Immune System Part 1 Flashcards
(91 cards)
1
Q
Categories of Immunity
(2)
A
Innate
Only recognizes self vs. non-self and requires no previous experience to pathogen to fight it (with same intensity and speed regardless of # of encounters)
Adaptive (Acquired Immunity)
Part that learns, responds to pathogens more intensely and efficiently with more exposure “acquired immunity”
2
Q
Overview of Immune System
- Cells of the Immune System (3)
- Organization of the Immune System (2)
- Molecular Communication in the Immune System
A
- WBC (leukocytes), Cytokines that allow for communication between immune cells, Surface markers
- The Lymphoid System, The Reticulo-endothelial System (RES) - where are cells located, activated, and where they travel
3
Q
Innate Immunity Components
(3)
A
- The Front line of Host Defense
-
Second Line of Defense: The Inflammatory Response
- Acute Inflammation: Events and Mediators
- Induced (Systemic) Innate responses to infection
- Tissue Repair and Chronic Inflammation
4
Q
Components of Innate and Adaptive Immunity
- A______
- Innate Immunity (4)
- Adaptive Immunity (2)
A
- Antigen
-
Innate
- Structural/Chemical Barriers
- Phagocytic/Scavenger Cells
- Inflammation
- Plasma Protein Systems (ie Complement System)
-
Adaptive
- B Lymphocytes (Antibody mediated immunity)
- T Lymphocytes (Cell-mediated immunity)
5
Q
Innate and Adaptive Immunity (Notes)
-
Pathogens
- _______ (pink dot) = occupies ______ space
- _______ (black line) = genetic material in the form of DNA or RNA is _____ space/parasites that can’t replicate on their own, needs a host to make copies of itself
- P______ worms, Pro_____, F_____
- Prion =
-
Antigens =
- HLA’s =
A
- Pathogens
- Bacteria = extracellular
- Virus = intracellular
- Parasitic, Protozoa, Fungus
- Proteins that can replicate themselves by interacting wtih other proteins by causing that protein to mimic its shape
- Surface identity markers - that allows you to identify a specific pathogen (self. vs. non self)
- Protein that is most dissimilar from person to person
6
Q
Innate and Adaptive Immunity (Notes)
-
Innate Immunity =
- Chemical Barriers =
- Scavenger Cells =
- Inflammation =
- Plasma Proteins =
-
Adaptive Immunity =
- B Lymphocytes =
- T Lymphocytes =
- Effector Cells =
- What is the relationship between Innate and Adaptive Immunity
A
- Fights pathogens with same efficacy and speed no matter how many encounters, needs no previous experience
- Skin, mucous membranes, our microbiome
- Neutrophils, Macrophages, etc.
- “Big hammer” powerful but causes some tissue damage
- Comprises the Complement System “Probably the most important” can destroy pathogens whether we’ve had previous experience with them (also used by adaptive immunity)
- learns and gets better at fighting pathogens with every subsequent encounter
- Antibody mediated immunity
- Fights pathogens that occupy intracellular space
- Recognizes infected or abnormal host cells and target them for removal
Interconnection of the two - innate has to trigger adaptive immune responses and adaptive can use components of the innate system to target particular pathogens with specificity (Innate = weapons, Adaptive = soldiers who use those weapons)
7
Q
Cells of the Immune System
Cells of the Immune System are pretty much what blood cell? Also known as?
-
Pluripotent Hematopoietic Stem Cell =
- Lymphoid Progenitor Cells (3)
- Myeloid Progenitor Cells (3) - (5)
- One cell that is produced by both lymphoid and progenitor cells?
A
WBC (Leukocytes)
- Origin cell found in red bone marrow found in trabecular long bones (hip bones) (long bones of arms and legs are actually yellow bone marrow composed mostly of fat) that gives rise to both lymphoid progenenitor and myeloid progenitor cells
- B cell, T cells, NK cells
- RBC, Platelets, Granulocytes (Neutrophils, Eosinophils, Basophils, Mast cells, Monocytes)
- Dendritic Cells
8
Q
Cells of the Immune System
- Hematopoietic stem cells go through Differentiation process -> ______ cell -> _______ differentiated cell (most _______ mature, but loses ability to _____)
- Function of B cells?
- Function of T cells?
- Function of NK Lymphocyte?
- Function of Dendritic Cells? How?
