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General Pathology > The Innate Immune Response > Flashcards

The Innate Immune Response Flashcards

1
Q

Immunology

A

is the study of the physiological mechanisms that humans
and other animals use to defend their bodies from invasion by other
organisms

  • Your body defends you from all things that are not you – we call
    these things that are not you “anitgens”
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2
Q

Antigen

A

are any molecule that binds specifically to an antibody, also any molecule that can produce peptides that bind specifically to a T-cell receptor

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3
Q

Intrinsic epithelial barriers

to infection

A
  • Skin, mucosa, epithelium = MECHANICAL barriers
  • Enzymes in tears, sweat, saliva = CHEMICAL barriers

• There are good bacteria in your body = MICROBIOLOGICAL barrier – you need these in our gut to keep pathogenic bacteria from being able to
grow (healthy bacteria are taking up all the resources and space

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4
Q

Breaking the Physical

Barrier

A

As soon as you break barrier (stab yourself with an explorer) you start recruiting inflammatory cells to this area; INNATE IMMUNE RESPONSE IS FIRST!!! at the same time, inflammatory cells that are at the site of infection (dendritic cells) are going to change states and “schlep” off to the nearest lymph node; once they get to the lymph node, they will get ADAPTIVE IMMUNITY started

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5
Q

Breaking the

Microbiological Barrier

A
  • This can happen if you were on antibiotics and killed off good bacteria, leaving space for pathogenic bacteria to grow
  • Vomiting and diarrhea until you can combat this; i.e. neutrophils and red blood cells leak into gut between injured and epithelial cells
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6
Q

Nonspecific Immune Cells Part of Innate

Immune Response

A
  • Neutrophils
  • Macrophages
  • Dendritic cells
  • Natural killer cells
  • Mast cells
  • Eosinophils/basophils
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7
Q

Soluble Molecules

A
  • Complement
  • Antibodies (secreted by B-cells)
  • Cytokines (secreted by any cell)
  • Chemokines
  • Vasoactive mediators
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8
Q

Specific Immune Cells

A
  • B cells

* T cells

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9
Q

Small Lymphocytes

A

Production of antibodies (B cells) or cytotoxic and helper functions (T cells)

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10
Q

Plasma Cells

A

Fully differentiated form of B cell that secretes antibodies

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11
Q

Natural Killer Cell

A

kills cells infected with certain viruses

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12
Q

Neutrophil

A

Phagocytosis and killing of microorganisms

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13
Q

Eosinophil

A

Killing of anti-body coated PARASITES through release of granule contents

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14
Q

Basophil

A

Controlling immune responses to parasites

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15
Q

Dendritic Cell

A

Activation of T cells and intitiation of adaptive immune responses

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16
Q

Mast cells

A

Expulsion of parasites from body through release of granules containing HISTAMINE AND OTHER ACTIVE AGENTS

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17
Q

Monocyte

A

Circulating precursor cell to macrophage

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18
Q

Marcophage

A

Phagocytosis and killing of microorganisms. Activation of T cells and initiation of immune responses

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19
Q

Dichotomies

A

Innate (nonspecific cells) VS. Adaptive (specific cells)

Humoral (mediated by antibodies) VS. Cell Mediated Immunnity (CMI) mediated by TH1 T cells and macrophages

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20
Q

Innate Immunity

A

•Fast and will show up within hours of
Infection
• Fixed # of things; they do their specific job and then die
• Limited number of specificties
• Constant during response
• Innate does not recognize viruses and can only recognize certain antigens on bacteria

**BOTH ARE NECESSARY TO REMOVE AN INFECTION!!!!!!!!!!!!**

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21
Q

Adaptive Immunity

A
  • Longer response (days to weeks)
  • Is specific to each pathogen and each person
  • Gets better over time
  • Variability: meaning that it is very specific to that pathogen; numerous highly selective specificites

