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Immunology > Immuno Test 1 (Part 2) > Flashcards

Immuno Test 1 (Part 2) Flashcards

1
Q

Integumentary System

A
  • 2 Components:
    1) Skin
    2) Epidermal derivatives (nails, hair, sweat and sebaceous glands and mammary glands)
  • 3 layers:
    1) Epidermis (ectoderm)
    2) Dermis (mesoderm)
    3) Hypodermis aka Subcutaneous layer = Superficial fascia (mesoderm)
  • Thick skin: greater than 5 mm (palms and bottom of feet)
  • Thin skin: 1 to 2 mm (everywhere else)
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2
Q

General Features of Skin

A
  • Differential Diagnosis:
    • Jaundice (yellow)
    • Cyanosis (blue-gray)
    • Anemia (pale)
  • General functions:
    • Protection
    • Water barrier
    • Regulation of Body temp
    • Defense (mechanical and organisms)
    • Excretion of salts
    • Synthesis of precursors of Vit D
    • Sensation
  • Fingerprints are produced by epidermal ridges and underlying dermal papillae and are permanent
    • Cut across cleavage lines = decr healing time + scar
    • Cut with cleavage lines = Fast healing + less scar
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3
Q

Structure of Skin

A

1) Epidermis
- Ectoderm
- Epithelial barrier able to regenerate
- Stratified squamous, KERATINIZED EPITHELIUM

2) Dermis
- Mesoderm
- Mechanical Strength
- Reservoir of defensive elements

3) Hypodermis = Subcutaneous layer = Superficial fascia
- Deep Fascia
- Connective tissue between superficial fascia and muscle = epimysium or periosteum

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4
Q

Epidermis

A
  • 5 layers:
    1) Stratum Basale (Hemodesmosimes bolt layer down to Dermis)
    2) Stratum Spinosum (cells have lots of processes)
    3) Stratum Granulosum (Last layer where cells have NUCLEI)
    4) Stratum Lucidum (CORNIFIED)
    5) Stratum Corneum
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5
Q

General Features

A
  • Display a tight fit interface at epidermal-dermal junction
  • Primary epidermal ridge interlocks with subjacent dermal ridge
  • Epidermal INTERPAPILLARY PEG interlocks with the dermal ridge
  • DERMAL PAPILLAE project upward into the epidermal layer
  • Primarily found in thick skin
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6
Q

Structure of Skin

A

Dermis of thick skin

  • Dermal Papillae
    • Papillary layer
      • Connect the dermal layer with the epidermal layer and fit into pits of the epidermal layer
      • Adds strength against mechanical shear forces
      • Papillae are highly innervated and vascularized
  • Reticular Layer
    • Collagen bundles and coarse reticular fibers for support
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7
Q

Bullous Pemphigoid Antigens

A
  • Acute or chronic AUTPOIMMUNE SKIN DISEASE, involving blisters (bull) at the space between the skin layers periderms and dermis
  • Type II Hypersensitivity reaction
  • Bulae formed by initiation of IgG autoantibodies targeting DYSTONIN or BULLOUS PEMPHIGOID ANTIGEN 1 and/or BULLOUS PEMPHIGOID ANTIGEN 2 or TYPE XVII COLLAGEN, which is a component of hemidesmosomes
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8
Q

Structure of Skin (Plexus)

A
  • Subpapillary plexus and cutaneous plexus are in the DERMIS
  • Subcutanous plexus is in the HYPODERMIS
  • These are important for nutrition because cells in the basal lamina don’t get blood so they have to get nutrients from the Subpapillary plexus
  • If want to lose heat, supply more blood to subpapillary plexus
  • If want to retain heat, supply blood to subcutaneous plexus
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9
Q

Structure of Skin (Thick vs Thin)

A
  • Thick:
    • around 5 mm thick
    • Thick, plentiful dermal papillae
    • Palms of hands and soles of feet
  • Thin:
    • 1 to 2 mm thick
    • Fewer and flatter dermal papillae
    • Most skin of the body
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10
Q

Stratum Basale

A
  • Cuboidal or columnar
  • Rest on basement membrane
  • HEMIDESMOSOMES
  • MITOTIC FIGURES
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11
Q

Stratum Spinosum

A
  • Flattened Polygons
  • Oval nuclei
  • Lots of Desmosomes
  • Spine-like cell processes
  • PRICKLE CELLS
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12
Q

Stratum Granulosum

A
  • Flattened cells, flattened nuclei
  • KERATOHYALIN GRANULES
  • Increased lamellar bodies
  • Increased tight junctions
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13
Q

Stratum Lucidum

A
  • KERATONOCYTES have NO NUCLEI
  • Intermediate layer between granulocytes and stratum corneum
  • FORMS A BARRIER TO WATER
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14
Q

Stratum Corneum

A
  • KERATINOCYTES are flattened, NO NUCLEI
  • Contain Keratin filaments cross linked with FILAGGRIN to form a cornfield layer
  • Aids in permeability barrier
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15
Q

Keratinized vs Nonkeratinized

A

Keratinized:

  • Epidermal (outside mouth)
  • Looks more dense and cells look flattened

Non-Keratinized:

  • Oral Mucosal (inside mouth)
  • Looks thick and cells look plump
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16
Q

Permeability Barrier

A
  • MULTI-Layered Lipid outside of the Cornfield Cell Envelope
  • Has a Kertain-Filaggrin Complex under the Loricrin
  • Tight Junctions in stratum granulosum
  • Filaggrin is used to aggregate the Keratin filaments
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17
Q

Epithelium Permeability Barrier

A

1) Stratum Lucidum and Corneum
- Compound cell envelope
2) Stratum Granulosum
- Filaggrin, induces the aggregation of keratins
- Lipids form lamellar bodies
3) Stratum SPinosum
- Keratins 1 and 10 replace
- Keratins 5 and 14 when basal keratinocytes migrate to the stratum spinosum
4) Stratum Basale
- Keratin 5 and 14 are major products of basal keratinocytes

