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Immunobiology > Pensum noter > Flashcards

Pensum noter Flashcards

1
Q

Barriers and non-immune antimicrobial defenses

A

Epithelial cells with tight junctions (skin) cilia, mucus saliva and tears, digestive tract, microbiota. Neutrophils.
Production of anti-microbial proteins = defensins, cathelicidins, histatins. All are activated by proteolysis→ a pro-region is cleaved of for activation and the result is an amphiaphatic antimicrobial peptide
Defensins - disrupts cell membranes of bacteria and fungi, and envelopes of some vira (epithelial and neutrophils) by forming a pore.
Cathelicidins - cationic amphipathic plasmide that disrupts membranes and is toxic to microorganism (Neutrophils)
Histatins - Cationic peptides that are active against fungi and promote rapid wound healing (oral cavity)

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2
Q

Pathogens:

A

Extracellular - interstitial spaces , blood, lymph (complement, phagocytosis, antibodies, autophagy) and epithelial surfaces (antimicrobial peptides and antibodies)

Intracellular - cytoplasmic (NK cells and cytotoxic T cells), vesicular (T cell and NK cell dependent macrophage activation)

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3
Q

Tissue damage Infection

A
  • Direct damage:
    Exotoxin production, endotoxin and direct cytopathic effect
  • Indirect damage
    Immune complexes, anti-host antibody and cell mediated immunity
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4
Q

escape the immune system and non immune system

A

-Anti-Crispr proteins
-MHC-1 cannot migrate to the surface and therefore cannot present viral peptides to CD8 t cells.
-Escape the phagosome into the cytosol.
-many others

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5
Q

Innate immune system

A

Macrophage, dendritic cells, Neutrophils, Eosinophils, Basophils, Mast cells, NK cells, Autophagy and Complement system

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6
Q

Macrophages

A

Tissue residents
- Antigen presentation
- Secretion of cytokines
- Production of complement and macromolecules needed for tissue repair
- Can activate complement
- M1 and M2

Activation
- Cytokines
- Pamps (TLR, NLR)
- Complement receptors (C5a and C3a)

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7
Q

Dendritic cells

A

-PAPC (presents both MHC class I and II)
- lymphoid organs, blood, tissues
-Macro and pinocytosis
- Capture antigen and bring it to the secondary lymphoid organs where an immune response is initiated

Activation
- By pamps and cytokines

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8
Q

Types of dendritic cells

A

Conventional dendritic cells
- Circulates peripheral tissue
- Binds antigen and migrate to secondary lymphoid organs
- PAPC most potent stimulators of T-cell response

Plasmacytoid dendritic cells
- Can also act as antigen presenters
- Main function during inflammatory response is the production of antiviral interferons

Follicular dendritic cells
- present antigens to B-cells
- Reside in lymphoid follicles
- recognizes BAFF and APRIL, promote B-cell survival and proliferation

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9
Q

Cross presentation

A

presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8(+) T cell responses.
There will however occur a leak of MHC class II, in the vacuolar pathway.

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10
Q

Neutrophils

A

-Phagocytosis and killing of ingested microorganisms
-Phagosome fuses with granules to destroy internalized bacteria= oxygen dependent respiratory burst
-First to arrive at the crime scene
-NOT APC’s

Activation
Activated by cytokines for recruitment to the site of inflammation. Rolls over endothelial cells and via various ligands and receptors gets into the infected site. (vasodialation slows down the bloodflow, so the neutrophil has time to make proper contact)

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11
Q

Oxidative burst

A

Rapid release of reactive oxidative species
- fMet activates Rac
- RAC assembles NADPH oxidase complex
- NADPH oxidase transfer free electrons to O2, generating superoxidase ions and other free oxygen radicals
- Acidification leads to lysosomal protease activation and formatting of H2O2, killing all microbes.

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12
Q

Eosinophils

A
  • engage both in secretion of pre-formed granule-stored contents, including eosinophil specific toxic proteins, enzymes, cytokines, chemokines, and other bioactive mediators
  • Masters of exocytosis
  • Killing of antibody-coated parasites

Activation
Can be activated by cross-linking IgG and IgA Fc receptors by agarose beads with IgG, IgA or secretory IgA (being the most potent). Activation by cytokines.

