11 - adaptive immunity
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Adaptive Immunity
Immunity: Third Line of Defense• Red bone Marrow Stem cells T and B cells• Specific reaction to microbial infection
Humoral Immunity Cell Mediated Immunity
B-cells
RecognizeSpecific Antigens
Make Antibodies against them
T-cells
RecognizeSpecific Antigens
Make Cytokines against them
Antigens & Antibodies• Antigens (Antibody generators)• proteins or large polysaccharides• Components of invading microbes• Non-microbial antigens:• pollen, egg white, serum proteins, blood cells etc
• Epitopes = specific region that interacts with Ab.
• Antibodies• globulin proteins (immunoglobulins) Y-shaped• Made in response to antigen; bind specifically to Ag• At least two identical sites that bind to epitopes• Bivalent molecule
Bivalent antibodies binding epitopes
Classes of ImmunoglobulinIgG:
• Y-shaped “Monomer”• readily cross vessel walls into inflammation site• ~80% of serum antibodies• Protects against bacteria and viruses• Neutralizes toxins• Enhances phagocytosis• Triggers complement• Confers immunity to fetus
AFM of a bivalent (monomer) antibody
Classes of Immunoglobulin
IgM:• Pentamer (can be monomer too)– Too big to cross into tissue from blood
• First Antibody response to 1 response• Dominates ABO blood group response• Effective in Complement Activation• Highly effective at Agglutination– Cross-links several Antigens
Classes of Immunoglobulin
IgA:• Dimer– Serum IgA (monomer)– Secretory IgA
• Mucus membranes and secretions– Mucus, tears, saliva, breast milk– Prevents pathogen attachment to mucosal surface– Colustrum• Decreases infant risk to GI infections
Dimeric IgA antibodies
Classes of Immunoglobulin
IgD:• Monomer• Blood, lymph, B-cell surface• No defined function
– 0.002% serum antibodies
IgE:• Monomer• Allergic Reactions, Parasitic Infections• Signals for complement and phagocytes• Binds mast cells/basophils histamine allergy
B-cell Activation
• Stem Cells B-cells– Each B-cell has surface Igs against specific Ag
• Binding of specific Ag activates THAT B-cell• Activated B-cell clonal expansion Plasma
cells Antibodies– Some activated B-cells become Memory cells
Antigen-antibody binding
• Antigen-Antibody Complex– Specific interaction• Affinity: strength of bond• Specificity: ability to distinguish minor differences in AA
– Binds at epitope– Complex formation tags foreign cells• Destruction by phagocytes and complement
Outcomes of Ab-Ag binding
• Agglutination– Clumping of Antigens
• Opsonization– Ab coats microbe– Enhances phagocytosis
• Neutralization– prevents Ag binding host cell
• Antibody-dependent cell-mediated cytotoxicity– Ab coats microbe– Ab binds T-cells/NK cells/other immune cells– Cytokines released lyse microbe
• Complement Activation– IgG, IgM– Binds C1– C1 C2, C4 C3 complementation cascade
T-cells and cellular immunity
• T-lymphocytes• Combat pathogens within host cells– Not exposed to circulating Antibodies
• Two Types– T-helper Cells (TH: TH1 and TH2)
– Cytotoxic T-cells (Tc)– Surface Receptors• Glycoproteins • CD (clusters of differentiation)
Antigen Presenting Cells
• B-cells• Phagocytes– Dendritic cells– Macrophages
• Chew up Microbe/ Antigen– Present parts of the Antigen on surface– Presentation involves a phagocytic receptor• MHC (major histocompatibility antigen)
The MHC-antigen complexMHC = major histocompatibility complex• Collection of genes that encode proteins found on all
nucleated mammalian cell membranes• Presence of MHC identifies the host
- Keeps immune system from making antibodies against host cells
Class II – found on APCs like B-cellsClass I – found on almost any cell of the host• Makes it possible for cytotoxic T-cells to attack
host cells that have been altered
T-Helper Cells (CD4+)- bind to MHC class II molecules
Activation of TH cells:1. TH cell recognizes an antigen in complex with MHC class II
presented on the surface of an APC2. TH cell proliferates and differentiates into TH1 and TH2
cells – secrete cytokines
TH1 = cytokines activate macrophages, enhance complementTH2 = cytokines stimulate production of antibodies important for allergic reactions, and eosinophils that protect against extracellular parasites
APC (dendritic cell) and TH cell
Antigen fragment
Antigen