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18
Q

Keratin 5 and 14

A
  • cause of EPIDERMOLYSIS BULLOSA SIMPLEX (EBS)
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19
Q

Keratin 1 and 10

A
  • cause of EPIDERMOLYTIC HYPERKERATOSIS
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20
Q

Keratin 2e

A
  • causes ICHTHYOSIS BULLOSA of SIEMENS
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21
Q

Keratin 9 defect

A
  • EPIDERMOLYTIC PALMOPLANTAR KERATODERMA
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22
Q

Melanocytes (melanin)

A
  • Produce melanin that absorbs the UV rays and attempts to prevent the skin from burning
  • Sunburn occurs when your skin cannot produce melanin quickly enough to prevent UV rays from injuring blood vessels close to the skin’s surface
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23
Q

Melanocytes (description)

A
  • Specialized cells found in the stratum basal
  • Originate as NEURAL CREST CELLS
  • Melanocytes produce melanin (melanosomes) which are transferred to keratinocytes
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24
Q

Melanocytes (mutation)

A
  • MITF (Microphthalemia- associated transcription factor)
    - Regulates the differentiation of melanocytes
    - Lack of MITF= OCULAR ALBINISM TYPE 1
    - Excess of MITF= associated with melanoma
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25
Q

Langerhans Cells

A
  • Dendritic cells derived from bone marrow and located in STRATUM SPINOSUM (invade the skin like macrophages)
  • Clear Cytoplasm, irregularly shaped nucleus, BIRBECK GRANULES contain proteins like lantern that are involved in the uptake and delivery of antigens
  • Involved in immune response
  • Antigen-presenting cells
  • Monitor foreign antigens that contact epidermis
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26
Q

Langerhan Cells (function)

A

1) Phagocytic cells that leave the epidermis
2) Enter the lymphatic system
3) Travel to the Lymph Nodes and interact with T cells
4) Activated T cells then travel back to the epidermis through the blood stream and release pro-inflammatory cytokines to neutralize the antigen

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27
Q

Psoriasis

A
  • Inflammatory skin disorder
  • Initiated by Langerhans cells
  • Excess proliferation of epidermal keratinocytes from stratum basale to stratum corner
  • Increased inflammatory cells from microabcesses
  • Stratum corneum thickens and form plaques
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28
Q

Ezcema or Dermatitis

A
  • Dermatitis (eczema) is inflammation of the skin
  • Characterized by itchy, erythematous, vesicular, weeping, and crusting patches
  • The cause is unclear. One possibility is a dysfunctional interplay between the immune system and skin
  • Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells
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29
Q

Role of Filaggrin

A
  • Loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, has been identified as the cause of the common skin condition ICHTHYOSIS VULGARIS
  • Mutations in Filaggrin carried by 10% of people
  • Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells
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30
Q

Merkel Cells

A
  • Resemble Keratinocytes
  • Develop from neural crest
  • Found in STRATUM BASALE of specialized areas of the body such as fingertips and are associated with the BASAL LAMINA
  • Transporting sensory stimulus from the skin back to the CNS
  • Mechanoreceptors connected to a myelinated nerve fiber in the dermis
  • Irregularly shaped nucleus with granular cytoplasm
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31
Q

Wound Healing

A

1) Formation of a Fibrin-Platelet Clot (Coaggulation)
- Platelets are embedded in a fibrous mesh of fibrin
- Thrombin cleaves fibrinogen to form fibrin
- Platelets release platelet-derived growth factor

2) Leukocyte Recruitment
- Keratinocytes and endothelial cells express CXC and CXC receptor which recruit Neutrophils, Monocytes, and Lymphocytes
- Monocytes become macrophages
- Neutrophils release pro-inflammatory cytokines and activate fribroblasts and keratinocytes

3) Neovascularization and Cellular Proliferation
- New Blood Vessels form and organize granulation tissue
- Repairing the damage

4) Tissue Remodeling
- Keratinocytes from the stratum basal migrate from the edges of the wound
- Hemidesmosomes detach and allow movement (signal from fibroblast)
- Matrix metalloproteinases are produced by fibroblasts
- Epidermal growth factor facilitate re-epitheliazation
- Underlying dermis contracts to bring edges of the wound together
- Fibroblasts infiltrate and produce TYPE III COLLAGEN

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32
Q

Sensory Receptors Associated with Skin

A
  • Exteroceptors (External environment)
  • Proprioceptors (position and movement of body)
  • Interoceptors (internal organs)
  • Mechanoreceptors:
    • Respond to stretch, vibration, mechanical deformation
  • Thermoreceptors
    • Respond to cold or heat
  • Nociceptors
    • Respond to pain
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33
Q

Meissner Corpuscle

A
  • Present in dermal papilla
  • Tactile receptor
  • Shape and Texture!!!!
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34
Q

Merkel Cell

A
  • Nerual cert-derived cell in the BASAL layer of the epidermis
  • Tactile receptor (high resolution)
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35
Q

Free Nerve Endings

A
  • Lack myelin
  • Schwann cells
  • Respond to pain and temperature
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36
Q

Ruffini End Organ

A
  • Responds to stretching
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37
Q

Pacinian Corpuscle

A
  • Sensitive to Pressure and Vibrations!!!
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38
Q

Peritrichial Nerve Ending

A
  • Nerve FIbers wrapped around the base of the hair follicle’ stimulated by hair movement
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39
Q

Hair

A

1) Bulb epidermis stem cell pathway:
- Stem cells migrate upward not the epidermis along the basal lamina
- Keratinocyte stem cells proliferate within the stratum basal and differentiate vertically into the keratin-rich cells of the stratum corner

