Week 15 Flashcards

Question

Vacinia virus

Answer 1

Cowpox virus that has been passaged numerous times to render it apathogenic; used to inoculate against smallpox via skin scarification

Answer 2

S1P agonist that prevents lymphocyte egress from the LNs

Answer 3

I.m. administration is often preferred because it is easy to perform and generally well tolerated, with a low risk for adverse reactions at the site of injection Skin vaccination has recently been shown to be a potentially superior method of inoculation, as it is more immunocompetent than muscle sites. There were no differences in humoral immunity between i.m. and s.c. routes, but much higher adverse effects in s.c. in trials, so IM became the dominant method.

Answer 4

Adjuvants will often assist with the licensing of the DCs - without synchronous licensing, the immune response is blunted.

Answer 5

CD8a expression delineates DC populations in mice, but not in humans, who do not express CD8a on DCs. CD8a+ DCs make up 20-30% of spleen and LN DCs at homeostasis, are semi-mature (CD86-mid), and reside within T cell zones. CD8a- DCs (in mice) mostly reside in the MZ and the red pulp f the spleen and migrate to T cell zones after microbial stimulation.

Answer 6

alum enhances antigen uptake by DCs, cell recruitment to the injection site and stimulation of immune cells via the inflammasome, although there was some dispute regarding the specifics of the latter mechanism However, taken together, some common themes emerge: alum affects antigen uptake, induces danger signals, recruits various types of immune cells and elicits TH2 responses. Alum is TLR-independent (still works in MyD88/TRIF KO mice). Uric acid may be required for the activation of inflammasome.

Answer 7

Dose sparing (less antigen per vaccine increases the global supply) fewer doses needed per person More rapid response More broad response to combat antigenic drift Greater antibody titer magnitude

Answer 8

Classical adjuvant including a range of aluminium precipitated under basic conditions, usually aluminum sulfate mixed with sodium or potassium hydroxide plus a variable amount of phosphate sensed by NLRP3 inflammasome

Answer 9

antigen depot mild irritant (recruits leukocytes) does not enhance CD8 triggers some necrosis, which contributes to inflammasome activation Alum salts promote DNA release with consequent activation of IRF3 and enhanced migration of inflamatory monocytes to dLNs. Depends on IL-1B, uric acid

Answer 10

Pregnant women are routinely screen for anti-rubella antibodies because it is important that they have immunity to this TORCH infection. For HIV, the presence of antibodies is not a correlate of protection at all

Answer 11

Haemophilus influenzae type b pneumococci meningococci Correlates of protection are opsonophagocytic or bactericidal antibodies

Answer 12

Alum induces strong humoral immune responses, but is a poor inducer of cellular immunity, which is required for protection against these diseases.

Answer 13

Formed within 4h post-injection due to interactions between alum and fibrinogen. Are thought to serve as a 'depot' for slow release of antigen, although this has come under question, as removing the nodules after their formation does not appear to affect immune response. Additionally fibrinogen-deficient mice seem equally unaffected.

Answer 14

NLRP3-deficient mice have abrogated vaccine responses.

Answer 15

Adjuvant System 04 (AS04), which is composed of alum and the TLR4 ligand, monophosphoryl A

Answer 16

a role for macrophages in the pathogenesis of SLE was first proposed following the discovery that SLE macrophages were defective in their ability to clear apoptotic cell debris, thus prolonging exposure of potential auto-antigens to the adaptive immune cells

Answer 17

Neutrophils from SLE patients have been shown to have increased NETosis and decreased clearance of NETs, providing additional genetic material for the formation of autoimmunity

Answer 18

type I interferons bind to heterodimeric IFNARs and signal through JAK1 and TYK1 to form STAT1/STAT2 heterodimers that form a heterotrimer with IRF9. This heterotrimer is also called ISGF3, and binds DNA elements termed interferon-sensitive response element (ISREs)

Answer 19

IFN-γ binding to its receptor activates JAK1 and JAK2, and predominantly STAT1 homodimers. STAT1 binds a distinct DNA element termed a gamma- activated site (GAS) and directly activates a distinct set of ISGs, notably chemokines such as CXCL10 and transcription factors including IRFs

Answer 20

RNA helicases that sense RNA from viruses in the cytoplasm and induce inflammatory cytokines and type I interferons broad expression in tissues Consist of mainly two sensors: RIG-I and MDA5

Answer 21

N-terminal domain - CARD domains that are essential for downstream signaling A central DExD/H box RNA helicase domain that is required for ligand recognition or binding but also has ATPase activity C-terminal repressor domain essential for autoregulation.

Answer 22

STING is downstream of cGAS, AIM2 and is associated with the ER MAVs is downstream of RIG-I/MDA5 and is associated with the mitochondria

Answer 23

The ligand for TLR9 (CpG) fits into the groove created by the endosomal domain of two receptors - they cannot recognize the ligand or be activated by it as monomers.