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13
Q

Mast cells

A
  • Release of granules containing histamine and active agents
    -Found in tissues not blood
    -Express IgE and complement receptors

Activation
Activated by IgE bound to mast cells

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14
Q

Basophils

A

-Promotion of allergic responses and augmentation of anti-parasitic immunity
-Induce inflammation
-Can function as APC in inducing Th2 response against helminth parasites allergens.

Activation
activated by antigen crosslinking of FceRI receptor-bound IgE to undergo rapid degranulation and release their cellular contents and by inflammatory mediators (complement factors C5a and C3a)

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15
Q

NK-cells

A

-Releases lytic granules that kill some virus-infected cells and tumor cells
- NK cells are either activated by ITAM or inhibited by ITIM

Activation:
If they do not bind MHC-class 1, they release granules which kill the target cell (important in cancer regulation)

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16
Q

ILC

A
  • promote host defense and contribute to tissue and metabolic homeostasis, wound healing and immune surveillance
  • effector cells which lack re-arranged antigen-specific receptors
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17
Q

Autophagy

A

Happens inside the cell, and is induced by starvation, pathogens (pamps) protein aggregates and ssRNA. Promoted by NOD1 and NOD2 sensors, p62, NDP52, Optn and TLR7.
TLRs are dependent on the classical pathway NOD is not.

  • Mechanical stress Inhibit TOR, which inhibits ATG, this induce autophagy.
  • ATG6 and class III P13K complex activates ATG
    1. ATG16 conjugate system, ATG12,5,16 complex
    2. ATG8 conjugate system
  • ATG induces isolation membrane expansion, in creation of autophagy vacuoles
  • Fusion with lysosomes and the degradation of protein
    LC3 is a marker for autophagy

Functions in the recycling of intracellular components, host defence and degradation of harmful proteins.

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18
Q

Complement:

A
  • Lectin
    Triggered by the PRR, MBL and ficolins
  • Classical
    Triggered when C1q recognizes a microbial surface directly or binds to antibodies
  • Alternative
    Utilizes spontaneous C3 deposition onto microbial surfaces, augmented by properdin and amplification loop for the two other pathways.

All pathways generate C3 convertase, which is cleaved to C3a and C3b. C3a is free and C3b is bound to the microbial surface.
- C3a and C5a recruits phagocytic cells to site of infection and induce inflamation
- Phagocytes with C3b receptors bind and undergo phagocytosis
- All pathogens generate a C5b convertase that leads to formation of C9 molecule membrane attack complex (MAC), which disrupts cell membranes.

C3b → cleavage of C5 to C5a.

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19
Q

Inhibitors and regulation of complement

A

Factor I → cleaves C3b to iC3b
CR1 and DAF inhibits C3 convertase formation
Factor H → binds to C3b, and thereby inhibits further binding

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20
Q

Cytoplasmic acid sensors

A

Induce type 1 interferon INF-alpha, beta and w
RIG-1
- Detects viral dsRNA by sensing differences at 5´-capped end (triphosphate)
- Activates CARD to induce production of type 1 interferon
MDA-5
- Detects longer viral dsRNA
- do not need 5´-capping to detect
cGAS
- Binds directly to cytosolic DNA
- Activates STING through cGAMP binding, which stimulates interferon genes

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21
Q

Adaptive immune system

A

B- and T-cells

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22
Q

T cells

A
  • Resting T-cells: Express CCR7 and reside in T-cell zones
  • Activated T-cells: induce CXCR5
  • Some T-cells retain EB12 and remain

CD4 function: T helper cells, amplifies and regulates responses to infection, helps b cells in affinity maturation, binds to MHC II.
CD8 function: Cytotoxic T-cells. Kills cells in intracellular infections

