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Role of Interferon in Innate Immunity

IFN- group of cytokines that are the 1st line of defense against viral infection
-Has anti-proliferative and immuno-regulatory properties
-inhibit viral replication by INDUCING anti-viral pathways
-act in an autocrine/paracrine manner

Types of IFNs

1. IFNa (type 1):
-made by: leukocytes
-induced by: mixed leukocyte rxn, viruses
-found on: all cells
2. IFNb (type 1):
-made by: fibroblasts, epithelial cells
-induced by: dsRNA
-found on: all cells
3. IFNy (type 2):
-made by: immune cells
-induced by: antigens, plant lectins
-found on: immune cells

What are the functions of IFNs?

1. induces CD4 & CD8 T cell activation
2. induces NK activation
3. induces anti-viral state
4. induce dendritic cell maturation
5. anti-proliferative
6. up regulates MHCI expression

What are the inducers of endogenous IFN?

1. PAMPs/Pathogen associated molecular patterns
-unmethylated viral DNA
-dsRNA viral replication intermediate
-uncapped ssRNA viral replication intermediates
2. Synthetic inducers that mimic PAMP
-artificial molecules
-ampligen synthetic RNA
-natural small molecules

How can we administer exogenously produced IFN?

1. Alpha IFN + peg-alpha IFN: recombinant + leukocyte derived
2. Beta IFN: recombinant
3. Gamma IFN: recombinant

How does the addition of PEG to IFNa change it?

PEG-IFN= increases molecular weight of molecule= increase half-life in vivo without changing binding to receptor in appreciable amount

IFN Pathway

1. Membrane sensors of PAMPs (TLR 3, 7, 9) and/or
2. Cytosolic sensors of PAMPs (RIG1/retinoic acid induced gene)
3. Activation of sensors by PAMPs triggers IFN production
4. IFN/IFN-R engagement- activates STATs and IFN-sensitive gene expression (*people with mut here will get severe infections)
5. Uninfected cell now protected by IFN induced gene expression

What is the difference between IV and IM administration?

IV has higher conc in blood and decreased half-life.
IM has lower conc in blood and increased half-life.

What are the 5 genes induced by IFN?

1. PKR/Protein Kinase RNA
2. 2'5' OAS/ 2'5' oligoadenyate synthetase
3. Adenine deaminase
4. Human Mx protein
5. iNOS/inducible nitric oxide synthase

Protein Kinase RNA (PKR) Pathway (EIF-2a)

1. inhibits translation (protein synthesis) via EIF-2a
2. norm: EIF-2a charges the 1st met to add to tRNA
3. PKR phosphorylates EIF-2a so it can NOT add the 1st met to tRNA- this inhibits the initiation of translation (protein synthesis)

Protein Kinase RNA (PKR) Pathway (NFkB)

1. norm: iKB binds NFkB so NFkB can NOT get into the nucleus and activate inflammatory genes
2. PKR phosphorylates iKB, releasing NFkB from iKB, now NFkB can go into nucleus and activate inflammatory genes
3. activation of inflammatory genes activates the ADAPTIVE (T + B cell response)

2'5' oligoadenylate synthetase (2'5' OAS)

1. viral RNA is recognized by PAMPs
2. IFN induces 2'5' OAS to become 2-5A Trimer (via 3 ATP)
3. 2-5A Trimer activates RNase L which degrades ssRNA
4. RNA virus is destroyed since this is its genome, but normal cells can just make more RNA

Adenine deaminase

1. A pairs with T (in RNA)
2. adenine deaminase converts A to inosone
3. inosine pairs with G
4. this changes the genetic code of the RNA virus

Human Mx protein

1. Human Mx protein = GTPase
2. Virus uses GTP to transport molecules in a cell
3. MX protein evolved to protect against influenza
4. Mx protein sequesters influenza virus and keeps it from getting into the nucleus

Inducible Nitric Oxide Synthase (iNOS)

1. iNOS partially overcomes the defect in chronic granulomatous disease (CGD)
2. CGD is a defect in NADP oxidase- kids can't make ROS- so they are more susceptible to infection
3. iNOS helps the cell make RNS in an effort to partially overcome the defect in CGD

Toxicity associated with IFN Therapy

1. Common:
-decline in Hgb (bc of antiproliferative effects)
2. Less common:
-loss of executive fctns

Clinical Uses of IFN ALPHA

1. Hairy cell leukemia (HCL)
2. Kaposi's sarcoma (KS) in pts with AIDS (HHV-8)
3. Chronic Hepititis B virus infection
4. Chronic Hepititis C virus infection
5. Condyloma acuminatum (HPV)
6. As an adjuvant with conventional cytotoxic cancer therapy regimens

Combination therapy for Chronic HCV and HBV

Chronic HCV:
ribavirin + IFNa + viral protease inhibitor

Chronic HBV:
IFNa + inhibitor of RT (reverse transcription)

There is a HPV vaccine!

Clinical Uses of IFN BETA

MS: reduces frequency and severity of demyelination in MS

Clinical Uses of IFN GAMMA

CGD patients

Benefits of IFN

1. anti-viral
2. anti-proliferative
3. immune regulatory

Viral resistance to IFN

1. IFN decoys bind to receptors without activating them
2. inhibition of IFN signaling
3. inhibitors of PKR and 2'5' OAS
4. use of internal ribosomal entry sites (IRES) or Cap independent translation

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