BSCI422 Final

Last 1/4 of Immunology notes

NK cells

Natural killer cells - part of the innate and can be part of adaptive immune response - are cytotoxic in a way that is very similar to CTL cells

Type I IFN

Type 1 interferons - IFN a and IFN B - cytokines important for anti viral responses - innate production of this responds very quickly to viral infection, this response is followed by NK cells after - they can activate NK cells

TLR3

Toll like Receptor 3, found inside the cell on endosomal membranse, signals through TRIF (TIR domain containing) - activates IFN3 and IFN 7 to turn on production of Type I IFNs (a and B)

RIG-I and MDA-5

soluble cytosolic pattern recognition receptors that recognise viral RNA and activate IRFs to give IFN-1 response

cGAS

recognise double stranded DNA in cytoplasm and activates STING that produces IFN1

IFN 1 receptors

presented on all cells, binds to IFN1 a or B - when they bind IFN1, signal cascase activates 2-5A synthase and PKR which both lead to the inhibition of protein synthesis

2-5A synthase

activation of this via IFN1 binding its receptor leads to the degredation of mRNA and subsequently inhibition of protein synthesis

PKR

activation of this via IFN1 binding its receptor - it phosphorylates initiation factors (rendering them non functional) and preventing the initiation of transcripts - also inhibits protien synthesis

Killer Inhibitory Receptors (KIR)

Inhibitory receptors on NK cells recognise MHC I on cell surface (all cells express this) and transmits negative signal into NK cell to not kill that cell → a cell may show an activating or stress induced ligand, but if it has MHC I on it, the + signals will be overcome by the negative signals

Activating receptors

on NK cells - recognise stress on a cell via stress induced ligands and send + signals into the NK cell to induce killing of the target cell

Stress induced ligands

sit in the cytosol of cells and get pushed to the plasma membrane when the cell becomes stressed, inducing + sigal in NK cells

Missing self concept

when a cell is missing its MHC I, there is no negative signal for NK cells, triggers NK cells to kill that cell - or if they just have low levels of MHC I → this is caused by viral stress a lot of the time (ex: SARS covid)

ITIMs

Immuno based tyrosine inhibition motifs (I_Y__L) (Y is tyrosing and L is lysine) - KIRs signal via these - singular tyrosine - recruit phostphotases that inhibit activating signals associtated with ITAMS - they antagonise ITAMS that are activating receptor motifs

not just receptors that have these motifs, some adaptors in NK cells can also

ITAMs

signaling tyrosine motifs on activating receptors or adaptor molecules like DAP12 that when activated lead to the activation of cytotoxicity in NK cells

SHP1, SHIP

phosphotases that ITIMS recruit to inhibit tyrosine phosphorylation in ITAMS

DAP10

adaptor protein in NK cells that has YINM motif and activates cytokine production by recruiting P13 kinase (NK cells are important sources of cytokines)

DAP12

different adaptor protein in NK cells that has an ITAM sequence that will initiate cytotoxicity

NKG2D

activating receptor on NK cells that binds cell ligands induced by stress such as MIC-A, MIC-B and the RAET1 family

NKG2A

inhibitory NK receptor

examples of when MHCI won’t be expressed

viral infection leads to decreased MHCI expression on cells

turmor cells have decreased MHC I expression and induced stress ligands

ADCC

antibody dependant cellular cytotoxicity: NK cells have Fc receptors that bind Ab and trigger cytotocixity in the NK cell - means NK cells can also be part of adaptive immunity

Autoimmunity

state in which the immune system attacks self tissues - can involve an / all parts of the immune system - is normally prevented by self tolerence, but genetic or environmental factors can lead to breakdown of self tolerance and activate self reactive lymphocytes

Clonal deletion

mechanism of self tolerance - essentially negative selection of B cells in bone marrow and T cells in thymus that self react during lymphocyte development

AIRE

Autoimune Regulator: transcription factor that allows expression of low levels of tissue specific antigen (Ag from tissues outside the thymus) in thymus, leads to negative selection of autoimune T cells - in absence of this, self reactive tissue specific Ag mature and leave thymus

Clonal Inactivation

also known as clonal anergy: mechanism of self tolerance where self reactive lymphocytes are functionally inactivated due to lack of co stim / inflammatory activation or lack of T cell help

Immunological Ignorance

mechanism of self tolerance - you have an Ag that the immune system can’t detect - in a place the immune system doesn’t have access to / at too low levels to detect

Immunologically Priveliged sites

mechanism of self tolerance - Ag is available, presented in a way to induce tolerence specifically - sites include: brain, eye, fetus / uterus / testes

communication between sites and the body is atypical - there are anti inflammatory cytokines in these sites, and expression of Fas ligand on tissues of the sites (Fas ligand induces apoptosis)

