Immuno Test 2 (Part 2) Flashcards
(171 cards)
1
Q
The Infectious- Nonself Model
A
- APCs recognize EVOLUTIONARY DISTANT PATHOGENS
- APCs activated via PRR
- PRR recognize PAMP on bacteris
- Upon activation, APC up-regulate COSTIMULATORY SIGNALS, process the bacterial ANTIGENS, and PRESENT them to passing T CELLS
***The PRR allow APC to DISCRIMINATE between “INFECTIOUS-NONSELF” and “NONINFECTIOUS-SELF”
2
Q
Danger Theory Model
A
- APCs are ACTIVATED by DANGER/ DAMAGE Signals
- Danger Signals are generated by:
1) Injured Cells
2) Pathogens
3) Toxins
4) Mechanical Damage
3
Q
What is the Danger Signal?
A
Potential Danger Signals:
1) Infection by Microbial Pathogens
2) Products of Injured (Necrosis) or Stressed Cells
3) Immunostimulatory Compounds (HEPARAN SULFATE)
4) Inflammatory Cytokines (IFN-alpha/ beta or TNF-alpha)
5) Rupture of vessels or chemotaxis of Blood-Borne Cells
- ***For POTENT ACTIVATION:
1) MHC Signal
2) CD28 to B7
4
Q
Humoral Response to Danger Signals
A
- Activation of Complement
- Activated Immune Cells Release:
1) Chemokines
2) Leucotrienes and Prostaglandins
3) Reactive Oxygen Intermediates (ROI)
4) Nitric Oxide (NO)
5
Q
Necrosis Generates Danger Signals and Inflammation
A
***NECROSIS: a Passice, Catabolic cell DEATH in response to EXTERNAL TOXIC FACTORS
- Necrosis is a dirty FORM of cell death characterized by SWELLING and RUPTURE of cell membrane (cell lyse) which may cause INFLAMMATION or harm other neighboring cells
**INFLAMMATION: a response to the INNATE IMMUNITY that involves activation of leukocytes and release of inflammatory mediators
- Immune cells are activated by the DANGER SIGNALS
6
Q
Necrosis and Danger/ Damage Signals
A
1) HMGB1: High Mobility Group Box 1, is a protein passively released during Necrosis:
- Activates NF-kB pathway
- RAGE is a receptor for HMGB1
* * HMGB1 is an ENDOGENOUS DANGER SIGNAL*
2) URIC ACID is another diffusible danger signal:
- Activated NF-kB
3) HSPs are another danger signal:
- HSPs induce NF-kB pathway and release Inflammatory cytokines (TNF-alpha and IL-1beta)
HSP: Heat Shock Proteins
RAGE: Receptor of Advanced Glycation End Products
7
Q
Acute Inflammatory Response
A
1) Increased BLOOD SUPPLY to the affected areas —> REDNESS and HEAT
2) Increased in CAPILLARY PERMEABILITY —> Leak from the BLOOD VESSELS —> SWELLING AND PAIN
3) Massive INFLUX of NEUTROPHILS
4) Arrival of MACROPHAGES (16-48hrs)
5) Macrophage mediated PHAGOCYTOSIS of debris, restoring the HOMEOSTASIS
8
Q
Stages of Acute Inflammatory Response
A
1) DETECTION of Danger/ Damage Signal:
- VERY EARLY
- The inflammatory process begins with VASCULAR COAGULATION (clotting) and the DETECTION of pathogens or cellular injury by PATTERN RECOGNITION RECEPTORS (PRR)
- MAST CELLS release HISTAMINE
2) LEUKOCYTE RECRUITMENT and ELIMINATION Stimuli
- Signaling through PRR induces RELEASE of Inflammatory mediators which ACT ON BLOOD VESSELS (Endothelial cells) to PROMOTE recruitment of Leukocytes and EXUDATION of plasma into the DAMAGED TISSUE
- PHAGOCYTOSIS of OPSONIZED pathogens and cellular debris!!!!!
3) RESOLUTION:
- After ELIMINATION OF MICROORGANISMS and necrotic tissue, Leukocyte Recruitment ceases and apoptotic neutrophils are phagocytized by Macrophages
* *** MACROPHAGES clean cell debris using SCAVENGER RECEPTORS (another type of PRR)!!!!!!!!
4) WOUND HEALING:
- Tissue repair and remodeling involves the development of NEW BLOOD VESSELS (Angiogenesis), RESURFACING of the WOUND (Re-epithelization) and COLLAGEN DEPOSITION
* *** MACROPHAGES stimulate Fibroblasts by releasing TGF-beta!!!!!!1
9
Q
Inflammation in Atherosclerosis
A
1) Monocytes recruites though the activated endothelium differentiate into MACROPHAGES
2) Several endogenous and microbial molecules are recognized by TLRs and ACTIVATE THE CELLS
3) Inflammatory CYTOKINES, CHEMOKINES, ROI, NO, and other inflammatory molecules are released
4) Inflammation and tissue DAMAGE OCCURS
5) MACROPHAGE accumulate LIPIDS and become FOAM CELLS
10
Q
Apoptosis vs Necrosis
A
- Cell Death may occur by Necrosis or Apoptosis:
1) NECROSIS: is a DIRTY form of cell death characterized by SWELLING and RUPTURE of cell membrane (cell lyse) which may cause INFLAMMATION or harm other neighboring cells
2) APOPTOSIS: is a CLEAN form of cell death in which any harm done to the organism by this process is MINIMIZED!!!
- Apoptotic cells are removed WITHOUT TISSUE INFLAMMATION
- Apoptosis is NORMAL PHYSIOLOGICAL PROCESS occurring in embryonic development and immune response
- DANGER SIGNALS are NOT RELEASED
- When Ag is ELIMINATED, then only MEMORY CELLS left
11
Q
Apoptosis and Anti-Inflamamtory Response
A
Immunological Tolerance is the process by which the Immune System does not respond to Ag*
- Apoptosis provide NO DNAGER SIGNALS —> NO Immune Response
- HMGB1 is NOT RELEASED during Apoptosis
- APOPTOSIS can render APCs into a Tolerant State
- Anti-inflammatory IL-10, TGF-beta, and Regulatory T cells may contribute to the process
12
Q
Molecular Mechanisms of Apoptosis
A
1) Triggers:
- DNA Damage
- Cytokine Starvation
- Hypoxia
- Temperature
- Death Receptor
2) Regulators: PRO-APOPTOTIC: - Death Domain Factors - Cytochrome C - p53 ANTI-APOPTOTIC: - BCL-2 Family - Myc/ Oncogenes
3) Executioners
- Capsase 9 (Intrinsic) and Capsase 8 (Extrinsic) activate CASPASE 3 for cell death!!!!!
- Each cell express Fas, but only ACTIVATED LYMPHOCYTES express Fas LIGAND (FasL)
13
Q
Caspases in Apoptosis
A
- Caspases are the Major Executioners
- Caspases are CYSTEINE PROTEASES
- Caspases directly and indirectly ORCHESTRATE the MORPHOLOGIC CAHNGES of the cell during APOPTOSIS
- Capsases exist as LATENT PRECURSORS
- When activated, Caspases initiate apoptosis by DESTROYING KEY COMPONENTS of the Cellular Infrastructure
14
Q
Intrinsic Mitochondrial Pathway
A
3 Main Triggers:
1) Bcl-2 Family proteins
2) CALCIUM!!!!!!!!
3) FREE RADICALS!!!!!!!
4 Downstream Regulators:
1) CYTOCHROME C!!!!!!!!!
2) Protein Smac/Diablo
3) Apoptosis-inducing factor
4) Endonuclease G
EXECUTIONERS:
- Caspase 9
- CASPASE 3!!!!!!!
- Apaf-1
15
Q
Extrinsic Apoptotic Pathway
A
1) Fas Ligand binds to Fas!!!!
2) FADD recruits to the intracellular portion of the Fas receptor (Death Domain)
3) Caspase 8 is ACTIVATED and activates CASPASE 3 (Caspase Cascade)!!!!!!
- Once Caspase 3 is made there is no turning back
4) APOPTOSIS
- Mitochondrial damage
- Membrane Changes
- Proteolysis
- Nuclear Condensation and DNA fragmentation
16
Q
Apoptosis In Action
A
-
Once Viral CLEARANCE happens then the CTL Response will also decrease**
- CTL will go through APOPTOSIS when there is no more Viral Antigens
17
Q
Autoimmune Lymphoproliferative Syndrome (ALPS)
A
*** The Majority of ALPS patients have HETEROZYGOUS MUTATIONS in the gene encoding fas
Patients have:
1) CHRONIC ADENOPATHY and/or SPLENOMEGALY in the early years of life
2) CHRONIC PERSISTENCE and ACTIVATION of BOTH T CELLS that stimulate B-CELL maturation (Abs in BLOOD)
3) The EXTENDED SURVIVAL of LYMPHOCYTES due to the DEFECTIVE Fas-mediated APOPTOSIS may allow MALIGNANT TRANSFORMATION to occur!!!!!
18
Q
Overview of Immune Responses to Microbes
A
- Survival and Pathogenicity of microbes is influenced by the ability of microbes to EVADE or RESIST the effector mechanism of immunity
- Many microbes establish LATENT, or PERSISTENT, INFECTIONS in which the immune response controls but DOES NOT ELIMINATE the microbe and the microbe survives WITHOUT PROPAGATING the INFECTION
- Tissue INJURY and disease may be caused by the host response to the MICROBE (COLLATERAL DAMAGE) RATHER THAN by the microbe itself
- Inherited and acquired DEFECTS in innate and adaptive IMMUNITY are important causes of SUSCEPTIBILITY to INFECTIONS
19
Q
What happens without Immunity?
A
- Lack of INNATE IMMUNE MECHANISMS leads to very quick expansion of the pathogen
- Without ADAPTIVE IMMUNITY the infection is initially controlled by Innate Immunity, however, the PATHOGEN can NOT be ELIMINATED completely
20
Q
Immune protest against Extracellular Microbes
A
1) Antibodies are PRESENT
2) Complement is PRESENT
3) Neutrophils are PRESENT
4) Th2 are PRESENT and ACTIVE (DOMINATES!!!!!!!)
