4 - Tolerance and Autoimmunity Flashcards

1
Q

How does the immune system recognize all pathogens? What is inherent to this diversity and what suppresses this?

A

Lymphocyte antigen receptors (T and B cells) through random DNA rearrangement of receptor gene segments.

Inherent generation of autoreactive lymphocytes - the immune system suppresses these (immunologic tolerance)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What occurs if tolerance of T and B cells to self antigens fails?

A

Autoimmunity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Why is immunologic tolerance important? What are examples?

A

Abnormal immune responses to self or non-pathogen antigens can cause disease.

Loss of tolerance to self-autoimmunity

Immune response to environment - allergy

” “ transplant - transplant rejection/graft vs host disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is central tolerance?

A

When immature lymphocyte in the generative lymphoid organs encounter antigen (BM for B cells, Thymus for T cells).

This is not complete: small pop of self reactive lymph. escapre but are usually quiescent.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is peripheral tolerance?

A

When mature lymphocutes encounter self-antigen in peripheral tissues (lymph nodes, spleen, MALT, peripheral tissues).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the mechanism by which central tolerance occurs for B and T cells? What is the exception to this mechanism?

A

In thymus/BM, immature B/T cells that recognize high avidity self-antigens are apoptosed

Exception: T regulatory cells are self-reactive CD4 T cells that suppress immune responses and express Foxp3

B cells can edit receptors to make new ones instead of being apoptosed.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How does the B cell edit its receptor?

A

The light chain of the immunoglobulin locus can rearrange and form a new antibody

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is peripheral tolerance and what three things can occur to make sure you don’t react?

A

When self-reactive T/B cells encounter self antigen in the periphery.

1. Apoptosis:

  • Fas/Fas ligand
  • Cytokine withdrawl
  • AICD
  1. Anergy: functional inactivation of T and B lymphocytes
  2. Suppression: T reg cells suppress T cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECEP)? What is the classic triad and the underlying defect?

A

Classic triad:

  • Autoimmune hypoparathyroidism
  • Autoimmune adrenal insuff.
  • Candidiasis

Defects in AIRE gene (autoimmune regulatory gene), a TF that induces expression of self-antigens by thymic medullary epithelial cells (this is how the body makes self so that central tolerance can occur)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What happens when the AIRE gene is lost?

What is this defect an example of?

A
  1. Self-reactive T cells are not deleted
  2. Self reactive T regulatory cells are not generated

This is an example of failure of central tolerance.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Describe what is necessary for T cell activation?

A
  1. TCR on T cell sees antigen on MHC (on APC)
  2. Co-stimulation: CD28 on naive T cell with B7 (CD80/86) on APC
  • B7 upregulated when APC encounters microbe
  • When no B7 is present on APC - Anergy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is Anergy?

A

Functional inactivation of lymphocytes, occurs when APC lacks co-stim molecule:

  • When APC lacks B7 (which normally binds to C28)
  • When you have CTLA-4 instead of CD28 (CTLA-4 binds and inactivates B7)

OR PD-1 checkpoint inhibitors, which are induced in T cells and prevent T cell activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What happens when microbes (pathogen-associated molecular patterns -PAMPs) are recognized by PRRs compared to when self is regognized by PRRs?

A

They induce B7 molecules on APC surface so APC can activate T cell; this is a danger signal that promots an immune response.

Self antigens don’t stimulate APCs (no PAMPs), they promote anergy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

T and B cells expand rapidly during an immune response and must die after the response is over, what are the mechanisms by which this can occur?

A
  1. Activation-induced cell death: repeated activation of mature T cells by self-antigen triggers apoptosis of T cell (and thus removal of self-reactive lymphocytes)
  2. Fas/Fas Ligand: CD4+ activation ^ expression of Fas “Death receptor” and it’s ligand FasL. Fas:FasL binding causes apoptosis.
  3. Cytokine withdrawl: Activated T cells (TCR:CD28) express IL2 which allows survival and growth, when stimulus is gone, IL2 isn’t make and there is apoptosis.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is autoimmuen lymphoproliferative syndrome (ALPS)? What are the clinical characteristics?

A

Mutations in Fas or FasL - immuen cells dont die properly.

Causes widespread lymphadenopathy, splenomegaly, and autoimmune cytopenias.

Failure of peripheral tolerance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What role do T regulatory cells play in central tolerance?

A

Express TF Foxp3 - activated in the periphery by self antigen and IL-2 to blunt/suppress actication of T cells through contact-depdendent or contact-independent mechanisms.

Generated by self-antigens in thymus (AIRE)

17
Q

What disease results from a lack of T regulatory cells? What causes this disease?

A

IPEX: immune dysregulation polyendogrinopathy, enteropathy, Xlinked.

Caused by a mutation in Foxp3 and loss of T regulatory cells. LEads to death if not aggressively treated.

18
Q

Are tolerogenic self antigens found in generative organs? What about immunogenic foreign antigens?