A
- secondary, terminally, functionally, replicate
- Part of adaptive immune system, B cells more for bacterial infections
- Part of adaptive immune system, T cells more for viral infections
- Part of our innate immune system ->like T cells v important in fighting intracellular (viral) infections but does so NONspecifically bc no specificity in innate system
- Phagocytic cell produced by both lymphoid and myeloid progenitor cells -> primary job is initiating adaptive immune responses
- Found in connective tissue throughout the body and do this thing called extracellular drinking (takes sips of ECF frequently) - and if they happen to trap a pathogen they go find cells necessary to trigger adaptive immune response
9
Q
Myeloid Cells
(6)
-
(2) are the primary phagocytic cells that engulf pathogens and destory them in intracellular vesicles, a function they perform in both innate and adaptive immune responses
- (1) can also present antigens to T cells and activate them
- (1) are phagocytic when they are ______ and can take up pathogens, after maturing they act as ___-_____ cells to __ cells initiating adaptive immune responses
- Function of other myeloid cells =
- Eosinophils =
- Basophils =
- Mast cells =
A
Macrophage
Dendritic Cell
Neutrophil
Eosinophil
Basophil
Mast Cell
-
Neutrophils, Macrophages
- Macrophages
- Dendritic Cells (immature), Antigen presenting to T cells (mature)
- Primarily secretory and release contents of their prominent granules upon activation via antibody during adaptive immune response
- Involved in attacking large antibody-coated parasites (WORMS)
- Function is less clear
- Trigger local inflammatory response by releasing substances that act on local blood vessels
10
Q
The Granulocytes
(6)
These cells are all _____
A
Neutrophils
Eosinophils
Basophils
Mast Cells
Monocytes -> Macrophages
Inducible: bone marrow can be induced to make more when needed for ongoing infection
Named dt large Granules
11
Q
Neutrophils
=
(3) Mechanisms
A
One of three scavenger cells - first cells to migrate to area of inflammation or infection, found in circultion “riot police that break into house”
- Release Reactive Oxygen species
- Release Lysosomal enzymes
- Phagocytize Bacteria
They cause a huge mess then eat up that mess and die
12
Q
Macrophages
=
- Circulating Macrophages
- Tissue Macrophages
A
2nd group of 3 phagocytic SCAVENGER cells that migrate to area and are much more smart and precise, clean up mess and eat dead neutrophils, and if they ingest a pathogen will go and trigger adaptive immune response
- AKA monocytes
- Scattered throughout the body and live in connective tissue, epithelial barriers, mucous membranes (where pathogens enter/infection)
- starts off at monocytes -> no active infection -> left bone marrow -> migrates to tissue -> turned into macrophages and stayed dormant “guards at the door” some stay dormant for decades ie liver tissue macrophages
13
Q
Basophils
=
A
Filled with histamine and pro-inflammatory mediators
Identical in function to mast cells - only diff is mast cells live in tissue
14
Q
Eosinophils
=
2 conditions
A
Rise under 2 major conditions, granules filled with chemical mediators that degrades the plasma membrane of whatever its trying to kill
- Parasitic worm infection
- Allergic Response
15
Q
Mast Cells
=
A
Mast cells are also filled with histamine and inflammatory mediators -> located in tissue but always close to circulation
16
Q
Monocytes
=
A
Immune cells produced by bone marrow that when activated turns into macrophages
17
Q
Dendritic Cells
=
A
3rd Phagocytic Scavenger Cell
“like the spy” bc doesn’t have any actions that attack pathogens, it just sits in tissues and constantly takes samples of ECF to trap foreign antigens -> if it traps then will travel towards adaptive immune system
18
Q
Overview of Inflammatory Response (Notes)
- 1st wave of cells =
- 2nd wave of cells =
- Both neutrophils and macrophages release (2) but also
- Eat up dead _____, cellular ____, and _____ that might be there
- Then they determine if inflammatory response needs to go down and trigger ________
A
- Neutrophils
-
Macrophages
- Reactive oxygen species and Lysosomal enzymes
- neutrophils, debris, pathogens
- Trigger healing
19
Q
Where are Cells Found?
- Resident in Tissue =
- In Circulation =
- Circulating numbers induced to _____ during infection
A
- Dendritic Cells, Mast Cells, Macrophages
- Neutrophils, Eosinophils, Basophils, Monocytes
- Increase
20
Q
Lymphocytes
=
(3)
- Derived from?
- Involved in?
A
Cells that comprise the adaptive Immune System
-
B Lymphocytes
- Bone marrow derived (formed in bone marrow)
- Antibody mediated immunity
-
T Lymphocytes
- Thymus derived (formed in bone marrow)
- Cell mediated immunity
-
NK Cells
- Part of innate immunity - v important for viral infections (they fight with NON-specificity)
21
Q
Surface Markers
=
- B Cell Surface Markers (2) =
-
T Cell Surface Markers (2) =
- CD4 =
- CD8 =
Therefore, if an adaptive immune response is triggered - Antigen presents to ____ cell -> which then activates appropriate ____ or ____ cell that is needed to fight that infection
A
Identify the lymphocyte and determine is function and specificity
- Igm and IgD: antibodies (looks like a Y) where the antigen binding site resides and tells you what pathogen this B cell is destined to fight
-
CD4 and CD8: Determines T lymphocyte Function
- Helper T cells -> helps Coordinate, regulate, and control all adaptive immune responses “general of the army”
- Is our Suppressor, Cytotoxic T cell which Kills abnormal cancer cells or virus infected host cells
CD4 cell -> activates B cell or CD8 T cell
22
Q
The Thymus
Which cells are thymus derived?
Which cells are bone marrow derived?
A
T cells form in the bone marrow then migrate to thymus gland to mature “Thymus derived T cells”
B cells form and mature in the bone marrow
23
Q
The Distribution of Lymphoid Tissues in the Body
- Lymphocytes arise from stem cells in the? And differentiate in the central lymphoid organs (2)
- They migrate from these tissues and are carried in the bloodstream to the peripheral or secondary lymphoid organs (5)
- The peripheral lymphoid organs are the sites of lymphocyte _____ by antigen, and lymphocytes recirculate between the blood and these organs until they encounter specific antigens.
- T cells receive survival signals from ______ cells in the periphery, whereas the source of survival signals for B cells it thought to be in the lymphoid ______.
- Lymphatics drain extracellular fluid from the peripheral tissues, through the LN and into the _____ duct, which empties into the left _____ vein.
- This fluid, kown as lymph, carries _____ taken up by DCs and macrophages to the lymph nodes and recirculating lymphocytes from the LN back into the blood.
