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What are some events marked the Historical Perspectives of Immunology
1. Thucyclides (430BC)
-- survivors of the plague could nurse the sick w/o becoming sick
2. Chinese (11th C)
-- induced immunity w. variolation
3. Lady Mary W Montague (1718)
-- introduced variolation to Europeans
What does "Immunty" mean?
* ability to resist infection (originally)
* Being immune doesn't mean you're not infected, it means you don't show symptoms of being infected
Older Terminology of Immunity
cellular immunity and humoral immunity
Cellular Immunity
- early work on macrophages
- focus on cells that “attack”
* T cell immunity
-- T cells “attack” with specificity
* Problems w. T-cells immunity:
-- some T cells don’t “attack”
-- T cells secrete cytokines
-- requirement for antigen presentation
What are the four basic requirements for expert testimony?
[1] Subject matter must be appropriate for expert testimony;

[2] must be qualified as expert;

[3] should possess reasonable certainty or probability regarding the opinion;

[4] the opinion must be supported by proper factual basis
Current Approach of Immunity
-- importance of innate immunity
-- importance of antigen presentation
-- interdependence between “branches”
-- regulation is everything!
Other Terms for immunity: Primary vs. Memory, Generative vs. Peripheral,
Naïve vs. Activated,
Innate vs. Adaptive
Innate immunity
vs
Adaptive Immunity
Innate Immunity:
- not antigen specific
- first response
- always available (no induction needed)
- no memory
Adaptive Immunity:
- antigen specific
- delayed response (takes time to work)
- antigen induced response
- memory develops
Adaptive is NOT Adoptive immune response (immunity transferred from 1person to another person, ie: via breast milk or immunoglobulin shots)
Overview of Immune System
Immune System:
1. Innate (nonspecific)
-- cellular components
-- humoral components
2. Adaptive (specific)
-- cellular components
-- humoral components
Terminologies for Various kinds of Antigens
* Antigen (Ag):
--any substance that binds to an antibody (Ab) or a T-cell Receptors (TCR)
* Pathogen:
-- any microorganisms capable of causing disease
* Immunogen:
-- any substance that elicits an adaptive immune response
* Allergen:
-- any antigen that elicits hypersensitivity (allergy)
* Toleragen:
-- any antigen (usually self Ag) that elicits tolerance
apoptosis (Programmed cell death)
1. Necrosis
-- chromatin clumping
-- swollen organelles
-- flocculent mitochondria
-- during integration cell bursts and released to intracellular content and cause inflammation
2. Apoptosis
-- mild convolution
-- chromatin compaction and segregation
-- condensation of cytoplasm
-- during disintegration, nuclear fragmentation, blebbing and apoptotic bodies.
-- cell parts are absorbed by other neighboring cells via phagocytosis
Genes that regulate Apoptosis
* bcl2 = inhibits (prevents) apoptosis
* bax = opposes bcl2 (promotes apoptosis)
* bcl-Xl (bcl-Long) = inhibits (prevents) apoptosis
* bcl-Xs (bcl-Short) = opposes bcl-Xl (promotes apopotosis)
* caspase (several kinds) = protease function (promotes apoptosis)
* fas = induces (initiates) apoptosis
Macrophage and Activated Function
* Phagocytosis and activation of bactericidal mechanism
* antigen presentation
* macrophages express receptors for many microbial constituents
Myeloid Cells in Innate & Adaptive Immunity with their Activated Functions (part I)
1. Macrophage:
-- phagocytosis and activation of bactericidal mechanism
-- antigen presentation
2. Dendritic Cell:
-- antigen uptake in peripheral sites
-- antigen presentation
3. Neutrophil:
-- phagocytosis and activation of bactericidal mechanisms
Myeloid Cells of Innate & Adaptive Immunity with their Activated Functions (part II)
4.Eosinophil:
-- killing of antibody-coated parasites
5. Mast Cell:
-- release of granules containing histamine and active agents
6. Basophil:
-- function is unknown
What is an epitope?
Epitope: a portion of a molecule to which an antibody binds (composed of sugars, lipids or amino acids)
Each antigen has several epitopes
1. Antibodies bind to epitopes displayed on the surface of the antigen
2. Epitopes recognized by T-cell Receptors (TCR) are often buried
3. Antigen first must be broken down to peptide fragments
4. Epitope peptide binds to a self molecule (MHC molecule)
5. TCR binds to a complex of a MHC molecule and epitope peptide
Antigen Presenting Cell (APC)
Rise from Hematopoietic stem cell, divides into:
1. common myeloid progenitor, produces:
a. langerhan's cell
b. interstitial dendritic cell

