Study of the Immune System

Now that we know all about microbes…..

What provokes us to fight against microbes? How do we know that they are foreign? What initiates the response?

Introduction to Antigens

Antigen (Ag) Any substance that stimulates

an immune response Requirements for antigenicity

foreignness (recognition of nonself)

large size complexity

most antigenic

Characteristics of Antigens

Epitope antigenic determinant small molecular group that

is recognized by: Antibodies B cells T cells

Defense Mechanisms of the Host

Immune system relies on a multilevel network of physical barriers,

immunologically active cells, and a variety of chemicals 3 main lines of defense:

first line of defense any barrier that blocks invasion at the portal of entry nonspecific

second line of defense protective cells and fluids inflammation and phagocytosis nonspecific

third line of defense acquired with exposure to foreign substance Stronger immune response produces protective antibodies and creates memory cells specific

Physical or Anatomical Barriers: First Line of Defense

• Skin and mucous membranes: outermost layer of skin

few pathogens can penetrate if intact flushing effect of sweat glands mucous coat impedes attachment and

entry of bacteria blinking and tear production stomach acid nasal hair traps larger particles Vaginal secretions

Structure and Function of the Organs of Defense and Immunity

Immunology study of the body’s second

and third lines of defense Functions of a healthy

functioning immune system:1. Constant surveillance of the

body

2. Recognition of foreign material

3. Destruction of entities deemed to be foreign

Blood Plasma

Serum - fluid portion complement proteins and

antibodies Three types of formed elements

Erythrocytes Platelets Leukocytes

Divided into granulocytes and agranulocytes

White Blood Cells White Blood Cells LeukocytesLeukocytes

Housekeeping and defenseHousekeeping and defense Scavenge dead or worn-out cellsScavenge dead or worn-out cells Disease organismsDisease organisms

Squeeze out of blood vessels and enter Squeeze out of blood vessels and enter tissuestissues

Develop from stem cells in bone marrowDevelop from stem cells in bone marrow GranulocytesGranulocytes

NeutrophilsNeutrophils EosinophilsEosinophils Basophils Basophils

Agranulocytes Agranulocytes MonocytesMonocytes Macrophages Macrophages

Lymphocytes Lymphocytes B-cellsB-cells T-cells T-cells

White Blood Cells

Neutrophils 55-90% lobed nuclei with lavender granules phagocytes

Eosinophils 1-3% orange granules and bilobed nucleus destroy eukaryotic pathogens

Basophils, mast cells 0.5% constricted nuclei, dark blue granules release potent chemical mediators

Lymphocytes 20-35% large nucleus involved in specific immune responses

B (humoral immunity) T cells (cell-mediated immunity)

Monocytes, macrophages 3-7% large nucleus Phagocytic

Dendritic cells Activate lymphocytes Produce cytokines

Innate Immunity

“Second” line of defense

Second Line of Defense

cells and mechanisms that defend the host from infection by other organisms

genetically-encoded to recognize: common pathogenic features foreign substances

does not confer long-lasting or protective immunity to the host

provide immediate defense against infection

Actions of the Second Line of Defense

• Recognition• Inflammation• Phagocytosis• Interferon• Complement

1. Recognition Toll-like receptors (TLRs)

protein receptors within cell membrane of macrophages

recognize structurally conserved molecules derived from microbes

Detect foreign molecules and signal the macrophage to produce chemicals cytokines

stimulate an inflammatory response (nonspecific)

promote the activity of B and T cells (specific)

2. Functions of inflammation

1. Mobilize and attract immune cells to site

2. Set mechanisms to repair tissue damage

3. Destroy microbes and block further invasion

2. Inflammatory ResponseClassic signs and symptoms

characterized by: Redness

increased circulation and vasodilation in injured tissue

Warmth heat given off by the increased

blood flow Swelling

increased fluid escaping into the tissue as blood vessels dilate

edema WBC’s, microbes, debris and fluid

collect to form pus helps prevent spread of infection

Pain stimulation of nerve endings

Possible loss of function

Fever

Initiated by circulating pyrogens cytokines produced by some leukocytes reset the hypothalamus to increase body temperature signals muscles to increase heat production and

vasoconstrict

Benefits of fever: inhibits multiplication of temperature-sensitive

microorganisms impedes nutrition of bacteria increases metabolism and stimulates immune reactions

