Lecture 3/4: Immunology Flashcards
Role of leukocytes
(aka white blood cells)
cells of the immune system that are involved in defending the body against both infectious and foreign materials.
Different types of leukocytes
Lymphocytes
Monocytes
Neutrophils
Eosinophils
Basophils
What happens to leukocytes when blood is centrifuged?
All leukocytes and platelets separate at the buffy coat
1% of blood sample
Two types of leukocytes
Granular leukocytes
Agranular leukocytes
How are granular leukocytes characterized?
by the presence of differently staining granules in their cytoplasm
e.g. neutrophils, eosinophils, basophils
How are agranular leukocytes characterized?
by the absence of granules in their cytoplasm
e.g. monocytes, macrophages, lymphocytes
What are lymphocytes?
A subset of agranular leukocytes that mediate innate and adaptive immunity
i.e. involved in immune response
Where are lymphocytes commonly found?
Lymphatic system
Cellular characteristics of lymphocytes
Deeply staining nucleus which may be eccentric in location
Relatively small amount of cytoplasm
Examples of lymphocytes
T cells
B cells
NK cells
% leukocytes in blood, descending order
Neutrophils (54-62), Lymphocytes (28-33), Monocytes (2-10), Eosinophil (1-6), Basophil (<1)
No macrophages and no dendritic cells present
What are neutrophils main function?
Bacteria, Fungi
What are basophils main function?
Release histamines for inflammatory responses
What are eosinophils main function?
Larger parasites
Allergic responses
What are lymphocytes main function?
B cells make antibodies
T cells regulate immunity to viruses, bacteria, cancer, autoimmunity
What are monocytes main function?
Phagocytic in blood stream.
Differentiate to macrophages in tissues
Majority found in spleen
What are macrophage main function?
Phagocytosis in tissues
Antigen processing and presentation
Not in blood
What are dendritic cell main function?
Antigen processing and presentation*
T cell activation*
Not in blood
Antigen definition
something that stimulates an immune response
Can be any molecule - components of pathogens, chemicals, self proteins, etc.
Antibody definition
a family of defensive proteins your body makes when it is stimulated by an antigen.
Antibodies contain sites that specifically bind one Ag and not another.
Lymphoid organ definition
Anatomical site where immune cells
and immune responses are generated
What are the two types of lymphoid organs?
Central or primary lymphoid organs
Peripheral or secondary lymphoid organs
Central or primary lymphoid organs
Sites of generation and education of lymphocytes (bone marrow, thymus)
Peripheral or secondary lymphoid organs
Sites where adaptive immune responses are initiated and where lymphocytes are maintained (eg. spleen, lymph nodes)
Essential characteristics of immune system
Highly specific: Adaptive is specific; innate is relatively non-specific
Self non-self discrimination (self recognition): Respond to foreign and tolerate self
A way of selectively amplifying particular immune responses
Diversity: converting one response into multiple effector types
Self Regulation: Turning responses off so that they don’t get out of control
Memory: Ability to remember previous encounter with same pathogen
Redundancy: Multipleback-ups,fail-safe mechanisms and alternatives
The ability to respond to a changing environment by inventing new Ag receptors: Highly polymorphic and endless combination of genetic segments for receptor coding
2 components of optimal immune response
Innate immunity
Adaptive immunity
Main function of innate immune system
A system that can respond virtually instantly to readily identifiable potential pathogens
Key characteristics of innate immunity
Constitutive
Quick to develop/initiate
Ag non-specific
Multiple effector mechanisms: both cell
-mediated and humoral components
Goal of innate immune system
Contain the pathogen in the initial hours and days of infection, giving more sophisticated defenses time to expand and be deployed.
Assets of innate immunity
Rapid (minutes to hours for full activation) , covers the 4-10 days needed for an adaptive immune response to develop
Intense (essential role in inducing a strong inflammatory response)
Natural Killer cells, eosinophils, basophils, macrophages, neutorphils, and dendritic cells
Main liabilities of innate immune system
No adaptability to new stimuli: hence no protection from novel pathogens (i.e. new flu variants)
No memory: no capacity to “learn from previous infections” (an innate immune response is the same speed, type and intensity on the first or 10th exposure to a pathogen)
Poor regulation: self/nonself discrimination not efficient resulting in collateral tissue damage
Poor amplification: Magnitude of response always same
How is innate immunity activated?
