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Immunology > Lecture 19 - Perturbations in the Super System > Flashcards

Lecture 19 - Perturbations in the Super System Flashcards

1
Q

What are 3 ways that super antigens differ from conventional peptide antigens?

A
  1. Superantigens react with MHC II in UNPROCESSED form
  2. portion of TCR that reacts with them is NOT WITHIN the classic peptide binding groove or antigen specific antibody receptor on B cells
    - can push Th0 to CD4 (up to 20%) without processing
  3. They elicit massive IMMEDIATE PRIMARY POLYCLONAL response in T cells

** activation varies with MHC II locus polymorphism**

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2
Q
  1. SUPERANTIGENS Cause massive outpouring of __________
  2. Can lead to severe ________ syndromes

What is the end result of something like an infection with staph bacteria due to super tampons? What is this due to?

What gets shut down?

A
  1. pro-inflammatory cytokines
  2. cytokine storm
  3. SYSTEMIC TOXICITY
    = Toxic Shock Syndrome

** due to TMMI response and macrophage activation**

—-End result - patient becomes short term culture media for the pathogen - causes massive shut down of IMMUNE RESPONSE

(This crude method might be OK for bacteria but not for viruses)

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3
Q

The intensity of the systemic toxic shock syndrome depends on what in the host’s MHC II and TNF gene?

A

POLYMORPHISM

  • discovered when same bacterial strain might cause death in some patients and hardly any clinical disease in others

** MHC binding characteristics dictated the magnitude of T cell activation**

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4
Q

State the steps that cause Toxic Shock syndrome.

What component causes the loss of endothelial integrity and decreased vascular resistance?

A
  1. Super antigen brings 2 cells together to start TH1 response
  2. release of INF- Gamma ( 20 – 30% of all T cells = A HUGE ACTIVATION OF T cells)
  3. TNF – a is released
  4. Leads to complete breakdown of endothelial integrity
    decreased vascular resistance which leads to SHOCK
  5. Ischemia, lactic acidosis, DEATH

TNF - Alpha

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5
Q

Why are super antigens not an elegant way to get around the immune response?

How do viruses mediate many of their effects? (3)

A

The hot doesn’t last long
–> viruses require a living host for their own survival and propagation

  1. Increasing or decreasing production of cytokines
  2. upregulating or suppressing cytokine receptor display
  3. Making soluble decoys
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6
Q

What are some examples that viruses than evade the immune system?

A
  1. Downregulate the TLR of choice
  2. Interfere in methods MHC I transports antigen to surface so it can be camouflaged from CD8 cytotoxic T cells
    - piracy of genes that produce INHIBITOR SIGNALS FOR NK CELLS
    (NK - then can recognize an altered MHC I but cannot do anything)
  3. Inhibit apoptosis by increasing BcL display or blocking the CASPASE system
  4. Induce CD4,25 T cell production (Treg) that specifically block responses against them
  5. Suppress DC function
  6. Worms(parasites) can prevent IgE production
  7. Bacteria can “hide” their pathogenic proteins/genes until favorable time for infection arises
  8. Express suppressive microRNAs
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7
Q

What happens when viruses case the following to occur:

  1. Produce inhibitory cytokines like IL-10 or other IL-12 inhibitors
  2. Encode genes that produce SOLUBLE CYTOKINE RECEPTORS thus blindfolding cytokines generated during the I.R.
  3. Parasites switch on Th1 system and prevent IgE
  4. Induce Treg cells
A

All examples of ways that viruses can evade destruction by immune system

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8
Q

What causes autoimmunity?

What are some common diseases?

What 3 things play a role?

Examples?

A
  1. Self reactive T and B cells
  2. Lupus, rheumatoid arthritis, diabetes, MS celiac disease
  3. a- inheritance
    b- gender
    c- environment

monozygotic twins at high risk if on has an Autoimmune disease

FEMALES HAVE MUCH HIGHER PREVALENCE

Environment:

  • gluten/celiac
  • MS related to HIGHER ALTITUDES
  • river in S. amebic causes pemphigus
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9
Q

Just because a woman has autoantibodies does not mean she has what?