5) Th1 small number present so NOT MUCH ACTIVITY
6) Macrophages are present in a low number
7) Cytotoxic T cells are NOT PRESENT
8) NK Cells are PRESENT along with CYTOKINES
21
Q
Defenses Against Extracellular Bacteria
A
- Complement
- Phagocytes
- Antibodies
22
Q
Steps of Immune Response Gains Infections with Extracellular Bacteria (Steps 1 -6)
A
1) Break in epithelial surface allows BACTERIA ENTRY and PROLIFERATION
2) Surface LIPOPOLYSACCHARIDES may activate the ALTERNATIVE COMPLEMENT pathway or MANNAN-BINDING LECTIN pathway leading to BACTERIAL LYSIS
- Other complement activators operating at this stage include C-REACTIVE PROTEIN, which binds Bacterial COAT POLYSACCHARIDES
3) MAST CELL DEGRANULATION enhance BLOOD Flow!!! The increased blood flow and LOCAL EDEMA are perceived as ITCHINESS and IRRITATION in the inflamed areas
4) ROLLING, MARGINATING Neutrophils adhere to the vein wall as locally released cheekiness and bacterial derived molecules (ENDOTOXINS) ACTIVATE both the ENDOTHELIUM and the NEUTROPHILS, resulting in ADHESION BETWEEN THE TWO
5) BACTERIAL PRODUCTS (Formyl-Methionyl-Leucyl-Phenylalanine tripeptide), COMPLEMENT FRAGMENTS (C5a) and CHEMOKINES (IL-8/CXCL8) ATTRACT Neutrophils to the site (CHEMOTAXIS)!!!!!!!!
6) Opsonized Bacteria are RAPIDLY ENGULFED and KILLED by Neutrophils. DENDRITIC CELLS Engulf and Internalize Bacteria, are ACTIVATED via PATTERN RECOGNITION RECEPTORS (Toll-Like Receptors) and MIGRATE via the LYMPHATICS
23
Q
Steps of Immune Response Gains Infections with Extracellular Bacteria (Steps 7-11)
A
7) Dendritic Cells enter the Local LYMPH NODES and moves to GERMINAL CENTER.
- Local Inflammation leads to UPREGULATION of ADHESION MOLECULES on high Endothelial VENULES of Lymph Node, and Lymphocytes enter directly from the blood
- Many lymphocytes become TRAPPED in the LOCAL INFLAMED NODE, and the consequent SWELLING, along with local HYPEREMIA, leads to the symptom of SWOLLEN PAINFUL/TENDER LYMPH NODES!!!!!
8) Th cells are RECRUITED and ACTIVATED by PROFESSIONAL APCs in the Lymph Node, and by B CELLS, promoting the production of BACTERIA-SPECIFIC ANTIBODIES
- Naive T Cells become differentiated towards Th1 and Th2, according to the DENDRITIC CELL SIGNALS
- Initially IgM CLASS AB is PRODUCED, followed by CLONAL EXPANSION and SWITCHING to other classes (IgG or IgA) for MUCOSAL PATHOGENS
9) Early ANTIBACTERIAL AB production is of the IgM CLASS.
- This relatively LOW AFFINITY interaction is enhanced by the FIVE ADHESION sites on IgM, leading to HIGH EFFICIENCY of BINDING
- IgM is a VERY POTENT Complement ACTIVATOR and OPSONIN
- Opsonized bacteria are LYSED by Complement
10) Following the resolution of the BACTERIAL INFECTION, protective mechanisms for future encounters are put in place by laying down of MEMORY CELLS and PRODUCTION OF ABs
11) In the Resolution of an infection, bacterial debris is removed by LOCAL MACROPHAGES and NEUTROPHILS, or by ANTIBODY as SOLUBLE immune complexes!!!
- IgM is not a good SOLUBLE Ab because it is a pentamer and does not go into tissue easily
- IgG is more likely to go into the tissue because of its Monomer Configuration
24
Q
Immunity to Extracellular Bacteria
A
- EXTRACELLULAR bacteria are capable of REPLICATING OUTSIDE host cells in the blood, Conn Tissue, Epithelial surfaces, the GI Tract etc
PATHOGENIC Extracellular Bacteria have 2 MECHANISMS:
1) INFLAMMATION causes tissue DESTRUCTION at side of infection
2) Bacteria produce TOXINS which ahem diverse Pathological effects
Bacterial Toxins have 2 Categories:
1) Endotoxins:COMPONENTS OF BACTERIA CELL WALLS
2) Exotoxins: SECRETED BY THE BACTERIA
- ENDOTOXIN (LPS) of Gran Neg bacteria is a POTENT ACTIVATOR of Macrophages, Dendritic Cells, and Endothelial cells
- Many EXOTOXINS are CYTOTOXIC including:
1) DIPHTHERIA TOXIN: Shuts down protein synthesis in infected cells
2) CHOLERA TOXIN: Interferes with ion/ water transport
3) TETANUS TOXIN: Inhibits Neuromuscular transmission - Other Exotoxins interfere with Normal Cellular functions without killing cells, and yet other EXOTOXINS STIMULATE THE PRODUCTION OF CYTOKINES THAT CAUSE DISEASE
25
Innate Immunity to Extracellular Bacteria
PRINCIPLE MECHANISMS:
1) Complement Activation
2) Phagocytosis
3) Inflammation
26
Complement Activation
- PEPTIDOGLYCANS (Gram Pos Bacteria) and LPS (Gram Neg Bacteria) activate complement by the ALTERNATIVE PATHWAY
- Bacteria that EXPRESS MANNOSE on their surface may bind Mannose-Binding Lectin, which activates complement by the LECTIN PATHWAY
1) MAC lyses Bacteria (Neisseria) are particular susceptible to LYSIS
2) C3a and C5a stimulate Inflammatory responses by RECRUITING and ACTIVATING LEUKOCYTES
3) Complement Activation results in OPSONIZATION and enhanced PHAGOCYTOSIS of the bacteria
27
Complement Mediated Killing
1) CLASSICAL Pathway:
- Requires IgM or IgG; not exactly an INNATE IMMUNE RESPONSE
- C3 Convertase: C4bC2a
- C5 Convertase: C4bC2aC3b
2) MBL Pathway:
- Does not use C1!!!!!!
- When MBP binds MASPs are ACTIVATED
- C3 Convertase: C4bC2a
- C5 Convertase: C4bC2aC3b
3) ALTERNATIVE Pathway:
- C3 undergoes spontaneous HYDROLYSIS and C3 CONVERTASE (C3bBb) is formed presence of Factors B and D!!!!!!!!!!!!!!
- Eventually C5 CONVERTASE (C3bBbC3b) is formed!!!!
- PROPERDIN stabilizes CONVERTASE
28
Complement Role In Host Defense
1) COMPLEMENT-MEDIATEDKilling
- C3b binds to microbe
- Activation of late components of complement
- Formation of the MAC
- OSMOTIC LYSIS OF MICROBES
2) OPSONIZATION and PHAGOCYTOSIS
- Binding of C3b (or C4b) to microbe OPSONIZATION
- Recognition of bounds C3b by PHAGOCYTE C3b receptor (CR1!!!!!!!!)
- Phagocytosis of microbe
29
Phagocytes and Inflammation
- Neutrophils and Macrophages use surface MANNOSE RECEPTORS and SCAVENGER RECEPTORS to recognize extracellular bacteria, and they use FC RECEPTORS and COMPLEMENT RECEPTORS to recognize bacteria opsonized with ABS and COMPLEMENT PROTEINS
- Microbial products activate TOLL-LIKE RECEPTORS (TLRs) on Phagocytes and other cells
- MANNOSE and SCAVENGER receptors PROMOTE PHAGOCYTOSIS of the MICROBES
- TLRs stimulate the MICROBIAL ACTIVITIES of the Phagocytes (mainly TLRs)
- The FC and COMPLEMENT RECEPTORS promote PHAGOCYTOSIS and ACTIVATION of the phagocytes
- Activated phagocytes SECRETE CYTOKINES, which induce Leukocyte infiltration into site of infection (Inflammation)
- The RECRUITED LEUKOCYTES ingest and DESTROY the BACTERIA
30
Opsonization and Phagocytosis Components
- CR1 is a common receptor for Complement
- CR2 binds to C3d and only needs a small amount of C3d to activate the Complement Cascade
- CR1-4 are Complement Receptors
- Fc receptors bind to the FC REGION of the Antibodies
31
Opsonization and Phagocytosis Steps
1) Recognition and Attachment
- Microbes bind to phagocyte receptors
2) Engulfment
- Phagocyte membrane zips up around microbe
3) Killing and Degradation
- PHAGOSOME of ingested microbe fuses with a LYSOSOME to form a PHAGOLYSOSOME
- The ROS, NO in the Phagolysosome cause for the microbe to be DEGRADED
- PRR-mediated PHAGOCYTOSIS IS SHOW!!!!!
- Complement and Ab-mediated Phagocytosis has the same mechanism
32
Microbicidal Mechanisms of ROI and NO
Harm Effectos of ROI:
1) Damage of DNA
2) Lipid Peroxidation
3) Oxidations of Amino Acids in proteins
4) Oxidative Inactivation of enzymes by Oxidation of co-factors
33
Peroxynitrite (ONOO-) Causes Apoptosis or Necrosis
1) ONOO- causes NECROSIS by:
- Lipid Peroxidation
- Protein Oxidation
- Protein Nitration
- Inactivation of enzymes
2) ONOO- causes APOPTOSIS by:
- Caspase activation by the release of Cytochrome C from the mitochondria
- AIF activation from the mitochondria
- Peroxynitrite is a result of L-arginine losing a NO and converting to Citrulline!!!!!!!