3. Phagocytosis

nonspecific defense mechanism

clear microbes from infected tissues

capture and digestion of foreign particles

Phagocytes3 main types of phagocytes:

1. Neutrophils • general-purpose• react early to bacteria and other foreign materials,

and to damaged tissue

2. Eosinophils • attracted to sites of parasitic infections and

antigen-antibody reactions

3. Macrophages • derived from monocytes• scavenge and process foreign substances to

prepare them for reactions with B and T lymphocytes

4. Interferon

Type of cytokine Produced in response

to viruses, RNA, immune products, and various antigens

Bind to cell surfaces and induce expression of antiviral proteins

Inhibit expression of cancer genes

5. Complement (C)

Consists of 26 blood proteins proteins are activated work in concert to destroy

bacteria and viruses

Adaptive Immunity

“Third” line of defense

Adaptive Line of Defense

acquired immunity stronger immune response as well as

immunological memory Production of specific antibodies

dual system of B and T lymphocytes in response to an encounter with a foreign molecule

allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells

Specific Immunity – Adaptive Line of Defense

Two features that characterize specific immunity: specificity

antibodies produced function only against the antigen that they were

produced in response to memory

lymphocytes are programmed to “recall” their first encounter with an antigen

respond rapidly to subsequent encounters

Classifying Immunities Active immunity

person is challenged with antigen that stimulates production of antibodies

creates memory, takes time and is lasting Passive immunity

preformed antibodies are donated to an individual does not create memory, acts immediately, and is short

term Natural immunity

acquired as part of normal life experiences Artificial immunity

acquired through a medical procedure such as a vaccine

Combinations of acquired immunity

Natural active immunity acquired upon infection and

recovery Natural passive immunity

acquired by a child through placenta and breast milk

Artificial active immunity acquired through inoculation

with a selected Ag Artificial passive immunity

administration of immune serum or globulin

Development of the Immune Response System

Cell receptors or markers confer specificity and identity of a cell

Major functions of receptors are:

1. perceive and attach to nonself or foreign molecules

2. promote the recognition of self molecules

3. receive and transmit chemical messages among other cells of the system

4. aid in cellular development

Acquired Immunity Generates Two Responses to Most Pathogens B lymphocytes

(B cells) involved in producing

antibodies against epitopes

Humoral immune response

T lymphocytes (T cells) provide resistance through

lysis of infected or abnormal cells

Cell-mediated immune response

Lymphocyte Receptors

Lymphocyte’s role in surveillance and recognition is a function of their receptors

B-cell receptors bind free antigens

T-cell receptors bind processed antigens

Antibody Structure and Functions Immunoglobulins Large Y-shaped protein Contains 2 identical fragments (Fab) with ends

that bind to specific antigen Fc binds to various cells and molecules of the

immune system

Classes of Antibodies

IgD important in B cell activation

IgM released by plasma cells during the primary immune

response IgG

crosses the placenta and confers passive immunity IgA

helps prevent attachment of pathogens to epithelial cell surfaces

IgE causing histamine release when activated

B-cell Activation and Antibody Production

Antibodies in Serum (Antiserum) The 1st introduction of an Ag to the immune system

produces a primary response gradual increase in Ab titer

The 2nd contact with the same Ag produces a secondary, or anamnestic, response due to memory cells produced during the initial

response

T Cells & Cell Mediated Immunity

Cell mediated immunity requires the direct involvement of T lymphocytes

T cells act directly against Ag and foreign cells when presented in association with an MHC carrier

T cells secrete cytokines that act on other cells Sensitized T cells proliferate into long-lasting memory

T cells

Antibody-Antigen Interactions Opsonization

process of coating microorganisms or other particles with specific antibodies more readily recognized by phagocytes