2. common lymphoid progenitor, produces:
a. myeloid dendritic cell
b. lymphoid dendritic cell
Natural Killer (NK) Cell
Function:
-- release lyctic granules that kill some virus-infected cell
Organs of the Immune System
1. Primary Organs (site of the cell generation) =
-- thymus
-- peyer's patch in intestine
2. Secondary (site of cell "activation") =
-- adenoid tonsil
-- lymph node
-- appendix
-- spleen
-- peyer's patches in the intestine
Bone Marrow
* site of hematopoeisis for all blood cells but T-cells finish development (mature) in thymus
* structure is not well defined
* need physical interaction between developing cells and stromal/dendritic cell
* fetal liver is site for hematopoeisis during fetal/ early development

**in bird, there's a specialized organ called the "bursa of fabricus", which function for development of B-cells
Thymus
* site fot T-cell maturation
* weighs 15gr @ birth, 35gr during puberty (height of T-cell maturation), 25gr during the twenties, less than 15gr in the sixties, and less than 5gr in the seventies of age (aka: thymus involution or the shrinking of the thymus)
Peyer's Patch
Peyee's Patch are covered by an epithelial layer containing specialized cell (M-cell) which have a characteristic membrane ruffles
M.A.L.T
aka: Mucous Associated Lymphoid Tissues
* is a diffuse system of small concentrations of lymphoid tissue found in various sites of the body such (GI tract, thyroid, breast, lung, salivary glands, eye, and skin)
* MALT is populated by lymphocytes (T cells and B cells) as well as plasma cells and macrophages
Burnet's Clonal Selection Theory
(postulates of the clonal selection hypothesis)
1. Each lymphocyte bears a single type of receptor with unique specificity
2. Interaction between foreign molecule & a lymphoid receptor capable of binding that molecule w. high affinity leads to lymphocyte activation
3. Differentiated effector cell derived from an activated lymphocytes will bear receptors of same specificity to parental cells from which that lymphocyte was derived
4. Lymphocytes bearing receptor specific for omnipresent self molecules are deleted at early stage lymphoid cell development, therefore absent from collection of mature lymphocytes
Clonal Selection Process
1. Each progenitor cell gives rise to a large # of lymphocytes, with distinct antigen receptor
2. Removal of potential self reactive immature lymphocytes by clonal deletion
3. Mature naive lymphocyte will mature and start to divide when a foreign antigen react with receptor on the cell.
4. It will give rise to a clone of identical progeny all of whose receptors bind to the same antigen.
5. Antigen specificity thus maintained as progeny proliferate and differentiate into effector cells
Cells of the immune system
I. MYELOID Cells:
1. Granulocytic:
-- Neutrophils
-- Basophils
-- Eusinophils
2. Monocytic:
-- Macrophages
-- Dendritic cells
-- Kuppfer cells
II LYMPHOID Cells
1. T-cells
-- T-Helper cells (Th)
-- Cytotoxic T-cells (Tc)
-- Suppressor T-cells (Ts)
2. B-cells
-- Plasma cells
3. NK cells
Cells of the Innate (Non-specific) Immune System
1. Neutrophils
2. Macrophages
3. Eosinophils
4. Natural Killer (NK cells)
What are the functions of activated Neutrophils?
* Polymorphonuclear (PMN) cells are recruited to the site of infection to phagocytize invading organisms and kill them intracellularly.
* PMNs also cause collateral tissue damage during inflammation (bactericidal mechanism)
What are the functions of Macrophages?
* phagocytosis and activation of bactericidal mechanisms
* antigen presentation
* induce specific immune response
What are the function of dendritic cells?
* antigen uptake in peripheral sites
* antigen presentation
What is the function of eosinophil?
killing antibody-coated parasites
what is the function of mast cells?
release of granules containing histamine and active agents (induce inflammation)
what is macropinocytosis?
a phagocytosis process by continually ingest large amount of extracellular fluid and its content
what are Antigen Presenting Cells (APCs)?
highly specialized cells that can process antigens and display their peptide fragments (and other stimulatory proteins) on the cell surface needed for naive T-cells activation
what is an ANTIBODY?
= a protein that bind specifically to a particular antigen
(antibody is antigen-specific)
what is ANTIGEN?
= any molecule that binds specifically to an antibody (able to generate antibodies)
* some antibody can't elicit antibody production by themselves
Immunogens= antigens that can induce antibody production)
Steps of Dendritic Cells initiate Adaptive Immune Responses:
1. immature dendritic cells reside in peripheral sites to take up macropinocytosis
2. dendritic cells migrate via lymphatic vessels to regional lymph nodes, arriving as fully mature dendritic cells (with antigens and stimulatory molecules to activate naive T-cells)
3. those mature dendritic cells activate naive T-cells in lymphoid organs (ie: lymph nodes)