- NO + O2- = ONOO-
34
Innate Immune Evasion by Extracellular Bacteria
1) Inhibition of Complement Activation
- Many bacteria
2) Resistance to Phagocytosis
- Pneumococcus, Neisseria meningitidis
3) Scavenging of reactive oxygen Species
- Catalse- Positive Staphylococci
35
Role of Abs in Elimination of Microbes
1) Neutralization of Microbes
2) Opsonizatoin and Phagocytosis of microbes
- Fc gamma Receptor on Phagocyte
3) Antibody dependent cellular Cytotoxicity
- NK cells
4) Lysis of Microbes
5) Phagocytosis of Microbes Opsonized with Complement Fragments (C3b)
6) Inflammation
36
Neutralization of Bacteria and Toxins by ABs
1) Antibody blocks BINDING of Microbe and INFECTION of cell
2) Antibody blocks INFECTION of ADJACENT cell
3) Antibody blocks BINDING of TOXIN to CELLULAR RECEPTOR
37
Ab Mediated Phagocytosis
******IgG******
1) Opsonization of Microbe by IgG
2) Binding of Opsonized Microbe to Phagocyte Fc Receptors (FcGammaRI)
3) Fc receptor signals activate phagocyte
4) Phagocytosis of Microbe
5) Killing of ingested Microbe
38
Fc Receptors and Phagocytic Cells
- Phagocytes like Macrophages and Neutrophils express Fc receptors for IgG (FcGammaRI) and IgA (FcAlphaRI)!!!!!!!!!!!!
- FcgammaRI and FcalphaRI interact with Ab-Ag complexes only
- Abs bind to PATHOGEN or TOXIN to form COMPLEXES
- COMPLEXES are removed by PHAGOCYTIC CELLS (Neutrophils, Monocytes, and Macrophages) via FcGammaRI and FcAlphaRI
EXCEPTION:
- MAST CELLS, Eosinophils, and Basophils express FcEpsilonRI that most strongly binds IgE!!!!!!!
- FcEpsilon is unique because it bids FREE IgE (NO AG REQUIRED)!!!!!!!!
39
IgG
*** 200 Binding Strength***
- FcGammaRI!!!!!!!
Cell Type:
- Macrophages
- Neutrophils
- Eosinophils
- Dendritic Cells
- Effect of IgG ligation:
- Uptake
- Stimulation
- Activation of Respiratory Burst
- Induction of Killing
40
IgE
*** 20,000 Binding Strength***
- FcEpsilonRI!!!!!!!
Cell Type:
- Mast Cells
- Eosinophils
- Basophils
- Effect of IgE ligation:
- Secretion of Granules
41
IgA1, IgA2
*** 20 Binding Strength***
- FcAplhaRI!!!!!!!
Cell Type:
- Macrophages
- Eosinophils
- Neutrophils
- Effect of IgE ligation:
- Uptake
- Induction of Killing
42
Bacterial Strategies to Evade Immunity
1) Antigenic Variation:
- Bacterium or virus alters its surface proteins in order to evade a host immune response
- Neisseria gonorrhoeae
- Escherichia coli
- Salmonella typhimurium
2) Inhibition of Complement:
- Bacterial capsules, decay of C3 Convertase, Blocking MAC formation (VITRONECTIN)
- Many bacteria
3) REsistance to Phagocytosis:
- Interfere with Complement activation and/or deposition at bacterial surface, injection of anti-phagocytic effectors into the cell
- Pneumococcus
4) Scavenging ROI:
- CATALSE Positive pathogens deactivate the Peroxide radicals and thus survive unharmed within the host
- Catalase- Positive Staphylococci
43
Diversity in Immune System
1) Immunoglobulins
2) T Cell Receptors
3) Major Histocompatibility
- A combination of shuffling of gene segments by SOMATIC RECOMBINATION and High MUTATIONAL VARIABILITY for some segments, leads to a LARGE GENETIC DIVERSITY for ANTIBODY PRODUCTION
- Theoretically 10^14 different possible antibodies
44
Development of Immunity
- During development, individual segments of certain genes are rearranged into different combinations, producing immune cells that contain different genetic information such that each is adapted to attack ONE PARTICULAR ANTIGEN
- Mechanism requires relatively FEW GENES to begin with but provides an enormous diversity of cells capable of responding to an equally ENORMOUS NUMBER of FOREIGN Substances
45
Immune Response B cells
- Humoral Immunity = B Cells
- Each Initial B cell undergoes genetic rearrangement so that is it will recognize and respond to ONLY ONE KIND OF FOREIGN ANTIGEN
- Each AB produced by plasma cell, will only respond to and BIND TO A SPECIFIC ANTIGEN. Receptors specific for a given ANTIGEN will also be produced on the surface of B cells
- Immune response occurs when appropriate Antigen binds to one of these receptors
46
Immune Response T cells
- Cellular Immunity = T Cells
- They develop receptors on the cell surface that response to a unique Antigen
- T cells work in concert with Macrophages, which initially recognize an Antigen and which also present pieces of the antigen to appropriate T cells
- In order for T cells to function properly they must bind to a SPECIFIC ANTIGEN and bind to SELF ANTIGEN, a MAJOR-HISTOCOMPATABILITY COMPLEX
- The bidding to the MHC ANTIGEN helps to mark that particular T cell as one that has UNDERGONE SELECTION during embryonic development WITHIN the THYMUS
47
Immune Response Proteins
1) Immunoglobulins
2) T Cells Receptors
3) Major Histocompatibility Antigens (HLAs)
- Same plasma cell can secrete one or more kinds of immunoglobulins (different isotope or classes), but they will all respond to the same antigen
Isotype: Classes of Ab
Idiotype: Affinity for Ag
48
Immunoglobulin Structure
Immunoglobulins (Antibodies):
- Synthesized by B cells
- Synthesized and secreted by Plasma Cells:
- Terminally differentiated B cells
- IMMUNOGLOBULINS with specificity for an Antigen are referred to as ANTIBODIES
49
Immunoglobulin Structure
- Consist of FOUR POLYPEPTIDES linked by DISULFIDE BONDS:
- Two Identical HEAVY CHAINS (VDJC)
- Two Identical LIGHT CHAINS (VJC)
50
Light Chains
- Immunoglobulin molecule contains two identical light chains (isotopes):
1) Either TWO IDENTICAL KAPPA Chains:
- Encoded on Chromosome 2!!!!!!
2) Or TWO IDENTICAL LAMBDA Chains:
- Encoded on Chromosome 22
- NEVER ONE OF EACH TYPE!!!!!!!!!!!!!!1
Light Chain Domains:
- Variable (VL) domain (110AA)
- Constant (CL) domain (110AA)
51
Heavy Chains
- Immunoglobulin molecule contains two IDENTICAL HEAVY CHAINS
- Encoded on Chromosome 14
5 TYPES of HEAVY CHAINS (Isotypes):
- Mu, Delta, Gamma, Epsilon, and Alpha
- M,D,G,E,A
Heavy Chain DOMAINS:
- One Variable (VH) Domain
- Three or Four Contant (CH) Domains
- D,G, and A chains have THREE CONSTANT DOMAIN (CH1-3)!!!!!!!!!!!!!!!
- M and E have an ADDITIONAL FOURTH CONSTANT DOMAIN (CH1-4)!!!!!!!!!!!!!!!!!!!!!
52
Antigen Receptors of Lymphocytes
B Cell Receptors: (IgM is first Ab produced)
- Immunoglobulins
- May be MEMBRANE BOUND
- May be SECRETED
T Cell Receptors:
- TCRs
- Exist only as MEMBRANE BOUND RECEPTORS
53
TCR Maturation
1) Double NEGATIVE (CD4-/CD8-) Seen in the SUBCAPSULAR CORTEX region of the THYMUS!!!!!!
2) T cells then rearrange gene coding TCR and express both becoming DOUBLE POSITIVER (CD4+/CD8+), and they are seen in the CORTEX of the THYMUS!!!!
3) T cells whose receptors bind self-MHC molecules lose expression of either CD4 or CD8 and INCREASE levels of expression of TCR. These are called SINGLE POSITIVE T CELLS (CD4+/CD8-) or (CD4-/ CD8+) and are seen in the MEDULLA of the THYMUS!!!!!!!!
54
How Helper T Cells Help
1) A Macrophage (APC) processes phagocytised Ag that is then bound to CLASS II MHC and presented to T HELPER CELLS (Cell- Mediated Immunity)!!!!!!!!!
2) Activated Th cells divide by Mitosis to Incr population of Th cells at site of Ag presentation
3) Th cells INTERACT with B cells in the presence of APC to INDUCE 1) Immediate access of B cells to FREE Ag in Extracellular space 2) PROLIFERATION of B Cells
4) B cells with CELL SURFACE-SPECIFIC Immunoglobulin arrive at the site to RAPIDLY NEUTRALIZE free Ag
5) B cells DIFFERENTIATE into PLASMA CELLS that Secrete Immunoglobulin to BLOCK FREE Ag (Humoral Immunity)
55
Mechanisms for Generating Ag Receptor Diversity
1) Somatic Recombination
- COMBINATIONAL DIVERSITY
2) Junctional Diversity
3) Somatic Hypermutation
56
Germline Organization
1) Ig H CHAIN (Chromosome 14)
- C (mu) is always the first CONSTANT REGION expressed!!!!! (IgM produced first)
2) Ig Kappa Chain Locus (Chromosome 2)
- Has no D REGIONS!!!!
- Has ONLY ONE CONSTANT REGION
3) TCR Beta Chain Locus (Chromosome 7)
- Has D REGION
4) TCR Alpha Chain Locus (Chromosome 14)
- Has NO D REGION!!!!
57
SOmatic Recombination
Expression of an Ig Heavy Chain involved TWO GENE RECOMBINATION EVENTS:
1) D-J JOINING
2) V to DJ COMPLEX
- Intervening gene segments are DELETED
- Recombined gene is TRANSCRIBED
- VDJ SEGMENT IS SPLICED onto the FIRST HEAVY CHAIN RNA!!!!!!
- The mRNA is TRANSLATED to produce HEAVY CHAIN PROTEIN
- Ig LIGHT CHAIN (and TCR Alpha/ Beta Chains) follow the SAME sequence EXCEPT in the Ig LIGHT CHAINS and the TCR Alpha chain a V gene COMBINES DIRECTLY with a J GENE SEGMENT
- Light chains and TCR Alpha have NO D REGIONS!!!!!!!!
58
Light Chains: VJC
- B cells commits to Light Chain
- One V brought next to One J region gene
- RECOMBINATION
- V gene PROMOTER is brought CLOSE to ENHANCER between J and C regions
- mRNA TRANSLATION and L is removed as protein is transported to ER
- Light Chain and Heavy Chain ASSEMBLE IN ER!!!!!!!!!
59
Gene Segments
- Genes coding for the different chains are composed of Segments
- Segments for the Human Kappa Gene:
- 30-35 V (variable) segments
- 5 J (Joining) segments
- 1 C (Constant) segment
60
Kappa/ Lambda Gene Organization
1) Lambda Light Chain
- Have 4 Constant Regions!!!!!!!