- Lymphoid tissue is also associated with other muchosa such as ____ lining (not shown in pic)
A
- Bone Marrow -> Bone Marrow, Thymus
- LN, Spleen, Lymphoid Tissues asctd with Mucosa (Gut asctd Tonsils, Peyer’s patches, Apeendix)
- activation
- Dendritic, Follicles
- Thoracic, Subclavian
- antigens
- Bronchial
24
Q
Organization of the Immune System (Notes)
2 Tissue Types
Definitions
A
- Lymphoid Tissue = any structure where lymphocytes form, mature, reside, and atc
- Reticular Tissue = Connective tissue, endothelial barriers, mucous membranes
25
Lymphoid Tissue
## Footnote
1. **Primary Lymphoid Structures =**
* **(2)**
2. **Secondary Lymphoid Structures =**
* **Examples:**
* Which are all _____ through lymphatic vessels
* **Where B and T Lymphocytes are \_\_\_\_\_\_** (ie. we eat alot of pathogens so GI tract)
* As fluid passes through LN/everything -\> it interacts with all of the lymphocytes so if you need to activate one of those lymphocytes, its going to get _____ there
1. Structure where lymphocytes form, mature, or reside and act
* **Bone Marrow, Thymus**
2. Where lymphocytes live and get activated
* **Spleen, LN, Adenoids, Tonsils, Heart, Kidney, Appendix, Thoraci Duct, Skin, GI tract (Peyer's patches), Resp tract** etc
* connected
* **Stored**
* antigens get trapped
26
Reticular Endothelial Tissue
## Footnote
* Where (3) live
* Even lymph nodes contain connective tissue so LN also have _____ and _____ cells
* Tissue macrophages, Dendritic Cells, Mast Cells
* macrophages, dendritic cells
27
Overview of the Immune System
## Footnote
1. Pathogens gain entry how?
2. Pathogen is detected how?
1. 2. 3. 4.
3. Phagocytic cells intiate an _______ response (more phagocytic cells are ____ to the area)
4. Phagocytic cells _____ antigen to ______ cell, how?
1. 2.
5. T helper cell intiates an _______ immune response
1. Activates (1) OR (1)
1. Encountering or Breaking Epithelial Barrier
2. Pathogen is detected by
1. Tissue phagocytic cells (macrophages/dendritic cells)
2. Peripheral lymphoid tissue phagocytic cells (via lymph fluid)
3. Spleen phagocytic cells (via blood)
4. By circulating B lymphocytes
3. Inflammatory, recruited
4. Present antigen to Helper T cell
1. Directly in lymphoid tissue/spleen
2. Phagocytic cell migrates to lymphoid tissue
5. Adaptive
1. Cytotoxic T cells OR B lymphocytes
28
Different Groups of WBCs, Where they are formed and live out their days
(5)
**Macrophages, Dendritic Cells, Mast Cells**
**Neutrophils, Eosinophils, Basophils**
**T Lymphocytes (Pre + Mature "Naive")**
**B Lymphocytes (Mature "Naive")**
**NK Lymphocytes**
29
Tissue Macrophages, Dendritic Cells, and Mast Cells
## Footnote
Formed where?
Live where?
Bone marrow and enter circulation early in development and migrate to these potential sites of infection
Skin, Brain, Liver, _LN, Spleen, MALT_, Respiratory Tract, Gut, Thymus, and others
30
Neutrophils, Eosinophils, and Basophils
## Footnote
Formed where? Live where?
Constantly produced by bone marrow throughout our lives and enter circulation where they live out their days in the circulation and get replaced by new cells
31
T Lymphocytes
## Footnote
Formed where? Live where?
Pre T lymphocytes formed in bone marrow -\> migrate to thymus to mature, get their CD4 or CD8 marker and T cell receptor and leave thymus gland into blood stream - but are called naive T lymphocytes bc never encountered the pathogen they are programmed to fight
In circulation briefly then migrate to secondary lymphoid tissue where they live out their days
32
B Lymphocytes
## Footnote
Form where? Live where?
Unique Characteristic =
B cells form and mature in the bone marrow where they get their B cell receptor and surface markers -\> leave bone marrow and enter circulation as mature but again naive B lymphocytes where they again migrate to secondary lymphoid tissue and live out their days
More constantly produced than T lymphocytes so when they migrate to secondary lymphoid tissue will occasionally encounter the pathogen they are programmed tof ight ("meeting your soulmate in preschool") - not the most common way but does happen
33
NK Lymphocytes
## Footnote
Form where? Live where?
NK lymphocytes form and mature in bone marrow
Leave bone marrow and occupy 2 spaces
* Mature NK cells in circulation
* Mature NK cells in secondary lymphoid tissue
Again will fight viral infections in a nonspecific way
34
Overview of the Immune System
## Footnote
1. Pathogens gain entry how?
2. Pathogen is detected how?
1. 2. 3. 4.
3. Phagocytic cells intiate an _______ response (more phagocytic cells are ____ to the area)
4. Phagocytic cells _____ antigen to ______ cell, how?
1. 2.
