1. Recognition of, and defense against foreign substances

*You immune system must be able to differentiate between self and foreign "cells" and materials

2. Establishment of immunosurveillance

*William Coley - role of immune system in cancer prevention

Innate and Acquired.

Innate is passed genetically from parent to offspring. It responds the same way every time to every disease. It has a rapid, fixed response, and limited specificity.

Acquired develops during the host's lifetime based on the host's exposure to infectious diseases that overcome the innate immune system. It has a "memory" and reacts stronger and faster each time the host is exposed to the pathogen. It is highly specific, but takes a while to kick in the first time (~1 week).

Both use common effector mechanisms for the destruction of pathogens.

Physical Barriers - skin, mucous membranes, cilia, competitive colonization

Phagocytotic Barriers - Metchnikoff - phagocytocis in starfish, macrophages

Inflammatory Barriers - vasodilatiton, increased capillary permeability, influx of phagocytets

Physiological Barriers - temperature, pH, chemical mediators (complement, lysozyme, interferon)

Rubor - redness

Calor - heat

Tumor - swelling

Dolor - pain

Functio laesa - loss of function

Erythrocytes - 5 mil/microliter

Leukocytes - 7,500/microliter

Most numerous of WBCs

Multi-lobed nucleus (2-5 lobes)

Nuclei stain dark blue

Small, pale orange-staining granules in the cytoplasm

10-12 micrometers in diameter

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Multi-lobed nucleus

Large granules that stain red (with eosin)

Numbers elevated during allergic attacks or parasitic infections

11-14 micrometers in diamter

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Least numerous of WBCs

Nucleus is bi- or tri-lobed

Large granules in the cytoplasm that stain blue

Granules often obscure the nucleus

8-11 micrometers in diamter

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Largest WBC

Large nuclei that often show indentations

Pale-blue staining cytoplasm (typically more than lymphocytes)

Occasionally can detect granules

12-15 micrometers in diameter

[image]

Second most plentiful WBC

Large, round nucleus

Very little cytoplasm

Made up of T and B cells, but can not differentiate in the differential stain we did in lab

6-11 micrometers in diamter

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Primary - (antigen-independent differentiation) thumus and bone marrow

Secondary - (antigen-dependent differentiation) lymph nodes, spleen, mucosal-associated lymphoid tissue (MALT), gut-associated lymphoid tissue (GALT)

Tertiary - cutaneous-associated lymphoid tissue

1) To provide an environment for the maturation of the immune system's immature cells

2) To concentrate lymphocytes into regions that drain areas of antigen insult

3) To permit the interaction of different classes of lymphocytes

4) To provide an efficient means for the dispersion of antibodies and other soluble factors from lymphocytes and other immune cells 

Parasites - common roundworm, malaria

Viruses - Hepatitis B, Chickenpox, Mononucleosis, Measles, Mumps

 Bacteria - Plague, typhoid fever, whooping cough, cholera, anthrax, leprosy

Fungi - Athlete's foot, pneumonia

Pathogens tend to evolve towards accomodation with their human host rather than killing off their food source rapidly. Humans have some built-in genetic resistance to endemic diseases such as chickenpox or malaria.

Influenza is usually overcome by the immune system despite it mutating each year, but pathogens that are new to humans (i.e. Ebola) often cause high mortality on first exposure.

1st defense - skin and mucosal membranes -- epithelia lining respiratory, gastrointestinal, and urogenital tracts -- epithelial cells secrete antimicrobial substances called defensins, tears and saliva produce lysozyme, acidic environments

2nd defense - innate immune response -- inflammation

3rd defense - acquired/adaptive immune system

1) Recognition -- soluble proteins and cell-surface receptors bind to the pathogen or to human cells (serum proteins) that become altered in the presence of the pathogen

2) Recruitment of destructive effector mechanisms that kill and eliminate the pathogen

By passing the barrier of the skin, the 1st line of defense has been brached. Washing away the dirt removes most of the pathogens. If the cut had not been washed, there may have been too many microorganisms for the innate immune system to fight. There are a few cells left, and those begin to divide.

Cells near the infection (macrophages) sense the invaders and send out soluble proteins called cytokines which interact with other cells to trigger immune response. Inflammation occurs as a result of the innate immune response.

The cytokines also induce local dilation of capillaries called vasodilation. This creates gaps between the cells of the endothelium. This causes increased leakage of blood plasma into the connective tissue, which causes swelling, putting pressure on the nerve endings, which causes pain. WBCs move through the induced openings in the endothelium from the blood into the inflamed tissue.