2) Kappa Light Chain
- Has 1 Constant Region!!!!!!!!!
61
Kappa Light Chain Genes
1 Constant Region!!!!!!
- Each Variable Region gene as two Exons:
1) One LEADER exon
2) One VARIABLE exon
- Joining region between V and C
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Lambda Light Chain Genes
4 Constant Regions!!!!!!
- One for EACH SUBTYPE!!
- Each variable region as TWO Exons:
- One LEADER
- One for MOST VARIABILITY
- Joining region between V and C!!!
63
Light Chains
- Most variable of all the regions in the light and heavy chains is the Fab region
- This VARIABILITY is produced through JUNCTIONAL RECOMBINATION
1) Some Genes in the V region can be deleted (PERMANENT)
2) Then the V and J regions will join together
3) An mRNA TRANSCRIPT will be made from this Light chain segment
4) Then there is a DELETION in the mRNA bringing the VJ and C gene TOGETHER!!!!!!!!
***** Ig Light Chains and TCR Alpha Chains LACK D REGIONS therefore the V region recombines DIRECTLY with J!!!!!!********
64
Formation of Ig Heavy Chains
1) Germline DNA at Ig H Locus
2) SOMATIC RECOMBINATION (D-J Joining) in TWO B CELL Clones
3) Then Transcription occurs so the Primary RNA is formed
4) The Primary RNA is spliced to form the mRNA!!!!!
5) The mRNA is TRANSLATED into Ig Mu (M) Chains in TWO B Cell Clones
Valence: How many Immunoglobulins Ag can bind to. Most Immunoglobulins have a Valence of 2
IgM is secreted in the PENTAMER FORM and when it is Membrane bound it is in DIMER FORM
65
Somatic Recombination
- Gene REARRANGEMENT that is occurring in SOMATIC CELLS
Combinational Diversity:
- TCR = 3 x 10^6 possibilities
- Ig = 10^6 possibilities
Junctional Diversity:
- TCR 10^16 possibilities
- Ig 10^11 possibilities
66
Heavy Chain VDJC
1) DJ Rearrangement
2) VDJ Rearrangement
3) TRANCRIPTION (Primary RNA)
67
Junctional Diversity
Diversity of Ag Receptor is Incr by:
1) COMBINATIONAL DIVERSITY
- Due to SOMATIC RECOMBINATION
- Involves V(D)J RECOMBINASE!!!!!!!!!
- Limited by Number of available V,D, and L gene segments
2) JUNCTIONAL DIVERSITY
- Almost UNLIMITED
- Due to:
- REMOVAL of Nucleotides from V, D, and J segments by EXONUCLEASE at time of Recombination
- TERMINAL DEOXYRIBONUCLEOTIDY TRANSFERASE (TdT)!!!!!!!!!!
68
V(D)J Recombinase
Collection of Enzymes:
- Expressed in IMMATURE B and T Lymphocytes
- Recognizes DNA sequences that FLANk all Ag Receptor V,D, and J gene segments
- BRINGS THESE SEGMENTS CLOSE TOGETHER
- Constists of:
- Recombinase-Activating Gene (RAG)-1
- Recombinase- Activating Gene (RAG)-2
- EXONUCLEASE cuts DNA at the ENDS of the segments
- LIGASES repair the Breaks
Recombination SWITCH Sequence:
- Found next to every VDJ Segment
- Consists of THREE Elements:
- A HEPTAMER
- A NONAMER
- A SPACER of 12 or 23 bp
- RAG-1 and 2 bind to 12 bp and 23 bp SPACER
69
Recombinase Activity
1) 2 RAGs bind to RSS on DNA (Next to V and D segments to be binded TOGETHER)
2) 2 RAGs loop the DNA to be cut out
3) The V and D segments are joined together and the excised DNA is cut off in a loop formation
70
Terminal Deoxyribonuelcotidyl Transferase (TdT)
- Takes Nucleotides that are not part of the Germline genes and RANDOMLY adds them to the sites of V(D)J RECOMBINATION
- Creates Individual variation for EACH Ig and TCR at site of V(D)J RECOMBINATIOn
- This JUNCTION ENCODES the Amino Acids of CDR3:
- One of the most VARIABLE of the CDRs (Complementary Determining Regions)
- SHORT HYPERVARIABLE Stretched of Amino Acids within the V Regions
- MOST IMPORTATN SITE FOR AG RECOGNITION!!!!!!!!!!!
71
IgA
- Dimer
- IgA1,2
- H Chain: Alpha 1,2
- Mucosal Immunity
DIMER has a Valence of 4
MONOMER has a Valence of 2
72
IgD
- Monomer
| - Naive B Cell Receptor
73
IgE
- Monomer
- Mast Cell Activation (Immediate Hypersensitivity)
- Defense against HELMINTHIC PARASITES
74
IgG
- Monomer
- IgG1-4
- Gamma (1,2,3, or 4)
- Opsiniation
- Complement Activation
- Antibody Dependent Cell-Mediated Cytotoxicity
- Neonatal Immunity
75
IgM
- Pentamer!!!!!
- Naive B cell Ag receptor
- Complement Activation
76
Isotype Switching
Constant Region = Isotype
- Switching Isotypes OCCURS IN DNA to produce IgM, IgD, IgE, IgA, and IgG
- Isotype (class) switching occurs by CLASS Switch RECOMBINATION
- DNA is DELETED (Permanent)
- Different Classes do different things when secreted
IgM is alway secreted FIRST because the C(Mu) is the first Constant Region available on the DNA!!!!!!!!
77
Heavy Chain Class Switching
IgG:
- Cleave DNA so a VDJC gamma (remove everything before Cgamma) mRNA is produced
IgE:
- Cleave DNA so a VDJC epsilon (Remove everything before Cepsilon) mRNA is produed
78
Somatic Hypermutation
Only OCCURS IN B CELLS!!!!!!!
- Occurs after B cells have been exposed to an EPITOPE
- Occurs when Memory B cells are RESTIMULATED and UNDERGO RAPID PROLIFERATION
- Occurs in the GERMINAL CENTERS of the Lymphoid Follicle and is followed by selection of HIGH-AFFINITY B Cells by Ag displayed by FOLLICULAR DENDRITIC CELLS
- B CELLS MAY SWITCH THEIR EXPRESSED ISOTYPE!!!!!!!!
- B Cells may accumulate POINT MUTATIONS in the DNA Encoding their VL or HL regions!!!!!!!
- Some MUTATIONS may Increase the AFFINITY of the Ab to the Epitope = AFFINITY MATURATION!!!!!!!!!!
79
Somatic Hypermutation Initaition
- Somatic Hypermutation is INITIATED when CYTOSINE bases are DEAMINATED and Converted to URACIL!!!!!!!
- URACIL bases are detected and REPLACED by DNA-REPAID Mechanism that are error-prone:
- The ORIGINAL CYTOSINE is often replaces with a DIFFERENT BASE, leading to a MUTATION (POINT MUTATION)
80
Affinity Maturation
- The longer after the Primary Ab is made, there are more MUTATIONS!!!
- The Secondary Ab has even more MUTATIONS
- The TERTIARY Ab has more MUTATIONS than the Secondary
Kd: the number of Ag that will bind to 50% of the Abs in Solution
- If an Ab mutates for HIGHER AFFINITY, then the Kd will go down because it will take less Ab to bind to 50% of the Ag
81
T Cell Receptors
- Structurally similar to Immunoglobulin and located on cell surface
- NOT SECRETED
- Composed of ONE Alpha and ONE Beta Polypeptide
- Genes that encode the Alpha and Beta Chains are organized much like those that encode the Heavy and Light Chains of Immunoglobulins
- Each gene is made up of Segments that undergo SOMATIC RECOMBINATION before the gene is TRANSCRIBED
- Valpha and Vbeta domains form the Ag Binding Portion of TCR
82
Major Histocompatability
MAJOR HISTOCOMPATIBILITY COMPLEX consists of a number of genes that code for the MHC proteins
- In Humans = HLA Ag
- Membrane proteins on APC that present Ag for T Cell recognition
- Principle determinants for GRAFT ACCEPTANCE or REJECTION!!!!!!!
- Divided into Class I and Class II
- Class I: all Nucleated Cells
- Class II: B cells, Macrophages, Dendritic Cells, and Thymus Epithelium
83
Major Histocompatibility Complex
MHC protein Characteristics
- Each MHC has ONE PEPTIDE BINDING SITE
- Each MHC CAN BIND DIFFERENT PEPTIDES
- DEGENERATE
- Highly POLYMORPHIC
- No two individuals (except Monozygotic twins) have exactly the SAME Set of MHC genes and molecules
- Molecules are MEMBRANE BOUND
- MHC alleles are CODOMINANT:
- Each expressed on the membrane of Nucleated cells
- Alleles Inherited from BOTH parents are EXPRESSED EQUALLY
- Peptides in the CYTOSOL:
- Associated with Class I MHC
- Recognized by CD8+ (Tc)
- Peptides from within VESICLES:
- Associated with Class II MHC
- Recognized by CD4+ Th Cells
- Class I and II genes encode molecules that PRESENT PEPTIDE fragments to T Lymphocytes vie the Ag binding Cleft of the MATURE HLA Cell Surface Protein
- This results in PRESENTATION of PROTEIN FRAGMENTS from within the cell to T cells in order fro an IMMUNE RESPONSE to occur
- MHC spans a region of more than 3 million BASE PAIRS on human CHROMOSOME 6!!!!!!!!!***********!!!!!!!!!!!!*******!!!!!!!