**BOTH ARE NECESSARY TO REMOVE AN INFECTION!!!!!!!!!!!!**

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22
Q

Two Places for Pathogens to Live

A

o Extracellular - Complement/toll-like receptors (not in intracellular)

o Intracellular - TD8 cell (only in intracellular) and DC

but other than these difference they are pretty much the same responses

FOR EXTRACELLULAR, you start out with dendritic cells and neutrophils; EVERYTHING IS DRIVEN BY RECEPTORS!! For complement/toll-like receptors

FOR INTRACELLULAR. You start with dendritic cells but there are no receptors against viruses and there is no effect by complement (one exception); if they worked on viruses (which look like host cells) they would be attacking host cells all the time which is how AUTOIMMUNE diseases work

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23
Q

Extracellular First

Responders

A

• Proteins
o Antibodies
o Complement (helps recruit immune cells)

• Innate immune cells (all are receptors for bacterial proteins)
o Dendritic cells
o Neutrophils
o Macrophages

• If a cell doesn’t have a receptor, it will not respond!

24
Q

Complement

A
  • A group of proteins that exist in inactive forms in the serum at all times
  • When you disrupt the capillary bed (poke yourself), the proteins in the serum migrate into the tissue and can start working very quickly
  • Conversion is done by activated forms of complement protein’s activating
25
Q

Classical Pathway Summary

A

1) Already existing antibodies to extracellular bacteria bind to the bacterial antigen
2) C1 binds to IGM (antibody)
3) Once it binds, C1 will then grab a hold of the next two pieces (C2 AND C4) and convert them to their active form
4) Once C2 and C4 are active and bind to the bacteria, they can convert the next piece: C3
5) C3 (ONCE ACTIVE) then binds to the bacteria and converts the NEXT piece: C5
6) C3 cleaves C5 and C5 converts C6,C7,C8
7) C6,C7,C8 form a complex which activates C9
8) C9 polymerizes and now you cause a hole in the bacteria and IT DIES

26
Q

Alternate Pathway Summary

A

In the absence of an antibody, C3 can self-cleave and combine with other things and become a C3 convertase in order to cleave itself

• C3 –> C3a + C3b

o C3a (chemotaxis) – C3a goes away and becomes a chemotactic factor – goes off into the blood stream to start telling immune cells to go in that direction (recruits neutrophils and monocytes to site
of infection)

o C3b binding causes opsonization (coating with butter)
- There is a receptor on neutrophils that recognize C3
- One of the properties of neutrophils and macrophages is phagocytosis
-We coat something with C3b and this gives it a high affinity for
neutrophils and macrophages to phagocytose them

• Membrane Attack Complex (MAC ATTACK!) – formation of a pore

27
Q

Function of C3

A 
(1) Opsonin (receptors on these cells) 
• Macrophages/monocytes
• Dendritic cells
• Neutrophils
• B cells

(2) Convertase – cleaves itself and gives us huge amplification loop to
create massive amounts of complement

(3) Activation of B cells – if there is a mutation in C3b you won’t get
antibodies (cannot live)

28
Q

How to Control Complement?

A

• Inactivating factors
> SOLUBLE: molecules floating around in the the serum which inactivate complement on bacterial AND host tissues

> MEMBRANE BOUND: inactivate complement ONLY FOUND ON HOST CELLS so the only cells that will inactivate the complement stuck to it are host cells which means the complement on bacteria are still active; this is how we protect our cells

• If you are going to design a complement system to inactivate complement
factors, you might want to start with C1 or C3

29
Q

C1INH (C1 Inhibitory

Factor)

A

• C1 neutralizer keeps it
inactive (C1INH) so it can’t cleave anymore

• Lack of C1 inhibitory
factor is the cause of
hereditary angioedema

30
Q

C4-binding protein

A

Membrane bound C-4 binding protein will
Bind to the C4 so that it will not cleave C3 and no
Pores will be formed on that cell to destroy (saves the host cells from destruction)

