Chapter 22 - Lymphatic System 2/2 A & P ii

Immunology

study of all biological chemical & physical events surrounding the function of the immune system

Defense mechanism: First line of defense

any barrier that blocks invasion at the portal of entry, innate and nonspecific

Defense mechanism: Second line of defense

protective cells/fluids, inflammation & phagocytosis - innate and nonspecific

Defense mechanism: Third line of defense

acquired with exposure to foreign substances, produces antibodiesd and memory cells - adaptive and specific

Pathogen

microorganisms that enter our bodies (through various organs to infect and cause disease)

includes bacteria, viruses, and parasites

Functions of the organs of defense

• making sure no foreign antigens have entered the body

• Tolerance, recognition of normal cells (self) vs foreign (nonself) material

The four major subdivision of immune system

fluids

tissues and organs

cells

cytokines

Main component of Fluid

lymph and blood

Where does the lymphatic converge and join the circulatory system?

the subclavian vein

Types of portals

respiratory, gastrointestinal, skin, blood, genitourinary

Fluids: Reticuloendothelial System (RES) - 2nd line of defense

loose connective tissue, with cells scattered and surrounded by fluid

A network of connective tissue fibers that interconnects other cells and meshes with the connective tissue network surrounding organs

Inhabited by phagocytic cells, the mononuclear phagocyte system, and macrophages that are ready to ingest microbes that pass the first line of defense

Primary lymphoid organs

thymus & red bone marrow

Secondary lymphoid organs

lymph nodes, spleen, tonsils, MALT/BALT

Most important cellular component of the immune system

White blood cell

WBC: Neutrophils

phagocytic, first cells that enter infected tissue, only last a few hours

releases cytokines/chemotactic factors that increase inflammatory response

WBC: Macrophages

Large phagocytic cells

Macrophages: dendrite cells

resident macrophages, permanent members of the system

WBC: Basophils/Mast

release histamine and leukotrienes, which promote inflammation

WBC: Eosinophils

secretes enzymes which kills parasites

Adaptive immunity: B Lymphocytes

produces antibodies/respond extracellular to pathogens

Adaptive immunity: T Lymphocytes

attack intracellular parasites (like virus infected cells)

Cytokines

chemical messengers of the immune system

causes cells to differentiate, proliferate

can act in an autocrine, paracrine, or endocrine fashion

Cytokines: Histamine

causes vasodilation, increased permeability of capillaries

released during inflammation and allergy

Interleukin 1

Interleukin 2

• produced by helper T cells during activation of cytotoxic T cells
• stimulates proliferation of cytotoxic T cell

1st line of defense: Physical barrier

Skin & Mucous membrane

Mucous Membrane Barrier

coated with mucus with hairs/cilia, found at openings of several systems (gastrointestinal, respiratory, genitourinary)

Mechanical barrier

designed to remove pathogens from the body

examples: skin shedding, peristalsis, sneezing, excretion, blinking, etc.

Chemical barrier

Skin - sebum & sweat

Digestive tract - saliva, HCI, Pancreatic/intestinal enzymes

Lysozyme

anti-microbial molecule

Diapedesis

The ability of the WBC to squeeze out of capillaries and go into tissues

You traveled to Africa and you came home with a parasitic gastrointestinal disease. Which WBCs would help you the most?

Eosinophils

Second line of defense “I prefer chicken fried in Nashville”

• inflammation

• phagocytosis

• complement

• fever

• interferon

• natural killer cells

Local inflammatory response

confined to a specific area of the body

Systemic inflammatory response *will not be on exam

occurs in many parts of the body, can cause widespread increased vascular permeability and a large volume of plasma can enter interstitial spaces, leading to shock and death

Symptoms of inflammation

Rubor, Calor, Tumor, Dolor

redness, warmth, swelling, pain

Inflammatory Response: Immediate reaction

• chemical mediators; endothelin and
  thromboxanes released by tissue cells and
  platelets cause vasoconstriction or vascular
  spasm (a few seconds to minutes)
  • allows clot to form

Inflammatory Response: Vascular reaction

• histamine release causes vasodilation and
seepage of fluid and out of vessels (vascular permeability)
• excess fluid in tissues

Inflammatory Response: Edema

• infiltration of neutrophils, “first responders” first phagocyte to arrive = engulf pathogen and digest it
• Excess fluid in tissues dilutes pathogen’s toxins
• neutrophils produce NET: fibrous material that traps bacteria
• accumulation of pus

Inflammatory Response: Resolution/Scar formation

• macrophages arrive “clean up crew” = phagocytize remaining pathogens, dead cells, pus
• Tissues repair

Phagocytosis

Engulfing the bacteria and eating it, assists the third line of defense

Phagocytes: Macrophages

processes foreign substances to prepare them for reactions with B/T lymphocytes

How do we recognize foreign cells?

protein receptors within the cell membrane of marcophages, AKA pathogen recognition receptors which detect foreign molecules called pathogen associated molecular patterns, AKA PAMPS

has to come into contact with pathogen to detect it

Phagocytosis: Chemotaxis

calling of the WBC to the pathogen, PRR recognizes pamps

Phagocytosis: Ingestion

Phagosome occurs (phagocyte uses pseudopods to grab/engulf the microbe into its cytoplasm within a cell membrane)

also known as endocytosis

Phagocytosis: Phagolysosome formation

the phagosome fuses with the lysosome, which has digestive enzymes, within the cell.