These cells are usually neutrophils, and they will phagocytose the invader and die, forming pus. The second most abundant granulocytic cell is eosinophil, which defends against worms and other intestinal parasites. The third is basophil, which may aid in regulation of the immune response to parasites.

It is more common in individuals who are malnourished, sleep-deprived, or stressed for the innate immune system to be incapable of overcoming an infection. In this case, the innate immune system will activate the adaptive immune system by calling on lymphocytes. This is a long-lasting, highly specialized defense system, and remains in immune "memory" after the infection. Lymphocyte cell-surface receptors are highly pathogen-specific. This is due to variants of the same basic receptor type, which creates millions of different kinds of receptors.

Only those lymphocytes which are specific to the pathogen are chosen to participate in the response. These then proliferate and differentiate. This is called clonal selection and clonal expansion.

This takes a lot more time than the innate immune system. If the same virus attacks again, the secondary immune response kicks in and is much stronger and faster than the primary immune response.

Granulocytes - neutrophils, eosinophils, and basophils

Mast cells - reside in connective tissue, major contributor to inflammation

Monocytes - mobile prgenitors of macrophages -- travel in the blood to tissues where they mature into macrophages -- may also mature into dendritic cells, which are star-shaped and act as celluldar messengers that are sent to call up an adaptive immune response -- those dendrites that reside in infected tissue will take some of the pathogens to one of the lymphoid organs that specialize in making adaptive immune responses

NK/T cell precursor  - can differentiate into natural killer (NK) cells - kill virus-infected cells and secrete cytokines that impede viral replication in infected cells or T cells

T cells - 2 kinds: cytotoxis - kill cells that are infected with viruses -- similar to NK, but adaptive

helper T cells - secrete cytokines that help some other cells of the immune system become fully activated effector cells -- ex: some activate B cells to become plasma cells, which are cells that secrete soluble forms of immunoglobulin called antibodies that bind to pathogens and their toxic products

C5 - is cleaved by C5 convertase (C3b₂Bb) into C5a and C5b. C5b initiates the formation of the membrane-attack complex.

C6 - Binds to and stabilizes C5b. Forms a binding site for C7.

C7 - Binds to C5b6 and exposes a hydrophobic region that inserts into the cell membrane

C8 - Binds to C5b67 and exposes a hydrophogic region that inserts into the cell membrane

C9 - Polymerization on the C5b678 complex to form a membrane-spanning channel that disrupts the cell's integrity and can result in cell death

plasma proteins made by the liver and present in the blood, lymph, and extracelluldar fluids

- coats the surface of bacteria and extracellular virus articles and makes them more easily phagocytosed

- many components are proteases

infection triggers this, proceeds by a series of enzymatic reactions where each protease cleaves and activates te next enzyme in the pathway

- each protease is highl specific for the complement protein it cleaves

- many belong to the family of serine proteases

1) alternative

2) lectin

3) classical

- Exposure and hydrolysis of the thioester bond in C3 forms iC3 (does not cleave the C3)

- iC3 binds to factor B

- factor D cleaves factor B

- small fragment Ba released

- large fragment Bb remains bound to iC3, called iC3Bb

- iC3Bb (a C3 convertase) cleaves C3 molecules into C3a and C3b

- some C3b covalenly binds to the surface of the pathogen

- the C3b bound to the pathogen binds factor B and facilitates its cleavage by factor D, which leads to the release of Ba and the formation of C3bBb

- C3bBb binds C3 and cleaves it, more C3b fragments become fixed to the pathogen, pathogen becomes rapidly coated due to his positive feedback

Properdin (factor P) - increases the speed and power of complement activation by binding to C3bBb (a C3 convertase) and preventig its degredation by proteases

Factor H - binds to C3b and facilitates further cleavage to a form called iC3b by factor I -- iC3b cannot assemble a C3 convertase -- negative feedback

Decay-accelerating factor (DAF) - Binds to the C3b component of alternative C3 convertase, causing dissociation and inactivation

Membranne co-factor protein (MCP) - same function, but binding of MCP to C3b maes it susceptible to inactivation by factor I

- C3b binds to C3bBb (the alternative pathway C3 convertase) to produce the alternative C5 convertase, C3b₂Bb.

- This cleaves C5 into C5a and C5b. C5b initiates the formation of the membrane-attack complex.

- C6 and then C7 bind to C5b. This exposes a hydrophobic site in C7, which inserts into the lipid bilayer.

-C8 then binds to C5b, and a hydrophobic site in C8 is exposed and inserted into the membrane.