5. T helper cell intiates an _______ immune response
1. Activates (1) OR (1)
1. Encountering or Breaking Epithelial Barrier
2. Pathogen is detected by
1. Tissue phagocytic cells (macrophages/dendritic cells)
2. Peripheral lymphoid tissue phagocytic cells (via lymph fluid)
3. Spleen phagocytic cells (via blood)
4. By circulating B lymphocytes
3. Inflammatory, recruited
4. Present antigen to Helper T cell
1. Directly in lymphoid tissue/spleen
2. Phagocytic cell migrates to lymphoid tissue
5. Adaptive
1. Cytotoxic T cells OR B lymphocytes
* Phagocytic cell takes that antigen in and go finds a helper*
* T cell to initiate adaptive immune response*
35
Secondary Lymphoid Structures
## Footnote
= Where B and T cells ____ and get ______ makes lots of ____ of itself and initiates an attack on the pathogen
* First experience with pathogen -\> immune attack will be a bit \_\_\_\_
* Subsequent encounters -\> attack will be very \_\_\_\_\_
live and get activated, copies
* sluggish
* fast
36
**Lymph Nodes**
* Found throughout the body at ______ points on lymphatic vessels
* Every LN has an a\_\_\_\_\_, v\_\_\_\_ and _____ vessels that carry lymph fluid into and ____ vessels carrying lymph fluid out (and fluid has to pass through all of the tissue of the node itself)
_Zones of the LN_
* **Medullary Cords (red) =**
* **Paracortical Area (blue) =**
* **Primary Lymphoid follicle (white) =**
* **Germinal Centers (yellow) =**
* bifurcation
* artery, vein, afferent, efferent
* packed with macrophages + dendritic cells
* mostly T cells
* mostly B cells
* where cells that are activated enter and start replicating (ex. T or B cell will replicate in these centers)
37
**Spleen**
* Similar makeup as \_\_
* Blue is __ cell area, Yellow is __ cell area, and Germinal center where cells are \_\_\_\_\_\_
_Types of Tissue_
* **Red pulp =**
* **White pulp =**
* LN
* T cell, B cell, replicating
* part of spleen that traps and processes rbcs
* lymphatic tissue located between artery that perfuses spleen and blood that drains away from spleen (so blood has to pass through white pulp)
38
**Peyer's Patches in Small Intestine**
Similar makeup again, T cell area, _____ B cell area, and Germinal Center
follicle
39
Molecular Communication in the Immune System
## Footnote
**Cytokines =**
**Pro-Inflammatory Mediators (3)**
* _One way Cytokines are used to create a response_
* What are the cells that live in our bloodstream? and they are all ______ = constantly produced by bone marrow
* During a bacterial infection, what do cytokines do?
**Cell derived chemical mediators responsible for communication between immune cells (Cyto means cell)**
**IL1, IL6, TNF Alpha**
* Cytokines
* Neutrophils, Eosinophils, Basophils, Monocytes - INDUCIBLE
* Act on bone marrow to trigger increased production of neutrophils
Ex) injured cell releases cytokines that will trigger mast cells to begin inflammatory process or when body has ongoing infection, cytokines communicate with bone marrow to trigger increase wbc production (pretty much anything going on the immune system going to be signaled and responded to by release of cytokines)
40
Innate Immunity
## Footnote
* Barriers to Infection (3)
* In\_\_\_\_\_\_
* _____ cells
* Plasma _____ systems (3)
* _____ Phase Response
* ____ \_\_\_\_ Cells and I\_\_\_\_\_\_\_
* Physical, Chemical, Microbial (1st line)
* Inflammation (2nd line)
* Phagocytic cells
* Plasma Protein Systems: Clotting System, Complement System, Kinin System
* Acute (Systemic inflammatory response)
* Natural Killer Cells and Interferon (part of our innate immunty that are cytokines that work together to fight intracellular infections)
## Footnote
Physical Barriers: skin, epithelial and endothelial boundaries, mucous membranes
41
Routes of Infection for Pathogens
## Footnote
_1st Line of Defense_
* Mucosal Surfaces
*
* *
* External Epithelial
*
* *
* Mucosal Surfaces
* Airway (flu)
* GI tract (contaminated food and water salmonella)
* Reproductive tract (HIV)
* External Epithelia
* External surface (Physical contact ie Athletes foot)
* Wounds and Abrasians
* Insect Bites (Vector that gets it across the epithelial like instects that inject ie Ticks)
42
Frontline of Defense: Barriers
(3)
Examples of each (3) (5) (1)
1. Mechanical Barriers
* Tight Junctions
* Flow of air or fluid across barriers to prevent lingering of pathogens
* Mucus and Cilia
2. Chemical Barriers (reduce pathogenic microbial proliferation)
* Low pH in stomach
* Fatty Acids
* Digestive enzymes in stomach
* Lysozyme (salivary enzymes) in saliva
* Antibacterial peptides
3. Microbiome
* Natural flora and microorganisms that live in our body
43
Second Line of Defense
=
Steps
1. Damaged tissue releases _____ increasing ____ flow to the area
2. Histamines cause capillaries to \_\_\_\_\_, releasing ______ and _____ factors into the wound
3. Phagocytes _____ bacteria, dead cells, and cellular debris
4. _____ move out of the capillary to ____ the wounded area
Inflammation
## Footnote
1. Histamines, blood
2. leak, phagocytes, clotting
3. Engulf
4. Platelets, seal
44
Inflammation (Notes)
## Footnote
* What needs to be present to cause an inflammatory response?
* (2) Responses
* Inflammatory responses are designed to be \_\_\_\_, short lived, cause a little more damage than originally happened, and followed by healing
* Chronic inflammation is always **\_\_\_\_\_\_, is not normal** -\> caused by **chronic ____ -\> f\_\_\_\_\_ r\_\_\_\_:** all attempts to heal are sabotaged by continuous inflammation
* Injury and Presence of a pathogen
* **Vascular Response, Cellular Response**
* brief
* **pathological, chronic injury -\> frustrated repair**
45
**Vascular Response (Notes)**
## Footnote
What happens?
