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Immunology > Innate immunity > Flashcards

Innate immunity Flashcards

1
Q

What are the cellular components of innate immunity?

A 
Macrophages
Neutrophils
Mast cells
Immature dendritic cells
Natural killer cells
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2
Q

MPS (mononuclear phagocyte system)

A

The mononuclear phagocyte system includes circulating cells called monocytes and tissue resident cells called macrophages (histiocytes).
Long term residents derive from yolk sac and are called kuppfer cells, microglial etc..

Adult bone marrow derived monocytes (which require M-CSF and GM-CSF) can be recruited incase of inflammation:
INF-gama for M1 (classic activation)- Are proinflammatory cells (Th1+th17 activation).

IL4 and IL13 for M2 (alternative activation)- which is actually an antiinflammatory response- they mediate wound healing, supress T cell responses etc.

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3
Q

Macrophages phagocytose cells when they find a “find me” or “eat me” signal - What are these signals?

What is the ‘’Tolerate me’’ signals?

A

Find me: IL8 and MCP-1 (Monocyte Chemoattractant Protein-1)

Eat me: Phosphotidylserine on PM

Tolerate me: IL-10, TGF-beta and PGE2 (these factors suppress the immune respons)

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4
Q

How does neutrophils kill stuff?

A

Exacellular DNA trap

Frustrated phagocytosis (The bacteria is to big. Attaches to the surface via Fc receptors, lysosomal contents are released into ECS)

Degradation by lysosomal enzymes eg elastase
Intravesical killing (oxygen dependent and independent) (peroxidase dependent and peroxidase independent). Nitric oxide pathway (INFgama and TNFa)
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5
Q

Defensins, lactoperoxidase, lysozyme: Function

A

..

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6
Q

Which disease is associated with Phagocyte oxidase deficiency?

A

CGD (Chronic granulomatosis disease)

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7
Q

Function of NK cells

A

Kill virus infected and tumor cells

NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named “natural killers” because of the initial notion that they do not require activation to kill cells that are missing “self” markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Situations:
If the NK cell examines a cell without MHC
molecules or activating ligands, there is no
response
 If the NK cell examines a cell which express
only MHC molecules, there is no response
 If the examined cell express an activating
ligand(s) and no MHC molecules, the cell is
perceived as a non-self cell which is attacked
and eliminated by the NK cell
 If the NK cell examines a cell expressing both
MHC molecules and activating ligands, the
response is determined by the balance of the
signals

They have activating and inhibitory receptors
NKG2A (inhibitory)
NKG2D (activating)

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8
Q

What kind of membrane PRR do we have?

A

Lectin receptors - are sugar binding receptors and includes the traditional mannose receptors that is involved in the recognition of some.
This group includes- mannose receptors.. dectins etc.

NK cell receptors - receptors which includes the inhibitory and activating types (see NK cells)

Scavanger receptors - are receptors that scavenge the body for molecules to be removed. For example, one type of scavenger receptor is inovled in the uptake of excess cholesterol in the peripheral tissues (cholesterol is one of the most important causative agents of atherosclerosis)

Complement receptors - are involved in the recognition of complement proteins that are associated with the innate immune system

Toll like receptors (E.g. PRR) - are extremely important for the innate immune system as these receptors recognize structurally conserved molecules derived from microbes (pathogen associated molecular patterns or PAMP’s)
char:
Horse shoe shape
Leucine-rich repeats in the EXTRACELLULAR region, giving specifity to hydrophobic parts such as LPS of bacteria.
recognize PAMP (pathogen associated molecular patterns) recognition
very conserved structures

N-formylmethionyl receptor - is able to recognize N- formylmethionyl which is an AA reidue found in bacterial proteins and act as strong chemoattractants.

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9
Q

Binding to TLR lead to?

A

1: Binding of MyD88 adaptor
2: Ser/Thr kinase cascade
3: Phosphorylation of IkB  degradation
4: NFkB translocation to the nucleus
5: Transcription of proteins (E.g. IL1)

This allows the transcription factor NFκB to be translocated into the nucleus where it induces the
expression of co-stimulatory molecules and various cytokine.
Cytokines include- TNF and IL1,
chemokines- CCL2, CXCL8
type 1 interferone.

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10
Q

What kind of soluble TLR do we have?

A

1) Filcolins (sugar binding lectin).

Collecting family: Including- 2) Lung surfactant- act as mediators of innate response in lungs
and 3) Mannose binding lectin (lectin pathway)

Pentraxins-Pentameric proteins include:
4) CRP- C reactive protein and 5) Serum amyloid P (SAP) which activate the complement by binding c1q and initiating the classical way.

6) C1q
7) Lipolacin
8) LL37

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11
Q

Intracellular PRR

A

Nod-receptor (NLR) - for intracellular bacteria -> inflammasome (cytoplasmic multiprotein oligomerassembled from NLR, ASC and caspase 1 upon activation)

RIG-I-like receptors: virus recognition, helicase domain, cytoplasmic dsRNA recognition.