2) Bulb-sebaceous gland stem cell pathway:
- Clonogenic keratinocytes of the follicular bulb respond to morphogenic signals to generate SEBACEOUS GLANDS

3) Bulb- hair stem cell pathway:
- Cells migrate downward and give rise to a population of cells located at the apex of the dermal papilla. Generate the internal root sheath, cortex, and medulla of hair

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40
Q

Hair formation

A
  • Hair forms in the stratum basal of the epidermis via INTERACTION WITH A HAIR GERM AND A FIBROBLAST from a DERMAL PAPILLA
  • Each shaft of hair is surrounded by a hair follicle which is an ingrowth of epidermis
  • The FOLLICULAR BULB is capable of regenerating hair and sebaceous gland
  • Hair follicles are associated with SEBACEOUS GLANDS and ARRESTOR PILI MUSCLES
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41
Q

Cutaneous Horns

A
  • Made of Keratin

- Benign or Malignant

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42
Q

Sebaceous Glands

A
  • Associated with hair follicles or empty directly onto the skin
  • Produce sebum which is a lipid rich substance that is oily
  • HOLOCRINE SECRETION: lose entire cell and cell disintegrates to release its contents
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43
Q

Eccrine Sweat glands

A
  • Long duct with cuboidal epithelium that empties into a sweat pore
  • Merocrine secretion
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44
Q

Apocrine Sweat glands

A
  • Located in specialized areas and empty into a hair follicle
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45
Q

Microorganisms in hair

A
  • Microorganisms (viruses, bacteria, and fungi) and mites cover the surface of the skin and reside deep in the hair and glands
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46
Q

Nails

A
  • CUTICLE: thick corneal layer of the eponychium extending on the dorsal surface of the nail plate
  • HYPONYCHIUM: represent the union between the nail bed and the nail plate at the fingertip. Its function is render nail bed impermeable. If structure disrupted, fungal invasion produces ONYCHOMYCOSIS
  • NAIL PLATE: consists of interdigitating cells CORNEOCYTES, lacking nuclei or organelles
  • NAIL BED: forms the bed or ventral surface of the nail plate. Formed by flattening of the epidermal cells, nucleur fragmentation. NAIL GROWTH IS ABOUT 0.2 to 1.2 mm PER DAY!
  • NAILS COME FROM THE ECTODERM
47
Q

Which cells are considered to be the sentinel (resident) cell of Innate Immunity?

A
  • Mast cells because they release the cytokines that wake up the tissue macrophages
48
Q

Which mediator causes vasodilation and increased vascular permeability?

A
  • Histamine causes the vasodilation and increased premeability
49
Q

Anatomic and physical barriers

A
  • Effectors: Skin and mucous membranes, temp, acidic pH (5.5), lactic acid, and chemical mediators
  • Function: limit entry, spread, and replication of pathogens
50
Q

Immune Cells

A
  • Effectors: Granulocytes
    • Function: Phagocytosis, release of mediators
  • Effectors: Macrophages:
    • Function: Phagocytosis, release of mediators, AG PRESENTATION
51
Q

Inflammatory Mediators

A
  • Complement = Lysis of pathogen (makes holes in CM)
  • Cytokines = Activation of immune cells
  • Lysozyme = Bacterial wall destruction
  • Acute-phase proteins = Mediation of response
  • Leukotrienes and prostaglandins = Vasodilation and Vascular permeability
52
Q

Skin

A
  • Mechanical: Flow of fluid, perspiration, sloughing off skin
  • Chemical: Sebum (Fatty Acids—> Water resistant, Lactic Acids, Lysozyme)
  • Microbiological: Normal Flora of skin
53
Q

Gastrointestinal Tract

A
  • Mechanical: Flow of fluid, mucus, food, food, and saliva
  • Chemical: Acidity, enzymes (proteases)
  • Microbiological: Normal flora of the gastrointestinal tract
54
Q

Respiratory Tract

A
  • Mechanical: Flow of fluid and mucus by cilia, air flow
  • Chemical: Lysozyme in nasal secretions
  • Microbiological: Normal flora of the respiratory tract
55
Q

Urogenital Tract

A
  • Mechanical: Flow of fluid, urine, mucus, sperm
  • Chemical: Acidity in vaginal secretions, Spermine and zinc in semen
  • Microbiological: Normal flora of the urogenital tract
56
Q

Eyes

A
  • Mechanical: Flow of fluid, tears
  • Chemical: Lysozyme in tears
  • Microbiological: Normal flora of the eyes
57
Q

Key Points of Innate Immune Cells (Functions)

A
  • Innate Immune system provide natural immunity against microorganisms via:
    1) Phagocytosis and intracellular killing
    - Neutrophils are disposable phagocytic solders
    - Macrophages are long lived in tissue and phagocytize2) Recruitment of other inflammatory cells
    3) Presentation of antigens
  • Natural Killers are LYMPHOCYTES in the Innate System
  • LEUKOCYTES: Neutrophils, Monocytes and tissue Macrophages, and Eosinophils
  • FIRST LINE OF IMMUNE DEFENSE
58
Q

Key Points of Innate Immune Cells

A
  • Neutrophils: first cells to arrive. Lead to respiratory bursts and release of granules
  • Macrophages: Enguld organisms and release many inflammatory cytokines
    • Macrophages never leave the battle while Dendritic cells leave to go recruit and activate T cells
  • Eosinophils: Contain cationic granule proteins; fight HELMINTHS and other parasites
  • NK Cells: Large granular lymphocytes that KILL INFECTED HOSTS by PERFORIN
59
Q

Neutrophils and Monocytes

A
  • Arise in bone marrow and circulate in blood
  • Ready to be recruited into tissues sites of infection or injury WITHOUT ACTIVATION
  • Enter tissue through POST-CAPILLARY VENULES except Parenchymal tissue (lungs, kidney, liver) where all blood cells enter through CAPILLARIES
  • Myeloid leukocytes ELIMINATE infectious pathogens, CLEAR dead tissues, and REPAIR the damage
60
Q

