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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