-This initiates the polymerization of C9, the componen that forms the transmembrane pores.

- They are called anaphylatoxins because thehy incude anaphylactic shock, which is an acute inflammatory response.

- They induce the contraction of smooth muscle and the degranulation of mast cells and basophils, which releases histamine and vasoactive substances that increase capillary permeability, which increases blood flow and vascular permeability

-Acts directly on neutrophils and monocytes to increase adherece to blood vessel walls

-Acts as a chemoattractant to direct their migration towards sites where complement is being fixed

A secondary enzymatic cascade of plasma proteins that is triggered by tissue dmage.

- Produces the peptide bradykinin, which increases the supply of soluble and celluldar materials of innate immunity to the infected site

There are alpha-defensins and beta-defensins. Defensin molecules are amphipathic (both hydrophobic and hydrophilic regions), which allows them to penetrate microbial membranes and disrupt their integrity.

- Alpha-defensins are expressed mainly by neutrophils and Paneth cells (specialized epithelial cells of the small intestine) There are at least 6.

-Beta-defensins are expressed by a broad range of epithelial cells, particularly those of the skin, respiratory tract, and the urogenital tract, at least 4

-To prevent defensins from disrupting human cells, they aresythesized as part of longer, inactive polypeptides that are cleaved to release the active fragment

-Set of defensins varies - number of copies of genes an indiviual inherits varies greatly

A family of signalling receptors, each of which is specific for a different set of microbial products.

-Transmembrane proteins composed of an extracelluldar domain that recgnizes the pathogen and a cytoplasmic signalig domain that conveys information to the inside of the cell

-Ex: TLR4 has specificity for the bacterial lipoplysaccharide (LPS) on Gram-negative bacteria -- seends signals to the macrophage's nucleus that change the pattern of gene expression, activating cytokines that induce innate immune resopnses and inflammation

- Mannose-binding lectin (MBL) - protein produced mainly in the liver, present in modeate concentrations in the blood and tissues

- MBL binds to mannose-binding lectin-associated serine protease (MASP)

- MBL grabs mannose on the surface of a bacterium, MASP functions like a convertase to clip C4 which bind to the surface of an invader

-MASP-2 can also cleave C2 -- complex of C4b and C2a is C4bC2a -- C3 convertase (classical C3 convertase)

*unique contribution is mannose-binding lectin and the activation of C4 and C2 by the MASP proteins

- Most spend much of their time residing in our tissues and phagocytosing dead cells and debris

- When they become alerted to an intruder, they up-regulate expression of class II MHC molecules, which display fragments of the invaders' proteins for helper T cells to see. --> they become alerted due to interferon gamma, which is produced mainly by helper T cells and NK cells

- They can be induced into a higher state of readiness called "hyperactivation" if they receive a direct signal from an invader, for example, from LPS

-Also when a macrophage binds to LPS or mannose, it knows for sure that there has been an invasion

-Hyperactivated macropages produce and secrete a cytokine called tumor necrosis factor (TNF) which can kill tumor cells and cells infected with viruses and can alert other parts of the immune system

-If at risk of becoming overwhelmed, call on the neutrophils

- Neutrophils come out of the bone marrow programmed to die in about 5 days

- They die by committing suicide (apoptosis)

- Do not present antigen -- are "on call" killers

- Exit the blood and phagocytose the invaders, release cytokines alerting other immune system cells to the infection

- Neutrophils are programmed to be short-lived b/c they would kill off our cells if they were allowed to live too long

-Neutrophils normally move very quickly throughout the blood in an inactive state --ICAM is normally on the surface of the endothelial cells that line blood cells, but the neutrophil receptor SLIG does not bind

-During an infection, "alarm" cytokines interleukin 1 (IL-1) and TNF begin to line the blood vessels nearby, which SLIG binds.

-Once SLIG binds to the cytokine, the neutrophil quickly produces integrin, which binds to ICAM. This stops the neutrophil from "rolling" away.

- The chemoattractant C5a leads the neutrophil to the infection

So that the right clls go to the right location

Eosinophils and mast cells must exit the blood and enter the tissue at the site of a parasitic infection.

Monocytes need o leave the blood to mature into macrophages.

B and T cells must exit the blood and enter lymph nodes, where they can be activatd.

