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IHO Week 5 > Regulation of the Immune Response > Flashcards

Regulation of the Immune Response Flashcards

1
Q

What are six ways that Immune Function could be disrupted?

A
  1. Cytokines (IL-2, IL-7, etc.)
  2. Cytokine Receptor (CD25, IL-7Ralpha, gammaC, etc.)
  3. Signal Transduction (JAK, STAT, MAP, etc.)
  4. Transcription Factor (activation - NFKB for example - NFKB, AP1, IRF3, IRF7, etc.)
  5. Transcription factor binding (promoter point mutations)
  6. Gene transcription/Translation/Protein Function (ORF point mutations) –> cytokines are produced by this and feed back into the top!
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2
Q

At the end of an immune response, reduced antigen exposure results in reduced expression of IL-2 and its receptor:

A
  • This leads to apoptosis of the antigen-specific T cells (cell numbers start to dwindle)
  • The majority of antigen-specific cells die at the end of an immune response
  • Small population of long-lived T and B cells survive and give rise to the memory population
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3
Q

What does the CD28-B7 interaction cause?

A

Leads to initial production of IL-2 by T cells bound to APC.

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4
Q

What is CTLA4 binding to CD80/CD86 on APCs?

A

This is a timed interaction between T & APC cells triggered by Treg cells.

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5
Q

In antigenic self tolerance, what is a mature dendritic cell characterized by?

A
  • Strong expression of MHC and co-stimulatory molecules.

- Induction of mature dendritic cells can be achieved through microbial or self-derived stimuli (danger signals)

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6
Q

In antigenic self tolerance, what happens with immature DCs?

A

-In the absence of stimuli, immature DCs express MHC and costimulatory molecules at low levels and antigen presentation induces T cell anergy or deletion depending upon the expression of low or high levels of self-antigen

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7
Q

What molecules are necessary for tolerogenic DC-T cell interactions?

A

E-caderin, PD-1 L, CD103, CD152 (CTLA-4), ICOS-L (CD275) and cytokines, including IL-10 and TGF-beta.

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8
Q

What happens in an immunogenic DC?

A
  1. Danger signal received by DC
  2. CD86, MHCII, CD40, CCR7 all high on DC
  3. DC receives antigen
  4. NFKB expression increased
  5. DC releases proinflammatory cytokines (IL-12, TNFalpha)
  6. T-cell proliferation, activation of effector functions
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9
Q

What happens a tolerogenic DC?

A
  1. CD86, MHC II, CD40, CCR7 all low on DC
  2. No antigen present and no danger signal received
  3. NFKB expression decreased
  4. Clonal deletion or anergy of antigen-specific T-cells
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10
Q

What do Treg Cells do?

A
  • Block effector T cells

- Provide class switch instructions for B cells

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11
Q

What are the four different types of Treg effector mechanisms used to control the proliferation and actions of other T cell populations?

A
  1. Immunosuppresive (anti-inflamamtory) cytokines
  2. IL-2 Consumption
  3. Cytolysis (killing other immune effector cells)
  4. Modulation of DC Maturation and Function
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12
Q

How does the Treg cell use Immunosuppressive (Anti-inflamamtory) Cytokines?

A
  1. Treg releases IL-10 (suppreses and blocks Th1 cells), TGT-beta, IL-35 (positive feedback loop to produce more Treg cells)
  2. These cytokines suppress effector T cell and cause it to undergo cell cycle arrest
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13
Q

How does the Treg cell use IL-2 consumption?

A
  1. Treg has IL-2Ralpha (CD25)
  2. It competes for IL-2 in this area. It scavenges IL-2 and blocks the growth of effector cells
  3. It soaks up the remaining amounts of IL-2 in the surrounding system
  4. This leads the effector T cells to undergo BIM-mediated apoptosis
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14
Q

How does Treg use Cytolysis (killing other immune effector cells)?

A
  1. Granzyme-mediated

2. Treg cell attaches to effector T cell and causes it to undergo apoptosis.

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15
Q

How does Treg use Modulation of DC maturation and function?

A
  1. Treg CD152 (CTLA4) attaches to DC CD80/86
  2. Then DC changes tryptophan to kynurenin which inhibits effector T cells.
  3. This causes effector T cells to undergo cell cycle arrest
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16
Q

What is immunologic tolerance?

A

Prevents or regulates unwanted immune responses
-B lymphocytes and plasma cells that produce antibodies that recognize self-antigens (auto-antibodies) pose a threat to the organism

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17
Q

What are the four different types of B cell tolerance mechanisms?

A

First, self antigen binds to self-reactive receptor on a lymphocyte:

  1. Clonal Deletion
  2. Receptor editing
  3. B-cell intrinsic mechanisms
  4. B-cell intrinsic mechanisms
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18
Q

What happens in the B cell tolerance mechanism Clonal Deletion?

A

Induction of apoptosis via inhibition of survival signals or activation of death receptors

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19
Q

What happens in the B cell tolerance mechanism Receptor Editing?

A

Continued V(D)J recombination to avoid self-reactivity

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20
Q

What two different things can happen in the B cell tolerance mechanism B-cell intrinsic mechanism?

A
  1. Anergy (state of immune unresponsiveness), down regulation of BCR, upregulation of CD5.
  2. Lack of T-cell help or survival factors. It responds to antigen but never receives T cell help.
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21
Q

What types of T cells produce IL-2?

A

Th0 (naive), Th1

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22
Q

What types of T cells produce IL-4?

A

Th2, Tfh, Th0 (naive) (NKT cells, specialized macrophages (M2), basophils), can block production of Th1 cells (produces mast cells, B cells/antibodies and eosinophils)

23
Q

What types of T cells produce IL-5?