MHC class II moleculesMicrobe
T helper cell
TH cell receptor contacting MHC-antigen complex
Cytotoxic T-cells (CD8+)• Recognize and kill altered or foreign cells• bind to MHC class I molecules
- found on all nucleated cells• Presented in complex with viral/parasitic antigens on
surface of infection-altered cells
Steps in destruction of target cells:1. Recognize foreign antigen/MHC class I protein
complex on cell2. Attaches and released perforin pore• Allows proteases to enter
3. Apoptosis = programmed cell death
Cytotoxic T-cells (CD8+)
1. Virus-infected cell with endogenous viral antigens (inside cell)
2. Abnormal antigen is presented on cell surface in complex with MHC class I molecules- TC cell with receptor for that antigen binds
3. TC cell induces destruction by apoptosis
AntigenMHC
class I
MHC-antigen complex
Cytotoxic T-cell
Apoptosis
Blebbing = external membranes bulge outward
Top: B-cell undergoing apoptosisBottom: Normal B-cell for reference
Antigen-presenting cells
Dendritic cells = Principle APCs to induce immune responses by T-cells• Long extensions = dendrites• Resemble nerve cell dendrites
1. engulf invading microbes2. degrade them3. transfer them to lymph nodes
for display to T-cells located there
Macrophages = (large eaters) • Innate immunity: important in
phagocytosis of apoptotic cells and other debris
• Adaptive immunity: become activated macrophages upon ingestion of foreign antigen- Appear larger and “ruffled”
1. Take in antigen2. migrate to lymph nodes3. present antigen to T-cells located there
Antigen-presenting cells
Extracellular killing
Natural killer cells = granular leukocytes that destroy virus-infected cells, tumor cells, and parasites• Part of innate immunity (non-specific)
- Not triggered by antigen• Remains external to target cell
Mechanism:1. Contact a target cell2. Determine if it expresses MHC class I self-antigen
(*tumor cells, viral-infected cells don’t)3. No expression induces lysis/apoptosis (similar to
that of cytotoxic T-cell)
Antibody-dependent-cell-mediated cytotoxicity
• Invaders too large to be phagocytized (euks) can be attacked by immune cells
• Uses antibodies of humoral system• NK cells, macrophages, neutrophils, and
eosinophils respond and kill targeted cells
Mechanism:• Target cell coated with antibodies• Immune cells bind to antibodies• Target cell is lysed by secretions
Antibody-dependent-cell-mediated cytotoxicity
Antibody-dependent-cell-mediated cytotoxicity
Eosinophils adhering to a parasite for external attack
CytokinesCytokines = chemical messengers of immune cells• Soluble proteins/glycoproteins• Produced by immune cells after a stimulus• Act only on a cell that has receptors for it
- Interleukins = cytokines that serve as communicators between leukocytes (WBCs)
- Chemokines = induce migration of leukocytes into areas of infection/tissue damage
- Interferons = protect cells from viral infection
Cytokines- Tumor necrosis factor (TNF) = cytokines that act in
inflammatory reactions; also target tumor cells- Hematopoietic cytokines = control development of
stem cells into red or white blood cells
Ex) Granulocyte-colony stimulating factor• Granulocyte precursors neutrophils
Cytokine storm = overproduction of cytokines- Damage to host tissues
Extracellular antigens
A B cell binds to the antigen for which it is specific. A T-dependent B cell requires cooperation with a T helper (TH) cell.
The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells.
Plasma cells proliferate and produce antibodies against the antigen.
Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite.
A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors).
Activation of macrophage (enhanced phagocytic activity).
The CD8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell.
B cell
Plasma cell
T cell
TH cell
Cytotoxic T lymphocyte
CytokinesCytokines
Lysed target cell
Cytokines activate macrophage.
Cytokines from the TH cell transform B cells into antibody-producing plasma cells.
Cytokines activate T helper (TH) cell.
Memory cell
Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen.
Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune systemControl of freely circulating pathogens Control of intracellular pathogens
Figure 17.20 The dual nature of the adaptive immune system.