Immune supression by regulatory T cells

mechanism of self tolerance: regulatory T cells / CD4+CD25+ T cells - they are dependant on IL-2 for survival - secrete inhibitory cytokines IL-10 and TGF-B

serve as a governor on immune system, can convert APC from activating to tolerating APCs

FoxP3

master TF for regulatory T cells

Activation induced cell death

mechanism of self tolerance: if you chronically induce T cells, they upregulate the Fas receptor / ligand (initiates apoptosis)

Injury

way autoimmunity starts: trauma releases Ag from immunologically privelaged site or increases Ag concentration past threshold of ignorance

Infection

way autoimmunity starts: pathogen may have cross reactive Ag, cause tissue damage or induce co stim with inflammatory response

spontaneous

way autoimmunity starts: underlying cause of most autoimmune diseases are unkown, but usually due to intrinsic issues in tolerance

Complement mediated lysis

what autoimune antibodies do: most cells can prevent this by removing pore forming proteins that come from complement, but this does effect RBCs, as they don’t invest a lot of energy into self defence - can lead to autoimmune hemolytic anema - is a type II hypersensitivity Rxn

Ab and Complement mediated opsonization

what autoimune antibodies do: also affects RBCs - are opsonized and get taken up by phagocytosis

Complement induced inflammation

what autoimune antibodies do: causes tissue damage - type II hypersensitivity rxn

Ag-Ab complex deposition

what autoimune antibodies do: can cause kidney damage

Blockage or stimulation of cell surface receptors

what autoimune antibodies do: causes neutralization

Pathogenic T cells

autoimmune T cells: activate B cells for auto antibody production, activation of innate immune cells, cytokine mediated inflammation and toxicity and direct kills of target cells

ABO blood type rejection

Ab dependant (IgM), but T cell independant - relies on pre existing Ab against surface carbohydrates - negatively select against your own alleles (if you are AB you don’t react to that etc)

donor RBCs can be destroyed by complement mediated lysis if not the correct surface carbohydrates

Rh antibodies

require prior exposure to antigen for there to be a response - antibodies can be IgG, meaning they are able to cross the placenta and attack RBC of fetus and newborn if n=mother and fetus are diff blood type (+ or -), can cause hemolytic disease of newborn if not treated with RHOGAM

RHOGAM

used to supress mothers immune reseponse against fetal RBC of different type (+ or -)

Autograft

a graft from the same person (taking a part of tissue from your own body and moving it elsewhere) ex: burn victims skin grafts

Synergetic graft

graft between genetically identical individuals - ex: lab rats or identical twins

Allograft

graft between people with different MHC - not genetically the same

Xenograft

graft from a different species

hurdles against organ transplant

blood types / diff MHC / minor histocompatability antigens

MHC differences are mediated by T cells - CD4 T cells are the most important for graft rejection → mismatch on MHC II is more likely to cause rejection than on MHC I

Direct recognition of graft

APCs directly see foriegn MHC and react to that

Indirect recognition of graft

Recipient APCs process and present peptides from the graft and cause reaction that way

Minor Histocompatability Antigens

small polymorphic peptides derived from normal cellular proteins that differ between transplant donors and recievers

graft rejects slowly with this if MHC is the same

Graft vs host disease

mature donor T cells contaminate allogenic bone marrow and recognise tissues of recepient as foreign - causes rashes, diharea, liver damage and severe inflammatory response

Hyperacute graft rejection

fast rejection of second / third graft due to the reciever generating Ab against one graft and the same Abs showing up in the next graft - results in a very rapid rejection

Fetus as an Allograft

fetus isn’t rejected for several reasons:

• fetal component of placents (troploblasts) don’t present MHC II or I - they don’t get rejected by NK cells by presenting negative ligands to NK cells

• fetus promotes local immunosupressive response - expresses enzyme that depletes tryptophan, causing T cells to become regulatory T cells (upregulate Fox P3 TF), stopping other T cells from initating immune response in placenta

• T cells express lower levels of TCR

Immunosupression

intentiona induction of immunodeficiencies - usually via drugs, used to stop graft rejection and stop unwanted immune responses like autoimmune diseases - 4 major classes of immunosupression drugs

Corticosteroids

most general immunosupressive drug - it is a stress response hormone that causes the body to take energy away from everything but core functions (takes energy away from the immune system)

They inhibit cytokine and Nitric Oxide production, downregulate adhesion molecules (for WBC exiting blood), induce apoptosis of active lymphocytes

Cytotoxic Agents

more specific immunospecific drug than corticosteroids: selectively kill dividing cells (target immune cells because they divide rapidly, killing activated but not resting lymphocytes) - also used as an anti cancer drug - used in small doses to help other immunosupressant drugs

some drugs inhibit DNA synthesis (needed for rapidly dividing cells)

another drug Cyclophosphamide is a DNA alkylating agent

Immunophilin-Binding Agents

Isolated from microorganisms - have fewer side effects than corticosteroids and cytotoxic agents - bind cellular proteins that gain novel function after binding the drug, and inhibit critical signalling pathways in immune cells

