2. B cells

3. Null cells
How are the different types of lymphocytes classified?

List the types of lymphocytes?
1. T cells
2. B cells
3. Null cells

Classified based on surface markers
What is characteristic about null cells?
They do not express any distinguishing markers

AKA Natural Killer (NK) cells
What do T and B cells have in common?
They progress through a similar cell cycle
What is the term used for cells that have not encountered an antigen?

Comment on name and size
Naive = Term of a cell that has not encountered an antigen

Size = Small = 6µm
What is the outcome of a cell that is arrested in G₀ phase?
Undergoes apoptosis if antigen is not encountered
What happens if an antigen interacts with the cell surface?
An antigen will stimulate progression through the cell cycle

Cells become larger (15 µm) = Lymphoblast

Lymphoblast completes progression through cell cycle

Division generates effector cells and memory cells
Conceptualize what a lymphoblast is
Lymphoblasts are immature cells which typically differentiate to form mature lymphocytes. Normally lymphoblasts are found in the bone marrow, but in acute lymphoblastic leukemia (ALL), lymphoblasts proliferate uncontrollably and are found in large numbers in the peripheral blood.

The size is between 10 and 20 μm.

Although commonly lymphoblast refers to a precursor cell in the maturation of leukocytes, the usage of this term is sometimes inconsistent.

The Chronic Lymphocytic Leukemia Research Consortium defines a lymphoblast as "A lymphocyte that has become larger after being stimulated by an antigen.

Lymphoblasts look like immature lymphocytes, and were once thought to be precursor cells.". Commonly, when speaking about leukemia, "blast" is used as an abbreviation for lymphoblasts.
Conceptually understand what a plasma cell is
B lymphocyte effector cell
Lacks surface associated B cell receptor (Antibody)
Divides rapidly, produces and secretes antibodies (2000/second)
Dramatically different intracellular structure

Extensive ER
Multiple Golgi
Essential for ↑ secretion
Short life spans (1-2 days)
What is the reasoning behind Extensive ER and Multiple Golgi for a plasma cell?
Dramatically different intracellular structure

They need tons of ability to secrete lots and lots of antibodies and need extensive "shipping coordinators" that can allow all these antibodies to become available.

Divides rapidly, produces and secretes antibodies (2000/second)

Hopes that energy consumptions is WORTH THE INVESTMENT and that you produce sufficient quantities of antibodies
What does a plasma cell lack?
Lacks surface associated B cell receptor (Antibody)
What are the three types of T cells?
1. T-h cells

2. T-c cells

3. T-reg cells
Conceptualize what the role of a T-h cell is
T-h cell = T-helper cell

Activated to produce effector and memory cells

Effector cells produce cytokines essential for activation for immune response
Conceptualize what the role of a T-c cell is
Activated to produce effector and memory cells (Same as T-helper)

Effector cell is the cytotoxic T cell

Mediates killing of altered hos cells or foreign cells
What role do cytotoxic T cells and T helper cells have in common?
Activate to produce effect cells

Helper - Also makes memory cells
Cytotoxic - Makes Immune cells
What do the effector cells of T-h cells produce?
Cytokines essential for activation of immune response
What do the effector cells of T-c cells produce?
Mediates killing of altered hos cells or foreign proteins
What is the T reg role?
T reg common marker with Th (CD4), suppresses the immune response
What is CD4?
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.

CD4 is a co-receptor that assists the T cell receptor (TCR) with an antigen-presenting cell. Using its portion that resides inside the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, known as the tyrosine kinase lck, which is essential for activating many molecules involved in the signaling cascade of an activated T cell.
Can you distinguish T and B cells underneath a microscope?

Can you distinguish them at all? What does this distinguishment allow for?
No

Yes; through differences in proteins on the surface

Allows for:
1. Discrimination between T and B
2. Discrimination of T-c and T-h
3. Determine stage of maturation of B, T-c and T-h

Crazy
What does CD stand for in immunology?

Comment on what they are used for

Comment on number around
Cluster of Differentiation

These are surface markers collectively referred to as CD markers

Over 250 exist

CD markers present perform critical roles in B cell function, not just for cool looks
What are B cells named for?
Site of maturation

Initially, this ID process stemmed from avian (Birds) studies

B cells were maturating in the bursa of Fabricius which was the site of hematopoiesis, a specialized organ that, as first demonstrated by Bruce Glick and later by Max Cooper and Robert Good, is necessary for B cell (part of the immune system) development in birds.)