-On call, short-lived

- Kill by forcing cells to committ apoptosis

- Do not kill cells expressing type I MHC

- Can be activated when receptors detect LPS -- then release interferon gamma, which primes macrophages

Classical - Precursor: C4 and C2,

Activating: C1S, C3 convetase: C4b2a, C5 convertase: C4b2a3b, C5 binding protein: C3

Lectin - Precursor: C4 and C2, Activating: MASP, C3 convertase: C4b2a, C5 convertase: C4b2a3b, C5 binding: C3

Alternative - Precursor: C3 and Factor B, Activating: Factor D, C3 convertase: C3bBb, C5 convertase: C3bBb3b, C5 binding: C3

- C1 is activated by joining C1q polypeptides with C1r and C1s.

- C1s cleaves C4, leading to the covalent attachment of C4b to the pathogen surface

-C1s also cleaves C2, leading to the formation of the classical C3 convertase C4bC2a.

-Continue down the lectin pathway

*unique contribution is C1q binding pathogens and of C1r and C1s inthe activation of C4 and C2

- Immunogens have the ability to induce and immune response and tend to be larger molecules

- Antigens have the ability to combine specifically with the final receptor.

-Antigens tend to be smaller portions of the immunogen. They may be a smaller piece that binds to the receptor, but does not stimulate an immune response

-Epitope is the small part that fits into the specific receptor

-To just have the epitope but not the immunogen is like having the tooth part of a key w/o the big part that enables you to turn it

- haptens are small molecules thatare antigenic, but incapable, by themselves, of inducing a specific immune response --> they lack immunogenicity

-Penicillin and poison ivy are haptens --> they modify your receptors to give them immnogenicity

1) Foreignness

2) Size

a) epitopes - vaccines are made of these, must be the small portion our immune system responds to

3) complexity - random more complex than ordered

a) chemical cmposition

b) heterogeneity

4) presentability

a) susceptibility to antigen processing and presentation

5) gentics

a) Major histocompatibility complex (MHC) - maes your cells your own -- presents the antigen

b) immunglobulin genes - produce antibodies

c) T-cell receptor genes - mount a response

6) Dosage of immunogen

a) tolerance - immunologic unresponsiveness

b) numerous exposures better than a single exposure

7) route of administration and adjuvants --> help immune response

a) nonspecifically stimulate lymphocyte proliferation

b) enhance co-stimulatory signals

c) induce granuloma formation

d) prolong antigen response

-Large, complex, organic molecules --> proteins are #1!

- Polysaccharides --> humoral - humans

-Lipids --> cardiolipin - Wassermann test

-Nucleic acids --> systemic lupus erythematosus

- Shaped like a "Y"

- 2 identical light chains and 2 identical heavy chains

-light and heavy give antige specificity

-After pepsin digestion, forms fc fragments (fragments that crystalize, the bottom portion of the "Y" which is part of the 2 heavy chains)

- F(ab')₂ - fragment responsible for antigen binding (the top 2 parts of the "Y"), light + heavy chain

- In the innate immune system, pathogens are recognized either by structures shared by many different pathogens or alterations to human cells that are commonly induced by the presence of pathogens. This is not specific, and genes encoding these are inherited from one generation to the next. There can be some mutations, but these rarely have an effect.

- In the adaptive immune response, B cells and T cells each recognize pathogens using cell-surface receptors of just one molecular type. Highly specific, adapts.

Shaped like a "Y" with 2 identical light chains and 2 identical heavy chains.

At the end are the antigen-binding site. The ends ar called amino-terminal variable regions that give the immunglobulin its specificity. The constant region is very similar between immunoglobulins. Angibodies are the secreted form of immunoglobulin, and are identical in structure except that they lack a transmembrane region.

The variable regions bind to antigens.

The constant regions contain binding sites for cell-surfce receptors on phagocytes and other inflammatory cells and also for complement proteins.

The secreted antibody acts as a molecular adaptor or bridge. With n site, it binds to pathogens, and with another it binds to effectr cells and molecules that can destroy the pathogen.

Consists of an alpha chain and a beta chain that are both anchored in te T-cell membrane.

Consist of a variable region and a constant region, with the variable regions forming an antigen-binding site.

IgG, IgA, IgM, IgE, and IgD

GAMED

Facilitate the engulfmet an destruction of extracellular microorganisms and toxins by phagocytes.

-Neutrophils and macrophaes bind to this

-On the surface of a pathogen, binds to a complement component that initiates the classical pathway of complement activation

- Causes the pathogen to become coated with C3b

-Not quite as efficient as IgG in facilitatig phagocytosis

-Always the first antibody to be secrete in the immune response

- binds to mast cells in response to parasitic infections

- in developed countrie, IgE is most often the antibody involved in unwanted allergic reactions