Answer 24

TLR7 and TLR9 are highly expressed in pDCs and B cells and lead to IFNa and antibody production. TLR8 is highly expressed in monocytes, mDCs, and neutrophils and leads to the production of TNF, IL-6, IL-1 etc. This is different in mice (very little TLR8 in mice, and more widespread TLR7 and TLR9 expression in myeloid cells), which makes murine research of these pathways complicated

Answer 25

A study looked at nonsense or damaging mutations in each of the TLRs from individuals across the world, and found that the majority of TLR mutations were in non-nucleic acid-sensing TLRs. Nucleic-acid sensing TLRs had nearly no mutations, suggesting a highly selective pressure on these receptors.

Answer 26

There is great redundancy in IFN signaling - even lacking nucleic acid TLR sensing, these humans can still make IFN in response to virus via multiple other cytosolic sensing pathways.

Answer 27

pDCs are typically the first cells to respond to a viral infection, through nucleic acid sensing via TLR7/9 that produces lots of IFN I. This is followed later by other sources of type I IFN, including cDCs, macrophages, B cells, monocytes, stroma etc. through TLRs, RLRs, DNA sensors, etc.

Answer 28

Activated pDCs at 8-10h post-activation will have over 60% of their gene expression be Type I Interferon production. At this stage they express little to no costimulatory molecules (CD86) This is more or less completely shut down after 48h. At this point, the morphology changes greatly to more of a DC-like morphology, and CD86 is highly upregulated.

Answer 29

They make lots of pre-formed IRF7 and keep it in the cytoplasm. Upon activation, this transcription factor is translocated to the nucleus for rapid IFN-I production

Answer 30

They recognize the antigen, produce lots of IFN-I, and this IFN-I makes everything work 'better'

Answer 31

Overexpression of TLRs is enough to promote autoimmunity/break tolerance TLR7 gene duplication is responsible for disease in yaa lupus model WT mice that overexpress TLR7 or TLR8 spontaneously develop lupus or arthritis, respectively.

Answer 32

Chronic inflammation or activation of pDCs leads to pDC-dependent lesions. It is the length (not the magnitude) of pDC activation that leads to pathology.

Answer 33

CXCL4 (also secreted by pDCs themselves) leads to higher IFNa secretion.

Answer 34

pDCs make less type I IFN with increasing stiffness of their surroundings - thus when fibrosis/wound-healing begins to happen the pDCs can sense this and begin to inhibit their IFN-I production.

Answer 35

IL-4, TGF-B, and IL-6.

Answer 36

Differs by five amino acids in mice, and this leads to an inability to recognize RNA appropriately. This makes it difficult to study TLR8 in mice.

Answer 37

pDCs infiltrate the skin of SSc patients and produce large amounts of IFN-a and CXCL4, which leads to fibrosis. This was recently shown to be dependent on 'ectopic' expression of TLR8 in pDCs.

Answer 38

the C-type lectin BDCA2 (also known as CLEC4C) and the immunoglobulin superfamily receptor immunoglobulin-like transcript 7 (ILT7; also known as LILRA4)

Answer 39

CXCR4+ ICOS+ CD40L+

Answer 40

DNase1L3 is an endogenously produced extracellular DNase targeting DNA from NETs and apoptotic cells. Mice deficient in this enzyme develop anti-dsDNA antibodies and SLE like disease.

Answer 41

pDCs and B cells (mostly)

Answer 42

glycoprotein expressed by apical side of M cells that recognizes bacterial FimH protein found in type I pili and likely facilitates their transcytosis to the underlying follicle.

Answer 43

CCL20 (CCR6 is ligand) | CCL9 (CCR1 is ligand)

Answer 44

mainly lymphocytes, nearly all of which are CD8 T cells in the SI

Answer 45

integrin a4B7 and CCR9

Answer 46

CCR7 and L-selectin

Answer 47

alpha-e:B7, which ligates E-cadherin on epithelial cells

Answer 48

Addressin expressed on the endothelial cells of blood vessels of the gut wall; binds to a4B7 expressed by lymphocytes activated in PPs or MLN

Answer 49

Chemokine expressed by the epithelial cells of the small intestine that ligates CCR9 expressed by SI-homing lymphocytes

Answer 50

Chemokine expressed by the colon that ligates CCR10 expressed by LI-homing lymphocytes

Answer 51

5-10% of mucosal DC population migrates to the MLN to present antigen every day. In the absence of infection, this produces Tregs that home back to the gut wall

Answer 52

Vitamin A derivative that is produced by stromal cells of MLNs and gut DCs and is required for the induction of IgA responses and Treg induction in mucosal immunity.

Answer 53

They require constant replenishment from blood monocytes. They do not migrate back to the draining lymph nodes and cannot present antigen to T cells. Their job is to engulf and degrade commensal products that breach the barrier, releasing anti-inflammatory cytokines all the while. They may in turn pass antigen to DCs for presentation to T cells.

Answer 54

anti-IgG autoantibody made by B cells whose BCR is cross-linked by immune complexes leading to rheumatoid arthritis

Answer 55

- physical barrier (blood/brain barrier, e.g.) - abundant TGFB that promotes Tregs - High levels of Fas ligand

Answer 56

autoantibodies produced against the acetylcholine receptor block receptor function at the neuromuscular junction, resulting in a syndrome of muscle weakness