84
Cleft Binding Class I
- Bind 8 to 10 AA
- Binding Depends on AA in GROOVE
- Each Class I molecule binds only CERTAIN PEPTIDES
85
Cleft Binding Class II
- Binds 13 to 25 AA
- Binding Depends on AA in GROOVE
- Each Class II molecule binds ONLY CERTAIN PEPTIDES
86
MHC Histocompatability Complex
MHC Diversity:
- Three POLYMORPHIC CLASS I genes:
- HLA-A, HLA-B, HLA-C
- Each person Inherits one set from each parent
- Any cell can express SIX different CLASS I Molecules
- Three POLYMORPHIC CLASS II genes:
- HLA-DR, HLA-DQ, HLA-DP
- Both Alpha Chain and Beta chain are POLYMORPHIC
- Alpha chain from one allele may Associate with the Beta Chain from another ALLELE
- Any cell can EXPRESS 10 to 20 DIFFERENT CLASS II MOLECULES
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MHC I GENES
IMPORTANT: (Polymorphic)
HLA-A
HLA-B
HLA-C
NOT IMPORTANT: (Limited Variability, Carb and Peptide fragments)
HLA-E
HLA-F
HLA-G
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MHC II Genes
MOST IMPORTANT (Polymorphic):
HLA-DP
HLA-DQ
HLA-DR
HLA-DM
HLA-DO
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Class I MHC Molecules
- Differences in individuals occur in Alpha1 and Alpha2 domains
- Alpha 3 is INVARIANT and binds to CD8+!!!!!!!!
- CD8+ T cells can only respond to Class I MHC
- Beta 2 Microglobulin associates with the molecule and hopes to MAINTAIN CONFORMATION
90
Class II MHC Molecules
- Differences among Individuals occur in Alpha1 and Beta1 domains
- CD4+ binds to Beta2!!!!!!!
- CD4+ T cells can only respond to Class II MHC
91
HLA Loci
- Class II MHC first
- Class III MHC in middle (Code Complement Proteins)
- Class I MHC last
92
Most Class I Variability
- Occurs in Alpha 1 and Alpha 2 region
| - These two are the DOMINANT REGIONS
93
Types of Grafts
1) Autografts
2) Isografts
3) Allogenic grafts
4) Xenogeneic grafts
94
Autografts
- Grafts where tissue is moved from ONE place to ANOTHER IN THE SAME INDIVIDUAL
- Skin Graft
95
Isografts (Synegeneic)
- Transplants between GENETICALLY IDENTICAL INDIVIDUALS
96
Allogenic grafts
- Grafts between GENETICALLY DIFFERENT MEMBERS of the SAME SPECIES
- Kidney Transplant
97
Xenogeneic grafts
- Grafts between members of DIFFERENT SPECIES
| - Pg Heart Valves in HUMANS!!!!
98
Testing for Tissue Transplantation
- ABO Blood Typing:
- ABO Incompatibilities will cause HYPERACUTE GRAFT REJECTION in the host
- HLA Typing:
- Larger number of Matched HLA ALLELES, the better the GRAFT SURVIVAL
- HLA typing typically focuses on HLA-A, HLA-B, and HLA-DR!!!!!!!!!!
- Only Loci that appear to predict the likelihood of rejection!!!
- Screening for preformed Ab
- CROSSMATCHING
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Haplotype
- A set of alleles of linked genes present on ONE PARENTAL CHROMOSOME
- Genes that determine different Ag but are CLOSELY LINKED and INHERITED as a unit!!!!!
- Onserved parents (various combinations) of ALLELES or GENES
- NEET TO MATCH ORIENTATION and TYPE of Genes!!!!
- HAPLOTYPE is MOST IMPORTANT, NOT the individual MHC Complexes!!!!
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Defense against Intracellular Bacteria
1) Cytotoxic T Lymphocytes
2) Phagocytes
- Minimal Ab
- Minimal Complement
- Low Th2
- High Th1!!!!!!
- High Macrophages!!!!!
- Cytotoxic T Cells present
- Some NK cells present (Cytokines
- Tc Cells kill the infected cells and remove the hiding place for the intracellular bacteria or viruses. This then makes the intracellular pathogens available for phagocytosis by macrophages because they are not protected by the host cell anymore
101
Innate Immunity to the Intracellular
- The Innate Immune response to Intracellular bacteria is mediated by Phagocytes (Macrophages) and NK cells
- Products of the bacteria are recognized by TLRs which activate the phagocytes
- Phagocytes ingest Intracellular microbes, but pathogenic Intracellular bacteria are RESISTANT TO DEGRADATION within phagocytes
- DC and Macrophages produce IL-12 and IL-15 which activate NK Cells
- NK cells produce IFN-gamma which activates Macrophages and promotes killing of phagocytize bacteria
- NK cells and Macrophages provide an EARLY DEFENSE against these microbes, before development of adaptive immunity
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Immunity: Intracellular Bacteria
- Innate Immunity: mediated by phagocytes and NK Cell interactions among which are mediated by IL-12 and IFN-gamma. May control bacteria growth but ELIMINATION of bacteria REQUIRES ADAPTIVE IMMUNITY
- Adaptive Immunity: CELL-MEDIATED immunity in which T CELLS ACTIVATES PHAGOCYTES to ELIMINATE microbes
- Adaptive Immunity usually kicks in after 7 days!!!!
103
Immunity against Intracellular Microbes
1) CD4+ Th1 Cells Recognize Ags of the microbes ingested by phagocytes and presented within CLASS II MHC
- Activated TH1 cells produce IFN-gamma that potentiates killing of Intracellular BACTERIA IN PHAGOSOMES by Macrophages
- Ex: Mycobacteria tuberculosis
2) CD8+ T lymphocytes also produce IFN-gamma, but CD*+ cells also KILL INFECTED cells with MICROBES IN THE CYTOPLASM . The CTLs recognize CLASS I MHC
- Ex: Viruses
- Th1 cells increase the proliferation of Cytotoxic T cells (IL-2) in a PARACRINE MANNER
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How CTLs Kill infected cells
1) Activated CD8+ CTLs recognize the Ag on CLASS I MHC. They then release GRANZYMES/ PERFORIN complexes ENDOCYTOSE by target cell. The Granzymes enter cytoplasm vie PERFORIN-DEPENDENT MECHANISM
- This causes activation of the INTRINSIC (Caspase 9 and 3) APOPTOTIC PATHWAY
2) Activated CD8+ CTLs recognize the Ag on CLASS I MHC. Then the FasL binds to the Fas (CD95!!!!) on the infected cell. This then activates the EXTRINSIC (Caspase 8 and 3) APOPTOTIC PATHWAY
105
Endogenous vs Exogenous Pathways
1) ENDOGENOUS PATHWAY, proteins from Intracellular pathogens (viruses) are degraded by Proteasome and the resulting peptides are shuttled into the ER by TAP proteins
- These peptides are loaded onto MHC Class I molecules and the complex is delivered to the cell surface, where it stimulates CTLs that KILL THE INFECTED CELL
2) EXOGENOUS PATHWAY. extracellular pathogens are ENGULFED by PHAGOSOMES
- Inside the Phagosome, the pathogen-derived peptides are loaded directly onto MHC Class II molecules, which ACTIVATE Helper T Cells that stimulate the production of Abs!!!
- Some peptides from ENTRACELLULAR Ags can also be presented on MHC Class I molecules. This is called CROSS -PRESENTATION!!!!!!!
- To activate Dendritic cells, it needs to bind its CD40 with the CD40L on Th cells, which in return make the Dendritic Cells more POTENT APCs to activate Tc Cells!!!!
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Infection with M. tuberculosis
1) Mycobacteria ligate TLR-2 as they infect Macrophages
2) Ligation of TLR-2 induces the Macrophages to produce NO Intracellularly and to secrete IL-12
3) Macrophages present Mycobacterial Ag to T cells. In the presence of IL-12, T Cells release IFN-gamma to stimulate Macrophages
4) IFN-gamma recruits more Macrophages, forming a GRANULOMA and activating them to kill Intracellular bacteria
- M. tuberculosis MAY SURVIVE phagosomes by preventing acid-containing LYSOSOMES from FUSING WITH PHAGOSOMES and creating Phagolysosomes
- CD4+ T Cells respon to Class II MHC associated with M. tuberculosis and produce IFN-gamma, which activates Macrophages to destroy the microbes in phagosome
- CD8+ T cells respond to Class I MHC associated peptides derived from cytosolic Ags (CROSS-PRESENTING) and Kill the infected cells
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Role of Th1/ Th2 Cells in Infection Outcome
- Naive CD4+ T Cells may differentiate into Th1 cells (Classical pathway Activation, IFN-gamma, TNF-alpha), which activate phagocytes to kill ingested microbes OR Th2 (IL-10, IL-4, IL-13) cells which INHIBITS this CLASSICAL Pathway of Macrophage activation.
- The Th1/ Th2 balance may influence the outcome of infections, as illustrated by Leishmania infection in mice and Mycobacterium leopard in humans!!!
- IL-6 stimulates B cells to become PLASMA CELLS
- IL-10 only works minimally inhibiting B cells, but it is MORE IMPORTANT as an ANTI-INFLAMMATORY Agent!!!
108
Immune Evasion by Intracellular Bacteria
1) Inhibition of Phagolysosome Formation (Ex: Mycobacterium tuberculosis, Legionella pneumophia)
2) Inactivation of Reactive Oxygen and Nitrogen species (Ex: Mycobacterium leoprae--> phenolic glycolipid)
3) Disruption of Phagosome membrane, space into cytoplasm (Ex: Listeria monocytogenes --> Hemolysin protein)
109
Defenses against Viruses
1) Type I Interferons - IFN alpha/ beta
2) NK Cells
3) Cytotoxic T Lymphocytes
4) Antibodies
- High amount of Ab
- Some complement (enveloped)
- High Th2 cells
- High Th1 cells
- Some Macrophages
- High Cytotoxic T Lymphoctes
- Some NK cells (lysis)
110
Steps of Immune Response Against Viral Infections (1-5)
1) Virus infects epithelial cells and replicates amongst them
2) Effect of Intracellular viral infection is the ACTIVATION of CYTOKINES and Cytokine-Receptor genes, especially the Type I Inteferons (IFN-alpha)
- Secretion of IFN-alpha involves autocrine feedback loop
- Local effect of IFN-alpha are INHIBITION of viral gene replication, and UP-REGULATION of MHC Class I molecules
- Viral peptides will appear in the MHC Class I peptide-binding groove
3) Viral infections results in cell death and viral replication. Viral components (ssRNA) ACTIVATE Dendritic Cells and locally released Cytokines and Chemokines AMPLIFY the Activation of Macrophages and APCs!!!!!
- These cells engulf and present Viral protein as well as cellular debris
- PROFESSIONAL APCs (Ex: Langerhan Cells in skin aka "Tissue Dendritic Cells") transport Antigen to local Lymph Node via lymphatics
4) Cytokines and Chemokines UP-REGULATE Endothelial cell EXPRESSION of Adhesion Molecules such as ICAM-1!!!