Agglutination Ab aggregation cross-linking cells or particles into large clumps

Neutralization Abs fill the surface receptors on a virus or the active site on a

microbial enzyme prevent it from attaching

Antitoxins special type of Ab that neutralize a bacterial exotoxin

Immunization

Passive immunization patient is given preformed antibodies

form of immunotherapy

Active immunization patient is vaccinated with a microbe or its

antigens providing a form of advance protection

Vaccines Type of active immunity Provide an antigenic stimulus

that does not cause disease Most vaccine preparations are

based on one of the following antigen preparations:1. Killed whole cells or inactivated

viruses

2. Live, attenuated cells or viruses

3. Antigenic molecules derived from bacterial cells or viruses

4. Genetically engineered microbes or microbial antigens

Disorders in Immunity

Immunopathology

Allergy, hypersensitivity misdirected expression

of immune responses to an allergen (antigen)

Autoimmunity abnormal responses to

self Ag Immunodeficiency

deficiency or loss of immunity

Four types…..

Type Systems involved

Examples

I Immediate Hypersensitivity

IgE

Mast cells

Hay fever

Asthma

II Antibody Mediated IgG Ab

IgM Ab

Blood group incompatability

III Immune Complex Mediated

IgG

Ab-mediated inflammation

Arthritis

Serum sickness

IV T-cell Mediated Delayed hypersensitivity

Cytotoxic rxns

Injection rxns

Contact dermatitis

Graft rxns

1. Type I Hypersensitivity

Two levels of severity: Atopy

any chronic local allergy Ex: hay fever or asthma

Anaphylaxis a systemic, often explosive reaction that involves

airway obstruction and circulatory collapse

Contact With Allergens

Generalized predisposition to allergies is familial not to a specific allergy

Allergy can be affected by age, infection, and geographic area

Atopic allergies may be lifelong or may be “outgrown” may also develop later in life

Mechanism of Type I AllergyDevelop in stages: Sensitizing dose

on first contact with allergen

specific B cells form IgE which attach to mast cells and basophils

generally no signs or symptoms

Provocative dose subsequent exposure with

the same allergen binds to the IgE-mast cell

complex

Chemical Mediators and Allergic Symptoms

General targets include: skin, upper respiratory tract,

GI tract, and conjunctiva Responses

rashes, itching, redness, rhinitis, sneezing, diarrhea, shedding tears

Systemic targets smooth muscles, mucous

glands, and nervous tissue Responses

vascular dilation and constriction resulting in change in blood pressure and respiration

Specific Diseases Atopic disease

hay fever, rhinitis; seasonal, inhaled plant pollen or mold

asthma Food allergy

intestinal portal can affect skin and respiratory tract

vomiting, diarrhea, abdominal pain possibly severe eczema, hives, rhinitis, asthma, occasionally

anaphylaxis Drug allergy

common side effect of treatment reaction from mild atopy to fatal

anaphylaxis Sudden respiratory and circulatory disruption

that can be fatal in a few minutes Bee stings, antibiotics or serum injection

Treatment and Prevention

General methods include:

1. Avoiding allergen

2. Use drugs • block the action of the

lymphocytes, mast cells• antihistamines

3. Desensitization therapy

• injected allergens

2. Type II Hypersensitivity

Involve antibodies and complement leading to lysis of foreign cells

Transfusion reactions ABO blood groups Rh factor

hemolytic disease of the newborn

Human ABO Antigens and Blood Types

Genetically determined RBC glycoproteins inherited as 2 alleles of A, B, or O

4 blood types: A, B, AB, or O type O persons lack both A and B

antigens Tissues other than RBCs also

carry A and B antigens

Antibodies Against A and B Antigens

Serum contains pre-formed antibodies that react with blood of another antigenic type-agglutination

