Perturbations Flashcards
How do superantigens differ from conventional peptides that require uptake and processing prior to presentation to T lymphocytes?
In contrast to conventional peptides that require uptake and processing prior to
presentation to T lymphocytes, superantigens interact with the ‘side’ of the MHC Class II - TCR complex.
molecules prod. by microorganisms that bind Class II and TCR. bind outside peptide binding groove, cross link MHC II to TCR. as many as 20% of T cells can be cross linked in this manner
so T cells are thus highly activated
These molecules bind TCR’s on many CD4 T cells and MHC class II molecules on APC’s, overstimulating the immune system, producing a cytokine storm.
The individual’s MHC and TCR binding characteristics dictate the magnitude of T cell
activation and hence the level of cytokine production. The advantage to the infecting
microorganism is that highly activated immune effector cells undergo widespread apoptosis and lose their ability to effectively react against the invading microorganism.
The intensity of the superantigen response is strongly dependent on the polymorphism of the host’s MHC class II. Which HLA might have a stronger effect?
the same bacterial strain might cause death in some patients (e.g. those
with TCR-Vbeta3 and specific HLA-DR molecules) and hardly any clinical disease in
others with differing HLA
What is thought to contribute to toxic shock syndrome toxin 1 (TSST1)?
Disease results from body’s response to staphylococcal superantigens
Why tampons can
result in the syndrome is not completely clear but may be due to abrasion of host tissue
and introduction of staphylococci
The disease is manifest not just in women but also in children and men likely due to abrasion of the skin.)
What is clear is that exposure to the microorganism and its
superantigens results in the syndrome, which include the signs and symptoms in Figure
2, and especially, a rash on palms and soles
Describe the polyclonal extensive activation of T cells caused by TSST1. Describe the cytokines and their effects.
Polyclonal extensive activation of T cells
Over-production of INF-γ
Activates Macrophages
Over-production of IL-1, IL-6 and TNF-α
Toxic shock syndrome toxin 1- when that happens those T cells interact w MHC through superantigen. T-Cells activated to prod. large quantities of IFNgamma. that wills stimulate macrophages to prod. IL1, 6, and TNFalpha (can cause fever). (TNFalpha will interact w capillaries and induce capillary permeability …therefore bp drops fever caused by these 3 cytokines TNF can interact w vasculature and (local interaction in this cause) causing platelets to aggregate causing localized coagulation effect. When this is severe- systemic effect and get DIC, multi-organ failure, coma and death. serious situation induced by super antigens.
What is DIC? Describe.
Disseminated intravascular
Coagulation
DIC leads to the formation of small blood clots inside the blood vessels throughout the body.As the small clots consume coagulation proteins and platelets, normal coagulation is disrupted and abnormalbleedingoccurs from the skin, the GI, therespiratory tract and surgical wounds. The small clots also disrupt normal blood flow to organs (such as thekidneys), which may malfunction as a result.
What do the following indicate clinically?
low blood pressure, fever, diarrhea, extensive skin rash, and shedding of the skin
Toxic Shock Syndrome
Fever
Hypotension
Rash
Desquamation 1 to 2 weeks after onset of illness, particularly involving palms and soles
What are s. aureus strains related to?
release toxic shock syndrome toxin (TSST-1)
What is CCR5? Describe its significance.
CCR5 is a receptor for chemokines that attract and direct the migration of T cells to the site of infection.
CCR5 is also a co-receptor (along with CD4) for binding and entry into human T lymphocytes by HIV-1.
Individuals that lack a functional CCR5 (known as CCR5-delta32) are not susceptible to HIV-1 but are susceptible to infection with WNV.
There are individuals who have been infected with HIV but whose disease has not progressed or has progressed slowly compared to the average experience. What
makes these people less susceptible to HIV?
HIV-1 needs two receptors to gain entry into human cells; the CD4 receptor and the chemokine receptor, CCR5.
Once HIV has bound to CD4 and CCR5 the
virus can fuse with the human cell, permitting entry of the viral genetic material into the cell.
What protein on the surface of HIV binds to T cells?
gp41 binds to CD4 positive T cells… can only bind though if CCR5 is present.
slide 9
Why do CCR5 deficient individuals succumb more easily to West Nile virus?
CCR5 is a receptor for chemokines that attract and direct the migration of T cells to the site of infection.
if T cells cannot migrate to site of infection, (no CCR5 present) then one succumbs to West nile which traffics to brain and causes encephalitis
T cells cannot get to site of infection without CCR5 bc there is not chemotactic responsivitiy
Protection from WNV encephalitis is dependent upon the accumulation
of CCR5+leukocytes including; CD4+, CD8+, CD14+ and CD56+.
What is the significance of homozygosity or heterozygosity for the CCR5-delta32 gene?
The individuals who seem to have complete natural resistance to the HIV virus are homozygous for the CCR5-delta32 gene. (CCR5-delta32 is a polymorphism in the gene
encoding CCR5 in which a segment of 32 base pairs has been deleted, resulting in a nonfunctional
protein.)
The individuals who are termed “slow progressors” are heterozygous for the CCR5-delta32 gene. Hence, the polymorphism in CCR5 does not permit HIV to bind and infect
cells when homozygous and reduces infection when heterozygous. Quite advantageous for those exposed to HIV.
Protection against WNV is dependent upon the accumulation of which leukocytes?
Protection from WNV encephalitis is dependent upon the accumulation
of CCR5+leukocytes including; CD4+, CD8+, CD14+ and CD56+.
What type of cells cause autoimmune disorders?
Autoimmune Disorders are caused by self-reactive T and B lymphocytes.
Normal immunity depends upon the ability to discriminate between self and non-self.
(for B and T cells to become auto-reactive- had to be break in tolerance to some sort)
Describe central and peripheral T tolerance. Describe B cell tolerance.
Central tolerance is dependent on the thymus.
Tolerance occurs by virtue of negative selection and clonal deletion of strongly self reactive thymocytes
Autoimmune regulator complex (AIRE) located in the medullary thymic epithelium expresses self peptides in the thymus.
T cells tolerarized in thymus. any T cell highly reactive against MHC I and II will be deleted. any T cell highly reactive against peptides (pres. of consequence of AIRE gene complex) will be deleted as well… thats central tolerance
Peripheral tolerance an active, antigen specific process enforced by CD4+25+ FoxP3+
T regulatory cells (T regs) that prevent auto-attacks by self-reactive T cells that have escaped deletion during thymic development.
B cell Tolerance. Deletion of self- reactive B cells during their development in the bone marrow is not as stringent as that for T cells.