Cyclosporin A

type of Immunophilin Binding agent drug, inhibits calcinurin adn TCR calcium signalling pathways - you have to be on it for your while lifetime, prevents long term tolerance

Rapamycin

type of Immunophilin Binding agent drug, inhibits mTOR pathway, prevents proliferation of T cells without blocking T cell activation, can lead to tolerance induction

Antibody / Recombinant Proteins

type of immunosupressant drug - targets lymphocyte subsets to give specific immunosupression

• Depleting Abs target and induce death of lymphocytes

• Non depleting Abs block receptor ligand interactions and induce specific tolerance

• Anti cytokine / receptor Abs block the effects of immune response

HIV

human immunodeficiency virus: is a retrovirus that kills CD4 T cells - RNA virus that converts its viral RNA to DNA via reverse transcriptase, establishing itself into the cellular genome - can also infect monocytes, as they express CD4 at low levels

GP120

surface protein on HIV that binds to CD4 and chemokine co-receptors (7 part transmembrane g protin coupled receptor) CCR5 or CXCR4 on T cells- uses these receptors to bind to and infect T cells

Viral infection of HIV step 1

gp120 binds CD4 on target cell, then recruits a co-receptor, mediating fusion

Viral infection of HIV step 2

nucleocapsid containing viral genome adn enzymes enters cell

Viral infection of HIV step 3

reverse transciptaise occurs

Viral infection of HIV step 4

retrovirus becomes part of DNA

Viral protease

cleave viral polyprotein precursors into functional subunits - a target of a lot of antiviral HIV drugs

AIDs

aquired immunodeficiency syndroms: when HIV causes CD4 T cells levels to get below critical level of 200 per ul - opens body up to infection by opportunistic infections associated with AIDs that are normally dealt with via CMI

HAART

highly active anti-retroviral therapy

can be reverse transcriptase inhibitors, protease inhibitors, intergrasin inhibitors… etc

Influenza virus

flu - segmented RNA virus - has almost chromosomes of RNA that allow it to switch segments with other viruses, allowing it to change rapidly (why we have to keep taking vaccines for flu)

Antigenic drift

small change in viral genome - a small mutation to escape immunity on the viruses part that means a new vaccine is needed

Antigenic shift

a large change in a virus where a virus swaps genes with another virus - gene reassortment that essentially means a new virus - can lead to an epidemic, a lot worse than drift

SARS COV-2

Covid - has spike glycoprotiens on cell surface that allow it to enter its target cell - said spike protein is like a spring, has a pre and post fusion conformation - binds to ACE2 receptor on cells

antibodies are more effective on the pre fusion conformation

the spike protein has undergone many mutations, why it is hard to target

Herpes virus

latency and reactivation - virus goes dormant and then reactivates under stress - it is a DNA virus and is a lot like mammilian genes - can replicate immunorepressor IL-10

Type 1 IFN

viral immunity - prevents protein synthesis

Tumor immunosurveilance

tumors have Ag that the immune system recognises

tumors have mechanisms of immune evasion though

Tumor antigens

Ags selectively expressed in human tumors - you can make Ab or T cells made in lab specific for tumor

Passive immunization

when yo get given the antibody for a pathogen - you don’t develop adaptive immunity from this (ex: RHOGAM with pregnancy and +- blood types)

Active Immunization

vaccines - giving a person small doses of the antigen so that they develop adaptive immunity to it

Polio vaccines

two types:

• inactivated polio vaccine (IPV) - Salk - induces humoral immunity - safer than attenuated

• Oral polio vaccine (OPV) - Sabin vaccine - live attenuated, causes CMI

Conjugate vaccine

links toxoid and polysaccaride to be used in vaccine

Antigen cross reactivity

molecule that triggers an immune response by binding to Ab or T cells origionally generated for a different Ag - ex: cowpox and smallpox

Attenuation

change the virus enough that it doesn’t grow on human cells but can still be used as a vaccine - delete the virulance genes via genetic engineering

BCG

tuburculosis vaccine - attenuated form of tuburculosis microbacterium - need attenuated version to induce CMI because it is an intracellular bacterium - killed virus induces humoral immunity which doesn’t work for intracellular viruses

DNA vaccination

doesn’t work?? would theoretically create a CD8 and CD4 response but is deemed too dangerous

mRNA vaccines

used against covid to stabalize the spike protein to the prefusion conformation on covid

Adjuvents

upregulate co stim on APC for T cell help - used in protein vaccines to trick immune system into generating immune response to Ag in vaccines