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23
Q

T cell maturation

A
  • T-cell progenitor develop in the bone marrow and migrate to the thymus
  • Commitment to T-cell lineage happens after Notch signalling, which initiate rearrangement.
    Double negative:
  • Pro-T cell
    1. DN1 → enters the thymus
    2. DN2 → enter Cortex
  • Pre-T cell
    3. DN3 → VDJ recombination
    4. DN4 → tested for MHC affinity
    Double positive: VAlpha → Jalpha recombination happens
    5. CD4 + CD8
    6. TCR
    7. Negative selection → high affinity to MHC undergo apoptosis
    8. Positive selection → low affinity to MHC survival signal is received
    9. Alternative selection → somewhat higher than low affinity to MHC, they become Treg
    Single positive:
    10. T-cells expressing TCR become CD4 or CD8 depending on THPok or RunX3 and affinity to MHC II or MCH I, interact with macrophage and epithelial cells.
    1 and 10 happens in medulla and 2-9 happens in cortex, in the thymus.
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24
Q

Fibroblast reticular cells (FRCs)

A
  • Lymph node stromal cell found in T-cell zone of lymph node cortex
  • Creates collagen-rich reticular fibers that guide DCs, T lymphocytes and B lymphocytes
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25
Q

T cell activation

A

T cells are activated when encountering foreign antigen presented on MHC I or II with the co stimulatory signal from CD28 and B7, combined with an array of different cytokines. It can also happen in a non MHC activating pathway, this is when a t cell is activated by an array of cytokines and an activation by microbes for example TLR and NLR activation.

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26
Q

TCR

A

T-cell receptor comlex is made up of a variable antigen-recognition proteins and an invariant signaling protein.
- Antigen-binding TCRalphabeta heterodimer is associated with CD3.
Signaling from the T-cell receptor is initiated by ITAMs (10 ITAMs)
Instead of a light and heavy chain, it has an beat and alpha chain
- Always reside in the plasma membrane.
- 1 antigen binding site

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27
Q

Allelic exclusion

A

Expression of one of two alternative genes of a gene
→ Restricted expression of antigen receptor genes => immunoglobulin and TCR of a single antigen specificity.

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28
Q

MHC I

A
  • Expressed on all nucleated cells
  • TCR recognizes MHC
  • CD8 binds to the side of the MHC
  • Intracellular peptides
    MHC class 1 binds to chaperone proteins, and binds to TAP via tapasin
    Cytosolic proteins are degraded to peptide fragments by the proteasome
    TAP delivers peptides to the ER. This is further cut by ERAAP.
    A peptide binds to the MHC class 1 molecule and completes its folding
    MHC molecule is released from the TAP complex and exported to the cell membrane
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29
Q

Detective Ribosomal products

A
  • Peptides translated from introns in improperly spliced mRNA, translation of frameshift, improperly folded cytoplasmic proteins and membrane or secreted proteins that fail to enter ER
  • Tag with ubiquitin for degradation
  • Might help to generate peptide substrates from self-proteins and pathogen proteins for presenting by MHC I
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30
Q

MHCII

A
  • Found on antigen presenting cells (B-lymphocytes, dendritic cells, macrophages)
  • CD4 binds to the side of the MHC
  • Extracellular peptides
    Invariant chain (Li) inhibits the binding of peptides and misfolded proteins, Li is cleaved in the acidified endosome. CLIP is still bound, CLIP peptide blocks the binding of peptides and prevents the migration of MHC II. HLA-DM binds to MHC II releasing CLIP, peptides can then bind to MHC II and MHC II migrates to the cell surface.
31
Q

Non-conventional T cells

A

MAIT
- Present in mucosal immune system
- respond to bacterially folate derivates presented by non-classical MHC MR1

INKT
- Innate-like lymphocyte carries T-cell receptor invariant alpha and beta chain
- Recognizes glycolipids presented by CD1 MHC class
- Surface marker NK1 (same as NK cells)

32
Q

T memory cells

A

IL-7 R is a true marker for memory T-cells that is only expressed on memory cells.

