Lecture 6: Inflamation and Innate Immunity Flashcards

1
Q

Goal of the Immune System

A

Recognition of the Pathogen

Respond to the Pathogen and remove it

Remember the Pathogen

Defense is achieved by the concerted actions of the innate and adaptive immunity

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2
Q

Innate Immune System

A

Provides physical and chemical barriers (tight junctions, paneth cells and keratinocites)

Non Clonnaly derived cells

Immediate, early response

Does not require prior exposure to pathogens

Germ line encoded receptors

Recognition of PAMPs

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3
Q

Adaptive Immune System

A

Clonally derriced effector cells that are specific to a particular antigen

Requires time

Requires prior exposure to the pathogen - memory

Receptors arise from gene rearrangment and somatic mutation

Recognition of processed papthogen derived peptides (foriegn peptide in the context of a MHC receptor)

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4
Q

Surface and Chemical Barriers

A

First Line of Defense

Mechanical - Tight junctions, air or fluid flow, and movemnt of mucus by cilia and flagella

Chemical - Secrtuin if defensins, low pH conditions, and other enzymes that make the environment inhospitable to foreign particles

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5
Q

Leukocytes

A

Second line of deffense

Neutrophils

Macrophages

Mast Cells

Eosinophils

Basophils

NK Cells

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6
Q

Phagocytes of the Innate Immune System

A

Neutrophils

  • Arise from a common myeloid progenitor from the bone marrow
  • Most abundant leukocyte in circulation
  • Short lived, forming nets after a respiratory burst
  • Rarely founf in healthy tissue
  • Kill pathogens through ohagocytosis the the release of enzymes, defensins, and NADPH oxidase release
  • If a patient in deficent in neutrophils, the neutrophils can be simulated with injections of GCSF and GMCSF

Macrophages

  • Mature form of monocytes
  • Found in resident tissues everywhere
  • Long lived
  • Highly efficent at phagocytosis and inflamatory cytokine production (TLR>MyD88>NFkB>IL1)
  • Facilitate adaptive immunity through antigen presentation (MHC 2) and Co stimulatory molecule expression
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7
Q

Innate Lymphocytes

A

Natural Killer Cells

Arrise from a common lymphoid progenitor in the bone marrow

Can kill virally infected cells and tumor cells

Use inhibitory/ activating receptors to decide whether or not to kill - A healthy cell presentsan aposing signal that sends a inhibitory signal to the NK cell, preventing the NK cell from killing the healthy cell

Virally infected cells downregulate MHC clas 1 receptors, which is recognized as missing self receptors by NK cells and the NK cell kills the infected cell

Abundant in tonsils

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8
Q

ADCC

Antibody Dependent Cell Mediated Cytotoxicity

A

Neutrophils, eosinophils, NK cells, and macrophages have Fc Receptors

If an FC receptor binds an antibody that is bound to an antigen the cells will release cytotoxic granules to kill the target cell

NK Cells are the most efficent ADCC

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9
Q

Inflamation

A

The local accumulation of fluid, plasma, and leukocytes initiated by physical injury, infection, or local immune response

Fundementally protective, intendend to create a hostile environment for the pathogen and destroy the patogen

Initiator of tissue repair

Destructive if prolonged

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10
Q

Cells Involved in Inflamation

A

Endothelial Cells

Cells lining blood vessels become activated during inflamation and release mediators and modify surface receptors to signal for other cells to come into the area

Platlets

Circulating anuclear cells that attach at the site of tissue injury. Activation causes degranulation and release of pro inflammatory and clotting mediators

Also involves mast cells which release histamine and tissue macrophages

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11
Q

Major Events in Inflamation

A

Alteration in blood flow

Increased vascular permeability - allowing the wbc to get out of the blood vessles and into the tissue

Activation and infiltration of leukocytes

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12
Q

Alteration in Blood Flow

A

In a cappillary bed of inflamed organ there is an opening of increased blood flow and periability of the endothelial cells lining the inflamed organ

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13
Q

Increased Vascular Permeability

A

Occurs from direct trauma to the endothelium or contraction of the endothelium

Increased vascular permiability allows for leakage of antibodies, leakage of compliment, and migration of pphagocytes to the inflamed area

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14
Q

Activation and Infiltration of leukocytes

A

Begins in minutes, lasts for days

Infiltration order

  1. Neutrophils
  2. Monocytes that become macrophages
  3. If necessary adaptive immunune cells are recruited and lymphocytes (T cells, B Cells, and NK Cells) arrive

Requires activation of the endothelium, allowing cells to recognize the location of the probelm

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15
Q

Cytokines produced at the sites of inflamation by leukocytes that promote the inflammatory response

A

IL1

TNFa

IL6

IL8

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16
Q

IL1

A

Activates vascular endothelium

Activates lymphocytes

Local tissue destruction increasess access of effector cells

IL1 can travell to the hypothalamus to increase body teperature

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17
Q

TNFa

A

Activates vascular endothelium and increases vascular permiablility

Increased entry of IgG complement, and cells to tissues and increased fluid drainage to lymph nodes

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18
Q

IL6

A

Lymphocyte activation and increased antibody production

19
Q

IL8

A

Acts as a chemokine that brings in other cells (neutrophils, basophilsm and t cells) to the site of infection