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12
Q

Function of RIG receptor

A

RIG-I-like receptors, abbreviated RLRs, are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system.

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13
Q

Examples for different TLR

A

TLR3: dsRNA
TLR4: LPS

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14
Q

What are the components of the “inflammasome” and what does it do? Is there any diseases associated with it?

A

Cytoplasmic multiprotein oligomer of NOD-like receptor (NLR), ASC (adapter protein) and caspase-1.

Important when cells are infected by bacteria.

When activated: Produce IL-1b, IL18, IL33 –> Proinflammatory mediators

Gout, atheriosclerosis, type 2 diabetes (hyperglycemia)
Shared feature: IL-1 beta secretion -> ”inflammasomopathies”

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15
Q

What is the function of M1 macrophages?

A
  • Proinflammatory
  • Antitumor immunity
  • Host defense
  • Promote TH1-TH17 immunity
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16
Q

What is secreted by M1?

A

IL-1
TNF
IL-12

17
Q

What is secreted by M2?

A

IL-1ra
decoy IL-1RII
IL-10

18
Q

What is the function of M2 macrophages?

A
  • Regulate wound healing
  • Suppress T cell responses
  • Suppress host defense
  • Suppress antitumor immunity
19
Q

Which factors are need to be present for M1 differentiation?

A

GM-CSF
LPS
IFN gamma
Bacterial products

20
Q

Which factors are need to be present for M2 differentiation?

A 
M-CSF
IL-4
IL-13
IL-10
Corticosteroids
PGE
VitD3
21
Q

Define opsonization

A

Facilitation of phagocytosis by binding of an antibody or a complement protein to the antigen.

22
Q

Fcγ receptor

A
  • Bind IgG
  • Facilitate phagocytosis (e.g FcγRI also called CD64)
  • Zipper mechanism, respiratory burst of macrophages
  • May supress the functions of B cells (via FcγR IIb, also called CD32 a subtype of this receptors.)
23
Q

Fcε receptor

A
  • Bind IgE

- High affinity form (FcεRI) is on mast cells and basophils, plays a role in allergy

24
Q

Poly Ig receptor

A
  • bind polymeric antibodies (IgA)

- play a role in transcytosis of antibodies through the epithelium of the mucous membrane

25
Q

FcRN receptor (neonatal)

A
  • bind IgG
  • transfer of passive humoral immunity from a mother to her fetus
  • protects IgG from degradation
26
Q

How does the intravesicular O2 dep killing by the neutrophils work?

A

In the oxygen-dependent mechanism, an enzyme located on the surface of phagosomes within the neutrophils, NADPH oxidase, are able to use O2 in order to generate ROS, like hydrogen peroxide (H2O2) which can attack and kill the internalized pathogen within the phagosome
-  Another pathway of the O2 dependent killing involves the myeloperoxidase enzyme which is associated with lysosomes
- This enzyme will utilize the H2O2 generated by the NADPH oxidase to produce other toxic oxidants like hypochlorous acid which will attack and kill the pathogen(s)
 In this way there are actually 2 O2 dependent pathways, the peroxidase-independent and the peroxidase-dependent pathway

27
Q

how does the intravesical O2 independent killing by the neutrophils work?

A

The O2-independent pathway utilize NO generated by inducible intracellular nitric oxide synthase (NOS), which can be activated by binding cytokines like TNF and IFNγ
- When activated, the NOS enzyme will generate citrulline and NO from arginine and O2, and the NO produced (which is highly toxic) are used to kill the pathogen(s)

28
Q

Innate vs adaptive

A 
Innate:
limited receptor specificity
no latency to react.
no memory
linear increase
Includes macrophages, granulocytes, mast cells, immature dendritic cells (DC), complement system, natural autoantibodies, innate lymphoid cells
Adaptive:
 high specificity
 latency (1-2 weeks)
 memory
 exponential amplification
 includes T,  B cells & antibodies
29
Q

Phases of immune response:

A
  1. Recognition Phase: activation and blast formation
  2. Central Phase: clonal proliferation and differentiation
  3. Effector: destruction and elimination of the pathogens
30
Q

Prim vs. Secondary immune response:

A
  • Primary: slower (longer latency), lower amplitude, predominantly IgM production
  • Secondary: faster (shorter latency), higher amplitude, predominantly IgG production
  • The primary takes so long because of selection, activation, proliferation and differentiation time
  • If the person meets antigen again, there is a secondary immune response which is much faster due to memory cells
31
Q

Homeostatic balance of the immune system- examples:

A

regulatory:
Treg, TH2, Breg, DCreg, Mreg (M2),
Inhibitory receptors (e.g. NKG2A)
Inhibitory cytokines (IL10, TGF

Effectors: 
T cells (TH1, TH17), B cell, DC, M, NK cell
Activating receptors (e.g. NKG2D)
TH1 cytokines (e.g. IFN)
32
Q