Central memory T-cells(TCM):
Arise from a primary T-cell response.
- Express CD62 and CCR7
- Recirculate in blood and secondary lymphoid organs.
When antigen is recognized they get a recall response, and undergo rapid effector T-cell proliferation.
Slower to acquire other effector functions,

Effector memory T-cells (TEM):
Arise from a primary T-cell response.
- Lack CD62 and CCR7, but express high levels of beta1 and beta 2 integrins.
- recirculate in blood and are rapidly recruited into inflammatory tissues where they initiate T-cell responses after restimulation.
- express receptors for inflammatory chemokines and can rapidly mature into effector T cells, that secrete effector cytokines (IFN-gamma, IL4 or IL17)

Tissue-resident memory T (TRM):
Take up longterm residency in various barrier sites
- Lack CCR7, but express other chemokine receptors (CXCR3 and CCR9) → allow migration into peripheral tissues
- Express CD69, which reduces S1PR1, thereby promoting retention in tissues.
- Can be both CD4 and CD8 T cells
- Rapid response to TCR signaling or cytokines
- surveillance and can initiate a particular immune module response locally

33
Q

Type 1 response

A

Activated by IL-12, IL-15 and IL-18

T- cells: TH1
Pathogens: functions against intracellular bacteria
Effect:
- IFN-gamma and CDL40 induce and activate M1 macrophages
- FAS ligand and LT-beta, produced by Th1 cells, induce apoptosis
- Il-2 produced by Th1 cells acts on activated naive CD4 and CD8 → alters balance to favor Th1 cells from TFh and CD8 CTLs and memory.
- IL-3 and GM-CSF stimulate production of monocytes in bone marrow
- Produce TNF-alpha and LT-alpha acts on blood vessels and induce binding and exit of monocyte.

Cytokines: IFN-gamma, CDL40, IL-2, IL-3, TNF-alpha and LT-alpha

Effector function: proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses, via induction of macrophages and monocytes.

34
Q

Type 2 response

A

Activated by IL-25 and IL-33

T-cells: Th2 cells
Pathogens: Helminth infections and parasites
Effects:
- IL-13 induce epithelial cell repair and mucus production → increased turnover and movement, which shreds parasitized epithelial cells. Mucus prevents adherence.
- IL-13 induce smooth muscle contraction → enhance infection expulsion
- M2 macrophages recruited via. IL-4 and IL-13 → enhance smooth muscle contractions and tissue repair.
- IL-5 recruits and activates eosinophils
- Mast cell recruitment via. IL-3 and IL-9 and specific IgE mast cell arms against helminths. → produce mediators as histamine, THF-alpha and MMCP → inflammatory response and remodel mucosa.

Cytokines: IL-13, IL-4, IL-5,IL-3, IL-9

Effector function: Increases epithelial turnover and mucus production, increase smooth muscle contraction, recruit and activate M2 macrophages → tissue remodeling and repair, recruitment and activation of eosinophils, enhance inflammatory response (mast cells)

35
Q

Type 3 response

A

Activated by IL-23

T-cells: Th17 cells
Pathogens: Infections agianst extracellular bacteria
Effects:
- IL-17 and IL-22 induce production of antimicrobial peptides → kills or inhibts growth of bacteria attached to epithelium
- IL-22 increase epithelial turnover
- IL-17 activates stromal cells and myeloid cells to produce G-CSF → stimulate neutrophil production
- IL-17 activates stromal cells and epithelial cells to neutrophil attracting chemokine production.
- CGL20 chemo-attractment of other Th17 cells

Cytokines: IL-17, IL-22, G-CSF and CGL20

Effector function:
recruitment of neutrophils and the stimulation of epithelial antimicrobial defenses at infection sites

36
Q

Treg

A

Activation: Inhibited by IL-6, produced by DCs

Function: Suppress immune responses, 1 and 2, and are able to inhibit T-cell proliferation and cytokine production, plays a critical role in preventing autoimmunity.

Markers: CD25 and CD127, FowP3 intracellular.

37
Q

TFH

A

antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer’s patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5

Function: Upon cellular interaction and cross-signaling with their cognate follicular B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate from T cell zones into these seeded germinal centers.