OCCURS ONLY ON HOST CELLS

31
Q

Soluble factors H and I

A

cleave the convertase part of C3 so it can’t convert but still have the oponsin for macrophages to eat and B-cells can still be activated

Leaves a receptor (iC3b) for macrophages and neutrophils to still eat

32
Q

DAF

A

DAF splits up the alternate pathway of C3

Membrane bound DAF can inactivate the alternate form of C3 so stop production of C3 and thus activation of C5 so that it cannot form the MAC attack on host cells

AGAIN THIS IS ONLY ON THE HOST CELLS!! IT WILL STILL WORK ON THE BACTERIAL CELLS

33
Q

MCP

A

Membrane bound MCP does a similar thing to DAF in preventing C3 from converting so you cant get the whole pathway on HOST CELLS

34
Q

CD59

A

• Host factor that prevents
polymerization of C9 (prevents formation of pore) – so you can’t
poke a hole in your own cells

• Keeps complement from doing damage to host cells, only bacteria, which is what we want

35
Q

How does Complement start Inflammation?

A
  • C3a, C5a are anaphylatoxins
  • Alter the vascular endothelium
  • Recruit inflammatory cells (Neutrophils are the first ones to arrive and the monocytes are shortly thereafter)
36
Q

Anaphylatoxins

A
  • Endothelium is a kind of epithelium – meaning it has tight junctions
  • If you are neutrophil/macrophage/proteins you cannot get through tight junctions
  • Activating anaphylatoxins increases vascular permeability, allowing antibodies and complements to the site of infection
37
Q

The Initial Response to

Extracellular Bacteria

A 
• Complement (START) 
• C3b – Receptors
• C3a, C5a –Inflammatory mediators
• Cell recruitment
    o Neutrophils
    o Monocytes 
          - macrophages
38
Q

How do you recognize an Extracellular Bacteria?

A

PATHOGEN ASSOCIATED MOLECULAR PATTERNS (PAMP)

39
Q

Pathogen Associated Molecular Patterns (PAMPs)

A

A unique glycoprotein structure to bacteria and our immune system has evolved to have receptors to recognize these structures

40
Q

Examples of PAMP

A

Methionine- Lysine-Phenylalanine is the first amino acids for all bacterial protein (fMLP) and the “f” stands for formulated (stick a formyl group on Met - which hosts cannot do) and because every bacteria has this, we have a receptor for it

LPS is on gram neg. bacteria - we have a receptor for that

Glycan and Mannose cannot be made by eukaryotes but we have a receptor against them on neutrophils, macrophages, and monocytes and dendritic cells

These receptors on the immune cells bind and allow phagocytosis of the bacteria and are called TOLL-LIKE RECEPTORS

CONVERSELY, VIRUSES are INTRACELLULAR and are MADE IN HOST and HAVE HOST STRUTURES (we do not have TOLL-LIKE RECEPTORS for viruses)

41
Q

Toll Receptors

A

are the receptors that recognize PAMPs and also mediate how the immune system will respond

Toll receptors are on the neutrophil and monocytes

• A family of receptors

- 10 members
- Cell membrane receptors (extracellular)
- Internal receptors (intracellular)

• There are TLRs against the PAMPs that are not
found on host cells

42
Q

Sensing microbial products inside and outside human
cells by different Toll-like
receptors

A

• Different TLRs activate different second
messengers
• Different second messengers turn on different
parts of the immune system
• First actions of immune response include TLRs
on dendritic cells and macrophages and
neutrophils which bind to extracellular
pathogens and initiate the immune response
• Depending on which type of toll-like receptor is binding the pathogen,
That is going to change the way the neutrophil,
Dendritic cell or macrophage. What cytokines that
Cell will secret which influences what type of
T cells are activated (is it primarily humoral or cell mediated)