Activated by “danger signals” (molecules widely conserved on pathogens)
Pattern recognition receptors (toll like receptors - TLRs) on innate cells recognize Pathogen-associated molecular patterns (PAMPS)
Generation of inflammatory response (cytokines, chemokine, immune cell recruitment etc)
What is the trade off for “quick to respond to widely expressed danger signals that bind to a small family of receptors (~20)”
Absence of
Ag specificity
Specialization
Adaptability to new pathogens
Hence, we evolved an Ag-specific immune response!
What is adaptive immunity?
Specific host defenses that are mediated by B and T lymphocytes following exposure to antigens, and exhibit diversity and memory.
Key characteristics of specific immune response (adaptive)
Specificity: ability to recognize and respond to many different microbes
Memory: Enhanced responses to recurrent or persistent infections
Specialization: Responses to distinct microbes are optimized for defence against these microbes
Non reactivity to self antigens: prevents injurious immune responses against host cells and tissues
Two types of adaptive immunity
Cell-mediated immunity
Antibody-mediated Immunity
What is cell-mediated immunity conferred by?
T lymphocytes
Where do T cells develop?
Thymus
What molecule do all T cells express?
CD3
Also bear T cell receptor for antigen recognition
Helper T cell (molecule expressed, role, importance)
Express CD4 molecule
Help B cells to make certain classes (IgG and IgE) of Ab
Important for immunity to intracellular bacteria and parasites
Augmenting killer T cell response (cross priming reaction)
Killer or cytotoxic T cell (molecule expressed, role)
Express CD8 molecule
Important for killing viral infected and tumor cells
What does humeral immunity depend on?
Antibodies
Where do B lymphocytes originate and mature?
Bone marrow
What is the B cell receptor?
Membrane bound antibody
How does antibody production from B cells occur?
Ag binding triggers division, differentiation and antibody production
What are the progeny of B cells? How do they differentiate?
Plasma cells - differentiated from memory B cells, secrete Ab
Memory B cells - expanded B cells that carry specific Ag
T cells can stimulate B cells in spleen to differentiate
Which Ab is first produced in primary responses?
IgM
Role of IgM
Opsonization, activates complement, neutralizing Ab
The West Nile Virus antibody tests detect WNV- specific IgM. Presence of IgG alone means previous infection
Which Ab has highest concentration in serum?
IgG
Which Ab is transferred transplacentally?
IgG
important for fetal immunity and immunopathologies
Role of IgG
Dominates memory (secondary) responses in serum
Opsonization, activates complement, neutralizing Ab
Where is IgA found?
at mucosal surfaces (hence mediates
mucosal immunity)
In colostrum, tears, GI and respiratory secretions
Which is the major Ab at mucosal surfaces?
IgA
Role of IgA
Opsonization
activates complement
neutralizing Ab
Role of IgD
Who knows?
[may have a role in activating B cells]
Role of IgE
Parasite defense
mediate immediate type
hypersensitivity reactions
Relative abundance of IgE
~10,000x lower levels than IgG, even in allergic individuals
How antibodies work
Neutralization
Antibody-mediated cytolysis
Opsonization
Complement activation
Neutralization (Ab)
binding to toxins or pathogens block their interaction with cell receptor
Antibody-mediated cytolysis
binding of Ab couples pathogen to a cell with capacity to destroy pathogen
Opsonization (Ab)
Ab-coated particles are easier for phagocytes to ingest
Complement activation (Ab)
Leads to release of inflammatory mediators
What is immunologic memory?
Ability of the immune system to respond more rapidly and effectively to pathogens that have been encountered previously
pre-existence of clonally expanded lymphocytes with specificity for that antigen.
Hallmark of adaptive immunity
How is immunologic memory produced?
either by previous infection or by vaccination
Schematic representation of memory response
See figure
How do you tell different cell types apart?
Physical appearance
Clister of differentiation (CD) Ag system
How is physical appearance used to tell different cells apart?
Lymphocytes small, granulocyte larger with granules that stain in different ways with dyes used in lab.
(Differential cell count)
How is CD used to tell different cells apart?
~320 cell surface proteins (Ag) distinguished with Abs used as a diagnostic tool.
Allows us to positively identify different cell types, function, state of activation (~150 cell types).