Vasospasm
**Vasodilation**
**Increased Capillary permeability (redness, heat, edema)**
**Deyated Vascular Stasis**
"delivering blood and fluid to flush the wound and gets flushed into lymphatic system"
46
Cellular Response
## Footnote
What happens?
* **Chemotaxic _____ of ______ to area**
* First wave:
* **Collateral damage:**
* Second wave:
* **Transmigration =**
* **migration of leukocytes**
* Neutrophils -\> release reactive O2 species and lysosomal enzymes -\> provides debridement
* also damage to healthy tissue dt ROS/lysosomal enzymes
* Monocytes that turn into macrophages will clean up the mess and **switch to anti-inflammatory and healing response when things settle down**
* ****Macrophages that have gobbled up bacteria in interstitial space is cleared by fluid entering lymphatic system - and if macrophage has an antigen is going to present it in the LN to activate adaptive immune response
* Leukocytes **adhere** then squeeze out of blood vessel to enter interstitial space
47
Inflammation Summary
## Footnote
I\_\_\_\_ or _____ of a _____ triggers inflammation (how?)
1. Injured tissue releases ______ that activate \_\_\_\_\_\_
2. Injury activates ____ Cells which release?
3. Macrophages detect/\_\_\_\_\_ pathogen then release?
4. Activated ______ stimulate _____ cells to release?
* \_\_\_\_\_\_\_\_
* Vasodilation, Increased permeability (redness, heat, edema), Delayed Vascular Stasis
* _____ \_\_\_\_\_\_
* Chemotaxic migration of leukocytes to area
* ______ of \_\_\_\_\_\_
* Pathogens phagocytized or destroyed via ________ killing
* Phagocytic cells carry ____ through ____ fluid to the nearest?
Injury or Presence of a Pathogen
1. cytokines -\> macrophages
2. Mast cells -\> pro-inflammatory mediators
3. ingests -\> pro-inflammatory mediators
4. Macrophages -\> Mast Cells -\> pro-inflammatory mediators
* Vascular
* Cell Migration
* Attack of Pathogens
* extracellular
* antigen -\> lymph -\> lymph nodes
48
Inflammation Summary (Notes)
## Footnote
**\*\*Cellular Initiators of Inflammation\*\* =**
Edema happens due to?
**Delayed Vascular Stasis =**
Neutrophils will ___ but Macrophages carry antigens to lymph nodes and present to _____ \_-cells (\_\_\_) incase it needs to activate an immune response
**Tissue Macrophages and Mast Cells**
leaking of albumin (swelling)
Caused when fluid leaks out, what is left is very sluggish viscous fluid - which keeps leukocytes in the area and isolate potential area of infection (3rd response of inflammation in the cascade)
die, Helper-T cells (CD4)
49
How Macrophages are Inflammatory Mediators
## Footnote
Activated Macrophage Secretes a range of Cytokines
Key ones to focus on are? and their functions?
1. 2. 3.
1. **IL1** = _activates mast cells_
2. **TNF alpha** = _causes vasodilation and increased capillary permeability_
3. **IL6** = important for the _systemic inflammatory response_
50
Things that Activate Mast Cells
(4)
* **Injury**
* **Interleukin 1** (coming from macrophage or straight from injured cells)
* **IgE** (allergies)
* **Complement Proteins (C3a and C5a)**
51
2 Things that Happen When we activate Mast Cells
(2)
Definitions
* **Degranulation:** Immediate response - of all the mast cell's secretory granules, it releases all of the stuff in its granules (an immediate response)
* **Synthesis of Leukotrienes and Prostaglandins:** Long term response - make the inflammatory response painful (prostaglandins)
* vascular effects -\> increased permeability -\> exudation
52
Degranulation
## Footnote
What is secreted? and what are their effects?
(3)
* **Histamine** -\> Vascular effects -\> dilation, increased permeability -\> exudation (potent vasodilator to increase permeability)
* **Neutrophil chemotactic factor** -\> attracts neutrophils to site -\> phagocytosis
* **Eosinophil chemotactic factor** -\> attracts eosinophils
53
Vascular Events Location
## Footnote
Where do vascular events during inflammation happen?
Flow of blood?