43
Q

Activation of Different Toll-Like Receptors

A

• Secondary Messenger systems
• Transcription Factors
• Differentiation of T cells
o CD4 T cells
o CD8 T cells
o T reg cells
• If you make an antibody response against mycobactiera, you die quickly, if
you make a cell mediated response you live longer – for everything else it
doesn’t really matter as much if you have an antibody or cell-mediated
immune response

44
Q

Macrophage Activation (TLR)

A

• Neutrophils show up first
(phagocytosis), followed by monocytes which
differentiate into
macrophages

• TLR makes the macrophage phagocytic

• Cytokine secretion by macrophages
     o IL-1 (IL-18)/IL-6/TNFa
     o CXCL8 (IL- 
 (chemokine – recruits other cells)
     o IL-12
45
Q

Cytokines

A

Cytokines are small soluble proteins (short-lived) with a lot different functions and lots of overlap released by cells

46
Q

IL-1 beta = interleukin 1 beta and TNF- alpha = tumor necrosis factor alpha

A

These two cytokines also activate endothelium so that you have spaces between endothelial cells to make it easier
for immune cells to get into the extracellular space

47
Q

IL-6

A

IL-6 goes off to bone marrow to upregulate the production of macrophages/neutrophils; also goes to the hypothalamus to cause fever (so does IL-1)

bacteria replicates slower in higher temps

48
Q

CXCL8

A

Is a chemokine (similar to cytokines but its job is to recruit cells); tells macrophages/monocytes in bone marrow to go to site of infection

49
Q

IL-12

A

Activates another innate immune cell called a NATURAL KILLER CELL

In the absence of natural killer cell the IL-12 can kill some bacteria

50
Q

General Principles of

Cytokine Biology

A
  • Pleiotrophic: every cytokine has many activities
  • Redundant: activities of cytokines are so important that more than one cytokines can do the same activity

• Broad activity
> Non-immune effects in addition to immune functions

  • Families (structurally similar and similar functions)
  • Second messengers: receptor turns on second messenger, which turns on a transcription factor
51
Q

Cytokine Receptors

A

All cytokines work through receptors and, LIKE CYTOKINES, RECEPTORS COME IN FAMILIES

• Variable structure – by changing the structure you can change the
function of the cytokine
• Shared chains – this is why you have redundant function
o gp130
o gammac
o ßc

52
Q

IL-1 (IL-18) (interleukin)

A

Macrophage ctyokine

o Soluble inflammatory mediators

o Activate vascular endothelium

o IFNg production

o Systemic effects - goes to liver and cause C reactive proteins to go the bone marrow and increase production of innate cell and go to hypothalamus to cause fever

o Dendritic cells

53
Q

TNFa (tumor necrosis factor)

A

o Soluble inflammatory mediator
o Activate vascular endothelium

o Collapse venous return (ONLY TNFa does this)

o IL-1 production
- Wickedly potent activator OSTEOCLASTS!!!! (in tissue of mouth destroys bone)

o Systemic effects- goes to liver and cause C reactive proteins

o Dendritic cells

o Apoptosis

54
Q

Why is collapse of venous return good?

A
  • By clamping off venous return, the bacteria can only go into the lymphatic system, drain into lymph node, and destroy it (prevents bacterial spreading)
  • BUT what if you had cells throughout the body that could do this?
    > anaphylaxis shock!!!
55
Q

Adhesion and Diapedesis

A 
• Diapedesis allows leukocytes to go
through the endothelium to the site of
infection
• Leukocytes roll along the endothelium
and look for a space to crawl out of the
blood vessel wall into the surrounding
connective tissue
• When it rolls it makes and breaks low
affinity interactions with molecules on
the endothelium
• Red blood cells, on the other hand, do
not interact with the vessel wall
• This is only in the veins, not the arteries
CXCL8 on the endothelium
binds to the receptor on a
neutrophil, stopping it from
rolling, which allows
neutrophils/monocytes to
go through the cells
(diapedesis) to the site of
infection

General Pathology (2 decks)

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