How Neutrophils Come to Tissue

A
  • Inflammation activated ENDOTHELIAL CELLS increase expression of E-SELECTIN (ES) and P SELECTIN (PS) adhesion molecules
  • Neutrophils constitutively EXPRESS LIGANDS for ES and PS

Steps:

1) Neutrophils SLOW DOWN AND ROLL along the endothelium
- Rolling action between SELECTIN LIGANDS (leukocyte) and SELECTINS (endothelial cells)

2) TIGHT BINDING- interaction between INTEGRINS (leukocyte) and INTEGRIN LIGANDS (endothelial cells)
3) DIAPEDESIS- TRANSMIGRATION through endothelium
4) CHEMOATTRACT (IL-8) controls MIGRATION of Neutrophils in to Inflammatory sites
- IL-6 is the MOST IMPORTANT for recruitment of Acute Phase Proteins

61
Q

Integrin Activation

A
  • Integrins normally in LOW-AFFINITY state
  • When rolling of leukocytes occurs, cheekiness can BIND CHEMOKINE RECEPTORS on the LEUKOCYTES
  • Chemokine receptros signaling then occurs, which ACTIVATES THE LEUKOCYTE INTEGRINS, increasing their affinity for their ligands on the endothelial cells
  • Ribbon diagrams: show BENT (low affinity) and EXTENDED (high affinity) of leukocyte integrin
62
Q

Transmigration of Leukocytes

A

1) Capture and Rolling: SELECTINS (E-Selectin)
2) Activation fro Rolling to ARREST: CHEMOKINES (IL-8, MCP-1!!!!!)
3) Arrest to Firm Adhesion: ADHESION MOLECULES (VCAM-1, ICAM1)
4) Transmigration

  • MCP-1: Monocyte Chemoattractant Protein
63
Q

MIcrobicidal Mechanisms of Neutrophils

A
  • Defensins: (3.5-4 kDa) are CATIONIC (rich in Arg) antibiotic peptides:
    • Insert into microbial membranes —> destabilize ion channels
    • Effective against all Gram pos, Gram neg bacteria, Fungi, and Enveloped viruses
  • BPI: increases permeability of bacterial membrane
64
Q

Transmigration of Monocytes

A
  • Chemoattractants for monocytes are Macrophage Inflammatory Protein-1alpha (MIP-1 ALPHA and MIP-1 BETA)
  • Transmigration monocytes mature into TISSUE MACROPHAGES
65
Q

Classically vs Alternatively Activates Macrophages

A

1) Classical Macrophage Activation: induced by TLRs and by IFN-gamma
- Classically activated Macrophages are called M1, and involved in DESTROYING MICROBES AND INFLAMMATION
- Chemokines: IL-1, IL-2, IL-23

2) Alternative Macrophage Activation: Induced by IL-4 and IL-13
- Alternatively activated Macrophages are called M2, and important for TISSUE REPAIR AND TO CONTROL INFLAMMATION
- IL-10, TGF-beta: Antiinflammatory
- Proline Polyamines, TGF-beta: Wound Repair

66
Q

PRR- Triggered Responses in Neutrophils and Macrophages

A

1) N-formylmethionul Peptide (fMet) is present in Prokaryotes
2) Phagocytes use it to help distinguish SELF FROM NON-SELF
3) Polymorphonuclear cells can bind proteins starting with fMet, and use them to INITIATE PHAGOCYTOSIS
- TLRs activation leads to Production of CYTOKINES, REACTIVE OXYGEN INTERMEDIATES —> Killing of Microbes
- Mannose Receptor activation leads to PHAGOCYTOSIS of microbe in PHAGOSOME —> Killing of Microbes

67
Q

Lingans and Function of PRRs

A

1) C-type LECTION:
- Receptor: Mannose Receptor
- Microbial Ligand: Terminal Mannose
- Function: Phagocytosis, Macrophage activation

2) Scavenger Receptor
- Receptor: SR-AI, SR-AIII
- Microbial Ligand: Anionic Polymers
- Function: Phagocytosis, Macrophage activation

68
Q

Function of NK cells

A

1) Direct Involvement in Immune Response:
- NK cells RECOGNIZE infected or stressed cells
- Release granules and KILL DYSFUNCTIONAL CELLS
- USE PERFORIN TO KILL CELLS

2) Indirect Involvement:
- NK are activated by IL-12, produced by Macrophages
- NK SECRETE IFN-gamma that activates Macrophages to Phagocytize pathogens

69
Q

How NK Cells Find the Target

A
  • NK cells have NO SPECIFIC RECEPTORS for microbial Antigens
  • Use two surface receptors, ACTIVATING and INHIBITORY RECEPTORS which recognize Ags normally expressed on host cells
  • ACTIVATING RECEPTORS is always “ON”
  • INHIBITORY RECEPTOR (KIR, Killer-cell immunoglobulin-like receptor) is engaged and activated only if there is no change in expression of CLASS I MHC
    • Inhibitory Receptor is “ON” if CELL IS NORMAL (no changes in Class I MHC)
  • In Virus-infected cells, the level of CLASS I MHC is DECREASED that truncates the inhibitory signal and allows activating receptors to dominate the activating NK cells to DESTROY THE TARGET CELL!!!
    • Inhibitory Receptor is DECREASED in cell affected WITH VIRUS
70
Q

Inhibitory Receptor on NK Cells

A

1) Healthy Cell:
- ACTIVATING RECEPTORS of NK cells recognize ligands on target cells and activate PROTEIN TYROSINE KINASE (PTK)
- PTK is INHIBITED by Inhibitory Receptors that recognize Class I MHC molecules and ACTIVATE PROTEIN TYROSINE PHOSPHATASE (PTP)