Phagocytosis: Destruction

dies due to lysosome products

Enzymes = lysozyme, DNase, RNase, proteases,
lipases, amylase
• Reactive oxygen products = hydrogen peroxide,
hydroxyl ion, superoxide ion

Phagocytosis: Elimination of debris

digested microbe within the cell is eliminated by exocytosis, small molecules of the pathogen are placed in the MHC-II receptor, which is important to activate the 3rd line of defense

Complement

Similar to clotting within the process

The group of 20 proteins that circulate the blood in an inactive form

becomes activated through a complete cascade

What is the common point of all complement pathways?

C3b which then activates c35b

What can activated complement protein achieve?

activated complement protein form the membrane attack complex (MAC), which makes channels that can kill bacteria (c5b-c9 pokes holes into it)

Complement: Alternative Pathway

part of innate immunity, attracts macrophages.

Complement: Classical Pathway

part of adaptive immunity. Requires antibodies bound to antigens

Opsonization

Coating of the pathogen cell by complement 3b or antibodies, enhances phagocytosis

Fever

body temp is regulated by hypothalamus, usually set at 98.6

initiated by circulating pyrogens, rests internal thermostatand signals muscles to increase heat

99-101 low fever

102-103 moderate

104-106 high fever

Sources of pyrogens

exogenous- products of infectious agents, vaccines

endogenous pyrogens - cytokines produced by immune cells (ex. Interleukin-1

Fever Mechanism

• Hypothalamus monitoring system
• Pyrogen present within the bloodstream
• The body is currently at 98.6°F, but pyrogens cause the hypothalamus to reset core temperature to 102F
• Symptoms: feel cold, shiver

• Hypothalamus monitoring system
• Pyrogens are now absent from the bloodstream
• The core body temperature at 102F but absence of pyrogens cause the hypothalamus resets core to 98.6oF
• Symptoms: feel hot, start sweating

What are the four stages of complement cascade and its function

Complete cascade: initiation

3 pathways: alternative classical & lectin

**all end common point is in C3b

Complete cascade: Amplification/Cascade

C5 factor is acted on by C3, converting it to C5b. C5b is bound to the membrane and serves as the starting molecule to the rest of the chain

Complete cascade: Polymerization

Complete cascade: Membrane Attack

What is a benefit of fevers?

Prevents the nutrition of bacteria by reducing the availability of iron

Interferons

proteins that protect against viral infections/forms of cancer.

Virus-infected cells produce interferons, which cannot help the infected cell, but bind to neighboring cells to stimulate production of antiviral proteins

Artificial IFN

Used to treat disorders such as hepatitis C, genital
warts, multiple sclerosis, Kaposi sarcoma – a cancer that can
develop in AIDS patients

Virus-infected cells produce interferons which cannot aid the infected cell but can bind to the surfaces of neighboring cells and stimulate them to produce antiviral proteins that will then stop viral replication in
the neighboring cells

What kind of chemical interaction is this: autocrine, paracrine, or endocrine?

Paracrine

Examples of Extracellular Pathogens

Bacteria, parasites, worms

Examples of Intracellular pathogens

Viruses, some bacterias, and some parasites

2nd Line of Defense: Natural Killer Cell

Subtype of T-cell, has natural nonspecific cytotoxic powers

How do natural killer cells defend the body?

once stimulated by a cytokines (like an interferon), it produces NK cells to kill infected cells

Once perforin polymerizes and forms a hole in a membrane, granzymes enter the perforin hole. When the cell commits apoptosis, a macrophage then engulfs the dying cells.

NK Cell: Perforins

poke holes in infected cell

Nk Cell: Granzymes

causes the cell to commit suicide (apotosis)

This chemical is released by a virus-infected cell of
the body to decrease the spread of virus to nearby
cells

Interferons

What is the main product of the complement system?

MAC

How does the natural killer cell destroy virus infected cells?

With granzymes and perforins

APC

Antigen representing cell

Antigen

Large, foreign molecules

Self-Antigens

produced by the body. Used as markers to allow adaptive immune response to differentiate self from non-self.
• Immune cells will recognize and not attack cells with self-antigens.
• Three exceptions:
• Response to self-tumor antigens helpful.
• Transplant rejection
• Response to self-antigens resulting in tissue destruction: auto immune diseases

Natural Molecules (Markers)

All of our cells also have molecules present in the cell membrane that
tell the immune system that they belong to the body

one important set called: Major histocompatibility complex or MHC
• There are two classes: MHC I and MCH II

Major histocompatibility complex

On all antigen-presenting cells (like an ID tag)

activates B/T lymphocytes for third line of defense)