Vaccines
• suspension of organisms/ parts of organism used to INDUCE immunity
• Artificial Active Immunity
Vaccine: Types
• Live attenuated whole-agent• Inactivated whole-agent• Toxoids• Subunit Vaccines– Recombinant subunit vaccines
• Nucleic acid Vaccines
Live attentuated Whole agent• living but attenuated (weakened) microbes
– Mutated virus– Related virus
• Attenuated viruses replicate in the body– Cell and humoral immunity
• Lifelong immunity• Counterindicated
– immune compromised– Attenuated microbes: from mutated strains can back-mutate to virulent
form
• Viral vaccines: MMR, Sabin polio, Smallpox, Flumist (influenza)• Bacterial vaccines: tuberculosis
Inactivated “Dead” Whole-agent
• Killed by formalin or phenol• Immunity not life-long– Boosters may be required– Primarily humoral response
• Examples:– Viral: Salk (polio, IPV), Rabies, Flu– Bacterial: Pneumococcal, Cholera
Subunit Vaccines• Highly immunogenic fragments
– Cannot replicate in host– Less side-effects/ dangers
• Recombinant vaccines– Desired Ag fragment expressed by unrelated, non-pathogenic microbe– Ex. HepB virion protein in GM yeast– Rabies glycoprotein in Vaccinia virus (V-RG)
• Toxoids– Tetanus, diphtheria– Several injections required for full immunity– Boosters every 10 years
• Conjugated Vaccines– Capsular polysaccharides: poor immunogens; T-independent Ags– Conjugate with Toxoid for maximal immunity– Ex. Hib
Nucleic Acid Vaccines (DNA vaccines)
• Newest “promising” vaccines• Plasmid DNA– Containing gene for immunogen of interest– Injected intramuscularly
• Gene gun• Conventional needle
– Expressed Protein Ag Red Bone Marrow humoral and cellular immunity• Long lasting immunity
• West Nile vaccine (horses)• Human trials underway
Types of Vaccine
Gene gun = DNA coated with gold or tungsten nanoparticles are “shot” into dermal cell cytosol• Inserted with glass micropipette
- Diameter smaller than cell- Punctures plasma membrane
• Eliminates• syringes/needles• refrigeration• lower costs
Recommended Immunization Schedule
Vaccine Development• Whole-agent vaccine– Grow in large amounts for use
• Early days– Smallpox scarified onto shaved calf bellies
• Cow “junk”
– Flu, Polio: grown in Eggs • Egg protein: allergen
– Human cells required• First HepB vaccine used Ags from chronically
infected as source
• Tissue cultureYolk sac
Allantoic cavity
Amniotic cavity
Chorioallantoic membrane
Current Vaccine Development
• Tissue Culture– Tissue slice– Digest with enzymes (trypsin)• Breaks down tissue into single cells
– Nutritive growth media• Cells adhere and divide to from a “monolayer”
– Infect with virus• CPE (cytopathic effect) caused by virus infection
Vaccine DevelopmentAdvancement in cultivation: cell cultureViruses may be grown in:Primary cell lines = derived from tissue slices; die out after a few generationsDiploid cell lines = develop from human embryos; maintained for ~100 generationsContinuous cell lines = (aka immortal cell lines)Cancerous cells; can be maintained indefinitelyEx) HeLa cell line• tend to have:
- Less round shape- Chromosomal abnormalities
Vaccine Safety: Risks v/s benefits• Disease caused by vaccine
– Smallpox• Variolation
– Incidence of disease decreased from 25% to 1%
– OPV (Sabin)• Poliovirus mutated• Reversion to wt
– Poliomyelitis
• Risk v/s Benefits– Public reaction
• Low perceived risk of contracting disease– Polio, measles
• Reports/ rumors of harmful effects– MMR autism– Flu Guillain Barre syndrome
• Herd immunity
Immune Disorders
Hypersensitivity
• Abnormal reaction to Antigen– Allergy– Sensitization to previous exposure to Allergen– Higher exposure to Antigen• Sensitized• Immune response to low levels of Ag
– Genetic predisposition
HypersensitivityHygiene hypothesis = sterile environments don’t provide enough stimulation for immune system
• Higher incidence in developed countries
• Eczema and hay fever less likely in children from larger families
• Allergies linked to antibiotic use in 1st year of life
• Asthma linked to use of household antibacterials
Hypersensitivity Reactions
• Type I: Anaphylaxis– Sytemic anaphylaxis (Anaphylactic shock)– IgE response
• Type II: Cytotoxic Reactions– IgM, IgG, complement response
• Type III: Immune complex reactions– IgG response against soluble Antigen
• Type IV: Delayed Hypersensitivity Reaction– Cell mediated response (CTL or ADCC)
Type I: Anaphylactic Reactions
• Rapid– 2-30 mins after exposure– Systemic
• Shock, breathlessness, can be fatal
– Localized• Hives
• IgE response– Binds basophils/ mast cells– Degranulation: release mediators
• Histamine• Leukotrienes• Prostaglandins
– Swelling, inflammation, runny nose, contraction of smooth muscles
Anaphylactic Reactions
Mediators: attract neutrophils and eosinophils to site of degranulated cell; and:Histamine• Increase vessel permeability
Swelling, redness• Smooth muscle contraction
Breathing difficulty
Leukotrienes & Prostaglandins• Not preformed in granules• Leukotrienes: prolonged smooth muscle contraction
asthmatic bronchial spasms• Prostaglandins: vasodilation, fever, pain
Systemic & Localized Anaphylaxis
• Systemic– Shock – Second or subsequent exposure to allergen
• Mediators vasodilation BP drop (shock)• Injected antigens (insect bites)
– Epinephrine• Constricts blood vessels
• Localized– Ingested or inhaled allergen
• Pollen– Inhalation
• Itchy eyes, runny nose, congestion, coughing, sneezing– Antihistamine (blocks histamine receptors)
– Ingestion• Food allergies• Hives, systemic anaphylaxis
Systemic & Localized Anaphylaxis
SEM of pollen grains, dust mite • common inhaled triggers of localized anaphylaxis
Ingestion: 8 foods = 97% food allergies• Eggs, peanuts, tree nuts, milk, soy, fish, wheat, peas
- 200 food allergy deaths per year in U.S.