Appropriate for humans = Bone Marrow
What is the distinguishing characteristics on B cells?
Presence of antibodies on surface of the cell

1.5e⁵ = 150000 antibodies

CD markers present perform critical roles in B cell function
What is the role of B220 (CD45R)?
B220 (CD45R) - transduces signal required for activation
What is the role of MHC Class II molecules?
MHC CLASS II MOLECULES - allow B cell to present antigens to TH cells
What is the role of CR1 (CD35)?
CR1 (CD35) - receptor for complement component C3b
What is the role of CR2 (CD21)?
CR2 (CD21) - receptor for complement component C3d
What is the role of FcγRII (CD32)?
FcγRII (CD32) - receptor for Fc region of IgG
What is the role of B7-1 (CD80) ?
B7-1 (CD80) - interaction with TH cells
What is the role of B7-2 (CD84) ?
B7-2 (CD84) - interaction with TH cells
What is the role of CD40 ?
CD40 - interaction with TH cells
Which CD markers interact with T-h cells?
B7-1 (CD80) - interaction with TH cells

B7-2 (CD84) - interaction with TH cells

CD40 - interaction with TH cells
Which CD markers are a receptor for Complement C3b and C3d respectively?
CR1 (CD35) - receptor for complement component C3b

CR2 (CD21) - receptor for complement component C3d
Which CD marker is a receptor for Fc region of IgG?
FcgRII (CD32) - receptor for Fc region of IgG
Which class of molecules allow B cell to present antigens to T-h cells?
MHC class II molecules
What are T cells named for?
Site of maturation; which takes place in the thymus
What do T-cells possess?

Be specific in:
Specificity
Similarity
Recognition capabilities
Membrane receptor for antigen - TCR (T-cell receptor)

1. Distinct from antibody associated with surface of B cell

2. Only similarity is antigen binding cleft

3. Cannot recognize free antigen, only in context of MHC
Do T cells have CD proteins? What is the caveat?
Yes they do

Some are common to T cells, others are distinct to T-h and T-c
What do all T cells express?
CD3 (Signal Transduction)
CD28 (B cell interaction)
CD45 (signal transduction)
What is CD3 used for?
Signal Transduction
What is CD28 used for?
B cell interaction
What is CD45 used for?
Signal Transduction
Which Cluster of Differentiation do T-h cells express?

What is the function of this CD marker?
CD4 - Recognize peptides presented by MHC Class II, only activated by antigen presenting cells
What is the role of CD4 marker?
CD4 - Recognize peptides presented by MHC Class II, only activated by antigen presenting cells
Activation of T-h cells expressing CD4 results in what?

What is the downstream effect of this activation?
Production / secretion of cytokines

Cytokines are essential for activation of T-c and B cells
Why is the type of cytokine produced important when discussing T-h specific CD marker activation?
Type of cytokine produced dictates the type of response
What are the two types of Cytokine responses when discussing T-h specific CD marker activation?
1. TH1 response produces cytokines triggering inflammation and activation of TC and MF (CMI)

2. TH2 response produces cytokines triggering proliferation of B cells and antibody production (humoral)
What is a TH1 response when discussing T-h specific CD marker activation?
TH1 response produces cytokines triggering inflammation and activation of TC and M∅ (Cell Mediated Immunity)
What is a TH2 response when discussing T-h specific CD marker activation?
TH2 response produces cytokines triggering proliferation of B cells and antibody production (humoral)
Which T helper cell response in responsible for Cell Mediated Immunity and which is responsible for humoral immunity?
1. TH1 response produces cytokines triggering inflammation and activation of TC and MF (CMI)

2. TH2 response produces cytokines triggering proliferation of B cells and antibody production (humoral)
What is the CD marker that is activated by T-c cells?

What is its function?
CD8 - Recognizes peptides presented by MHC class I, only activated by altered self
When is the only time CD8 is activated?

What is the result of activation?
Activated only by altered self by T-c cells

CD8 - Recognizes peptides presented by MHC class I, only activated by altered self

Activation results in differentiation into a CYTOTOXIC T LYMPHOCYTE (CTL)
Activation of CD8 results in what?
Activation results in differentiation into a CYTOTOXIC T LYMPHOCYTE (CTL)
What are the 4 characteristics of Cytotoxic T Lymphocytes?
1. Do not secrete cytokines

2. Do not participate in signaling of other immune effectors

3. Can now recognize and kill altered self cells

4. Sole purpose is destruction of infected/altered cells
What's important to remember about what Null Cells do not produce?