\_\_\_\_\_ surrounds capillary bed
**Microcirculation:** capillaries, arterioles, venules
Arterioles -\> capillary beds -\> Drains into venules
Tissue
54
Events of Transmigration
(3)
Migration to site
Adhesion
Transmigration
55
General Cell-derived Chemical Mediators Table
## Footnote
(Use as reference guide)
2 inflammatory mediators that cause the most **damage** **(2)**
2 major cells that release these are? (2)
* Reactive Oxygen Species
* Lysosomal enzymes
Neutrophils and macrophages
56
Cytokines (3)
Plasma Protein System (3)
57
Overview of Complement System
## Footnote
The complement system is made up of circulating _____ \_\_\_\_\_ that activate in a ______ of enzymatic _____ to accomplish (3) purposes
**Is the most potent part of?**
plasma proteins, cascade of reactions
1. **Promotes inflammation**
2. **Directly Kills pathogen**
3. **Tag a pathogen for later killing (opsonization)**
**Innate immunity**
A plasma protein system that all starts as inactive proteins that goes through a cascade and activates each other
This all happens before the stage of adaptive immunity
58
Purposes of the Complement System (Notes)
## Footnote
**Directly Kill Pathogens =**
**Opsonization =**
**Opsons =**
Some of the proteins assemble wtih each other and turn into a **pore (big hole) aka Membrane attack complex** that inserts itself into the pathogen -\> water rushes in and cell dies **(Lyse)** - "these proteins flip a switch and kill bacteria like transformers"
**Tagging a pathogen for later killing**
**A protein tag** that attaches to the membrane of the pathogen and tags it for phagocytic killing by macrophage or neutrophil
59
Ways to Activate the Complement System
(3)
1. **Presence of Pathogen**
2. **As part of a Systemic Inflammatory Response (the acute phase response)**
* In chronic inflammation, increased concentrations of **cytokines IL1, IL6, TNF alpha** reach high lvls start triggering a systemic response -\> fever, increased wbc, acts on **liver to produce systemic inflammatory proteins (CRP, MBL)**- which triggers complement system
3. **Can be activated by adaptive immunity (antibody-mediated)** - B lymphocytes produce antibodies that attach to surface of pathogens and trigger activation of complement system
60
Specific Pathways for Complement Activation
## Footnote
**(3)**
All three pathways will activate **(1) critical step that will activate the whole cascade**
1. **Classic Pathway**
2. **MB-Lectin Pathway**
3. **Alternate Pathway**
## Footnote
**C3**
61
Classic Pathway
## Footnote
The only pathway we knew for a very long time
Involves the activation of the **\_\_\_\_ complement protein C\_** by
1. **Binding ______ to the pathogen**
2. **Binding to a _______ (2)**
3. **Binding to an \_\_\_\_\_\_**
**first complement protein C1**
1. **Directly binding to the pathogen** surface by encountering it in the bloodstream
2. **Binding to a protein (CRP, MBL) -** proteins produced by liver during systemic inflammatory response, go off and try to bind to any pathogens in circulation, make activation of C1 easier) already attached to pathogen's surface
3. **Binding to an antibody** attached to the pathogen (so your body mounts an adaptive immune response against the pathogen and produces antibodies that attracts C1
* Main takeaway, back to last slide on ways to activate complement
* Presence of pathogen can activate complement bc can directly bind to complement proteins
* As part of systemic inflammatory response bc CRP and MBL make it easier
* As part of adaptive immune response bc the antibody attached to pathogen can activate it
62
MB Lectin Pathway
=
Involves MBL attaching to pathogen surface and activation of proteins farther down in complement cascade (similar to MBL involved in activating C1 just activating other complement proteins)
63
Alternate Pathway
=
Involves direct activation by binding of C3 to pathogen surface
64
Function of the Proteins of the complement System (Notes)
## Footnote
1. **Promotes Classic Inflammation** (vaso\_\_\_\_, increased \_\_\_\_\_, recruits \_\_\_\_/\_\_\_\_)
2. **Directly Kills Pathogens** (why its considered the most _____ component of ____ immunity)
* Some of the proteins actually assemble with each other and turn into a ____ that inserts itself into the pathogen and causes the pathogen to \_\_\_\_\_
* Ex) strep -\> triggers complement proteins and assemble into the ____ \_\_\_\_ ____ (forms a big hole) -\> inserts themselves into bacteria, ____ rushes in and cell dies
* "these proteins flip a switch and kill bacteria" (like transformers)
1. **Opsonization (\_\_\_\_ a pathogen for _____ killing)**
* ****The terminal complement protein acts as a **(1):** **a protein tag** that attaches to the membrane of the pathogen and tags it for phagocytic killing by macrophage or neutrophil
1. vasodilation, increased permeability, recruits neutrophils/macrophages
2. powerful, innate
* pore, lyse
* membrane attack complex, water
3. **tagging pathogen for later killing**
* **Opsons**
65
The Kinin System
## Footnote
* Activated Clotting Factor ____ synthesizes
* _________ which converts ______ to \_\_\_\_\_
* Kinins then have 4 effects =
* Factor XII (XIIa)
* **Kalikrein, Kinongens -\> Kinins (Bradykinin)**
* 4 effects
1. **Stimulate complement system**
2. **Promote localized vasodilation and increased capillary permeability**
3. **Activate pain receptors** (along with prostaglandins)
4. **Act as chemotaxins** - to draw more neutrophils and macrophages to the area
66
The Kinin System (Notes)
## Footnote
Another plasma protein system that intersects with the clotting system
* Activated by ______ and potentiates inflammation by producing more inflammatory \_\_\_\_\_
* Inflammation -\> _____ arrive and release _____ -\> triggers blood ____ and **convert inactivated kininogens to active Kinins**
* **Kallikrein =**
* **Kinins =**
* (2) both cause the **pain** asctd with inflammation
* Bradykinin also produces?
* inflammation -\> mediators
* neutrophils, Kallikrein -\> blood clots
* activated form of factor 12 which is the first protein in the clotting cascade
* (similar in structure to bradykinin)
* Bradykinin and Prostaglandins
* Secondary area of pain (that's larger than the primary area ie skin around a cut also tender - zone of pain that protects against maniupulation of the damaged part) allodynia
67
The Clotting Cascade
## Footnote
3rd Plasma Protein system
* Intrisic Pathway = damage to?
* Extrinsic Pathway = damage to?
* Starts with activation of?
* Wherever you start, end point is a single reaction of **inactive _____ to active \_\_\_\_\_** -\> which converts **\_\_\_\_\_\_ (individual strings of spaghetti) to ______ (spaghetti clumps)**
* What does fibrin do?
* What does thrombin do?