A

Just because a woman has autoantibodies DOES NOT MEAN SHE HAS THE DISEASE

ex: lupus or rheumatoid arthritis are phenomena but NOT DISEASE CAUSING

screening is the bane of organized medicine (screening for autoantibodies)

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10
Q

Which alleles enhance susceptibility to autoimmune diseases?

Why?

A

MHC - D alleles

  • dictate TLR and cytokine expression and influence the intensity and composition of antigenic peptide presentation
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11
Q

What modules the clinical expression of autoimmunity in females?

A

SEX HORMONES

  1. females have more vigorous Th1 responses
  2. Females have more vigorous antibody responses

ESTROGEN & PROGESTERONE have concentration dependent effects on Th1, Th2, Treg, and inflammatory responses

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12
Q

What is the percentage of affected siblings based on 2 HLA haplotypes shared? 1? 0? (For type 1 diabetes)

If no HLA association? (2 HLA haplotypes shared, 1, 0)

A

2 = 58%

1 = 37%

0 = 5%

NO HLA association

2= 25%
1 = 50%
0 = 25%

TYPE 1 diabetes

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13
Q

Autoimmunity represents a loss of ______.

What are 2 ways to achieve this?

Is it learned or innate? Active?

A
  1. Loss of SELF TOLERANCE
  2. central and peripheral
  3. LEARNED and ACTIVE
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14
Q

Central tolerance is dependent on what?

How does it occur?
(2 ways)

How does AIRE work?

Where is AIRE found?

A
  1. Thymus
    a) . NEGATIVE SELECTION and clonal deletion of strongly self- reactive thymocytes during thyme maturation
    b) AIRE driven development of Tregs
    - AIRE takes the cells that have passed through positive & negative selection and were mildly auto reactive and converts them to Tregs specific to auto-reactive antigen!!!
    c) found in CORTICO-MEDULLARY JUNCTION
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15
Q

What happens if the TCR of any T cell reacts with the AIRE self antigens?

What transcription factor do they use?

What happens if a self-epitope is missing?

A

It is converted to a protective CD4, CD25 regulatory cell (Treg)

  • use FOXP3

(alternate hypothesis: Aire deletes self reactive T cells and then programs another T cell to be a T reg specific for the tissue antigen)

  1. Anti-thyroid cell is vetted by AIRE, but cell escapes and there is now an ANTI-THYROID T effector cell in periphery!!
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16
Q

Peripheral tolerance
is an active, antigen specific process enforced by _______that have either come from where?

There is also increasing evidence that AIRE is also expressed in ______tissue and mandates regional tolerance

A
  1. CD4,25 FoxP3 Tregs
  2. Emigrated from the thymus
  3. Or developed in the periphery as a regulatory step during an immune reaction by induction with TGF beta or IL-10
  4. peripheral lymphoid

** regional role in both TOLERANCE ENFORCEMENT and controlling the shutdown of a normal immune reaction

17
Q

3 ways that peripheral tolerance develops.

A
  1. left the thymus and prevent auto-attacks by self reactive T cells that have escaped deletion during thyme development
  2. inducible Tregs that develop in periphery as na normal regulatory step during an ongoing immune reaction
18
Q

REVIEW OF Tregs:

T reg function is controlled by ______which in turn is controlled by FoxP3

T regs are influenced by the ratio of _____ to _____

T regs dependent on _____ from exogenous sources
( Polymorphisms of this cytokine can determine T reg function)

What determines whether a Treg or Th17 response occurs?

A
  1. CTLA4
    - CTLA4 on T cell surface acts as a brake
  2. TGF-β to IL - 6
  3. IL - 2
  4. the balance between TGF - B and IL - 6
19
Q

If TGF - B is present, what does this imply?

What if no Il-2 is present?

What is the major site of tolerance enforcement?

A

Treg is functioning –> used to suppress the immune response

No IL - 2 = NO Tregs!!!

  1. GUT!
    - Bacteria that are symbionts (ie. they need us and we need them) exploit our TLR system with their PAMPs
20
Q

Symbiont PAMPs drive the TLRs to induce ______, not activation of the innate immune system.