What else are they deficient at doing?
Do not produce membrane associated antigen receptors

No immunological memory or specificity, consist mainly of NK cells
Draw the difference in a B cell and a plasma cell
What is the critical role of NK cells / Null Cells?
Critical in destruction of tumor and viral infected cells
What are the two ways in which null cells can participate in destruction of cancer cells?
1. Can mediate killing directly (recognized depletion of surface antigens)

2. Can undergo ANTIBODY DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC)
- Antibody attaches to cell due to presence of foreign antigen
- Fc receptor on null cell attaches to antibody
What is antibody dependent cell mediated cytotoxicity?
Antibody attaches to cell due to presence of foreign antigen
- Fc receptor on null cell attaches to antibody

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection. Classical ADCC is mediated by natural killer (NK) cells
What are the characteristics of NK 1-T cells?
Hybrid between NK cell and T cell

Possess T cell receptor

Binds to MHC like molecule CD1

Express CD 16 - typical of NK cells

Actively kill cells like cytotoxic T cells

Actively secrete cytokines that stimulate immune system like TH cells

Believed to be rapid response to early infection, takes time for TH to become activated and proliferate
Do NK1-T cells possess T-cell receptor?
Yes
What are NK 1-T cells a hybrid between?

What are the similarities between T cells and what are the similarities of NK cells?
NK cell and T cell

Express CD 16 - typical of NK cells

Actively kill cells like cytotoxic T cells

Actively secrete cytokines that stimulate immune system like TH cells
What CD do NK 1-T cells express?
CD16 - Typical of NK cells
What do NK 1-T cells bind to?
Bind to MHC like molecule CD1
What is believed about NK1 - T cells in there functional role?
Believed to be rapid response to early infection, takes time for TH to become activated and proliferate
What are the two cells that comprise the mononulcear phagocytic system?
1. MONOCYTES - circulate in blood, non-phagocytic

2. MACROPHAGES - monocytes differentiate into MF when they exit the blood stream and enter into tissues
Monocytes are phagocytitic?

Where do they circulate?
Yes

Blood
What is the primary difference in a monocyte and a macrophage?
MACROPHAGES - monocytes differentiate into MF when they exit the blood stream and enter into tissues
What are the morphological changes that accompany the change from a monocyte to a macrophage?
1. Cells becomes much larger (5 to 10 fold), becomes phagocytic

2. Number and complexity of organelles increases

3. Increases production of hydrolyitic enzymes

4. Capable of production of soluble factors (cytokines)
What are the names of different macrophages within different tissue. Name all of them
1. Alveolar MF - reside in lung
2. Histocytes - reside in connective tissue
3. Kupffer cells - reside in liver
4. Mesangial cells - reside in kidney
5. Microglial cells - reside in brain
6. Osteoclasts - reside in bone
7. Intestinal - GI tract
What are the macrophages that reside in the:

lung?
In the kidney?
Brain?
Bone?
GI tract?
Connective tissue?
1. Alveolar MF - reside in lung
2. Histocytes - reside in connective tissue
3. Kupffer cells - reside in liver
4. Mesangial cells - reside in kidney
5. Microglial cells - reside in brain
6. Osteoclasts - reside in bone
7. Intestinal - GI tract
How does a macrophage change when it moves to different tissue?
Only the nomenclature changes
What state are macrophages in when they enter tissue?

What do they need to do in order to perform role in immune system?
Resting state

They need to be activated
What are five mechanisms that can Wlead to macrophage activation?
1. Phagocytosis of particulate antigens (bacteria) can activate

2. Cytokines produced by TH enhance activity

3. Mediators of inflammatory response (histamine)

4. Bacterial cell wall components

5. γ-interferon produced by TH cells
Are NK-1 Cells capable of recognizing antigens?
No
Are monocytes weakly or strongly phagocytic?
Weakly phagocytoic
Conceptually understand what diapelsis is
The movement or passage of blood cells, especially white blood cells, through intact capillary walls into surrounding body tissue.
What are the macrophages that reside in the alveoli?
Alveolar MF - reside in lung
What are the macrophage that reside in connective tissue?
Histocytes - reside in connective tissue
What are the macrophage that reside in liver?
Kupffer cells - reside in liver
What are the macrophage that reside in kidney?
Mesangial cells - reside in kidney
What are the macrophage that reside in brain?
Microglial cells - reside in brain
What are the macrophage that reside in bone?
Osteoclasts - reside in bone
What are the macrophage that reside in GI tract?
Intestinal - GI tract
What form of macrophage is the most phagocytic form?
The activated macrophage are more phagocytic than the resting macrophage
What are the differences in activated macrophages and resting macrophages?
Activated MF are more phagocytic than resting MF

Also produce more hydrolytic enzymes, more capable of killing engulfed microbes

Increase secretion of mediators of inflammatory response

Increase secretion of cytotoxic proteins, clears pathogens

Increased expression of MHC class II, increased ability to activate TH cells

Once TH cells activated, secrete cytokines that further activate MF

Therefore MF and TH work synergistically to activate each other
If you have an increased expression of MHC class II receptors, what is the result (reference consequences of macrophage activation)
Increased expression of MHC class II, increased ability to activate TH cells