- Chemokines (IL8, CXCL-8) begi to attract cells through the Endothelium towards the site on infection
- Some locally released cytokines rom cells such as Macrophages and T Cells (IL-1, TNF-alpha) ENTER BLOODSTREAM and have SYSTEMIC EFFECTS of Fever and Arthralgia/myalgia
5) Dendritic Cells enter Lymph Nodes, and move to Germinal Center
- Local Inflammation leads to UP-REGULATION of Adhesion molecules on High Endothelial VENULES of Lymph Node, and Lymphocytes enter directy from the blood
- Many lymphocytes becomes trapped in the LOCAL INFLAMED NODE, and the consequent Swelling, along with local Hyperemia, leads to symptoms of SWOLLEN PAINFUL/ TENDER Lymph Nodes
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Steps of Immune Response Against Viral Infections (6-10)
6) CDs and other ACPs are surrounded in the Lymph Node Germinal Center by T cells, where presentation of Viral peptides takes place. T Cells prossessing TCRs COMPLEMENTARY to the Class II MHC molecule/ viral peptide complex are ACTIVATES and BECOME Th CELLS!!!
- Naive B cells, acquiring viral particles through attachment to surface IgM or IgD, process and present viral peptides to Th2 cells, and in turn RECEIVE POSITIVE GROWTH and DIFFERENTIATION SIGNALS.
- IgM ANTIVRIAL Ab is PRODUCED as a result (PRIMARY Ab response) while some B cells DIFFERENTIATE and CLASS SWITCH, leading later to production of HIGH AFFINITY ANTIVRIAL IgG (SECONDARY Ab Response)
7) Viral peptide is presented by Class II MHC molecules to a Complementary TCR on a Th cell
- The interaction is stabilized by CD4/ Class II MHC and CD80/86 (APC) binding to CD28 (Th Cells), which also provides CO-STIMULATORY SIGNALS to the Th Cell!!!!!!!
8) Th1 Cells recruit and Activate Virus-specific CYTOTOXIC T Lymphocytes (CTLs)
- The CTLs recognize virus peptides CROSS-PRESENTED by DCs
- The same viral EPITOPES will be presented on the SURFACE of INFECTED TARGET CELLS
9) Th and CTLs leave the Lymph Node via DRAINING LYMPHATICS toward the other Lymph Nodes, and ultimately ENTER THE BLOOD
- At this stage their key attributes are:
1) Virus-specific TCRs
2) Up-Regulated ADHESION MOLECULES, to allow migration into the inflamed tissues
3) Up-Regulated CYTOKINE PRODUCTION
10) NK Cells may be recruited at two points at least during the virus infection
- They may have an EARLY, INNATE ANTIVIRAL role following activation by epithelium-derived cytokines
- Alternatively, at a LATER STAFE they are Activated by the Th1 cells SPECIFIC for the VIRUS
112
Steps of Immune Response Against Viral Infections (11-12)
11) Virus-infected cells secrete and express Viral proteins
- These may be NEUTRALIZED or REMOVED by AB int he form of Immune Complexes, which are cleared, or Ab may be used to GUIDE Fc RECEPTOR-Expression NK Cells!!!
12) After RESOLUTION of the Infection, Virus-specific Memory T and B cells reside long term in Lymph Nodes, Spleen and Bone Marrow
- PLASMA CELLS ensure Long-term circulation of PROTECTIVE, Virus-NEUTRALIZING Ab!!!!
113
Anti-Viral Properties of IFN alpha/ beta
1) Uninfected Cells:
- Expression of enzymes that block Viral Replication:
- PKR16
- 2', 5' OligoAdenylate SYNTHETASE
- RNase L18
- ANTIVIRAL STATE
2) Infected Cells:
- Expression of molecules that ENHANCE SUSCEPTIBILITY to CTL mediated killing:
- Class I MHC!!!
- CTL Killing of INFECTED CELL
114
Anti-Virla Immunity
1) Cytotoxic T Lymphocyte:
- Produce IFN-alpha
- Kills Cell
2) Th1 Cells:
- IFN-gamma activates Macrophages
- Macrophage produces IFN-alpha and NO!!!
3) NK Cells:
- ADCC Killing!!!! (IgG)
4) Complement:
- IgM or IgG binding to Infected cell wall and then C1 binds!!!
115
Cytotoxic Mechanisms of NK Cells
1) Inhibitory Receptor Engaged = NK not Activated and No Cell Killing
2) Inhibitory Receptor Not Engaged = NK Activated and Cell Killing
116
Ab Dependent Killing Infected Cells
- NK cell is activated upon recognition via Fc Receptor FcGammaRIII) and releases mediators causing Apoptosis of Infected cells
*** Needs IgG for FcGammaRIII to bind!!!******
117
Viral Strategies to Evade Immunity
1) Antigenic Variation
- Influenza
- Rhinovirus
- HIV
```
2) Inhibition of Antigen Procession:
A) Blockade of TAP TRANSPORTER:
- Herpes Simplex
B) Removal of Class I Molecules from ER:
- Cytomegalovirus
```
3) Production of Cytokine Receptor Homologs:
- Vaccinia
- Poxviruses (IL-1, IFN-gamma)
- Cytomegalovirus (Chemokine)
4) Production of Immunosuppressive Cytokine:
- Epstein-Barr Virus (IL-10)
5) Infection of Immunocompetent Cells:
- HIV
118
Defenses Against Parasites
1) Mast Cells
2) Basophils
3) Eosinophils
4) Phagocytes
5) Antibodies
- High amount of Ab
- Some Complement
- Some Neutrophils
- Some Th2
- High amount of Th1
- High amount of Macrophages
- NO CYTOTIXIC T CELLS
119
Host Defense Against Parasites
- An Immune response against Parasties is a Th2 type of response
- Activation of MAST CELLS and EOSINOPHILS is VERY IMPORTANT!!!!!!!!
- IL-4 and 6 lead to isotope switching and production of IgE to activation Mast Cell/ Basophil Degranulation (Activation)!!!
- IL-4 and 5 lead to Eosinophil Degranulation (Activation)!!!!
120
IgE Cross-Linking and Activation of Mast Cells
1) Resting Mast Cell has PREFORMED GRANULES with Histamine and other Inflammatory Mediators
2) Only Mast cells express FcEpsilonRI, a receptor for IgE
3) Multivalent Ag cross-links IgE Antibody (At least two IgE involved) bound at the mast cells because of FcEpsilonRI
4) This CAUSES ACTIVATION of Mast Cells and the RELEASE of preformed Inflammatory Mediators
121
Defense Against Multi-Cellular Parasites
1) Alternative Complement Activation
2) Classical Complement Activation
*** The Parasites are CONTAINED BY A CAPSULE but NOT KILLED!!!!!*********
Important Mediators:
1) Mast Cells (Degranulation and IgE activation)
2) Eosinophils (MBP and ROI)
3) Th2 Cells
4) B Cells for Ab production (IgG and IgE)
5) Macrophages (ROI and NO) ---> IFN-gamma
6) Neutrophils (ROI and NO) ---> TNF-alpha
7) Platelets ---> TNF-alpha
122
Defenses Against Fungi
1) Phagocytes
2) Complement
3) Antibodies
- Some Antibodies produced
- Some Complement
- Some Neutrophils
- Some Th2 Cells
- High amount of Th1!!!!!!!
- High amount of Macrophages!!!!!!
- NO Cytotoxic T Cells!!!
123
Immune Response to Fungi
1) Fungi are recognized by PRRs (TLRs and C Lectin-like receptors) binding the PAMPs
- the detection of BETA-GLUCAN by DECTIN 1 is IMPORTATN!!!!!!!
2) Cytokine production and Th1, Th2, and Th17 cell DIFFERENTIATION then occurs
3) IL-12 (Th1) and IL-23 (Th17) have IMPORTANT DIFFERENTIATION and Activation roles!!!
4) Th2 Cells and Ab production is LESS IMPORTANT
5) T Cell ACTIVATION triggers Inflammation and the Recruitment of HUMORAL and CELLULAR factors of Innate Immunity
- In general, Th1 RESPONSE is REQUIRED for CLEARANCE of a FUNGAL INFECTION, while Th2 immunity usually results in SUSCEPTIBILITY to INFECTION!!!!!!!!!
124
PRR Dectin 1 Binds Beta-Glucans
- The Macrophage Receptor (MR) has historically ben considered the MAJOR receptor INVOLVED in the NONOPSONIC RECOGNITION of FUNGI!!!!
- DECTIN 1 is a recently discovered PRR that plays an important role in ANTIFUNGAL Innate Immunity
- Dectin 1, which is expressed on Macrophages is a SPECIFIC RECEPTOR for BETA-GLUCANS!!!!!!
- Beta-Glucans are Polysaccharide PAMPs that CONTAIN ONLY GLUCOSE as structural components
- Dectin 1 binds and INTERNALIZES Beta-Glucans and mediates the production of REACTIVE OXYGEN SPECIES (ROS), Activation of NF-kB and subsequent secretion of Proinflammatory Cytokines!!!!!!!
- Beta-Glucan TRIGGERS NF-kB Activation ONLY via Dectin 1!!!!!!!!!
- Dectin 1 and TLR2/TLR6 signaling COMBINE to ENHANCE the RESPONSES triggered by Fungi
125
Immunity Against Fungi
1) Innate Immunity:
- IL-12 (Th1)
- IL-10
- IL-4 (Th2)
- IL-1 (Th1)
- TNF-alpha (Th1)
- IL-5 (Th2)
- PRR!!!!!! DECTIN 1!!!!!!!