  • Play a critical role in mediating the selection and survival of mature B cells or germinal center-dependent memory B.
38
Q

B cells

A
  • Resting B-cells: Express CxCR5 and reside in follicles
  • Activated B-cells: induce CCR7 and EBI2
39
Q

B cell maturation

A

Stem cells responds to cytokines to coordinate VDJ recombination and development of B-cells.
- Early pro-B cell D-J rearranging heavy chain
- Late pro-B cell V-DJ rearranging heavy chain
- Large pre-B cell VDJ rearranged, mhy chain transiently at surface
- Small pre-B cell V-J rearranging light chain
- Immature B cell VJ rearranged light chain → IgM expressed on surface
Rag is high during the rearranging of light and heavy chain

The immature B-cell is tested for autoreactivity (central tolerance)
1. Multivalent recognition of self-antigen → apoptosis or receptor editing
2. Weakly cross-linking self-antigen → apoptosis due to unresponsiveness
3. Non-crosslinking antigen → immunological ignorance to antigen
- Complete maturation in spleen → tested for BAFF-R, BCR, affinity and cross-linking. (if low affinity and non-crosslinking => mature B-cell)

40
Q

Secondary and primary diversification

A

VDJ recombination → Primary diversification
Recombination occurs between gene segments on the same chromosome
- RAG1/2 is essential for the recombination and is followed by the NHEJ and DSBR
1. Binding of RAG1/2 to 23 RSS and 12RSS → leads to cleavage of DNA
2. Ku70/Ku80 binds DNA ends
a. Artemis:DNA-PK opens hairpin structure, the cut ends are modified which randomly add and remove nucleotides → then ligated by DNA ligase IV
b. DNA ligase IV ligase DNA.

CDR1 and CDR2 reside in the V region, CDR3 is formed by the VJ joining.

AID → secondary diversification
Enzyme important in secondary diversification
- Initiates somatic hypermutation and class switch recombination
AID → MMR
TLS → BER → APE1 → gene conversion → class switch recombination
- Happens at the immunoglobulin V-region

41
Q

Somatic hyper mutation

A

Mutations in V-region DNA of rearranged immunoglobulin genes that produce variant immunoglobulins, for higher affinity to antigen.
-Increases affinity and specificity towards the antigen

42
Q

Class switch

A
  • Somatic gene recombination in activated B-cells
  • Replace a heavy-chain constant region with a different isotype
  • Switching immunoglobulin isotype (IgI→IgA)
43
Q

Allelic exclusion

A

Expression of one of two alternative genes of a gene
→ Restricted expression of antigen receptor genes => immunoglobulin and TCR of a single antigen specificity.

44
Q

B-cell activation

A

First signal required for B-cell activation is delivered through BCR  migrates to germinal center of secondary lymphoid tissue
- B-cells take up antigen through BCR phagocytosis and present antigen derived peptides on MHC class II
- T cells express CXCR5 and B cells express CCR7
- TFH cells recognize MHC II secrete cytokines, to deliver the second signal
- CD40L binds to CD40
- NF k beta is activated
- NFk beta activates NIK, which stimulates pro-survival genes eg. Bcl-2
- B cells migrate near the follicular and proliferate into B cell plasmoblasts and B cell memory cells

45
Q

B cell types

A

B1: Secretes IgM (anti polysaccharide antibody) and binds IL-5 without help form T-cells.
- Plasmacells: secrete antibodies
- Plasmoblasts: Secrete antibodies, but retain surface Ig and MHC II molecules, migrate to bone marrow

B2(follicular): B-2 cells are a subtype of B cell. They form part of the adaptive immune response and mediate humoral immunity. B 2 cells can produce high-affinity antibodies and generate immunological memory. B-2 cells are often used synonymously with classical B cells.

B-memory cells:
B memory cells arise from germinal center reaction during primary response. They express a class-switched surface and reside in the blood. They are poised to generate more rapid and robust antibody.

46
Q

Primary lymphoid tissues

A

Bone marrow
b cells develop in the bone marrow and is checked for central (self) tolerance before leaving.