Once TH cells activated, secrete cytokines that further activate MF

Therefore MF and TH work synergistically to activate each other
What is the primary role of an activated macrophage?
Engulf undesirable material - phagocytosis
What is the difference in reference to exogenous material and endogenous material (phagocytosis)

Also, is phagocytosis complex or simp
May be exogenous material
Particulate matter (dirt)
Whole microorganisms

May be endogenous matter
Dead or damaged tissue
Cell debris
Blood clots

VERY complex involving several steps
How can you conceptualize chemotaxis?
CHEMOTAXIS

phagocytic cell attracted to infection - microbial products, components of WBC or damaged tissues, complement
Conceptualize Adherence in phagocytosis
ADHERENCE - attachment of phagocyte to organism, may be inhibited by presence of capsule, may require OPSONIZATION if capsule present
Conceptualize ingestion in phagocytosis
INGESTION - involves pseudopods, fusion of pseudopods results in internalization, internalized organism in specialized vacuole - PHAGOSOME
Conceptualize a phagosome
Phagosome is a vesicle formed around a particle absorbed by phagocytosis.

The vacuole is formed by the fusion of the cell membrane around the particle.

A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested.

Phagosomes fuse with lysosomes in their maturation process, forming phagolysosomes.
Conceptualize opsinization
Antibody opsonization is the process by which a pathogen is marked for ingestion and destruction by a phagocyte.

Opsonization involves the binding of an opsonin, e.g., antibody, to a receptor on the pathogen's cell membrane.

After opsonin binds to the membrane, phagocytes are attracted to the pathogen. The Fab portion of the antibody binds to the antigen, whereas the Fc portion of the antibody binds to an Fc receptor on the phagocyte, facilitating phagocytosis.

The receptor-opsonin complex can also create byproducts like C3b and C4b which are important components of the complement system.

These components are deposited on the cell surface of the pathogen and aid in its destruction
Conceptualize a phagolysosome
A phagolysosome is a cytoplasmic body formed by the fusion of a phagosome, or ingested particle, with a lysosome containing hydrolytic enzymes.

The enzymes digest most of the material within the phagosome.

After fusion, the food particles or pathogens contained within the phagosome are usually digested by the enzymes contained within the lysosome.

Phagolysosome formation follows phagocytosis. It is common in immunological functions of macrophages and forms the home of several infectious agents.
Conceptualize what digestion is in phagocytosis
DIGESTION - phagosome fuses with lysosome, results in creation of PHAGOLYSOSOME

lytic enzymes digest bacteria (lysozyme, proteases, nucleases, lipases), produce superoxide anion, OH -, and H2O2
Conceptualize what a residual body is
Some material can't be digested - forms RESIDUAL BODY

Residual body migrates to plasma membrane

Fusion releases waste materials, recruits other phagocytes

Wiki - In lysosomal digestion, residual bodies are vesicles containing indigestible materials. Residual bodies are either secreted by the cell via exocytosis (this generally only occurs in macrophages), or they become lipofuscin granules that remain in the cytosol indefinitely.
When you have fusion of the cell membrane with a phagolysosome, what occur due to this process?
Fusion releases waste materials, recruits other phagocytes
What are the cellular products of digestion?
produce superoxide anion, OH -, and H2O2
What is created upon fusion of lysosome and phagosome?
Creates a harsh environment that uses Oxygen dependent killing mechanism
What are the steps in oxygen dependent killing mechanisms?
1. Membrane bound OXIDASE converts O₂ into 2O⁻

2. MYELOPEROXIDASE generates Cl-

3. NITRIC OXIDE SYNTHASE creates NO - enhances O⁻ activity
What is the role of oxidase in oxygen-dependent killing mechanism?
1. Membrane bound OXIDASE converts O₂ into 2O⁻
What is the role of myeloperoxidase in oxygen-dependent killing mechanism?
2. MYELOPEROXIDASE generates Cl-
What is the role of nitric oxide synthase in oxygen-dependent killing mechanism?
3. NITRIC OXIDE SYNTHASE creates NO - enhances O⁻ activity
Describe the pathway of oxygen-independent killing mechanisms
Bacteria exposed to LYSOZYME - degrades bacterial cell wall

Phagolysosome also contains DEFENSINS - insert into bacterial membranes and creates pore - lyses bacteria

Kills most bacteria that have been phagocytosed, some species of bacteria resist killing and multiply
Conceptualy understand what a lysozyme is
Bacteria exposed to LYSOZYME - degrades bacterial cell wall