What are the microbial-component receptors expressed on Macrophages?
* Mannose receptor (from yeast, bacteria, and fungi)
* Glucan receptor (from yeast, bacteria, and fungi)
* LPS (LipoPolySaccharide) receptor, aka: CD14
* TLR (Toll-Like Receptor)
--TLR2 binds to cell wall of gram-neg. bacteria
--TLR4 binds to cell wall of gram.pos bacteria
*Scavenger Receptor (from bacteria, yeast and fungi)
what is PAMPs (Pathogen Associated Molecular Pattern)?
=describe molecules association with groups of pathogens and which are recognized by cells of the innate immune system
* PAMPs present on many micro-organisms but not on body's own cells
what are PRRs (Pattern Recognition Receptors)?
= receptors that recognize PAMPs and other non-self structures (LPS, mannose, glucan, etc)
what is clonal expansion?
= process of proliferation of antigen-specific lymphocytes in response to antigenic stimulation, leading to differentiation into effector cels
** essential step in adaptive immunity
Steps of Clonal Selection
1. A singel progenitor cell gives rise to a large numbers of lymphocytes, ea. with different specificity
2. Lymphocytes that mind omnipresent self-antigens are eliminated before maturation (to ensure tolerance to self-antigens)
3. Mature naive lymphocytes is activated and ready to divide when exposed to foreign antigen
4. That mature lymphocyte gives rise to a clone of identical progeny, whose receptors bind to the same antigen (forming a clone of effector cells)
What is the schematic structure of an antibody molecule?
* antibody molecule is secreted by activated B-cells, as an antigen-binding effector molecule
* an antibody is composed of 2 identical heavy chains and light chains
* each chain has a constant region (effector function) and variable region (antigen-binding site)
* Ea. arm of the antibody molecule is formed by a light chain and a a heavy chain so that variable parts of the 2 chains come together, creating a variable region that contains antigen binding site.
* stem is formed from constant parts of the heavy chain and involved in elimination of the bound antigen
what is the schematic structure of a T-cell receptor?
* composed of 2 chains: α-chain and β-chain each with a variable and a constant part.
* like an antibody molecule, variable parts of the 2 chains create a variable region, which forms the antigen-binding site.
* T-cell receptor is not produced in a secreted form
What are the 2 signals Hypothesis in lymphocyte activation?
lymphocyte activation required 2 signals:
1. Mature naive lymphocyte become activated via antigen receptor (first signal)
2. The second signal from APCs:
*For T-cell= dendritic cell
*For B-cell= an activated T-cell which recognizes antigenic peptides taken up, processed and presented by B-cell on its surface
What are the 4 classes of pathogens that our immune system protect us agains?
1. extracellular bacteria, parasites and fungi
2. intracellular bacteria and parasites
3. viruses (intracellular)
4. parasitic worms (extracellular)
Antibodies can participate in host defense in 3 ways
1. NEUTRALIZATION
-- cells with toxin receptors bind with bacterial toxin, neutralize (inactivate toxin), then degraded by macrophages (antigen/ antibody complex)
2. OPSONIZATION
-- antibodies coating a bacterial antigen to further be ingested and destroyed by phagocytosis (macrophages and neutrophils)
3. COMPLEMENT ACTIVATION
-- complement coating favors and taking up and destroying of the bacterium by phagocytes, leading to lysis and ingestion
what is the mechanism of host defense agains intracellular infection by viruses?
* cells infected by virus are recognized by cytotoxic T-cells (Tc), which kill infected cells directly.
* killing mechanism involves the activation of enzyme called caspases (contain cysteine in their active site, and cleave after aspartic acid) * these in turn activate cytosolic nuclease in the infected cell, which cleave host and viral DNA
what is the mechanism of host defense against intracellular infection by mycobacteria?
* mycobacteria engulfed by macrophages but resist on being destroyed by preventing intracellular vesicles where they reside from fusing with lysosomes containing bactericidal agents, thus, bacteria are protected from being killed.
* in resting macrophages, mycobacteria persist and replicate in these vesicles.
* when phagocyte is recognized and activated by Th1 cell, phagocytic vesicles fuse with lysosomes and bacteria can be killed
* macrophage activation is controlled by Th1 cells to avoid tissue damage and to save energy
The diversity in lymphocyte antigen receptors is generated by somatic gene-segment rearrangement
1. Parts of variable regions of antigen receptors are inherited gene segments
2. unique combination of segments becomes joined by somatic gene rearrangement
3. chains, pairs to give unique receptor for each lymphocytes

**random rearrangement is repeated for the set of the other chain to produce 2types of polypeptide chains, forming unique antigen receptor on lymphocyte surface