2) Virus- infected Cell:
- A virus INHIBITS Class I MHC expression on infected cells, the NK cell inhibitory receptor is not engaged
- If the Inhibitory receptor is no engaged, the the PTK stays activated and activates the NK to kill
- The activated NK cell kills target cells
- COULD ALSO HAPPEN IN STRESSED OR AGED CELLS

71
Q

Complement System General Facts

A
  • About 30 proteins in circulation form Complement System
  • Initiated by THREE distinct pathways
  • All pathway lead to PRODUCTION OF C3B
  • C3B initiates ACTIVATION OF C5
  • CASCADE COMPLEMENT activation, culminating in formation of the MEMBRANE ATTACK COMPLEX
    - It created holes in the plasma membranes and KILL PATHOGENS
  • Complement can be activated by TWO IgG (Monomer) or ONE IgM (Pentamer)
72
Q

I. C3 Convertase Formation

A

*** CLASSICAL ACTIVATION is initiated by the binding of IgM or two IgGs on Microbial Surface

1) C1 protein complex binds IgG or IgM deposited on bacteria

2) Once activated, C1 cleaves both C2 and C4
- One activated C1 can cleave many C2 & C4 molecules

3) C4B can attach covalently to MICROBIAL SURFACE
4) C2A binds to the surface ATTACHED C4B and the C3 CONVERTASE is FORMED!!!
5) C3 CONVERTASE cleaves C3 into C3B (formation of C5 Convertase) and C3A (inflammation and chemokines)

73
Q

II. Formation of C5 Convertase

A

1) C3 Convetase cleaves off C3A fragment of C3
2) C3B fragment can be deposited on the surfaace of bacteria
3) Surface-bound C3B serves as an OPSONIN “tag” and INCREASES PHAGOCYTOSIS by phagocytic cells
4) C3B can for a complex with C3 Convertase to give rise to the C5 CONVERTASE (C4B, C2A, &C3B)!!!!!

74
Q

Formation of Membrane Attack Complex (MAC)

A

1) C5 Convertase cleaves C5 into C5B and C5B
2) C5B fragment is responsible for initiating the SELF-ASSEMBLY of the MAC (lytic pathway)
3) C5a ANAPHYLATOXIN is a potent mediator of inflammatory responses
4) The MAC contains C5b, C6, C7, C8, together with many molecules of C9
5) The MAC is responsible for creating the TRANSMEMBRANE CHANNELS that lead to CELL LYSIS

75
Q

Functions of Complement

A

1) Lysis of Foreign cells and bacteria
2) Opsonization and bacterial phagocytosis
3) Chemotactic Anaphylatoxin
4) Solubilization and clearance of Immunocomplexes
5) Enhancement of Immune Responses

76
Q

Acute Phase Proteins

A
  • Part of Systemic acute-phase response
  • Accompany Inflammation
  • Produced by HEPATOCYTES
  • Production is REGULATED BY CYTOKINES (IL-6)
  • Functions: highly variable and diverse

*** C-Reactive proteins- Increase the Inflammation in the body

77
Q

Linking Innate and Adaptive Responses

A
  • Pathogen recognition through PRRs is an important BRIDGE BETWEEN INNATE AND ADAPTIVE IMMUNITY
  • Causes activation and maturation of ANTIGEN PRESENTING CELLS (APC)
  • APC processed Ag is presented to NAIVE T CELLS
  • Secreted CYTOKINES assist development and MATURATION OF T CELLS
  • ** IL-12 drives responses towards intercellular responses, therefore it activates CYTOTOXIC T LYMPHOCYTES
  • If no IL-12, then the activation of the Th cells will occur and will activate B cells
78
Q

Major Concept in Immunology

A
  • Concept of Ag presentation by one immune cell to another
  • Plays central role in ADAPTIVE IMMUNE RESPONSE
  • Cells that present Ag to T cells are called AG-PRESENTING CELLS (APCs)
  • Three cell types can act as PROFESSIONAL APC using CLASS II MHC:
    1) Dendritic Cells: present Ag to NAIVE T CELLS
    - DC bring the Ag into the lymph nodes to increase the likelihood that the T cells will come into contact with the Ag that activates them
    2) Macrophages: present Ag to ACTIVATED (EFFECTOR) T CELLS
    3) B CELLS: present Ag to ACTIVATED (EFFECTOR) T CELLS
  • NON-PROFESSIONAL APC: all other NUCLEATED cells—> use CLASS I MHC
79
Q

Properties of MHC Genes

A
  • Total of 6 Genes encoding HLA are in each denial
    • 3 HLA genes (A,B,C) x 2
      • Mother & father genes = 6
  • HLA genes are high POLYMORPHIC and have CO-DOMINANT expression
  • To match a recipient donor for an organ transplantation, we match the CLASS I MHC! This is because all of the cells are covered with CLASS I MHC and if it is different than the host Class I MHC, then the Immune system will attack the organ
80
Q

Cell Expression of Class I and II MHC

A
  • Only PROFESSIONAL APCs express CLASS II MHC

- All NUCLEATED cells (NON-PROFESSIONAL) express CLASS I MHC

81
Q

Ags Presentation in Adaptive Immunity

A
  • Class I MHC only has alpha chains (alpha1,2,3) and a Beta2- microglobulin
  • Expressed by NON-PROFESSIONAL APCs!!!
  • Class II MHC has an alpha chain and a beta chain (alpha 1,2 & beta 1,2)
  • Antibodies are distinguished by their HEAVY CHAINS
82
Q