Lysozymes, also known as muramidase or N-acetylmuramide glycanhydrolase, are glycoside hydrolases, enzymes (EC 3.2.1.17) that damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrins.
Conceptually understand what defensins are
Phagolysosome also contains DEFENSINS - insert into bacterial membranes and creates pore - lyses bacteria
Show the flowchart of independent vs. dependent killing mechanisms
What are the three main mechanisms used by organisms that survive phagocytosis?
Three main mechanisms used by organisms that survive phagocytosis

1. Prevent fusion of phagosome and lysosome

2. Possess unique cell wall that protects them from harsh environment within phagolysosome

3. Have mechanism to escape from phagosome before fusion with lysosome occurs, replicates in cytosol
What unique enzymes are contained within phagolysosome?

What are these enzymes function?
Proteases - Function is to break proteins into small peptides
Conceptually explain what an MHC class II molecule is
MHC (major histocompatibility complex) Class II molecules are found only on antigen-presenting cells and lymphocytes.

The antigens presented by class II atoms are derived from extracellular proteins (not cytosolic as in class I); hence, the MHC class II-dependent pathway of antigen presentation is called the endocytic or exogenous pathway.

Loading of MHC class II occurs by phagocytosis; extracellular proteins are endocytosed, ingested in lysosomes, and created by the class II MHC molecule prior to the molecule's migration to the cellular membrane.
Conceptually explain what an MHC class I molecule is
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other one being MHC class II) and are found on every nucleated cell of the body (and thus are scarce on red blood cells and platelets: the presence of MHC class I antigen on these anucleated cells is presumed to be owed to their genetically active nucleated cell-line precursors).

FXN - is to display fragments of proteins from within the cell to T cells; healthy cells will be ignored, while cells containing foreign proteins will be attacked by the immune system.

Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.
What is the overall antigen presentation and processing by the macrophage?
Phagolysosome also contains proteases

Breaks pathogen proteins into small peptides

Some peptides can be bound by MHC class II molecules

MHC class II/peptide complex transported to cell surface when residual body fuses with plasma membrane

Extremely efficient in activated MF - elevated level of MHC classII expression

Allows efficient activation of TH
What are all the factors that macrophages secrete the heighten the immune response?
Includes signaling molecules IL-1, IL-6, and TNF-a

Work coordinately to raise body temperature (fever)

IL-1 also essential for TH activation

Also produce and secrete complement proteins, important factor of non-specific immune response

Secretes hydrolytic enzymes in lysosome, contributes to inflammation

Also secrete cytokines that stimulate inducible hematopoiesis
Conceptualize what granulocytic cells are

Comment on name derivation
How many types?
Names of each with function?
Which are phagocytic?
Termed granulocytes due to presence of granules in cytosol

Three types, distinguished based on type of stain that can be used to visualize granules

1. NEUTORPHILS - multi-lobed nucleus, granules stain with both acid and basic dyes, also called polymorphic neutrophils (number of lobes in nucleus varies)

2. EOSINOPHILS - bi-lobed nucleus, granules stain red with eosin

3. BASOPHILS - lobed nucleus, granules stain blue with methylene blue

Neutrophils and eosinophils are phagocytic, basophils are not
What is the major circulating WBC?
Neutrophil (50-70%)

1. NEUTORPHILS - multi-lobed nucleus, granules stain with both acid and basic dyes, also called polymorphic neutrophils (number of lobes in nucleus varies)
Conceptualize Neutrophils
1. NEUTORPHILS - multi-lobed nucleus, granules stain with both acid and basic dyes, also called polymorphic neutrophils (number of lobes in nucleus varies)
Conceptualize Eosinophils
2. EOSINOPHILS - bi-lobed nucleus, granules stain red with eosin
Conceptualize Basophils
3. BASOPHILS - lobed nucleus, granules stain blue with methylene blue
Which granulocytic cells are phagocytic?
Neutrophils and eosinophils are phagocytic, basophils are not
Give the relative percentages of each type of WBC subtype
Conceptualize all the characteristics of Neutrophils
Major circulating white blood cell (WBC) - 50% - 70%

First immune effector cell at site of infection, infections usually stimulate increased production - LEUKOCYTOSIS

Circulating neutrophils enter tissues within 7-10 hrs of being released into circulation - EXTRAVASATION

Factors produced during inflammation serve as CHEMOTACTIC FACTORS

Once arrive at infection execute similar functions as MF, phagocytic cells

Slight differences
Which WBC is the first "on scene" at the sight of an infection?
Neutrophil

First immune effector cell at site of infection, infections usually stimulate increased production - LEUKOCYTOSIS
Conceptualize what leukocytosis is
Leukocytosis is a white blood cell count (the leukocyte count) above the normal range in the blood.