Major histocompatibility complex: Endogenous Antigens

proteins produced through genetic expression and protein synthesis = viruses

Major histocompatibility complex: Exogenous Antigens

substances obtained from the
external environment, usually by phagocytosis and then broken down in the cytoplasm = most bacteria and parasites

Major histocompatibility complex: Class I

• found on all nucleated cells = self
antigen
• display endogenous antigens, such
as viruses reproducing inside
• Involved in activating cytotoxic T
cells

Major histocompatibility complex: Class II

Found only in Antigen Presenting Cells –
macrophages and dendritic cells
• display exogenous antigens to helper T cells
• MHC class II/antigen complexes on a cell’s surface can bind to T-cell receptors on T cells

Clonal Selection

The process of gaining a receptor that will detect foreign antigens

Activates the adaptive immunity, making mature (immunocompetent) B/T cells from immature B/T Cells

results in a mechanism that results in a large population of almost identical lymphocytes called clones

**This process occurs before birth

Clonal Selection: Positive selection

Ensures the survival of lymphocytes that react against antigens.
These then proliferate and form clones

Clonal Selection: Negative selection

Eliminates clones of lymphocytes that react against self-antigens = T regs (regulatory T cells)

Activation of 3rd line of defense

Involves co-stimulation, touching the antigens and cytokine (chemical stimulus)

also activates produces effector cells (fight current infection) and memory cells (fight any future exposure to the antigen)

Activation of Helper T Cells

.Macrophage = antigen presenting cell goes to the lymphoid tissue to find helper T cell that recognizes the antigen. Physical stimulus: Helper T cell contacts antigen in MHC II of macrophage with its TCR and stabilizing arm CD4

Activated helper T cell divides to create:
- . clones of effector helper T cells:
-. function is to activate cytotoxtic T cells and B cells
-. Clones of memory helper T cells, which become active in future encounters with the
same antigen.

What is the function of Helper T Cells

activate cytototxic T & B cells

Lymphocyte Proliferation

Helper T cells proliferates and activates B cells and cytotoxic T cells
• B-cell activation results in plasma cells and memory B cells.
• Cytotoxic T cell results in a cell that actively kills
infected cells (viruses, parasites, or cancer cells)

Activation of Cytotoxic T cell

1. APC processes the antigen and places in MHC I
• Physical stimulus: Binding of the T-cell receptor to the MHC class I/antigen complex is a signal for activating cytotoxic T cells.
• Binding with CD8 stabilizes the connection.

2. Helper T cells provide chemical stimulus by releasing interleukin-2, which activates cytotoxic T cells

3. The activated cytotoxic T cell divides, the resulting daughter cells divide, producing many effector cytotoxic T cells and memory cytotoxic T cells (active in future encounters with the same antigen)

4. When viruses infect cells, some viral proteins are broken down and become processed endogenous antigens that are combined with MHC class I molecules and displayed on the surface of the infected cells.
• Effector cytotoxic T cell recognizes virus-infected cells by MHC I/antigen complexes that are on the surface of infected cells
• Cytotoxic T cell produces granzymes and perforins to kill virus infected cell

** MAKE INTO FOUR SLIDES LTR

Cell-Mediated Immunity: Cytotoxic T Cells

Cell-mediated immunity most effective against cytoplasmic
microbes through the action of cytotoxic T cells responding to
endogenous antigens

Genetic Disorder: SIDS (Severe Immunocompromised Disorder)

Both T/B cells are compromised within an individual and causes severe disease

Cytotoxic T cells function

Lyse virus-infected or parasite-infected cells, tumor cells, and
tissue transplants. Major lysin is perforin, which forms a hole in
the plasma membrane of the target cell, then granzymes tell the
cell to commit suicide or apoptosis

*Cytotoxic T cells & NK cells kill the same way

Humoral Immunity/Antibody Mediated: Activation of B Cells

1. Before a B cell can be activated by a
helper T cell, the B cell must take in and
process the same antigen as the
activated helper T cell was stimulated by.
2. Physical stimulus: B cell uses an MHC
class II molecule to present the
processed antigen to the helper T cell
• Helper T cell binds to antigen in MHC II
of B cell
• Stabilizing arm of helper T cell, CD4
binds to MHC II
3. Chemical stimulus: B cell occurs through
surface molecules, such as CD4, as well
as through the release of interleukins by
the helper T cell.

Humoral Immunity/Antibody Mediated: Proliferation of B Cells

Stimulated B cell divides, and the
resulting “daughter” B cells divide, and so
on, eventually producing effector B cells
(plasma cells) and memory B cells (which
respond to the same antigen in the future
encounters).

Effector B cells function to make antibodies:
• Plasma cell produces IgM first
• Plasma cell produces IgG second

Antibody-Mediated Immunity

Antibodies produced by Plasma cells provide antibody-mediated immunity

• Effective against extracellular antigens including
bacteria, viruses, protozoans, fungi, parasites, and toxins
when they are outside cells.

Anti-Bodies

Antibodies are proteins produced by
plasma cells in response to an antigen.

Also called gamma globulins or immunoglobulins (Ig)

Classes of Antibodies

IgG, IgM, IgA, IgD ,IgE