Perturbations in the System Flashcards
What are ways the immune system can become hijacked?
- superantigens produced by bacteria and viruses
- genetic polymorphisms, exploited by viruses
- immune evasion by viruses
- autoimmune diseases
Define superantigen. What do they lead to?
- do not require uptake and processing
- bind to the side of the MHC Class II and CD4+ TCR
- causes overactivation of TCR => cytokine storm
List examples of superantigens.
- TSST-1 (Toxic Shock Syndrome Toxin-1)
- SE (Staphylococcal enterotoxin)
Describe the mechanism of pathology in Toxic Shock Syndrome.
- TSST-1 causes activation of T cells => Th1 => IFNg
- IFNg activates macrophages to produce IL-1, IL-6, and TNFa
- TNFa causes increased capillary permeability => hypotension; also causes disseminated intravascular coagulation
- IL-1 and IL-6 cause fever, rash
- Altogether, this can lead to coma and death
Describe the importance of MHC Class II polymorphism in TSS.
- MHC Class II polymorphism dictates intensity of response
==> some people may die from TSS and other have no clinical symptoms - the polymorphism dictates the binding to TCR, activation of T cells, and cytokine production
List clinical symptoms of TSS.
- fever
- hypotension
- rash
- desquamation of the palms and soles (shedding)
Define DIC.
Disseminating Intravascular Coagulation (DIC)
- occurs in TSS
- creates clots in the blood
- depletes clotting factors in other places
- leads to bleeding
What causes TSS? Who does it affect?
- staphylococcus aureus strains release TSST-1
- typically associated with tampon use (can cause skin abrasions, providing entry for S. aureus)
- can also occur in men and children (all you need is point of entry)
Describe the relationship between genetic polymorphisms and disease susceptibility.
- TSS is exacerbated by certain MHC II polymorphisms
- can increase susceptibility OR resistance to certain immune disorders
What is the relationship between CCR5 genetic polymorphisms and disease?
If you have a defect or nonfunctioning CCR5 gene…
- increases resistance to HIV (yay!)
- increases susceptibility (decreases resistance) to west nile virus (boo!)
Why is CCR5 defect protective against HIV?
HIV requires costimulation by CD4 and CCR5 to be able to gain entry to the host cell
- no CCR5 = no HIV
Define CCR5.
- chemokine receptor
- expressed on immune effector cells
- activation of CCR5 allows migration of T cell to site of infection
Describe how hetero vs homozygous CCR5 genetic defects present.
- homozygous for CCR5 defect = completely protective
- heterozygous for CCR5 defect = slow progression of disease
How does the CCR5 defect affect west nile virus resistance?
Decreased Resistance
- normally, WNV causes chemokines to bind to T cells and recruit them to the CNS to fight off the infection
- without CCR5, the T cells cannot be recruited => infection persists => fatal viral encephalitis
List ways of viral immune evasion.
- induce production of IL-10 => immune suppression
- produce viral IL-10 => immune suppression
- produce or induce chemokines => recruit cells to infect
- express chemokine receptors => migration of infected cells into other areas to spread virus
- alter activity of host chemokine receptors => inhibit immune response or migration
Describe the mechanism by which IL-10 aids in viral immune evasion.
Typically, infection leads to production of IFNg => macrophages, DCs, Th1
- some viruses also induce production of IL-10
- lowers activation of macrophages and DCs
- increases Th2 response, which inhibits Th1 and antibody formation
- viral IL-10 orthologs do the same thing
Describe the mechanism by which chemokine production/chemokine receptor modulation aids in viral immune evasion.
- chemokine secretion attracts susceptible cells
- chemokine gradient attracts infected cells to other tissues
- inhibition of chemokine receptor prevents immune activation
What key factors play a role in the development of autoimmune diseases?
- genetics
- gender (females have stronger Th1 and antibody response => more likely to develop)
==> problems occur after puberty => sex hormones play a role
What causes autoimmunity?
loss of tolerance
Peripheral tolerance is enforced by…?
Tregs
- prevent attacks by autoreactive T cells
What can cause a loss of central tolerance?
mutations in AIRE
– self-reactive T cells are not negatively selected b/c not exposed to the self peptides
What can cause a loss of B cell tolerance?
- not exposed to peptide in bone marrow
- during somatic hypermutation, can produce auto-antibodies (typically checked by Tregs)
List organ-specific autoimmune diseases.
- IDDM (pancreas)
- Graves (thyroid)
- Goodpasture’s (lung and kidney
- Myasthenia Gravis (neuromuscular)
- Multiple Sclerosis (brain)
List systemic autoimmune diseases.
- Systemic Lupus Erythematosus
2. Rheumatoid Arthritis