A

Th2 (produces mast cells, B cells/antibodies, eosinophils)

24
Q

What types of T cells produce IL-10?

A

Treg, Th2 (inhibits production of IFN-gamma by Th1)

25
Q

What types of T cells prodcuce IL-13?

A

Th2

26
Q

What types of T cells produce IL-17?

A

Th17 (neutrophil recruitment/inflammation)

27
Q

What types of T cells produce IL-35?

A

Treg

28
Q

What types of T cells produce IFN-gamma?

A

Th1, Th0 (macrophage activation, inhibits proliferation of Th17 and Th2)

29
Q

What types of T cells produce TNF-alpha/beta?

A

Th1

30
Q

What are the two mechanisms of Antibody-Dependent B Cell Suppression?

A
  1. Antibody blocking

2. Receptor Cross-linking

31
Q

How does antibody blocking work?

A
  1. Ag binds to soluble Ig which binds to membrane Ig and block eh antibody on the B cell.
  2. Any one antigen could trigger a B cell to stop growing/get killed.
32
Q

How does receptor cross-linking work?

A
  1. There’s so much soluble IgG, that the antigen is all bound up by that IgG! This means that the B cell is no longer getting growth signals
  2. Ag cross-links membrane Ig with soluble Ig. Soluble Ig binds to FcgammaRIIb which is bound to SHP-1 and blocks growth signals to the B cells/triggers B cell to get killed.
33
Q

What is Antibody-Dependent B Cell Augmentation?

A

-Antibody (IgM) can bring antigen coated with complement to FDC in lymph node that has a complement receptor and can help present this antigen to B cells undergoing class switch recombination –> Gives B cells pro-proliferative signals

34
Q

What is IPEX?

A

(Immunodysregulation, polyendocrinopathy, enteropathy, X-linked)

  • Inborn lack of Treg cells (CD4+/CD25+ cells)
  • Failure of peripheral tolerance due to defective Treg cells
  • Causes severe autoimmune inflammation
35
Q

What are the symptoms of IPEX?

A

Shows up 6-9 months after birth: rashes/atopic dermatitis, diarrhea, weight loss, quality of life poor, high blood glucose levels (autoimmune diabetes! type I), sparse hair, cervical, axillary nodes and spleen enlarged, failure to thrive
-Later: thrombocytopenia (deficiency in blood platelets)

36
Q

What mutation causes IPEX?

A

Mutation in FOXP3 (forkhead transcription factor) gene which results in no Treg cells

37
Q

What did Billy need to maintain his weight?

A

Parenteral (intravenous) nutrition

38
Q

What is seen in intestinal tract of IPEX?

A

Almost total villous atrophy - an absence of villi in the lining of the duodenum with dense infiltrate of plasma cells and T cells.

39
Q

What do IPEX patients produce autoantibodies toward?

A

Glutamic acid decarboxylase (the GAD65 antigen)

40
Q

What do the labs of an IPEX patient show?

A
  • Normal WBC count, normal hemoglobin count, normal platelet count, percentage of eosinophils was high in blood at 15% (normal 5%), IgE elevated
  • Anti-platelet antibodies
41
Q

What causes both elevated eosinophils and elevated IgE in IPEX?

A

High IL-5!

42
Q

Why can’t you give vaccines to kids with IPEX?

A

Without Treg you can’t control the response to the vaccine.

43
Q

What treatment is used for IPEX?

A
  • Immunosuppresive therapy: Cyclosporin, Tacrolimus
  • Bone marrow (stem cell) transplant (esp. for thrombocytopenia) from HLA-identical sibling
  • IVIG used to forestall or ameliorate infections in these patients
44
Q

Why is full engraftment not necessary in patients with IPEX?

A

Only need a few Treg cells to sufficiently immune regulate - Billy only had 30% engraftment.

45
Q

What are the symptoms of APECED?

A

Very dry skin, around 18 months, movements sluggish, very low height and weight, TSH elevated, hypothyroidism, thickened, ridged, notched fingernails, patches of hair loss (alopecia areata), lost eyebrows, developed fissures at angle of mouth (due to infection with C. albicans), darkly pigmented scrotum and areolae, Addison’s disease (adrenal insufficiency)

46
Q

What is given to treat hypothyroidism seen in APECED?

A

Thyroid hormone

47
Q

What can happen in Addison’s disease? How is it treated in APECED?

A

ACTH at 3X normal.

Treatment: Steroid prednisone, Fluorinef (conserves sodium and potassium excretion)

48
Q

What is APECED?

A

(Autoimmune polyglandular syndrome (APS) type I)

  • Autosomal recessive inheritance
  • Increased susceptibility to Candida albicans
49
Q

What autoantibodies are present in APECED?

A

Autoantibodies against (1) organ-specific antigens of the endocrine glands (2) antigens in the liver and skin, blood cells (platelets)

50
Q

What gene is mutated in APECED?

A

AIRE (autoimmune regulator) on chromosome 21 (Finns, Sardinians, Iranian Jews). Gene encodes transcriptional regulator that induces expression of 1,200 genes of organ-specific antigens.

  • AIRE is expressed on DC in thymus
  • Deletion of 13 bp in exon 8 of AIRE
51
Q

What autoantibodies are produced in APECED?

A

Autoantibodies to IL-17 and IL-22

52
Q

How to treat APECED?

A

No known cure. Treatment directed at symptoms.

53
Q

What is seen in the lab of APECED?

A

Low level of gammaglobulin antibodies in blood (hypogammaglobulinemia) and an abnormally low T4/T8 white blood cell ratio (as in AIDS)

IHO Week 5 (7 decks)

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