Where is CD3 found?
T cells
Not B cells
Two main subgroups of T cells
CD4: helper T cells
CD8: cytotoxic T cells
What CD markers are found on B cells but not T cells?
CD19
CD20
Where is CD56 found?
is on NK cells but not other types of lymphocytes.
How is self/non-self discrimination achieved?
Achieved by early and continuous presence of self-antigens
What is self/non-self discrimiation? Importance?
Property of the adaptive immune system to recognize and mount specific/targeted responses to foreign antigens without responding to self
Important for self tolerance and control of autoimmunity
What is self tolerance?
Ability to remain “tolerant” to self while retaining the capacity to mount response to non-self.
Self/non-self discrimination with in-built fail-safe mechanisms are key
How do the innate and adaptive immune responses talk to each other?
See figure
What is inflammation?
A “protective” cellular and vascular connective tissue reactions to injurious insults
Can be acute or chronic
Major aims of inflammation
Dilute
Destroy
Isolate
Initiate repair
Characteristics of inflammation
Redness
Hotness
Swelling
Pain
Loss of function
What is acute inflammation?
Immediate and early response to tissue injury (physical, chemical, microbial, Immunologic, etc.)
What happens during acute inflammation
Vasodilation: Accounts for warmth and redness
Vascular leakage and edema: Protein leakage increases interstitial osmotic pressure
contributing to edema (water and ions)
Leukocyte emigration (mostly PMNs): Leukocytes leave the vasculature to mediate phagocytosis, degranulation and tissue damage
What are PMNs?
Polymorphonuclear cells
Other name for granulocytes
Due to varying shapes of nucleus
Possible outcomes of acute inflammation
Complete resolution
Scarring (fibrosis)
Abscess formation occurs with some bacterial or fungal infections
Progression to chronic inflammation
What occurs during complete resolution of acute inflammation
Little tissue damage (healing by first intention)
Tissue regeneration
What occurs during scarring (fibrosis) as an outcome of acute inflammation
Healing by secondary intention) usually resulting from infections,
malnutrition and immunodeficiencies
Tissues are unable to regenerate
Excessive fibrin deposition organized into fibrous tissue
What is chronic inflammation?
An inflammatory response of prolonged duration
weeks - months - years
What is chronic inflammation provoked by?
persistence of the causative stimulus
What occurs simultaneously with chronic inflammation?
presence of acute inflammation, tissue destruction and repair
What are the possible causes of chronic inflammation?
Infectious organisms that resist clearance and form a persistent infection in tissue or undrained abscess cavities
Exposure to irritant non-living foreign material that can not be removed
Potentially normal tissue components as seen in auto-immune diseases
Examples of infectious organisms that resist clearance and form a persistent infection in tissue or undrained abscess cavities
mycobacterium tuberculosis
actinomycetes
treponema palidum
Staph aureus (in bone and pleural cavities)
Examples of exposure to irritant non-living foreign material that can not be removed
implanted materials into wounds (wood splinters)
inhaled materials (silica, asbestos)
deliberately introduced material (surgical suture material or prosthesis)
Examples of normal tissue components as seen in auto-immune diseases
Beta islet cells in diabetes mellitus type I
Acetylcholine receptors in Myasthenia gravis
Characteristics of chronic inflammation
Lymphocyte, macrophage, plasma cell (mononuclear cell) infiltration
Tissue destruction by inflammatory cells
Fibrosis and angiogenesis (new vessel formation), resulting from unsuccessful attempts at repair
Outcome of chronic inflammation if not successfully repaired
Ulcers
Fistulas (ex: holes in stomach which can allow stomach acid to be released)
Granulomatous diseases (Chron’s, macrophages secrete substances that destroy tissues)
Fibrotic diseases (Scaring)
Adhesions (fibrotic masses, can block blood flow)
Cancer
combinations of the above
What is active immunity?
Your immune system actively
participates in building/developing the immunity
What is passive immunity?
Your immune system does not actively contribute to the development of the immunity.
It passively acquires it by transfer of pre-made immune effector molecules.