It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections.
Conceptualize what extravasation is

How does this relate to neutrophils?
Extravasation is the leakage of a fluid out of its container. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to the tissues surrounding them (diapedesis).

In the case of malignant cancer metastasis it refers to cancer cells exiting the capillaries and entering organs.

It is frequently used in medical contexts, either referring to urine, or to blood.

Neutrophils - Circulating neutrophils enter tissues within 7-10 hrs of being released into circulation - EXTRAVASATION
Factors that are produced from neutrophils being released secondary to an infection serve as what?

Once at the infection, what do these perform?
Factors produced during inflammation serve as CHEMOTACTIC FACTORS

Once arrive at infection execute similar functions as Macrophage, phagocytic cells
How do neutrophils destroy bacteria? (Phagocytic properties)

What is different about them?
Like MF, destroy bacteria with lytic enzymes and other antimicrobial substance

Unlike MF, aren't stored in lysosome, stored in granules
What's the primary difference in primary and secondary granules?

Which contain what orgalleles?

What do both have in common?

What is the overall function?
Larger denser PRIMARY GRANULES contain peroxidase, lysozyme, other hydrolytic enzymes

Smaller SECONDARY GRANULES contain collagenase, lactoferrin, and lysozyme

Both types fuse with phagosome

Contents digested and excreted
Conceptualize what Primary Granules are
Larger denser PRIMARY GRANULES contain peroxidase, lysozyme, other hydrolytic enzymes

An azurophil is an object readily stained with an azure stain. in white blood cells and hyperchromatin, imparting a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils loaded with a wide variety of anti-microbial defensins that fuse with phagocytic vacuoles.
Conceptualize what Secondary Granules are
Smaller SECONDARY GRANULES contain collagenase, lactoferrin, and lysozyme

Specific granules are secretory vesicles found exclusively in cells of the immune system called granulocytes. They are also known as secondary granules.

It is sometimes described as applying specifically to neutrophils, and sometimes the term is applied to other types of cells.

These granules store a mixture of cytotoxic molecules, including many enzymes and antimicrobial peptides, that are released by a process called degranulation following activation of the granulocyte by an immune stimulus.

Specific granules are also known as "secondary granules".
Which oxygen killing mechanism do neutrophils use?
Trick question

They use both
Conceptualize what a respiratory burst is
Nika - Due to ability to synthesize more reactive oxygen intermediates (O-) and more reactive nitrogen intermediates (NO)

Respiratory burst (sometimes called oxidative burst) is the rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) from different types of cells.

Usually it denotes the release of these chemicals from immune cells, e.g., neutrophils and monocytes, as they come into contact with different bacteria or fungi.

Respiratory burst plays an important role in the immune system. It is a crucial reaction that occurs in phagocytes to degrade internalized particles and bacteria.
What is a chemical that neutrophils produce in addition to "respiratory burst"?
Also produce higher level of DEFENSINS

Therefore, microbes more likely to be killed due to ingestion by neutrophils
Which granulytic cells are phagocytic?
Eosinophils and Neutrophils

Figure - Possible because of size?
What are eosinophils NOT apart in?

What do they typically have more involvement in?
Microbial clearance - NO

More involved in combating parasitic infections - YES
What do eosinophils secrete?
Contents of the granules which damage parasite membranes
What is the role of basophils?
Trick question

There is no defined role in immunology

However only known function is role in allergies due to secrete of granules
Where do Mast cells form and by what process?
Bone marrow by hematopoiesis
When mast cells are released into circulation, in what form are the cells in?
Undifferentiated form
When do undifferentiated cells differentiate into mast cells?
Do not differentiate into mast cells until leaving circulation and entering tissues
List all the locations of mast cell location
Found in:

1. Epithelial cells
2. Connective tissues of organs
3. All mucosal linings of respiratory, genitourinary, and digestive tracts
What do mast cells have heavy amount of?

What are these "thought" to have developed?