Thymus
t cells develop in the thymus, and are also checked for central tolerance before leaving.
t cells upregulate S1PR1 to leave thymus

47
Q

Secondary lymphoid tissues

A

Peyer´s patches
Mucosal immune system, gut associated lymphoid lymphoid tissues(GALT) Peyer’s patches

Peyer’s patches = groupings of follicles in the mucus membrane and is covered by an epithelial layer containing M-cells which have ruffels, reside in the small intestine

Lymph node
Paracortical area (T-zone) → produces T-cell and DC attracting chemokines (CCL21 → CCR7)
primary lymphoid follicle (B-zone) → produce a B-cell attracting chemokine (CXCL13 → CXCR5)
Germinal center
germinal centre (GC) of lymphoid organs is the main structure where antigen-activated B cells diversify their immunoglobulin genes by somatic hypermutation
-Follicular B cells in lymph nodes transport antigen to FDC’s

The spleen
Marginal zone: Dendritic cells, macrophages, and B-cells
B-cells in marginal zone transport antigens to FDC’s

Pals: T cells and dendritic cells

  • B and T-cells both migrate to follicular and interfollicular regions
  • B and T-cells aggregate at periphery of follicles (B-cells reduce CCR7)
48
Q

Antibody structure

A

-2 heavy chains
-2 light chains
-Held together by disulfide bonds
-Immunoglobulin fold= One β sandwich of two β sheets folded together and linked by a disulfide bond
-Variable regions(fab)= recognize antigen (proteins or haptens)
-Constant regions(fc)= dictate antibody class and isotype (effector function)
-Paratope= the region of the antibody that recognizes the epitope
-Idiotope= amino acid residues that do not have direct contact with antigen, but still contribute to antigen recognition
-Antibodies bind antigen via non-covalent interactions (e.g electrostatic forces)
-CDR= hypervariable regions that interact with antigen (v-type) CDR3 region is the most critical in antigen recognition and specificity (CDR1 and CDR2 are also important)
-C-type=no variability

-B-cell receptor can be in soluble or bound within TM domain

49
Q

IgA

A

Major antibodies in extracellular fluid. Neutralization. Can be secreted as dimer because of J-chain.

50
Q

IgD

A

Blood, not very abundant, effector function not well characterized

51
Q

IgM

A

Blood stream, constant region provides strong activation of the complement system. First antibody to be expressed on naive B-cells. Can be secreted as pentamer because of J-chain.

52
Q

IgE

A

mucosa. Often found in the skin. Associated with allergy. Defense against parasites by recruiting mast cells. Mast cells can secrete toxic compounds towards the parasite.

53
Q

Inflammation IgE:

A

Sensitization
- Der p 1 is taken up by DCs for antigen presentation and T-cell priming
- TFH/TH2 cell induce B-cell switch to IgE production
- IgE binds to FCepsilonRI on mast cell
- Mast cell granule content cause allergic symptoms
Re-exposure
- Mast cell IgE bound to FCepsilonRI recognizes antigen
- Mast cell secrete histamine, prostagladins and leukotrienes
- Inflammatory cascade produced by mast cell activation is amplified by eosinophils, basophils, TH2 lymphocytes and B cells

54
Q

IgG

A

most abundant isotype, in the blood. Several effector functions. Can be transferred to the fetus through the placenta. Activate complement (though not as strongly as igG).

55
Q

Therapeutic antibodies:

A

Opzonization, neutralization and vaccines

56
Q

Autoimmunity genetic

A

Allergy:
- Genetic
Main reason for developing an allergy= Susceptibility loci, these genes make it skewed towards TH2 response
IL4: IgE (promoter mutations high IgE)
TIM genes: Th1 and Th2
(p40) IL12 IL23: Th17

57
Q

Autoimmunity enviromental

A
  • Environmental
    Early exposure to ubiquitous microorganisms
    Eary depletion of microorganisms by repeated use of antibiotics
    Helminth infection
    Hepatitis A virus
    Composition of gut commensal microbiota.

Atopic individual: People who are allergic

58
Q

NON IgE autoimmunity

A

Hypersensitivity reactions can be mediated by TH1 and T17 cells and CD8 cytotoxic T cells.