Will be on the endothelium of inflamed tissue

20
Q

Halmarks of inflamation

A
  1. Calor - heat
  2. Dalor - pain due to the compression of perihrial nerves from swelling
  3. Rubor - redness due to increased blood flow
  4. Tumor - swelling
21
Q

3 Main Steps in Phagocytosis

A
  1. Particle/Pathogen Recognition
  2. Internalization
  3. Killing
22
Q

Particle/Pathogen Recognition

A

Several different types of receptors allow for recognition

PAMPS activate TLRs

MAnnose Receptor

Glucan Receptor

Fc Receptor

Coating a particle with antibody or complement enhances binding

23
Q

Internalization and Killing

A

Phagocytosis

  1. Pathogen attaches to the membrane
  2. Membrane forms a phagazome and the particle is engulfed
  3. The phagazome fuses with lysosomes and lysosomal enzymes digest the captured material - NADPH oxidase causes the release of these molecules resulting in a respiratory burst
  4. Digested products are presented on the cell surface in the context of a MHC class 2 receptor or extruded from the cell
24
Q

Binding of bacterial product to macrophages activates cytokine and chemokine gene expression

A

LPS binds to a receptor on a phagocytic cell

The complex recruits TLR4, which coalleces with the LPS activated recepter

The activated TLR4 releases Myd88 which stimulates NFkB translocation into the nucleus where a cytokine response is transcribed and translated

*in this case IL1 is activated (activation also occurs through the inflamasome)

25
Q

Macrophage Derived Cytokines

A

IL1

TNFa

IL6

IL8 (CXCL8)

IL12

26
Q

Macrophage Derived IL1

A

Activation of vascular endothelium

Activates lymphocytes

Local tissue destruction increases the access of effector cells

Results in Fever and the production of IL6

27
Q

Macrophage Derived TNFa

A

Activates vascular endothelium and increases vascular periability which leads to incread entry of IG complement and cell to tissues and increased fluid drainage to lymph nodes

Can cause fever and high levels can result in systematic shock

28
Q

Macrophage Derived IL6

A

Lymphocyte activation increased antibody production

Results in fecer and induces acute phase protein production

29
Q

Macrophage Derived IL8

A

Chemokine that recruits neutraphils, basophils, and some T cells to the site of infection

Helps neutrophils pas through the endothelial barrier in concert with other proteins

30
Q

Macrophage Derived IL12

A

Activates NK cells and induces the maturation of CD4 cells to Th1 cells

31
Q

BCL - CXCL13

A

Produced by stromal cells

Imortant for directing B cells to the follicle of lymph nodes

32
Q

Movement of Neutrophils through the endothelial cell layer

A
  1. S-LeX on the surface of neutrophils will recognize E selectin on the endothelial cell surface
  2. Receptors for IL8 on the neutrophil bind to IL8 on the endothelial surface - the endothelial surface is inflamed
  3. LFA-1 on the surface of neutrophils binds to ICAM-1 on the endothelial cells allowing for diapedisis of the neutrophil into the tissue
33
Q

How is the movement of neutrophils from the blood into the tissue diffrent from T cell and B cell entry into tissue?

A
34
Q

Chronic Inflamation

A

Chronic inflamation can lead to autoimmunity, persistant infection, granuloma formation, fibrosis, and tissue destruction

35
Q

Hashimoto Disease

A

A disease in which an individual recognizes the thymus as foreing and eventually destroys the thymus.

The individual mus be suplimented with thyroid hormones for T cell development/education and activation of B cells

Areas that look like lymph nodes will form in tissues the individual is immune to.

36
Q

Complement

A

A system of 30 plasma and membrane proteins that react with one another to coat pathogens and induce a series of inflamitory responses that help fight infection

When activated by Ag/Ab complexes or bacteria, these components interact in a highly regulated fashion to generate products that can help clear pathogens or promote certain aspects of the inflamitory response

37
Q

Complement Activation

A

Activation occurs on a surface such as a bacteria or antibody coated particle

Spontaneously activated complement components can also bind to pathogen surfaces

3 Pathways

  1. Classical complement activation pathway
  2. Alternative Complement Pathway
  3. MB Lectin Pathway

All three pathways generate a protease called

C3 convertase

38
Q

Classical Complement Pathway

A

Antibody/Antigen complexes activate C1, C2, and C4
to activate C3 Convertase

39
Q

MB-Lectin Complement Pathway

A

Manose binding lectin binds the manose on pathogen surfaces activating MBL, MASP, C2, and C4

This activates C3 convertase

40
Q

Alternative Complement Pathway

A

Pathogen surfaces activate C3, B, and D to activate C3 convertase

41
Q

Activation of C3 Convertase

A

Cleavage of C3 convertase results in 3 actions

  1. C3a, C5a - peptide mediators of inflamation, phagocytic recruitment
  2. C3b - binds to complement receptors on pathogens and opsonized the oathogenm recruiting inflamatory cells, and removal of immumne complexes
  3. C5, C6, C7, C8, C9 - forms a membrane attack comlex (pore formation), and cell lysis ocurs
42
Q

Consequences of Complement Activation

A

Lysis

Opsonization

Activation of Inflamatory Response

Clearance of Immune Complexes

Removal of Pathogens from the blood and into tissue

43
Q

Regulation of the complement system

A

Controlled by:

Decay Receptors

Regulatory Factors - inhibit initiation of enzymatic cleavage, enzymes within the cascade, and MAC formation

44
Q

Inflamatory Response Overview

A