2) Adaptive Immunity:
- IL-4 and IL6 (B Cell Activation)
- Antibody (Antibody Therapy)
- Complement (Binds Ab or MBL)
126
Membrane Attack
Immune Component:
- Defensins
- Complement
Groups of Pathogens:
- Gram-Neg Bacteria
Specific Pathogens:
- Pseudonomonas aeruginosa
- Neisseria species
127
Opsonophagocytosis
Immune Component:
- Neutrophils
- Macrophages
- CR1 (C3b)
- FcR (IgG)
Groups of Pathogens:
- Extracellular Bacteria
- Yeasts
Specific Pathogens:
- Staphylococcus
- Streptococcus sp
128
Intracellular Killing
Immune Component:
- Phagolysosomes:
- ROS and NO
Groups of Pathogens:
- Exracellular Bacteria
- Yeasts
Specific Pathogens:
- Catalase-Neg Bacteria and Fungi
129
Toxin Neutralization
Immune Component:
- IgM, IgG, IgA
- Immune Complexes
Groups of Pathogens:
- Exotoxin0producing microbes
Specific Pathogens:
- Clostridium tetani
- Staphylococcus aureus
130
Virus Neutralization
Immune Component:
- IgM, IgG, IgA
- Phagocytic Cells
- Mucus
Groups of Pathogens:
- Respiratory and GI Viruses
Specific Pathogens:
- Rhinoviruses
- Adenoviruses
- Rotaviruses
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Extracellular Killing
Immune Component:
- Neutrophils
- Macrophages
Groups of Pathogens:
- Filamentous Fungi
- Parasites
Specific Pathogens:
- Candida albicans
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Macrophage -mediated Intracellular Killing
Immune Component:
- Th1 Cells
- NK Cells
- IFN-gamma
- NO
Groups of Pathogens:
- Obligate or Faculative Intracellular Pathogens
Specific Pathogens:
- M. tuberculosis
- L. monocytogenes
- Candida albicans
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Cytotoxic T Cell Killing
Immune Component:
- CD8+ T Cells
- MHC Class I
- CD4+ Th Cells
- IL-2
Groups of Pathogens:
- Viruses and many Intracellular bacteria and fungi
Specific Pathogens:
- Herpes Simplex Virus
- Listeria monocytogenes
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Eosinophil- mediated Cytotoxicity
Immune Component:
- Eosinophils
- IgE
- FcElpsilonR
Groups of Pathogens:
- Intestinal Parasites (Helminths)
Specific Pathogens:
- Taenia saginata
135
Inhibitors of Intracellular Replication
Immune Component:
- Type I Interferons
Groups of Pathogens:
- Mostly Viruses
Specific Pathogens:
- Herpes Virus
136
NK Cell-Mediated Cytotoxicity
Immune Component:
- NK Cells
- MHC Class I
Groups of Pathogens:
- Many Viruses
Specific Pathogens:
- Herpes Viruses
137
Immunological Tolerance (IT)
- This is an UNRESPONSIVENESS to an AG
- All individuals are TOLERANT to SELF AGs
- BREAKDOWN of self tolerance results in AUTOIMMUNITY
- NEGATIVE SELECTION of self-reactive T lymphocytes in the Thymus IS NOT PERFECT
- There is a low level of PHYSIOLOGICAL AUTO-REACTIVITY that is crucial to Normal Immune function
- The challenge is to understand HOW IT BECOMES a PATHOLOGIC PROCESS and how T cells and B cells recognize sell and contribute to tissue injury
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Central and Peripheral Tolerance
- TOLERANCE IS AG SPECIFIC!!!!!
1) CENTRAL TOLERANCE: induced in IMMATURE self reactive Lymphocytes in the GENERATIVE Lymphoid Organs
2) PERIPHERAL TOLERANCE: induced in MATURE self reactive Lymphocytes in PERIPHERAL sites
- Central Tolerance ENSURE that mature Lymphocytes are NOT REACTIVE TO SELF AGs
- Central Tolerance is NOT PERFECT, and some self-reactive lymphocytes are present
- Peripheral Tolerance are needed to PREVENT ACTIVATION of these potentially dangerous lymphocytes
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Central T Cell Tolerance
- Immature T cells in the Thymus encounter SELF AG PRESENTED BY THYMIC EPITHELIAL CELLS
- Cells with TCR with NO AFFINITY for the complex of self peptides and self MHC molecules DO NOT RECEIVE A SURVIVAL SIGNAL and undergo spontaneous Apoptosis DYING IN THE THYMUS
- Cells whose TCR have a HIGH AFFINITY for such complexes receive the DEATH SIGNAL are also eliminated by means of APOPTOSIS
- Remaining T cells have INTERMEDIATE AFFINITY for these complexes, and these MATURE IN THE THYMUS and migrate to the PERIPHERY, where they can become ACTIVATED
****All T Cells are produced in the THYMUS!!!! Although the stem cell precursor for T Cells in produced in the Bone Marrow, T Cells are produced in the THYMUS
****THYMOCYTES serve as APC (Class I and II MHC) for CD4 and CD8 Lymphocytes!!!!!!!!!
140
Mutations Breaking the Central Tolerance
Gene:
* ** AIRE*****!!!!!!!!!
- AutoImmune Regulator
- Transcription factor selectively expressed in THYMOCYTES
- Ubiquitinately expressed TRANSCRIPTION FACTOR
Phenotype of mutant of knockout mouse:
- Destruction of Endocrine Organs by Antibodies, lymphocytes
Mechanism of Failure of Tolerance:
- Faulure of Central Tolerance
Human Disease:
- Autoimmune Polyendocrine Syndrome (APS)
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AIRE in Central Tolerance of T Cells
- NEGATIVE SELECTION of T Cells in the Thymus is necessary for the maintenance of Self Tolerance
- Medullary THYMIC EPITHELIAL CELLS have a key function as APCs
- They EXPRESS a large number of Self-Ags that are presented to DEVELOPING T CELLS
- Mutations in AIRE protein cause a BREAKDOWN OF CENTRAL TOLERANCE
- AIRE has been proposed to function as a TRANSCRIPTION FACTOR
- Mutations in AIRE is associated in DECREASED EXPRESSION OF SELF-AGs in the Thymus
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Function of AIRE
- The AIRE regulates the EXPRESSION OF TISSUE-RESTRICTED AGs (TRAs)
- Peptides from these AGs are DISPLAYED on the MEDULLARY THYMIC EPITHELIAL CELLS
- Ags are recognized by IMMATURE AG-specific T Cells, leading to the DELETION of self-reactive T Cells
- IN THE ABSENCE of functional AIRE, these SELF_REACTIVE T CELLS ARE NOT ELIMINATED and they can ENTER TISSUES where the Ags continue to be produced and CAUSE INJURY
143
Negative Selection and T Regulatory (Treg) Cells in Peripheral Tolerance
- TCR signaling in Immature T cells triggers MITOCHONDRIAL pathway of APOPTOSIS (NEGATIVE SELECTION)
- Strong recognition of self Ags by Immature T cells in the THYMUS leads to:
1) The DEATH of the cells by NEGATIVE SELECTION
2) The DEVELOPMENT of Treg CELLS that enter PERIPHERAL tissues
144
How Treg cells are Generated
- Treg cells develop in the THYMUS
- Treg cells are POSITIVELY ELECTED in the Thymus via STRONG TCR INTERACTIONS WITH SELF-AGS!!!!!!!!!!!!!!!!
- After recognition of Self-Ags they are NOT ELIMINATED by Apoptosis
- Treg cells are able to PRODUCE ANTI-APOPTOTIC MOLECULES which PROTECT them from NEGATIVE SELECTION in the Thymus
- The GENERATION of some Treg cells REGUIRES the TGF-BETA!!!!!!!!!!!!!
- TGF-Beta is produced by STROMAL CELLS!!!!!!!!
145
Treg Cells are CD4+, FOXP3+, and CD25 High
- Treg cells are CD4+ positive
- Treg cells are CD25+ (Unique for Treg)
- CD25 binds to IL-2!!!!!!!
- Tregs express FOXP3 Transcriptional Factor
- The SURVIVAL and functional COMPETENCE of Treg cells are dependent on IL-2!!!!!!
- Treg cells are ENDOGENOUS Long-lived populations of Self-Ags specific T Cells
- Treg cells serve to PREVENT potentially AUTOIMMUNE REACTIONS!!!!!!!!
146
Natural and Inducible Treg Cells
- The DEVELOPMENT and SURVIVAL of these REGULATORY T cells require IL-2 and FOXP3!!!!!!!!
- In Peripheral tissues, Treg cells SUPPRESS the ACTIVATION of SELF-REACTIVE LYMPHOCYTES
- Naive T cells become Treg cells by TGF-BETA!!!
- Treg cells produce IL-10 and FOXP3!!!!
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Close look how Treg cells work
1) Immunosuppressive Cytokines
- CD40 Decr
- CD80/86 Decr
- IL-12 Decr
- IL 10 INCR!!!!!!!!
2) Contact Inhibition on APC!!!!!!
- Loss of ability to induce effectors
148
Transforming Growth Factor Beta
- Inhibits the PROLIFERATION and effector FUNCTION of T CELLS
- INHIBIT the development of Th1 and Th2 subsets but PROMOTES Th17 in cooperation with IL-1 and IL-6!!!!
- INHIBITS activation of Macrophages
- Regulates the DIFFERENTIATION of peripheral FOXP3+ Treg Cells
- Stimulates the production of IgA by Inducing B cells to SWITCH to THIS ISOTYPE!!!!!!!!!!!!
- Promotes TISSUE REPAIR after local immune and Inflammatory reactions subside stimulating COLLAGEN SYNTHESIS and matrix-modifying enzyme production by Macrophages and FIBROBLASTS!!!!!!!!!!
149
Breaking the Peripheral Tolerance
- Impaired production fo REGULATORY T CELLS (FoxP3 DEFICIENCY causes IPEX Syndrome)
- DECREASED clearance and IMPARIED tolerance induction by APOPTOTIC CELLS (COMPLEMENTARY DEFICIENCY of C1q and C4)!!!!!!!!!!!