Why are these crucial?
Granules, which contain histamine

Released upon activation

Also believed to be apart of development of allergies

Crucial in development of inflammatory response
Describe the anatomy of a dendritic cell
Exhibit long extensive membrane extensions - resemble dendrites of nerve cells
Where are dendritic cells primarily function to do?
Primarily present antigens to TH cells for activation, present in several types of tissues
What are the four types of dendritic cells?
1. LANGERHANS CELLS - skin and mucous membranes

2. INTERSTITIAL DENDRITIC CELLS - most organs (heart, lungs, liver, kidney, gastrointestinal tract)

3. MONOCYTE DERIVED DENDRITIC CELLS - lymphoid tissue and thymus

4. PLASMOID DERIVED DENDRITIC CELLS - in circulatory system and lymph
Where are Langerhans cells found?
1. LANGERHANS CELLS - skin and mucous membranes
Where are interstitial dendritic cells found?
2. INTERSTITIAL DENDRITIC CELLS - most organs (heart, lungs, liver, kidney, gastrointestinal tract)
Where are monocytes derived dendritic cells found
3. MONOCYTE DERIVED DENDRITIC CELLS - lymphoid tissue and thymus
Where are plasmoid derived dendritic cells found?
4. PLASMOID DERIVED DENDRITIC CELLS - in circulatory system and lymph
What are five characteristics of dendritic cells?
Constitutively express high levels of MHC class I and class II

More effective at antigen presentation than B cells or MF

Obtain antigens through endocytosis or phagocytosis

Leave tissue and enter circulatory and lymph systems

Present antigens to T cells for activation
What are the three type of lymphoid organs in the immune system?
1. PRIMARY LYMPHOID ORGANS - sites of maturation of lymphocytes

2. SECONDARY LYMPHOID ORGANS - trap antigens and provide environment for interaction with mature lymphocytes

3. TERTIARY LYMPHOID TISSUES - import lymphocytes during inflammatory response
Conceptualize a primary lymphoid organ
1. PRIMARY LYMPHOID ORGANS - sites of maturation of lymphocytes

Site of maturation for lymphocytes - lymphocytes become committed to a specific antigen

Can only be activated by specific antigen

Once committed, is said to be IMMUNOCOMPETENT - capable of mounting an immune response

Two organs comprise the primary lymphoid organs
1. Thymus - site of T cell maturation
2. Bone marrow - site of B cell maturation
Conceptualize a secondary lymphoid organ
2. SECONDARY LYMPHOID ORGANS - trap antigens and provide environment for interaction with mature lymphocytes

Creates environment for effector cell/antigen interaction

Three major types of secondary lymphoid organs: lymph nodes, spleen, mucosal associated lymph node tissue (MALT)

LYMPH NODES and SPLEEN most highly organized of lymphoid tissues

MALT is less organized, associated with various mucousal membranes throughout body

Associated with Peyers patches in small intestine

Also associated with tonsils, appendix, upper airways, genital tract
Conceptualize a tertiary lymphoid organ
3. TERTIARY LYMPHOID TISSUES - import lymphocytes during inflammatory response
Conceptualize what immunocompetent means
Capable of mounting an immune response
What two organs comprise the primary lymphoid organs?
Two organs comprise the primary lymphoid organs
1. Thymus - site of T cell maturation
2. Bone marrow - site of B cell maturation
What a primary lymphoid organs the site of?

When can lymphocytes only be activated?
Site of maturation for lymphocytes - lymphocytes become committed to a specific antigen

Can only be activated by specific antigen
What is the site where T cell antigenic diversity develops?
Thymus
How are T cell receptors assembled?
Random gene arrangements
What is the process in which T cells are released into circulation?
Following assembly of T cell receptor, selection of T cells to be released into circulation involves a two step process

Involves thymic stromal cells that express high levels of MHC class I and class II antigens, present various antigens to T cells

T cells that recognize self antigens undergo apoptosis

T cells that fail to recognize foreign antigens also undergo apoptosis

Less than 5% of T cells ever leave thymus
What percentage of T cells actually leave the thymus?
5%
How are B cell receptors assembled?
B cell receptor also assembles through random genetic rearrangements
What type of cells directly interact with developing B cells?
Stromal cells in bone marrow interact directly with developing B cells
Stromal cells in bone marrow are directly interacted with what type of cell?
Developing B cells
How does the bone marrow facilitate maturation process?
1. Directly interact with developing B cells, source of self antigens

2. Stimulate with cytokines required for B cell development
What do cytokines induce for B cells?
Cytokines induce apoptosis for B cells capable of recognizing self antigens
What the "connecting factor" for primary and secondary lymphoid organs?
Immune system needs system to place effector cells and antigens together

Fluid portion of blood - PLASMA - seeps through capillary walls

Most returns to blood, remaining fluid called LYMPH

Flows through capillaries in connective tissues into larger vessles - LYMPHATIC VESSELS
Conceptualize what plasma is
Fluid portion of blood

Blood plasma is the straw-colored/pale-yellow liquid component of blood that normally holds the blood cells in whole blood in suspension. It makes up about 55% of total blood volume.

It is the intravascular fluid part of extracellular fluid (all body fluid outside of cells).