Types of active immunity
Natural: Recovery from natural infection
Artificial: Deliberate exposure (vaccination)
Advantages of active immunity
Stronger immunity
More diverse response (both humoral and cell-mediated)
Longer lasting (can last up to years; sometimes lifetime)
Memory develops
Disadvantages of active immunity
Takes several weeks to months to fully mature
Types of passive immunity
Natural: Transfer from mother to fetus (IgA and IgG)
Artificial: Injection of preformed immune molecules - Antibodies (antitoxins, antivenoms etc), immune cells
Advantages of passive immunity
Intense response
Immediate protection
Disadvantages of passive immunity
Short duration (rapid catabolism)
Development of allergic reactions (e.g. serum sickness)
No memory develops.
What is a vaccine?
A preparation of microbial Ag, often combined with adjuvants, administered to elicit protective, memory immune response against the original pathogen
Can be based on attenuated or dead organism or subunits
What is an adjuvant?
Substance added to a vaccine, which is unrelated to a vaccine
Starts mounting immune response before body detects Ag
What is the rational of a vaccine?
Elicit immunity against molecules found on the virulent pathogen without the same degree of risk associated with genuine infection.
What are killed vaccines?
Killed whole organism is used as vaccines
Polio, Hep A, rabies, diphtheria
Advantages of killed vaccines
It doesn t cause disease
There is no chance of reverting to virulence
Very cheap to make
Can be used in immunocompromised patients
Disadvantages of killed vaccines
Induce poor immunity (mostly antibody)
Immunity is not sustained (short duration)
Require booster immunizations
What are genetically engineered and live-attenuated vaccines
virulence factor has been removed
Body has to continuously fight
Ex: measles, smallpox, yellow fever, chicken pox
Advantages of genetically engineered and live-attenuated vaccines
They cause infection without pathology
Strong protection (humoral and cell-mediated)
Long-lasting immunity (due to memory)
Minimal booster immunization
Disadvantages of genetically engineered and live-attenuated vaccines
There is the fear of reverting to virulence
Cannot be used in immunocompromised patients (body is already fighting something else off)
Cold-chain sequence (stability in developing countries?)
What is a subunit vaccine?
Part of virus that is most antigenic is identified and used as vaccine
Advantages of subunit vaccine
Increased safety
Less antigenic competition since only a few components are included
in the vaccine
Vaccines can be targeted to the site where immunity is required
Ability to differentiate vaccinated animals from infected animals (marker vaccines).
Disadvantage of subunit vaccine
Generally require strong adjuvants
Duration of immunity is generally shorter than with live vaccines.
Peptide vaccines often need to be linked to carriers to enhance their immunogenicity
A pathogen can escape immune responses to a single epitope versus multiple epitope vaccines.
Characteristics of a useful vaccine
Very safe: Effective protection without significant danger of causing the disease itself or side effects (relative risk: death rate due to disease vs death rate due to immunization)
Effective over long period to time
Stimulate development of the right kinds of immunity
Chemically stable
Relatively affordable (economics of production and administration)
What is herd immunity?
Herd immunity is the phenomenon where non-immunized individuals can be protected by the fact that most of the population around them is immune
Protective immunity vs. hypersensitivity
Protective immunity: Desirable reaction
Hypersensitivity: undesirable reaction. All are secondary/memory responses
What are hypersensitivity diseases?
Excessive or aberrant immune response to foreign antigens
Deregulated or uncontrolled immune response
Immune response to foreign antigen may be directed to self
antigens
Clinical and pathologic features of hypersensitivity disease are varied depending on
Nature of antigen
Type of immune response
Host genetics
Gel and Coombs classification of hypersensitivity diseases
Type I - IgE ab
Type II - ab to tissue antigens
Type III - immune complexes
Type IV - cell mediated immunity
What happens during a type I hypersensitivity reaction?
Immediate
Initial meeting with allergen causes no symptoms, but sensitizes a susceptible person, which causes IgE Abs to be secreted that attach to the surface of mast cells and basophils
Later encounters with same Ag causes an immediate reaction in which Ag binds and cross-links IgE antibodies on the surface of cells.
Leads to massive release of histamines and other preformed mediators
Vasodilation and smooth muscle contractions
What is the most common type of allergy?