A

Tolerogenic self antigens: yes, high concentrations induce negative selection and Treg cellls (central tolerance)

Microbe: no, microbial antigens are concentrated in peripheral lymphoid organs

19
Q

Describe the persistence of antigen for tolerogenic self antigens vs. immunogenic foreign antigens?

A

Tolerogenic self antigens: long-liver, prolonged TCR engagement that may induce anergy or apoptosis

Immunogenic foreign antigens: usually short-lived; immune response eliminates antigen

20
Q

How is HLA/MHC linked to autoimmunity?

A

The “relative risk” of developing an autoimmune disease is higher in individuals who inherit particular HLA/MHC alleles

  • HLA affects which peptides are presented to lymphocytes
21
Q

Does everyone with a high risk HLA allele get autoimmunity? What is an example of this?

A

No, lots of people express them but DONT get disease. Complete deficiencies in genes directly involved in the immune response are more likely to cause autoimmunity than high-risk HLA alleles.

HLA-B27 is a strong risk factor for ankylosing spondylitis and about 6% of people are HLA-B27 HOWEVER, the prevelance of AS is only 0.5%

22
Q

How are environmental factors linked to autoimmunity?

A

In some cases microbial infection can trigger autoimmunity.

OR, infectious organisms can have antigens that look like self, resulting in autoimmunity (molecular mimicry)

23
Q

What are the four types hypersensitivity reactions? What is each mediated by?

A
  1. Type 1: immediate sensitivity (IgE mediated)
  2. Type 2: Antibody mediated
  3. Type 3: Immune complex
  4. Type 4: delayed type hypersensitivity
24
Q

What is a type 1 hypersensitivity reaction characterized by? What diseases does this include?

A

Immediate hypersensitivity: IgE mediated, requires TH2

Diseases: allergic rhinitis, asthma, eczema, and food allergies.

25
What is a type 2 hypersensitivity reaction? What is the mechanism by which this occurs?
**Antibody-mediated hypersensitivity: antibodies produced to self proteins** **Ab cause inflamm/disease by:** * Crosslink Fc receptors on mø/PMN to cause inflamm * Complement activation * Phagocytosis * Function blocking or activating antibodies (Myasthenia gravis/graces disease)
26
What is an exmaple of a type 2 hypersensitivity reaction?
Acute rheumatic fever (**JONES** Criteria) * Joints * Heart * Nodules * Erythema marginatum * Sydenham's chorea
27
What is the treament for antibody mediated disease when it's non-life-threatening vs life-threatening?
**Non-lifethreatening:** * _High dose IVIg_ - competition for Fc receptors, activates inhibitory Fc receptor * _Corticosteroids_ **Life thretening:** * _Plasmapheresis/plasma exchange_ * Remove plasma and antibody and replace with new
28
What occurs in a type 3 hypersensitivity reaction? What does this lead to?
When antigens/antibodies combine in circulation and **form immune complexes (IC)** These usually activate complement and lead to clearance of the immune complex Will get a complement-activated rash
29
What happens if there's a failure to clear immune complexes in type 3 hypersensitivity reactions?
Immune complexes can deposit in vasculature and lead to disease
30
What is an exmample of a type 3 hypersensitivity reaction? What are clnical symptoms?
**Systemic lupus erythematosus** - autoimmune disease characterized by auto-antibody production (particularly to DNA) * Nephritis, rash, vasculitis * Complement defects lead to early onset SLE * ICs go to kidney, joints, and skin: once deposited, complement activation leads to inflamm, PMN recruit, etc.
31
What is a type IV hypersensitivity reaction? What is an example?
Cell mediated disease (CD4/CD8) T cells - Leads to tissue injury Arthritis is an example.
32
What is the pathogenesis of arthritis? What is it mediated by?
_\*\*B and T cell Mediated\*\*_ **T cells:** * **in synovial space are oligoclonal:** autoreactive and expandingin the joint * **activate monocytes, mø, and synovial fibroblasts and release IL1, IL6, and TNF causing inflamm, macrophage activation, and bone resoroption** **B cells:** aggregate in synovium and may have autoantibodies
33
What is the pathology of arthritis?
Pathology shows panus formation of mononuclear cells (lymphocytes/macrophages)
34
What are the treatment options for arthritis?
1. **NSAIDs:** cyclooxygenase inhibitors inhiibt prostaglandins and leukotrienes 2. **Antimetabolites:** lead to inhibition of DNA synthesis (methotrexate and azathioprine) 3. **Glucocorticoids:** can't be used long-term due to side effects 4. **Biologic therapy:** monoclonal Ab to immuno molecules
35
What are examples of types of biologic agents used to treat arthritis?
Anti-TNF, Anti-IL-1, Anti-IL6, CTLA-4I, and Anti-CD20
36
Immune responses that cause tissue injury are called ______ \_\_\_\_\_\_\_, and the diseases caused by these are called __________ or \_\_\_\_\_\_\_\_\_\_.
Hypersensitivity reactions hypersensitivity diseases or immune-mediated inflammatory diseases
37