It is mostly water (93% by volume) and contains dissolved proteins (Major proteins are fibrinogens, globulins and albumins), glucose, clotting factors, mineral ions (Na+, Ca++, Mg++, HCO3- Cl- etc.), hormones and carbon dioxide (plasma being the main medium for excretory product transportation).
Conceptualize what lymph is
Lymph is the fluid that circulates throughout the lymphatic system.

The lymph is formed when the interstitial fluid (the fluid which lies in the interstices of all body tissues) is collected through lymph capillaries.

As the blood and the surrounding cells continually add and remove substances from the interstitial fluid, its composition continually changes and it changes into lymph fluid
Conceptualize what lymphatic vessels are
Lymph vessels (or lymphatic vessels) are thin walled, valved structures that carry lymph.

As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system.
What is the process when an antigen becomes trapped in tissues that enter the lymphatic system?
Antigens trapped in tissues enter lymphatic vessels

Transported to lymphoid tissues (lymph nodes), become trapped

Lymph accumulates immune effector cells as it progresses through lymphatic system

Results in accumulation of both antigen and effector cells in lymphoid tissues

Creates environment for antigen/effector cell interaction
What are the three major types of 2⁰ lymphoid organs?
Three major types of secondary lymphoid organs:

1. Lymph nodes
2. Spleen
3. Mucosal associated lymph node tissue (MALT)
What are the most highly organized of 2⁰ lymphoid tissues?
Lymph Nodes and Spleen
What are the least organized of 2⁰ lymphoid tissues?
MALT is less organized, associated with various mucousal membranes throughout body
What does MALT stand for and what is it associated with?
Mucosa-Associated Lymphoid Tissue

Associated with Peyers patches in small intestine

Also associated with tonsils, appendix, upper airways, genital tract
What are the roles of lymph nodes in order?
Antigens trapped by interdigitating dendritic cells

Engulf, process, and present with MHC class II molecules

Activates TH cells, secrete cytokines, allows activation of B cells

B cells interact with soluble antigens in lymph nodes

Activated lymphocytes rapidly proliferate

Exit lymph node through efferent lymph vessel

Lymph leaving node now enriched with antibodies and activated lymphocytes

May have 50 fold higher level of lymphocytes compared to lymph entering lymph node
What type of cells are antigens trapped in, in the lymph nodes?
Antigens trapped by interdigitating dendritic cells
What do lymph nodes activate, secrete and allow?
Activates TH cells, secrete cytokines, allows activation of B cells
What is the overall purpose of a lymphocyte entering the lymph node?
Lymph leaving node now enriched with antibodies and activated lymphocytes

May have 50 fold higher level of lymphocytes compared to lymph entering lymph node
In reference to anatomy, how does lymph exit the vessel?
Exit lymph node through efferent lymph vessel
How does the spleen function in the immune system?
Functions differently from lymph nodes

-Lymph nodes trap antigens from tissues

-Spleen traps antigens in circulatory system (blood)

Allows spleen to activate immune system in response to systemic infection

Antigens in blood captured by interdigitating dendritic cells, presented to TH cells by MHC class II molecules

Activation of TH allows subsequent activation of B cells

Blood leaving spleen enriched with activated lymphocytes and antibodies
What is the major site of entry for most pathogens?

Why is this crucial?
MALT - Mucosal Associated Lymphoid Tissue

Defense of mucous membranes against microbes (Specialized epithelial cells play a critical role in MALT function)
What are M cells function in the immune system?
M CELLS deliver small samples of antigen to MALT, located at INDUCTIVE SITES - small layer of mucous membrane over lymphoid tissue

Antigens transported interact with and activate B cells in tissue

B cells proliferate and secrete IgA

IgA secreted across mucous membranes, prevents attachment of pathogens
What are inductive sites?
INDUCTIVE SITES - small layer of mucous membrane over lymphoid tissue
What are the two types of cells that respond if the skin is broken and what are there responses?
1. KERATINOCYTES - specialized epithelial cells in outer layer

-Capable of secreting cytokines, invoke inflammatory response
-Capable of expressing MHC class II, antigen presentation

2. LANGERHANS CELLS

-Phagocytose antigens, migrate to lymph nodes
-Differentiate to interdigitating dendritic cells, activate TH and B cells
Conceptually understand what Keratinocytes are
1. KERATINOCYTES - specialized epithelial cells in outer layer

-Capable of secreting cytokines, invoke inflammatory response
-Capable of expressing MHC class II, antigen presentation
Conceptually understand what Langerhans cells are
2. LANGERHANS CELLS

-Phagocytose antigens, migrate to lymph nodes
-Differentiate to interdigitating dendritic cells, activate TH and B cells