Class I MHC

A
  • They have a small grove for protein fragments (peptides)
  • Peptides presented in Class I MHC are 8 to 11 AA long
  • Humans have 3 genes encoding Class I MHC
    • HLA-A
    • HLA-B
    • HLA-C
  • Polymorphic proteins have the same shape but their sequence DIFFER BY ONE OR FEW AA
  • There are:
    • Greater than 200 allotypes of HLA-A
    • Greater than 400 allotypes of HLA-B
  • Each Class I HLA binds another protein Beta2-MICROGLOBULIN
    • The Beta2 Microglobulin IS THE SAME!
83
Q

Class I MHC Presents Ag to CD8+ T Cells

A
  • Presents ENDOGENOUSLY processed peptides ONLY for CD8+ T CELLS
  • Peptide Ags (8-9AA) NON-COVALENTLY interact with both:
    1) Class I MHC via alpha 1 and alpha 2 domains
    2) The TCR via CDRs (Complementary Determining Regions)
  • CD8 stabilizes INTERACTION of TCR WITH CLASS I MHC
  • CD8 IS A SPECIFIC MARKER FOR CYTOLYTIC T LYMPHOCYTES (CTLs)
84
Q

Ag Presentation by Class I MHC

A
  • Class I MHC display on surface protein fragments (peptides) MANUFACTURED BY THE CELLS
  • ENDOGENOUS PROTEINS (inside)
  • These proteins are encoded by VIRUSES and INTRACELLULAR PATHOGENS which infected the cell
  • Class I MHC SAMPLE ALL PROTEINS being made IN THE CELL
  • Cytotoxic T Lymphocytes CONSTANTLY INSPECT the protein fragments within Class I MHC on each cell in body
  • CTLs determine whether the cell was INFECTED by a PATHOGEN
85
Q

Ag Presentation for Class I MHC (protein turnover)

A

1) Old proteins are chopped in proteasome in the cytoplasm
2) Peptides generated are carried out into ENDOPLASMIC RETICULUM by transporter protein TAP1 and TAP2!!!!!!!
3) These peptides become loaded into the groove of Class I MHC

86
Q

Class II MHC

A
  • Expressed by PROFESSIONAL APCs!!!
  • HIGHLY POLYMORPHIC (many versions)
  • Present Ag to CD4+ T Helper cells
  • Peptides that bind to Class II MHC are 13-25 AA
87
Q

Structure of Class II MHC

A
  • PROCESSED Peptide interact with alpha 1 and beta 1 domains on the Class I MHC
  • Allows presentation to CD4+ T Helper Cells
  • Interactions with the TCR are stabilized by CD4!
  • CD4 is a specific marker for T HELPER CELLS!!!
88
Q

Antigens for Class II MHC

A
  • Alarm cell about dangers OUTSIDE CELL
  • Taken up by PROFESSIONAL APCs:
    1) Phagocytosis (Macrophages)
    2) Receptor-Mediated Endocytosis
    3) Pinocytosis
  • Class II MHC is made up of TWO CHAINS, alpha and beta
  • MHC LOADED with Ags in ENDOSOMES!!!
  • NO EMPTY MHC molecules are displayed on the surface of APCs
89
Q

The Invariant Chain

A

1) When Class II MHC is synthesized in endoplasmic reticulum, it binds the 3rd protein called the INVARIANT CHAIN (never expressed on cell surface)
- Invariant chain sits IN TEH GROOVE of MHC Class II

2) The Invariant chain PREVENTS MHC class II to bind its own cell protein in ER but instead bind protein from outside of the cell
3) In the Invariant chain, a part called CLIP is REMOVED BY another protein termed HLA-DM!!!!
4) MHC is LOADED with Ags IN ENDOSOME

90
Q

Mechanism of Cross-Presentation

A

Rules:

1) MHC Class I present peptides from protein SYNTHESIZED WITHIN CELL
2) MHC Class II present EXOGENOUS PROTEINS

Exceptions:

1) PROFESSIONAL APCs have specialized capacity to process EXOGENOUS Ag into the MHC CLASS I PATHWAY!!!!
- This is know as CROSS-PRESENTATION, and provides the Immune System with an important mechanism for generating immunity to INTRACELLULAR PATHOGENS like VIRUSES!!!

91
Q

Steps in Cross Presentation

A

1) Endocytosed Antigens form endosome
2) Cytosolic diversion of endocytose Antigen (Ag leaks) to the CD8 pathway instead of the normal CD4!!!
3) Cytosolic Antigens put into a Proteasome to be degraded
4) Degraded Ag peptides are then expressed on CD8 MHC Class I and exported to the surface of the plasma membrane
- THESE VIRUSES WERE PICKED UP BY APCs (macrophages and dendritic cells) AND INSTEAD OF BEING EXPRESSED ON CD4 (supposed to) THEY ARE EXPRESSED ON CD8 BECAUSE ONLY Tc LYMPHOCYTES CAN KILL VIRUSES!!!!!

92
Q

Activation of T and B Lymphocytes

A

B cells:

  • No Need for APC for activation
  • Ags recognized by B cells can be in SOLUBLE or CELL-SURFACE ASSOCIATED form
  • Activated B cell is transformed into a PLASMA CELL that secretes ABS!!
  • Plasma cells are primarily FOUND IN LYMPHOID ORGANS (not PLASMA!!!!)