Type I
Virtually impossible to resolve
Treatment of Type I
Treatment of symptoms
Examples of Type I hypersensitivities
Allergic rhinitis
eczema
asthma
bee/wasp stings
drugs (e.g. penicillin, insulin)
food allergy (e.g. seafood and nuts)
Worst case of Type I hypersensitivity
Anaphylaxis
Need epinephrine (epi pen)
Clinical example of type I hypersensitivity
Penicillin skin tests detect IgE ! red bump right away your are allergic
Other name for Type II hypersensitivity
Ab-dependent cytotoxic hypersensitivity
Cause of Type II hypersensitivity
IgM/IgG binding to cell surface molecules results in usual effects: Complement activation, opsonization, RBC agglutination.
Abs specific for altered components of human cells: eg Penicillin adsorption on RBCs.
Examples of type II hypersensitivity
Transfusion reactions
Hemolytic disease of the new born
Drug-induced hemolytic anemia
Certain autoimmune diseases (Rheumatic fever, Autoimmune anemias, thrombocytopenias)
What happens during Type III hypersensitivity
- Ags are widely spread and antibodies (IgM and IgG) form insoluble immune complexes
- Complexes deposited in vessels
- Inflammation via complement activation. Damage to local tissues
Examples of Type III hypersensitivity
Rheumatoid Arthritis
SLE (lupus).
Other name for Type IV hypersensitivity
delayed-type hypersensitivity (DTH)
Triggers of Type IV hypersensitivity
Poison ivy
cheap jewelry/reactive metals
bacteria (TB)
virus (Hepatitis B)…
How are type IV hypersensitivities mediated?
T cells and their cytokines
Upon re-activation T cells secrete cytokines (that cause inflammation and kill (CTL), monocyte influx, swelling..
What types of cells are found at the site of inflammation in type IV hypersensitivities
Although initiated by T cells, more than 90% of cells at site of inflammation are non-T cells
Examples of Type IV hypersensitivities
Contact Dermatitis
Granulomas
Organ specific autoimmune diseases
What type of hypersensitivity is the tuberculin skin test?
DTH
Inject Tuberculosis protein (Mycobaterium tuberculosis) into the inner
surface of forearm
after 72hrs if there is a red bump, the person has been exposed to TB
Types of immunodeficiency
Congenital (primary) immunodeficiency
Acquired (secondary) immunodeficiency
Congenital (primary) immunodeficiency
Defects in lymphocyte maturation
Defect in activation and function
Defects in innate immunity
Acquired (secondary) immunodeficiency
HIV and AIDS
Malnutrition
Chemotherapy/irradiation
Cancer metastasis to bone marrow – Splenectomy
Gene therapy for immunodeficiency diseases
replacement of defective gene in self- renewing precursor cells
Very distant goal
Aims of current therapy for immunodeficiency
Minimize and control infections
Replace defective or absent component by adoptive transfer and/or transplantation
Agents used in replacement therapy for immunodeficiency
Pooled gammaglobulins for agammaglobulinemic patients
Bone marrow transplant for Secondary imunedeficienty
Enzyme replacement therapy for adenosine deaminase (ADA) and purine nucleoside phophorylase (PNP) deficiencies seen commonly patients with common variable immunodeficiency syndrome
How to treat secondary immunodeficiency
Control opportunistic infections
Treat primary cause
What is autoimmunity?
Refers to failure of an organism to recognize its own constituent parts as self
Allows an immune response against self cells, organs and tissues
Tissue damage usually resulting from inflammatory responses
What are the types of autoimmune disease
- Systemic Autoimmunity
- Organ-specific
See figure
Systemic autoimmunity
Autoimmune diseases involving several organs and tissues
Most involve both humoral and cell-mediated
immunity
Organ-specific autoimmunity
Immune response directed to specific organs leading to cellular damage and organ destruction
Factors influencing autoimmune disease development
Genetic: HLA, FcgR, FAS/FASL, Complement proteins
Environmental: microbes
Gender: females greater than males (estrogen?)
Others: injury
Treatment of autoimmune diseases
Conventional therapies
New therapies
Experimental therapies
Conventional therapies for treatment of autoimmune diseases
Anti-inflammatory agents
Immunosuppressive agents
Lymphocyte specific Abs
New therapies for treatment of autoimmune diseases
Blocking TNF receptor (e.g. Embrel)
Depletion of cells e.g. Rituximab (anti-CD20 mAb) to treat systemic lupus erythematosus (SLE) - B cells in SLE are hyper responsive
Experimental therapies for treatment of autoimmune diseases
Induction of Tolerance
Blocking peptides