59
Q

Chemokines

A
  • CXCL13 → produced in the follicle and the light zone of germinal centers that bind CXCR5
  • CXCL12 → produced by stromal cells in dark zone of germinal center binds CXCR4 expressed by centroblasts.
  • CCL21 → produced by DCs and stromal cells in T cell zones in lymph nodes that binds CCR7, attract naive T cells
60
Q

Cytokines

A

Pro-inflammatory cytokines
- IL-1 → macrophages and epithelial cells (permeable influence transport of immune components and sticky to leukocytes)
- TNF alpha → Macrophage, DCs, NK and T cells (epithel permeable influence transport of immune components and sticky to leukocytes)
- IL-6 → macrophages, T-cell and epithelial cells (promotes adaptive immune response)

  • IL-12 → macrophages and DCs
  • IFN alpha → DCs and viral infected cells
  • IFN beta → viral infected cells
  • IFN-gamma → see type responses above
  • IL-2 → T cell growth factor
  • IL-3 → monocyte and mast cell recruitment
  • IL-4 → B-cell activation and M2 recruitment
  • IL-7 → marker for memory B-cells
  • IL-13 → Stimulates turnover and smooth muscle contraction
  • IL-17 → induce activation of antimicrobial peptides and stimulate neutrophil production and attachment.
  • IL-21 → germinal maintenance
  • IL-22 → production of antimicrobial peptides
  • IL-25 → TH2 cytokine production, activates TH2 response and ILC-2
  • IL-33 →TH2 cytokine production, activates TH2 response and ILC-2
  • LT-beta → induces apoptosis
  • TNF-alpha → promotes inflammation
  • FAS and FAS ligand → cationic independent toxicity and apoptosis
  • TRAIL → apoptosis of tumor cells and activated T cells
  • APRIL → B cell proliferation
61
Q

Autokrine

A

Cytokines affecting behavior of the cell that releases the cytokine

62
Q

Parakrine

A

Cytokines affecting adjacent cells

63
Q

Endokrine

A

Cytokines affecting distant cells, depends on their ability to enter circulation and half-time in blood.

64
Q

Receptors, ligands and integrins

A
  • CCR7 → Expressed by all naive T and B cells, binds CCL19 and CCL21 made by DCs and stromal cells in lymphoid tissue.
  • CCR9 → expressed by DCs, T cells, thymocytes and binds CCL25 and mediates recruitment of gut-homing cells
  • CXCR5 → Expressed by circulating B cells and activated T cells, bind CXCL13 and direct cell migration into follicle
  • CD40 and CD40L → CD40 on B-cells and CD40L on TH cells, co-stimulatory molecules required for the proliferation and class switching. Also expressed by DCs and CD40-CD40L interaction provide co-stimulatory signals to naive T cells
  • CXCL8 → produced by monocytes, macrophages (under inflammatory response) attract neutrophils and naive T cells.
  • P-selectin → Reside on activated endothelial cells
  • LFA 1 (integrins) → Reside on leukocytes binds to I-CAM 1
  • I-CAM 1 → reside on activated endothelial and leukocytes, binds to LFA 1
  • G-proteins → act as molecular switch in signal pathways (GPCR) to induce high affinity with LFA 1.
  • CD28 → activation receptor on T cells that binds to the B7 co-stimulatory molecules present on APCs.
  • BAFF → acronym for B-cell activating factor, binds to BAFF-R and TACI promote B cell survival.
65
Q

CRISPR

A

Consists of cas genes, leader and repeat-spacer array
- Class 1 is a multiprotein complex
- Class 2 is a single protein
PAM adjacent protospacer motif and CRISPR protospacer is required for cas nuclease to recognize target and cut
1. Short viral DNA is incorporated as a novel spacer into CRISPR array
2. During expression CRISPR array is transcribed into pr-CRISPR RNA → mature crRNA with unique CRISPR spacer
3. During interference, crRNA guide CAS effector nuclease → sequence-specific cleavage
- Class 1, Cas 3 nicks DNA and Cas 10 cleaves
- Class 2, Cas 9 nicks DNA and Cas 12 offset two nicks
Altering CRISPR spacer or PAM → gain or loss of function
→ Can be used in antimicrobial, anti-infective and genome editing systems