T cells:

  • T cells are MHC-Restricted
  • T CELL is activated when TCR recognizes AG PRESENTED WITHIN MHC BY APC
  • T cells recognize PEPTIDE FRAGMENTS of Ags presented by APC
93
Q

B cell Receptor (BCR)

A
  • DOESNT REQUIRE APC!!!!!
  • BCR is composed of VARIABLE and CONSTANT regions
  • Has 2 LIGHT and 2 HEAVY chains
  • Surface Ig can be 2 classes:
    1) IgM
    2) IgD
  • Ig alpha and Ig beta are associated with BCR
    - Together they make up BCR COMPLEX
  • Can recognize any Ag (LIPIDS, CARBOHYDRATES, PROTEINS, and DNA)

** IGD is the major Ag receptor ISOTYPE coexpressed with IgM on the surface of most peripheral B cells in human!!!

94
Q

T Cell Receptor (TCR)

A
  • REQUIRES AG PRESENTATION BY APC
  • Most T cells have TCR composed of alpha and beta chains
  • Both chains have VARIABLE and CONSTANT REGIONS!
  • The chains are DISULPHIDE LINKED!
  • Associated with 3 different domains:
    1) Epsilon + Delta
    2) Gamma + Epsilon
    3) Zeta + Zeta
  • Together it forms the TCR COMPLEX
  • CD3 is and identification MARKER of ALL T CELLS!!!!!
95
Q

Antigen Presenting Cells

A
  • Recognition of AG PRESENTED WITHIN MHC is prerequisite for activation of T cells
    • But… this is not enough
  • T cells have to receive the second signal so called COSTIMULATION provided by APCs!!!
  • PROFESSIONAL APCs are special cells which can express HIGH LEVEL OF BOTH MHC
    - RESTING APC that expresses Class II MHC but not co-stimulatory molecules CANNOT ACTIVATE T cells
    - ACTIVATED APC expresses HIGH levels of MHC and co-stimulatory molecules
96
Q

Non-traditional Gamma/ Delta T cells

A
  • Many do not express CD4 or CD8!!!! (CD4-, CD8-)
  • Gamma/delta T cells are relatively few in number. Represent a small fraction (1-5%) of the overall T cell population
  • Gamma/delta cells are a major T cell population in EPITHELIAL TISSUES (greater than 50% of T cells)
  • T CELL REPETOIRE IS LIMITED!!!
  • These T cells are DIRECTLY ACTIVATED by pathogen-associated molecules patterns
  • Are believed to have prominent role in RECOGNITION OF LIPID ANTIGENS!!!!!
  • NO MEMORY CELLS!!!!!
97
Q

Activation of T and B Lymphocytes

A

B Cells:

  • NO need for APC for ACTIVATION
  • AGS recognized can be in SOLUBLE or CELL SURFACE-ASSOCIATED FORM
  • B cells transform into PLASMA CELLS that secretes ABS
  • Plamsa cells primarily FOUND IN LYMPHOID ORGANS (not in plasma)

T Cells:

  • MHC- RESTRICTED
  • T CELL activated when TCR recognizes AG PRESENTED WITHIN MHC BY APC
  • T cells recognize PEPTIDE FRAGMENTS OF AGS presented by APC
98
Q

Lymphocyte Ag Receptors

A
  • BRC (Ig molecule) and TCR are STRUCTURALLY SIMILAR

In BCR:

  • NH-TERMINUS of H and L chains (VH and VL) are HIGHLY VARIABLE
  • Ig-alpha and Ig-beta make up the signaling molecules for the BCR

In TCR:

  • NH-TERMINUS of V-alpha and V-beta are HIGHLY VARIABLE
  • CD3 (epsilon + delta, gamma + epsilon) make up the extracellular portion of the Signaling molecules while the Zeta + Zeta makes up the intracellular portion
  • Limited variability of CONSTANT (C) REGION
  • In a single B cell or T cell, BCR and TCR are identical
99
Q

BCR Function and Property

A

Antigen:

  • MACROMOLECULES (lipids, carbs, proteins)
  • Conformation and linear epitopes (primary structure)

Diversity:

  • Unique Specificity
  • Greater than 10^9 clones

Signaling:
- Ig alpha and Ig beta subunits

Effector Functions:
- Fc region of Ab

100
Q

TCR Function and Property

A

Antigen:

  • Peptides presented by APC
  • ONLY LINEAR (short sequence of AA) and only in Primary Structure

Diversity:

  • Unique specificity
  • Greater than 10^11 clones

Signaling:
- CD3 and ZETA Subunits

Effector Function:
-No effector functions

101
Q

TCR

A
  • Most T cels have TCR composed of ALPHA and BETA CHAINS
  • Both chains have VARIABLE AND CONSTANT REGIONS
  • The chains are DISULPHIDE-LINKED
  • Associated with 3 INVARIANT DOMAINS (Epsilon & Delta, Epsilon & Gamma, and Zeta & Zeta)
    - Together form TCR COMPLEX
  • CD3 is an identification MARKER for ALL T CELLS
102
Q

Antigen- Presenting Cells

A
  • Recognition of AG PRESENTED WITHIN MHC is prerequisite for ACTIVATION OF T CELLS!
    - Also, need second signal from APC called COSTIMULATION!!!!!
  • PROFESSIONAL APCs are special cells which can express HIGH LEVEL OF BOTH MHC and CO-STIMULATORY MOLECULES:
    • RESTING APC: express Class II MHC but not co-stimulatory molecules, cannot activate T cells
    • ACTIVATED APC: expresses HIGH level of MHC and co-stimulatory molecules
103
Q

Co- Stimulatory Molecules

A

***** AG SHOULD BE ACTIVATED BY RECOGNITION OF AGS FIRST!!!!!!!

  • RESTING APC express LOW level of co-stimulatory molecules that is below the threshold needed for activation
  • ACTIVATED APCs express high level of Class II MHC and co-stimulatory molecules:
    - B7-1 and B7-2 or by CD classification CD80 and CD86!!!!!!!!!
  • Costimulation involved a protein B7 on APC and a protein CD28 on T CELLS!!!
B7 = APC
CD28 = T Cells
  • Cytokines drastically increase activation of T cells!!!
104
Q

Activation of CD4+ T Cells Requires APC and Co-Stimulation

A

1) Co-stimulatory signal and Specific Signal = ACTIVATED T CELL
2) Specific signal ONLY = T CELL IS ANERGIC
3) Co-stimulatory signal ALONE = NO EFFECT ON T CELL
- Anergy: Lack of REACTION