- ALTERED IMMUNE SIGNALING thresholds (CTLA-4 POLYMORPHISM)
150
Mutations Breaking the Tolerance
1) C4
2) CTLA-4
3) Fas/FasL
4) FoxP3
5) IL-2, IL-2R alpha/beta
151
C4
- SLE: forms C3 Convertase
Cause:
- Defective clearance of Immune Complexes
- Failure of B Cell Tolerance
Result:
- SLE
152
CTLA-4
- Lymphoproliferation
- T Cells infiltrates in multiple organs, especially heart
- Lethal by 3-4 weeks
Cause:
- Failure of ANERGY in CD4+ T Cells
Result:
- CTLA-4 Polymorphisms associated with several Autoimmune disease
153
Fas/FasL
- Anti-DNA and the Autoantibodies
- Immune Complex Nephritis
- Arthritis
- Lymphoproliferation
Cause:
- Defective deletion of Anergic self-reactive B cells
- Reduced deletion of Mature CD4+ T Cells
Result:
- Autoimmune Lympho-prolieration Syndrome (ALPS)
154
FoxP3
- Multi-organ Lymphocytic infitrates
- Wasting
Cause:
-Defiency of Regulatory T Cells
Result:
- IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome)
155
IL-2, IL-2R alpha/beta
- Inflamamtory bowel disease
- Anti-erythrocyte and Anti-DNA autoantibodies
Cause:
- Defective development, survival, or function of Regulatory T Cells
Result:
- None known
156
CTLA-4
- Cytotoxic T-Lymphocyte Antigen 4
- When T cells recognizes self Ags, they may engage INHIBITORY RECEPTORS of the CD28 family, whose function is to TERMINATE T Cell responses
- The best ESTABLISHED INHIBITORY receptors are CTLA-4!!!!!!!!!!!!!!
157
CTLA-4 in Peripheral Tolerance
- Individual populations of T Cells undergo EXPANSION and CONTRACTION upon Ag encounter
- T CELL ACTIVATION is regulated by members of the B7-CD28 family of costimulatory molecules
- CTLA-4 is a CD28 family receptor
- CD28 = Cell Active
- CTLA-4 = Inhibit Cell Activity
- CTLA-4 is an INHIBITORY RECEPTOR
- CTLA-4 provides signals that TERMINATE IMMUNE RESPONSES and MAINTAIN SELF-TOLERANCE
158
CTLA-4 Expression and Functions
- CTLA-4 KNOCK OUT mice develop UNCONTROLLED LYMPHOCYTE ACTIVATION with massively ENLARGED LYPH NODES and SPLEEN and FATAL MULTI-ORGAN Lymphocytic Infiltrates suggestive of SYSTEMIC AUTOIMMUNITY!!!!!1
- BLOCKING of CTLA-4 with Abs also ENHANCES AUTOIMMUNE DISEASES in animal models
- POLYMORPHISMS in the CTLA-4 are associated with several autoimmune disease in humans, including TYPE 1 DIABETES and GRAVES' DISEASE
CTLA-4 has TWO IMPORTANT Functions:
1) CTLA-4 expression is LOW on RESTING T CELLS until the cells are Activated by Ags
2) Once expressed CTLA-4, TERMINATES CONTINUING ACTIVATION of these responding T Cells
- CTLA-4 is EXPRESSDE ON REGULATORY T CELLS and mediates the Suppressive Function of these cells by Inhibiting the activation go Naive T Cells!!!!!!!!
159
CTLA-4 in Peripheral Tolerance (Results)
1) APC binds MHC to TCR on T Cell = APOPTOSIS or ANERGY
2) APC binds MHC and CD80/86 to TCR and CD28 on T Cell = Proliferation, Differentiation, and Effector Function
- BLOCKING AUTOIMMUNITY!!!!!!!!!
3) APC binds MHC and CD80/86 to TCR and CTLA-4 on T Cell = Cell Cycle Arrest
- STIMULATE ANTI-TUMOR IMMUNITY!!!!!!!!!
- CTLA_4 is expressed in PARALLEL with CD28!!!!!!
160
Mechanism of CTLA-4 Action
1) T Cell may deliver INHIBITORY signals that terminate FURTHER ACTIVATION of that cell (Cell-Intrinsic Function of CTLA-4)
2) CTLA-4 on Treg or responding T Cells binds to B7 molecules on APCs or makes UNAVAILABLE to CD28 and BLOCKING T Cell ACTIVATION
3) CTLA-4 MEDIATED INHIBITION by Treg cells is CELL-ENTRINSIC ACTION of this Mechanism
161
Central B Cell Tolerance
1) Immature B Cells that recognize Self Ags in the Bone Marrow with High AVIDITY die by APOPTOSIS or Undergo RECEPTOR EDITING and change the specificity of their BRCs
2) WEAK RECOGNITION of self Ags in Bone Marrow may lead to ANERGY (Functional Inactivation) of the B Cells!!!!!!!!
162
Peripheral B Cell Tolerance
1) Mature B Lymphocytes that recognize self Ag in Peripheral tissues in the absence of specific Th Cells amy be rendered FUNCTIONALLY UNRESPONSIVE or DIE by APOPTOSIS
2) CD22 INHIBITORY RECEPTOR is Phosphorylated by LYN, and then recruits SHP-1 TYROSINE PHOSPHATASE and this ATTENUATING B Cell RECEPTOR SIGNALING!!!!!!!!!!!!!!!!!!
- Therefore, DEFECTS in:
1) LYN TYROSINE KINASE
2) SHP-1 TYROSINE PHOSPHATASE
3) CD22 INHIBITORY RECEPTOR
- lead to AUTOIMMUNITY!!!!!!!!!!!!!
163
Autoimmunity (General Facts)
- About 5% or 12-15 Million people suffer from Autoimmune disease in the US alone
- There are 60 to 70 diverse autoimmune DISEASES which affect various tissues of the human body
- There is NO KNOWN CURE of Clear UNDERSTANDING the cause for any of Autoimmune Conditions
- Most autoimmune diseases are TREATED SYMPTOMATICALLY!!!!!!!!
- Autoimmune disease binds the PARADOX proposition that "The body both is and is not itself"
-
164
Autoimmunity Details
- There is no FUNDEMENTAL DIFFERENCE BETWEEN the structure of Auto-Ags and NON-Self Ags because Ags are all PROTEINS
- PAthologic Immune RESPONSE AGAINST SELF Ags often clinically manifested as "IMMUNE -MEDIATED INFLAMMATORY DISEASE"
- Caused by the ACTIVATION OF T CELL or B CELLS, or both, in the absence of ongoing infection or other discernible cause
- A result of HYCPERSENSITIVE IMMUNE SYSTEM that causes one's own Immune system to ATTACK THE SELF
165
How Autoimmunity is Prevented
- Cells that are PHYSICALLY SEPARATED from their specific Ag (the Blood Brain Barrier) cannot become activated, a process termed IMMUNOLOGIC IGNORANCE
- T Cells that EXPRESS the FAS (CD95) can receive their signals from cells that EXPRESS FASL and undergo APOPTOSIS, a process know as DELETION!!!!!!
- CTLA-4 (CD152) that binds CD80/86 on APC INHIBITS T CELL ACTIVATION
- REGULATORY T CELLS can inhibit through the production of INHIBITORY CYTOKINES such as IL-10 and TGF-Beta!!!!!!!
166
Postulated Mechanisms of Autoimmunity
- Various genetic loci may confer SUSCEPTIBILITY to Autoimmunity, in part by influencing the MAINTENANCE of Self-Tolerance
- ENVIRONMENTAL triggers, such as infections and other Inflammatory stimuli, promote the INFLUX of Lymphocytes into tissues and the Activation of Self-Reactive T Cells, resulting in Tissue Injury
167
General Features of Autoimmune Disorders
- Autoimmune diseases may either by SYSTEMIC or ORGAN SPECIFIC, depending the the distribution of the Auto-Ag that are recognized
- VARIOUS EFFECTOR MECHANISMS are RESPONSIBLE for Tissue Injury in different Autoimmune diseases
- Autoimmune diseases tend to be CHRONIC, PROGRESSIVE, and SELF PERPETUATING
- FAILURE of the mechanisms of Self-Tolerance in T or B CELLS underlines cause of all autoimmune disease
- INFLAMMATION or an initial INNATE IMMUNE RESPONSE
168
Genetics of Autoimmunity
- Most Autoimmune diseases are complex POLYGENIC TRAITS
- Affected individuals inherit MULTIPLE GENTIC POLYMORPHISMS that contribute to disease SUSCEPTIBILITY
- Susceptibility GENES act with ENVIRONMENTAL FACTORS to cause the Diseases
- Among the GENES that are associated with Autoimmunity, the STRONGEST ASSOCIATIONS are with MHC GENES
- POLYMORPHISMS in NON-HLA genes is also associated with Autoimmunity
169
Etiology and Pathogenesis of Autoimmunity
1) Genetic Susceptibiity --->
2) Failure of Self-Tolerance (Clinically NOT Manifested) --->
3a) Functional Self-Reactive Lymphocytes --->
4) ACTIVATION of Self-Reactive Lymphocytes
5) Immune Response Against Self Tissues
3b) Environmental Triggers (Infections, Tissue Injury) ------>
- Cause Inflammation and Tissue Damage (Ags)
4) ACTIVATION of Self-Reactive Lymphocytes
5) Immune Response Against Self Tissues
170
Role of Environmental Triggers
Microbial Ags can Initiate Autoimmunity through:
1) Molecular MIMICRY:
- RHEUMATIC FEVER is triggered by STREPTOCOCCAL INFECTION and mediated by CROO-REACTIVITY between Streptococcal Ags and CARDIAC MYOSIN
- MULTIPLE SCLEROSIS: T Cells react with MYELIN BASIC PROTEIN and peptides from EPSTEIN-BARR VIRUS, INFLUENCE virus Type A, and Human PAPILLOMAVIRUS
2) POLYCLONAL (Bystander) Activation:
- Microbial Infection can also use POLYCLONAL activation of Autoreactive Lymphocytes (CYTOKINE FIELD)
3) Release of Previously Sequestered Ags:
- Microbed that Kill cells cause INFLAMMATION, the RELEASE of sequestered Ags, and AUTOIMMUNITY
171
Noninfectious Triggers
1) Autoimmune Diseases are much more COMMON in WOMEN than in men:
- ESTROGENS exacerbate SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) in mouse models of the disease by ALTERING THE B-CELL REPERTOIRE in the Absence on Inflammation
2) DRUGS can ALTER THE IMMUNE REPERTOIRE:
- PENICILLINS and Cephalosporins can BIND to RBC membrane and generate a NEOANTIGEN that Elicits an Auto-Ag that causes HEMOLYTIC ANEMIA
3) The BLOCKADE of TNF-Alpha (ENBREL or Other Inhibitors) can Induce Antinuclear Abs and even SLE and MULTIPLE SCLEROSIS (MS) in certain persons
- TNF-Alpha has INHIBITORY EFFECTS on ACTIVATED T CELLS, but it remains unknown how TNF-Alpha Induces Autoimmunity