Type II:Cytotoxic Reactions
• complement activation by IgG/ IgM with an antigenic cell
Ex) Transfusion reactions• RBCs destroyed by circulating antibodies
Type III: Immune Complex Reactions• IgG/ IgM against soluble antigens circulating in serum Immune complexes:• [Ag] > [Ab]• Complexes evade phagocytes• Soluble, circulating• “stuck” on capillaries, joints, organ tissues
• Activate complement: Transient Inflammation Attract neutrophils enzymes
- tissue destruction
Glumerulonephritis = inflammatory damage to kidney glomeruli
Type IV: Delayed Cell-Mediated Reactions
• T-cell activation• Development time: longer
– Days– T-cell and macrophage migration/ accumulation
• Sensitization– Macrophage phagocytoses Ag– Presents to T-cells– T-memory cells formed
• Subsequent exposure– Memory cells activated– Cytokines releases
• Attract and activate macrophages
Delayed Cell-Mediated Reactions
Ex) Allergic contact dermatitis = exposure to substances to which you have become extra sensitive• Fragrances• Metals• Plant oils (poison ivy)• Latex
Graft rejection Poison ivy plant
Catechols = oils secreted by poison ivy plant• Combine with skin proteins, become antigenic
immune response• First contact: sensitization• Second exposure: contact dermatitis
Comparison of the four types of hypersensitivity
Autoimmune Diseases
• Hosts immune response against self– Loss of discrimination between self v/s non-self– Thymic selection – >40 known ds., 75% women
• Autoimmune hepatitis– Hepatocytes display MHC-II to APCs• Viral infections (HepC, EBV)• Medications • Genetic predisposition
Autoimmune Diseases
• Immune complex reactions– Rheumatoid arthritis
• Immune complexes (IgG/ IgM) deposits in joint• Chronic inflammation• Damage to bone/ joint cartilage
– SLE (systemic lupus erythematosus)• Abs against cell components
– DNA– Tissue breakdown
• Cytotoxic autoimmune reactions– Graves Disease
• Abs that mimic TSH bind TSH-receptors• Increased production of thyroid hormones
– Hyperthyroidism– Goiter, bulging eyes
Immunodeficiencies
• Absence/ deficient immune response• Congenital
– DiGeorge’s syndrome (22q11.2)• Chromosome 22 • Defective/ missing thymus
– No CMI– Frequent/ severe infections
• Acquired: drugs, cancer, infectious agents– AIDS
• Final stage of HIV• Destruction of T-helper (CD4+) cells
– cancer, bacterial, viral, fungal, and protozoan diseases» Pneumocystis pneumonia, Kaposi’s sarcoma
• Diagnosis: CD4+ T-cell count below 200 cells/μl• Chemotherapy: inhibit viral enzymes
reverse transcriptase inhibitors
Types of Acquired Immunity: Active & Passive Immunity
Active immunity = acquired from an immune response to exposure of foreign antigens• Naturally acquired = exposure to antigens leads to
illness, recovery• Artificially acquired = vaccination
Passive immunity = acquired from transfer of antibodies from one person to another• Naturally acquired = mother to infant
- Transplacental, breast milk• Artificially acquired = injection of antibodies