105
Q

Multiple Functions of TCR

A
  • TCR can signal to T Cells to INITIATE MULTIPLE PROGRAMS that result in different outcomes:
    1) ACTIVATION of T cells
    2) APOPTOSIS (in thymus during “education”)
    3) ANERGY (in absence of co-stimulation)
  • COSTIMULATION CONTROLS THE FATE!!!
106
Q

Immunological Synapse

A
  • The binding between a TCR and MHC-peptide COMPLEX IS WEAK
  • The engagement of its TCR up regulates the EXPRESSION OF ADHESION MOLECULES on the T CELL
    * *******CHEMOKINE DEPENDENT!!!!!!!
  • It hold APC AND T CELL TOGETHER
  • The clustering of TCRRs and Adhesion molecules at the point of APC-T cell contact is called “IMMUNOLOGICAL SYNAPSE”

1) Weak adhesion —> NO T CELL RESPONSE
2) Singals delivered by Chemokines and Antigen RECOGNITION act on INTEGRINS
* ** INTEGRIN ACTIVATION
3) CLustering and increase in affinity of Integrins —> STRONG T CELL-APC Adhesion —-> T CELL RESPONSE
* ** T CELL-APC ADHESION

107
Q

The Immunological Synapse

A
  • Close contact between T Cell and APC —> IMMUNOLOGICAL SYNAPSE
  • A number of molecular pairs are participated:
    1) TCR/ MHC- peptide PAIR
    2) Co-stimulatory pair B7/ CD28
    3) Adhesion pair LFA-1/ ICAM-1!!!!!!!!!!
  • The immunological synapse ensure that effector molecules (cytokines) released by the cells are not affecting bystander cells

“LFA-1”: Lymphocyte Function-Associated Antigen-1
“ICAM-1”: Intercellular Adhesion Molecule

108
Q

T Cell Accessory Molecules

A

1) CD3: Signal Transduction in TCR Complex
2) Zeta: Signal Transduction in TCR Complex
3) CD4 (Th cell) —-Binds—–> Class II MHC(APC)
4) CD8 (Tc cell) —- Binds—-> Class I MHC (APC)
5) CD28 (T cell) —- Binds—> B7-1/B7-2 (APC)
6) CTLA-4 (ANALOG OF CD28) — Binds—> B7-1/ B7-2 (APC)
7) LFA-1 (T cell) —– Binds—-> ICAM-1 (APC in Endothelium)

109
Q

Non- Traditional Gamma/ Delta T Cells

A
  • Many do not express CD4 or CD8!!!! (CD4-, CD8-)
  • Gamma/delta T cells are relatively few in number. Represent a small fraction (1-5%) of the overall T cell population
  • Gamma/delta cells are a major T cell population in EPITHELIAL TISSUES (greater than 50% of T cells)
  • T CELL REPETOIRE IS LIMITED!!!
  • These T cells are DIRECTLY ACTIVATED by pathogen-associated molecules patterns
  • Are believed to have prominent role in RECOGNITION OF LIPID ANTIGENS!!!!!
  • NO MEMORY CELLS!!!!!

** Work by INNATE IMMUNITY ON THE EPITHELIAL CELLS!!!!!!

110
Q

B Lymphocytes

A
  • B cells become Ab-secreting PLASMA CELLS
  • ** Plasma cells are most found in LYMPHOID ORGANS (NOT IN PLASMA!!!!!!!!!!!!!!!!!!!!!!)
  • B cells act as PROFESSIONAL AG-PRESENTING CELLS to T cells
  • Can develop into MEMORY B Cells
  • CD19, CORECEPTOR for BCR, is a SPECIFIC MARKER OF B CELL!!!!!!!!!!!
111
Q

B Cell Receptor

A
  • DOESNT REQUIRE APC!!!!
  • Has 2 LIGHT and 2 HEAVY CHAINS
  • SURFACE IG can be of 2 CLASSES:!!!!!!!!!!!!!!!!!
    1) IgM
    2) IgD
  • IgALPHA and IgBETA are associated with BCR
  • Can recognize any Ag (Lipids, Carbohydrates, Proteins, DNA)
  • IgD is the major (50%) receptor isotope COEXPRESSED with IgM (50%) on the surface of most peripheral NAIVE B CELLS in humans!
112
Q

B Cell Activation

A

Two Possible Mechanisms:

1) PROTEIN AGS acivate B cells WITH ASSISTANCE OF T HELPER CELLS—-> THYMUS DEPENDENT or TD Ags
2) Ags of other chemical nature, i.e. Lipids, Carbs, Polynucleotides, ACTIVATE B CELLS WITHOUT HELP OF T CELLS —–> THYMUS INDEPENDENT or TI Ags

113
Q

B Cell Activation by Protein TD Ags

A

1) Antigen binding to B-cell receptor delivers the first signal to the B cell
2) Helper Th2 cell delivers the second signal vid CD40 Ligand and Cytokines!!! (CROSS LINKING)
3) B cell proliferates and differentiates into Plasma Cells
- Macrophages and T helpers cells can present the Ag to the B cells
- REMEMBER: CD40 and CD40L provides CO-STIMULATORY signal to complete B cell transformation INTO PLASMA CELL

114
Q

B Cell Activation by TI Ags

A
  • Multiple BCRs bind to a REPETITIVE EPITOPE ON BACTERIUM
    - Ex: LipoPOLYsaccharides have many repeating subunits denoted by the “POLY”!!!!!!!!!
  • This causes CROSS-LINKING for BCR and generates a SINGAL
  • This signal is transduced by IgALPHA and IgBETA!!!!!
  • IgAlpha and IgBeta catalyze phosphorylation of SIGNALING MOLECULES
  • Such Ags are called T-INDEPENDENT Ags

*** MULTIPLE B CELL RECEPTORS can bind to these units if they find their antigen!!!!!!!!!!!!

Immunology (6 decks)

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