Type A contains Abs that react against B antigens

Type B contains Abs that react against A antigens

Type O contains Abs that react against A and B

antigens Type AB

contains no Abs that react against A or B antigens

Rh Factor

Rhesus factor RBC antigen

type results from combination of 2 alleles Either there or not

Rh- Rh+

Inheriting one dominant gene results in the production of the Rh antigen

Rh Factor and Hemolytic Disease of the Newborn

Hemolytic Disease of the Newborn (HDN) Rh- mother forms antibodies to her

Rh+ fetus requires subsequent exposure to

the antigen to be hemolytic

Prevention use of passive immunization with

antibodies against the Rh antigen prevents sensitization of mother

3. Type III Hypersensitivity Large quantity of foreign Ag

stimulates Ab produce small, soluble Ag-Ab

complexes Immune complexes become

trapped in tissues and incite a damaging inflammatory response arthus reaction

local reaction to series of injected Ag to same body site

serum sickness systemic disease resulting

from repeated injections of foreign proteins

4. Type IV Hypersensitivity T cell-mediated Delayed response to Ag involving activation of and

damage by T cells Delayed allergic response

skin response to allergens tuberculin skin test, contact dermititis from plants, metals,

cosmetics

Graft rejection reaction of cytotoxic T cells directed against foreign cells of

a grafted tissue MHC markers of donor tissue (graft) are different

host may reject graft; graft may reject host

Immunodeficiency Diseases Components of the immune response system are absent

B and T cells, phagocytes, and complement 2 general categories:

primary immunodeficiency Congenital usually genetic errors T-cell or B-cell defect severe combined immunodeficiency (SCID)

secondary diseases acquired after birth caused by natural or artificial agents Chemotherapy AIDS

Evasion of the Immune System by Pathogenic

Microorganisms

Why develop a strategy for evasion?

Pathogen evolution Microorganism capable of causing disease Must subvert host immune system

Successful pathogens = effective evasion

Defenses against human host responses

Antiphagocytic factors Glycocalyx / Capsules (Encapsulation)

Host cell invasion Grow intracellularly Neighbor cell transfer Syncytium Latency

Genetic changes Antigenic shift Antigenic drift

Antiphagocytic Factors

The Bacterial Surface Coating Glycocalyx

Coating of molecules external to the cell wall

Functions: attachment inhibits killing by WBCs

Talaro, 2008

Capsules Formation correlates with pathogenicity Encapsulated cells protect against WBCs

Chemicals similar to those in human body Negative charges on capsule and

phagocyte surface Slippery

Pseudopodia cannot grip them

http://medicineworld.org/stories/lead/2-2009/how-a-deadly-fungus-evades-the-human-immune-system.html

Bauman, 2011

“Some Killers Have Pretty Nice Capsules”

S. pneumoniaeK. pneumoniaeH. influenzaeP. aeruginosaN. meningitidisC. neoformans

Streptococcus pyogenes

GAS Most serious

streptococcal pathogen

Many surface antigens that enable virulence and evasion

Talaro, 2008

Capsule made of hyaluronic acid (HA)

Chemically masked from HA in human tissues

M-protein Makes surface projections that resist phagocytosis

C-carbohydrates Protect bacterium from being dissolved by lysozyme

C5a protease Catalyzes cleavage of C5a protein

(hinders C-associated aspects & neutrophil response)

S. pyogenes…. “There’s an app for that”

Host Cell Invasion

Survive inside phagocytes after ingestion

Ingested by alveolar phagocytes Prevent fusion with

lysosomes

Multiply intracellularly After cell death, attract

more phagocytes and continue cycle

Mycobacterium

Bauman, 2011

Neighboring cell transfer

Can escape out of phagosomes

Transfer to neighbor cells w/o leaving host cell Not exposed to Ab

Listeria monocytogenes

Pommerville, 2007

Syncytium

Induces cells to fuse Multinucleate giant cell Allows pathogen to move

from cell to cell HIV RSV Paramyxoviruses

Talaro, 2008

Latency

Pathogen remains inactive for period of time

Reactivate at later date

Herpes

Bauman, 2011

Genetic Changes

Viruses

Glycoprotein spikes Adherence Recognized by host

immune system Influenza A & B

Contains two types of spikes

Hemagglutin (HA) Neuraminidase (NA)

Pommerville, 2007

Genetic changes of viruses

Antigenic drift Mutation in spikes

Change their aa composition Small changes Single strain

Antigenic shift Shift of gene strand with one

from another host Human, pig, birds, etc.

Abrupt, major change Reorganization of strains H1N1

Bauman, 2011