* Blood vessels
* Tissues (outside vessels)
* **Kallikrein (Factor 12)**
* **Prothrombin -\> Thrombin, Fibrinogen -\> Fibrin**
* Traps rbc and wbc to create **Bloot clots**
* Form the clot and enhances **inflammation via Protease activated receptor-\> edema**
68
What is this a picture of?
Interconnected FIBRIN that creates meshwork - to suspend rbc's and other blood born cells to turn blood from liquid to gel like state
69
Leukotrienes and Prostaglandins
## Footnote
Role in Inflammation =
Biosynthesis of Leukotrienes and Prostaglandins
1. **Arachidonic Acid =**
2. Arachidonic Acid interacts with either
1. **2 forms of \_\_\_\_\_\_** to produce \_\_\_\_\_\_
2. **2 forms of \_\_\_\_\_\_** to produce \_\_\_\_\_\_
Inflammatory mediators that are produced by all types of cells (when damaged)
1. Substance that all forms of leukotrienes and prostaglandins are derived from and is produced by our cell membrane phospholipids
2. interacts with
1. **Cyclooxygenase -\> Prostaglandins**
2. **Lipoxygenase -\> Leukotrienes**
70
Prostaglandins
## Footnote
Functions
* Some cause _____ and _____ vs. some cause \_\_\_\_\_\_
* Some inhibit and some enhance platelet \_\_\_\_\_\_
* Causes \_\_\_\_\_
* Vasodilation and Edema, Vasoconstriction
* Inhibit platelet aggregation, Enhance platelet aggregation
* Pain
71
Leukotrienes
## Footnote
Function
* Lipoxin A4 and AB
* Vaso\_\_\_\_\_
* Inhibit neutrophil \_\_\_\_\_
* Stimulates _____ \_\_\_\_\_
* Leukotriene C4, D4, E4
* Vaso\_\_\_\_
* **\_\_\_\_\_\_\_\*\* Classic ______ is dt leukotrienes**
* Increased \_\_\_\_\_\_
* Lipoxin
* **Vasodilation**
* Inhibits chemotaxis
* **Monocyte adhesion**
* Leukotriene
* Vasoconstriction
* **Bronchospasm\*\* - Anaphylaxis**
* **Permeability**
72
Few Tools to Reduce Inflammation
## Footnote
What are 2 major ones and how do they work?
**Steroids:** most potent anti-inflammatory durgs that act by blocking phospholipase - _synthesis of arachidonic acid_ -\> blocks leukotrienes and prostaglandins...however have so many SE
**NSAIDs (aspirin, indomethacin):** block cyclooxygenase (COX1 and COX2) however also have so many SE (ulcers/bleeding)
73
Interactions of Some Inflammatory Mediators
## Footnote
No need to memorize - just shows the events of inflammation is all \_\_\_\_\_\_
No matter who starts the inflammatory response -\> it all potentiates very \_\_\_
interconnected
quickly
74
Systemic Inflammatory Response (Acute Phase Response)
## Footnote
* Example Respiratory Infection
* Triggers local inflammatory response
* As infection gets larger, size of inflammatory response gets larger and larger - release of **3 key cytokines (3)**
* Once their _____ become high enough start to do what?
* **IL1, IL6, TNF alpha**
* concentrations become high enough start to bind to distant receptors and trigger systemic effects
75
Targets of IL1, IL6, TNF alpha
(5)
Effects
1. **Hypothalamus:** our body's thermostat -\> cytokines will raise temp and induce fever (decreases changes of viral/bacterial replication) + **sickness behavior** (fatigue, malaise - which is protective bc forces you to rest)
2. **Bone Marrow:** increase production of wbcs
3. **Fat and Muscle:** increase breakdown of protein and fat to increase body temp and feed fever (why we feel achy)
4. **Dendritic Cells:** to migrate to nearest LN -\> bc if dendritic cell has trapped that pathogen will initiate adaptive immune response ASAP
5. **Liver:** increase production of acute phase response proteins (which help _trigger complement system to attack pathogens)_
1. **CRP (C reactive protein), MBL (mannose binding lectin)**
76
Sepsis
## Footnote
= presence of bacteria in the ______ (bacteremia) - an exaggerated _____ inflammatory response and activation of innate immunity
* When bacteria exit tissue and interact with targets in the bloodstream -\> activates a large immune response (\_ _ \_ \_)
* LPS = lipopolysaccharides which are part of bacteria cell \_\_\_\_
bacteria in bloodstream, exaggerated systemic inflammatory response
* SIRS
* wall
77
Sepsis
## Footnote
Activation of **(4)**
* **Endothelium** (inner lining of blood vessels): triggers inflammation and coagulation when interacting with bacteria and LPS
* **Circulating Neutrophils:** will release free radicals, cytokines, and trigger inflammation in circulation
* **Circulating Monocytes**
* **Complement System**
78
Sepsis Effects
**\_ _ \_**
(4)
DIC
## Footnote
Hemorrhage dt running out of clotting factors (most often intracerebral or GI bleed)
* **Coagulation**
* **Fever**
* **Systemic Vasodilation** (drop of BP and shock)
* **Capillary Leak** -\> decreased perfusion to organs -\> organ failure -\> more tissue injury -\> more inflammation (potentiating vicious cycle)
79
Responses to Viral Infection
## Footnote
Infected cell detects ____ stranded RNA -\>
Host cell releases (2) -\>
1. Host cell produced ____ that ____ viral RNA and block production of viral protein
2. Host cell increases production of _____ (better _____ \_\_\_\_\_)
3. Activates ___ cells -\> which then ____ virus infected cells and releases (1) which potentiates the effects of interferon a and B
* these cells can also be activated by (1)
**double stranded RNA**
**Interferon a and B**
1. enzymes, degrade
2. MHC1 (better antigen presentation)
3. NK cells -\> Kills, Interferon y
* Macrophage-derived cytokines
80
Interferons (Notes)
## Footnote
Important for ____ attack of virus infected cells
* Double stranded RNA is ____ found in our genes but is common component of _____ cycle of viruses so our first clue that we are infected is the host cell detects double stranded RNA -\> **release of interferon alpha and beta**
* ****Activates ___ cells to kill virus in infected cell
* White its waiting for NK cells it does (2) things
* NK cells also release interferon y (gamma) to?