66
Q

NLRP3

A

Caspase 1 is a hallmark for NLRP3 activation and NOS2 is a hallmark for classical activated M1 (inflamasome deficient mice)
- NLRP3 form oligomers, which brings multiple NLRP3 pyrins together
- Interacts with ASC pyrine domain
- Aggregates ASC CARD domain
- Aggregates Caspase 1 CARD domain, including proteolytic cleavage of caspase 1 => caspase 1 activation
- Cleavage of IL-18 and IL-1 => cytokine release
Reduce amyloid-beta phagocytosis, which inhibit long term protentiation (LTP) and therefore contributes to ALZ

67
Q

Neutrophil trails

A

Essential for CD8 T-cell recruitment and effector functions.
- Neutrophils are important in initiating and maintaining immune reactions
- Leave CXCL12 trails on ICAM-1 coated surfaces
- Neutrophils leave behind membrane trail, containing CXCL12
- CD8 T-cells become more localized, with lower velocity and displacement

68
Q

Tuft cells

A

Pou2f3 gene is essential for tuft cell specification
- Produce IL-25 upon infection of helminths and percentage of proliferating tuft cells in crypts increase
- Regulate ILC2 and TH2 production
- Induces production of IL-4 and IL-13 which initiates a type 2 response, IL-13 also acts as a positive feedback loop, as they amplify tuft cell lineage
- Epithelial remodeling → goblet cell hyperplasia and changes in mucus composition

69
Q

RNF 213

A

RNF 213 acts as a E3 ligase and require the presence of ATP as well as E1 and E2 enzymes. RNF213 starts focally and spread around bacteria
- Independent of RING domain in autoubiquitination
1. RNF213 mediated ubiquilation
2. LUPAC recruitment
- Required for NEMO and Optn recruitment
- p62 and NDP52 only require RNF213
3. Addition of M1-linked ubiquitin chains
4. Recruitment of NEMO (induce inflammation) and Optn, p62 and NDP52 (induce autophagy)
RNF213 restore recruitment of autophagy marker LC3

70
Q

RNF 213

A

RNF 213 acts as a E3 ligase and require the presence of ATP as well as E1 and E2 enzymes. RNF213 starts focally and spread around bacteria
- Independent of RING domain in autoubiquitination
1. RNF213 mediated ubiquilation
2. LUPAC recruitment
- Required for NEMO and Optn recruitment
- p62 and NDP52 only require RNF213
3. Addition of M1-linked ubiquitin chains
4. Recruitment of NEMO (induce inflammation) and Optn, p62 and NDP52 (induce autophagy)
RNF213 restore recruitment of autophagy marker LC3

71
Q

Vaccines

A

Increased CD44 and decrease of CD62L and CD127 indicate activated CD8 and CD4 T-cells
- CD44 is an activation and maturation marker for T lymphocytes and correlate with increased lymphocytes in blood
EBOV suggest an late adaptive immune response, due to INF-gamme production in CD8 T-cells and the protection of recipients from EBOV challenge

72
Q

Methods

A
  • Tunnel assay detects DNA breaks in apoptosis.
  • Flow cytometry is a technology that provides rapid multi-parametric analysis of single cells in solution. Flow cytometers utilize lasers as light sources to produce both scattered and fluorescent light signals that are read by detectors such as photodiodes or photomultiplier tubes.
73
Q

Extrinsic pathway

A

-Trimeric Fas ligand (FasL) binds to and trimerizes FAS
-Clustering of the death domains (DDs) in the Fas cytoplasmic domains allows Fas to recruit FADD via it domain
-The clustered death effector domains (DEDs) of FADD recruit and activate pro-caspase 8 via similar DEDs in the pro-caspase
-Activated caspase 8 cleaves pro-caspase 3, which then cleaves I-CAD, releasing CAD to enter the nucleus and cleave DNA

74
Q

Intrinsic pathway:

A

Cytochrome C, specific for mitochondria is released into cytosol, and binds to Apaf-1. This complex binds to pro-caspase 9 and form a complex that activates pro-caspase 3. Pro-caspase 3 cleaves I-CAD, which activates CAD to enter the nucleus and cleave DNA.

Immunobiology (3 decks)

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