Bacteria can hydrolyze ______ to short chain fatty acids that promote T reg homeostasis

A
  1. tolerance
  2. fiber
    - some bacteria hydrolyze too much or too little fiber into SCFA = disrupts Treg homeostasis
21
Q

Autoimmunity occurs when either ___ or ____ fails.

What led to identification of Treg cells?

Families with numerous autoimmune diseases led to understanding of how ____ complex prevents autoimmunity.

A
  1. Central or Peripheral Tolerance
  2. Mutations in FoxP3
  3. AIRE
    - because the endocrine antigens were not displayed in the thymic medulla (corticomedullary)
22
Q

Loss of what 3 genes or mutations are associated with loss oh peripheral tolerance and defective function of Treg CD25, CD4 T cells?

What are 3 NON -T CELL sources of autoimmunity?

A
  1. FoxP3
  2. CTLA4
  3. AIRE
  4. TLR function
  5. DC function
  6. Over/under expression can lead to auto-immunity
  • presentation of nucleic acid antigens
  • cross reactions to viruses
23
Q

What can initiate or accelerate autoimmune diseases?

Which disease specifically?

A

Viral and bacterial infections

ex: Type I diabetes

24
Q

Viruses can:
directly infect pancreatic beta cells and initiate _____ attack against them

Exhibit antigens that mimic _____.

Infect ______ in the pancreas and incite collateral damage to beta cells

Unmask partial ____ defects that are linked to loss of tolerance for B cells.

Activate CD8 cells with _______ antigen specificities

A
  1. CD8
  2. Beta cell antigens
    - CD8 cells mistakenly attack Beta cells
  3. non beta cell sites
  4. AIRE
  5. dual antigen specifies
    - some CD8 cells recognize viruses AND self-antigens (myelin)
  • when the host is infected with the virus, the CD8 cell develops cytotoxicity for BOTH antigens
  • this has already been shown to occur in an animal model of multiple sclerosis
25
Q

TH17 cells:

A new sub-lineage of Th cells has been described.

Discovered when the T cells at auto-immune sites were Th1 but producing _____, not IFN-gamma and the transcription factor was _____, not T-bet

What cytokines are absolutely necessary for Th17?

What if only TGF B is present?

A
  1. IL-17
  2. ROR
  3. Il-23, Il-6, initiating cytokines (from DC!!)

TGF B is mandatory

  • if only TGF B = only Tregs develop
26
Q

CD3,4 cannot be forced to develop into IL-17+ cells if either ______ or _____are present.

If CHRONIC inflammation is present, this signals that which cytokine and Th cell is responsible?

Which cytokine recruits neutrophils in acute reactions? CHRONIC?

A
  1. IFN - Gamma
  2. IL-4
  3. IL - 17 and Th17!!

IL - 17 recruits neutrophils

acute = IL-8
chronic = IL-17
27
Q

Describe a normal Th17

What is different in Th17 AUTOimmunity?

A
  1. certain fungi bacteria
  2. IL-17 ILR
  3. lots of IL-23 (and IL-6 and TGF- B)
    4, Th0 forced to Th17
  4. make a lot of IL- 17 –> recruit NEUTROPHILS

** instead of fungi or bacteria, SELF - ANTIGEN present

28
Q

When can self reactive B cells develop?

What do they usually die from?

What happens if a self-reactive B cell is unchecked?

Because we always make auto-reactive B cell clones, why are they not productive?

A

During antigen driven SOMATIC HYPERMUTATION

  1. die from “neglect” (anergy) or are suppressed by Treg cells
  2. They may synthesize antibodies that block functions of cells, or may accelerate cell functions by mimicking agonists or promote cytotoxic responses
  3. 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
29
Q

______ are NOT A MANDATORY CAUSE of Type I Diabetes.

A

Auto-antibodies!!!

30
Q

Why are not all antibodies disease causing?

A

Many simply SIGNAL that there is an underlying defect in the immune system that is causing autoimmunity

31
Q 
A family with both thyroid and adrenal deficiency might have a:
A. IgG deficiency
B. IgM and IgA deficiency
C. A partial INF - G deficiency
D. Partial AIRE mutation
E. overexertion of FoxP3
A

partial AIRE mutation

Immunology (26 decks)

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