Perturbations in the super system

Question 1

3 ways superantigens differ from conventional peptide antigens

Answer 1

1. can react with MHC class II determinants in unprocessed form
2. they react with a portion of the TCR that is not within the classic peptide binding groove or antigen specific antibody receptor on B-cells but on the “side” of the mononuclear MHC class II TCR complex
3. elicit a massive immediate primary polyclonal response in T-cells

Question 2

Cytokine Storm

Answer 2

usually caused by bacterial pathogens that cause shock syndromes by producing toxins that act as superantigens. The rapid activation of T cells leads to massive release of vasoactive and proinflammatory cytokines

Question 3

polymorphisms in MHC

Answer 3

determine the intensity of the response. It is why the same bacteria may cause death in some patients and hardly any clinical disease in others. the individuals binding characteristics dictate the magnitue of t cell ativation

Question 4

super antigens

Answer 4

Cause massive outpouring of pro-inflammatory cytokines
Can lead to severe cytokine storm syndromes
Systemic toxicity and shock with the paradoxical effect of depressed immune responses
End result-patient becomes short term culture media for the pathogen
This crude method might be OK for bacteria but not for viruses

Question 5

toxic shock syndrom

Answer 5

t-cell infected by a super-antigen binds a macrophage and releases INF-gamma. The macrophage then releases massive amounts of TNF-a causing loss of integrity of the endothelium and decreased vascular resistance.

Question 6

Viruses mediate their effects to evade the immune system by

Answer 6

Increasing or decreasing production of cytokines
upregulating or suppressing cytokine receptor display
Making soluble decoys

Question 7

other methods viruses use

Answer 7

Downregulate the TLR of choice
Steal immune genes they can use to their advantage
Inhibit apoptosis by increasing BcL display or blocking the CASPASE system
Induce CD4,25 T cell production that specifically block responses against them
Suppress DC function
Worms can prevent IgE production
Bacteria can “hide” their pathogenic proteins/genes until favorable time for infection arises
Express suppressive microRNAs

Question 8

Autoimmune diseases are caused by

Answer 8

self reactive T and B lymphocytes. (either central or peripheral tolerance fails

Question 9

common autoimmune diseases

Answer 9

diabetes mellitus type 1, rheumatoid arthritis, systemic lupus, multiple sclerosis, celiac disease, and inflammatory bowel diease

Question 10

environment contributions

Answer 10

Environment may play a role
Gluten/celiac disease
MS and higher latitudes
River in S. America and pemphigus

Question 11

Central Tolerance

Answer 11

T cell related:
maintenance of central tolerance that develops by thymic deletion of self-reactive thymocytes.
AIRE driven development of Tregs

Question 12

Peripheral Tolerance

Answer 12

Is an active, antigen specific process enforced by CD4,25 FoxP3 regs that have either:
Emigrated from the thymus
Or developed in the periphery as a regulatory step during an immune reaction by induction with TGF beta or IL-10
There is also increasing evidence that AIRE is also expressed in peripheral lymphoid tissue and mandates regional tolerance

Question 13

T regs

Answer 13

T reg function is controlled by CTLA4 which in turn is controlled by FoxP3
CTLA4 on T cell surface acts as a brake
T regs are influenced by the ratio of TGF-β to Il-6.
T regs dependent on IL-2 from exogenous sources
Polymorphisms of IL-2 sources can determine T reg function

Question 14

peripheral tolerance in the gut

Answer 14

Bacteria that are symbionts (ie. they need us and we need them) exploit our TLR system with their PAMPs
Symbiont PAMPs drive the TLRs to induce tolerance, not activation of the innate immune system.
Bacteria can hydrolyze fiber to short chain fatty acids that promote T reg homeostasis

Question 15

Defects in T cell tolerance

Answer 15

1. Inadequate display of the Autoimmune regulator gene complex(AIRE) in the thymus
2. Complete loss of AIRE function is associated with multiple auto-immune endocrine diseases because the endocrine antigens were not displayed in the thymic medulla
   Families with loss of the AIRE gene have multiple autoimmune diseases
3. Complete loss of FoxP3 function mutations and is associated with widespread T & B autoimmune reactions
4. Partial loss of CTLA4 gene (complete loss is fatal) causes extensive autoimmunity

Question 16

Viruses and Diabetes Type 1

Answer 16

Viruses can:
directly infect pancreatic beta cells and initiate CD8 attack against them
Exhibit antigens that mimic Beta cell antigens. CD8 cells mistakenly attack Beta cells
Infect non beta cell sites in the pancreas and incite collateral damage to beta cells

Question 17

Th17

Answer 17

A new sub-lineage of Th cells has been described. Discovered when the T cells at auto-immune sites were Th1 but producing IL-17, not IFN-γ and the transcription factor was ROR, not T-bet
They are CD3,4+ and will develop into Th17 IF IL-23, Il-6 & from DC are the initiation cytokines. TGF-β is mandatory but the primary cell source is still unclear (most likely DC).
CD3,4 cannot be forced to develop into IL-17+ cells if either IFN-γ and/or IL-4 are present.
They can be found in very high concentrations at autoimmune inflammatory sites

Question 18

IF ONLY TGF-β present,

Answer 18

T regs develop. The co- presence of IL-6 and IL-23 prevent T regs and allow Th17 differentiation

Question 19

what conditions favor DC signaling with IL-23?

Answer 19

we don’t know…. ?viral or hormonal induced loss of T reg enforcement
?Genetic differences in TLR, DC
?Aire defects

Question 20

Loss of B cell tolerance

Answer 20

Deletion of self reactive B cells in the bone marrow during development not as stringent as thymus
B cells are constantly driven to make “better” antibody by somatic mutation- bound to make self reactive or cross reactive antibody in that quest
In fact all of us have autoreactive B cell clones but they are usually not productive because…
In most cases, a parallel auto-reactive T cell will not be there and a T reg will be there- so there is no T cell help and very little autoantibody formation
In women especially, autoreactive clones can make functional antibodies and we will see what happens when that occurs in the small group