Char. of the innate system response:

A

A universal and evolutionarily conserved
First line of defense
Its receptors are fixed in the genome, do not undergo rearrangement, non-clonal, all cells of a class have identical
Recognition of conserved molecular patterns
Found in all multicellular organisms
Defects in innate immunity are very rare and almost always lethal

33
Q

barriers of the innate system:

Molecules of the innate system:

A

Mechanical: skin, mucosal membranes, mucus, epiglottis & palpebral reflexes

Biological: normal flora

Chemical: skin pH: 5.5; stomach 1.2-3; vagina 4.5;
pus 5.5-6; pancreatic juice 8; sebum, ROS, NO

Biological: lactoperoxidase (saliva, colostrum), lysozyme (tear, sweat, saliva), maternal antibodies, natural IgM antibodies, polyamines

Molecules of the innate system:
Complement system

Natural autoantibodies

Other: soluble antimicrobial molecules:
Defensins:
Most defensins are amphipathic molecules that have clusters of positively charged amino-acid side chains (pink) and hydrophobic amino-acid side chains (green). They cause the formation of membrane ‘wormholes’.

Lyzozyme in saliva- - Lysozimes in saliva cut the peptidoglycan bacteria wall thereby killing them. This is present in saliva and tears,

  • Lactoperoxidase
    reaction: acceptor + H2O2→ oxidized acceptor + H2O
34
Q

Leukocyte extravasation

A

Endothelial cells are activated by TNF, IL-1 and express
E-selectin and P-selectin at postcapillary venules
This interact with Sialy-lewis glycolipids in leukocytes.

Chemokine mediated increase in affinity of integrins- eg. CXCL8R on leukocytes.

Stable integrin mediated adhesion of leukocytes to endothelium.
Endothelium express- Vcam-1 Binds to VLA-4 leukocytes.
It also expresses- ICAM which binds to LFA-1.

diapedesis follows with migration to a chemoattractant chemokine.

LTB-4= Leukotriene B4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammatory mediators and is able to induce the adhesion and activation of leukocytes on the endothelium, allowing them to bind to and cross it into the tissue.[1] In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosomal enzymes by these cells.

Cx3cr1 is a chemoattractant for later stages- monocytes etc.

35
Q

subtypes of dendritic cells:

A

The conventional dendritic cells (cDC, previously called myeloid dendritic cells) are divided into type 1 and 2
 Type 1 (cDC1) represents the majority, and express CD1c (they are CD1c positive)
 Type 2 (cDC2) are less numerous and express CD141 (CD141 positive)
 Both types express CD11c, however, cDC1’s are more CD11c positive

There is another type of dendritic cell that resembles plasma cells, hence their name, plasmocytoid dendritic cell (pDC). This type is also quite numerous and express/are positive for CD11c and CD123.
They produce a lot of type 1 interferon.

36
Q

surface receptors of phagocytes-

A

The opsonic receptors include the Fc and complement receptors which recognize materials that are wither labelled with complement molecules
(complement receptors) or antibodies (Fc receptors)

The PRR’s will recognize and internalize molecules based on their recognition of pathogen-associated molecular patterns (PAMP’s) which are conserved molecular patterns associated with various pathogen

37
Q

Leukocyte adhesion deficiency:

A

This is a rare immunodeficiency disease caused by the lack of adhesion molecules- LFA-1 and VLA-4.
(selectins or integrins) on immune cells like lymphocytes, monocytes and neutrophils
o This prevents these cells from migrating to infected tissues and often leads to
severe or even fatal bacterial infections, as the immune cells are unable to
reach the infected tissue to fight the pathogens/bacteria

38
Q

Which cells belong to the innate-like system?

A 
iNKT cells
MAIT cells
Gamma-delta T cells
B1 B cells
Marginal zone B cells
Innate like cells (ILCS)
39
Q

Innate lymphoid cells

A

These cells are a fairly new discovery, and their function is still being investigated.
What we do know is that they can be divided into 3 subtypes,
the type 1 which produce interferon γ (IFN γ, e.g. NK cells),
type 2 which produce cytokines originally attributed to T- helper 2 cells (e.g. IL-4)
type 3 which produce IL 17 and 22, and.

ILCs and T cell subsets allies in the immune system against microbes
They have diversity in cytokine production comparable to that of T cells
They are independent of Ag-specific interactions, they lack rearranged receptors
They represent optimal early defense against bacteria, parasites and viruses
They are also characterised by plasticity
ILCs lack markers of mature lymphoid cells
They bear receptors commonly found on lymphoid progenitors
They regulate homeostasis of the mucosa (gut, lungs), skin, adipose and lymphoid tissues
They have the capacity to secrete large amounts of cytokines
Their distinct subsets derive from a common precursor cell
Themselves do not give rise to further progenitors

Immunology (12 decks)

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