* How does the NK cell recognize that this is an infected cell?
* **Can NK cells eradicate the virus completely?**
Innate
* never, replication
* NK cells
* host cell produces enzymes that degrades viral RNA and increases production of MHC1 for better antigen presentation
* potentiate effects of interfern alpha and beta
* MHC1 helps it recognize that this is a host cell and the viral antigen attached to the MHC1 helps NK cell recognize that its infected
* **NO, NK cells stem the rise in viral rapid replication and make it plateau to hold it at a particular replication rate, buys enough time for CD8-T cells to come in and eradicate the virus completely**
81
Outcomes of Acute Inflammatory Response
(3)
**Resolution**
**Fibrosis +/- Abscess**
**Chronic Inflammation**
82
**Resolution**
* Clearance of (3)
* _______ of injured cells
* Function?
* injurous stimuli, mediators, and acute inflammatory cells
* Replacement
* Returns to normal
## Footnote
Undergoes healing that replaces injured cells -\> tissue looks like nothing ever happened, is IDEAL, completely healed and normal function restored
83
**Fibrosis**
## Footnote
**=**
**Abscess**
**=**
Loss of function, scar formation
When certain bacteria colonize the area and are difficult to clear, causes continuous cycle of recruitment and death of neutrophils - **pus = dead neutrophils** -\> the abscess can eventually celar as well as cause a scar
84
**Chronic Inflammation**
Caused by?
What happens is? "\_\_\_\_\_ \_\_\_\_\_\_"
* A\_\_\_\_\_
* Mononuclear cell \_\_\_\_
* _____ (scar) and ____ of function
**Persistent Injury**: ie. viral infections, chronic/autoimmune infections, HTN, hyperglycemia dt DM, smoking, HLD
**"Frustrated Repair":** Active inflammation and Attempted healing occurs simultaneously
* Angiogenesis
* infiltrates
* Fibrosis, loss of function
Fibrosis of skin is diff, but in chronic inflammation you can get fibrosis of artery walls -\> athersclerosis
85
Two types of Healing
## Footnote
**Primary Intention**
**Secondary Intention**
* Minimal tissue loss, clean closely apposed wound edges
* Involves sealing (epithelialization) and wound shrinkage (contraction)
* More tissue damage - open wounds
* Involves more extensive and prolonged epithelialization, scar formation, and contraction
86
Healing by First vs. Second Intention
## Footnote
1. First Intention
1. **Reconstruction phase:**
2. **Maturation phase:**
2. Second Intention
1. **Reconstruction phase:**
2. **Maturation phase:**
1. Neutrophils -\> Macrophages that continue inflammation -\> 2nd wave of macrophages that turn off inflammatory response triggers healing (reconstruction phase)
* Healing macrophages: release cytokines that cause tissue regeneration, healing
2. Wound tightens up and mature
1. Reconstruction phase takes longer with a larger wound (more susceptible to infection -\> more likely to leave a true scar)
2. Large amounts of granulation tissue and wound contraction
87
Another Flow Chart of Healing
## Footnote
Example of ______ -\> chronically inflamed liver will cause _____ of liver (which is the definitionof cirrhosis) - and liver loses its ____ -\> have to take away ___ before liver becomes fibrotic
Cirrhosis -\> fibrosis -\> loses function -\> alc
88
Causes of Chronic Inflammation
(3)
+ Examples of each
**Persistent Infections** microorganisms like tubercule bacilli, treponema pallidum (syphilis), viruses, fungi, parasites
**Prolonged exposure to potentially toxic agents** (endogenous or exogenous)
**Autoimmunity**ex) RA
Endogenous source: DM hyperglycemia damages tissues that line vessels and nervous tissue
Exogenous sources: air pollution, smoking, vaping
89
What is the immune cell responsible for switching inflammatory response to a healing response?
By releasing what ____ factors
**Macrophages**
**growth factors**
In chronic inflammation macrophages are going to release both inflammatory and healing mediators -\> frustrating both processes and resulting in fibrosis
90
**Persistent recruitment to and/or immobilization of Macrophages at site will cause ____ sets of mediators to be released concurrently leading to "\_\_\_\_\_ \_\_\_\_\_"**
**both**
**"frustrated repair"**
91
Persistent Stimulus (Chronic Inflammation)
## Footnote
Development of fibrosis in chronic inflammation. The persistent stimulus of chronic inflammation activates _____ and \_\_\_\_\_, leading to production of ____ factors and \_\_\_\_\_, which increases the synthesis of \_\_\_\_\_. Deposition of collagen is enhaced by decreased activity of m\_\_\_\_\_\_\_.
macrophages, lymphocytes -\> growth factors,cytokines -\> collagen, decreased activity of metalloproteinases = decreased collagen degradation
