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SMP - MIM Part 1 > Lecture 14 - Autoimmunity > Flashcards

Lecture 14 - Autoimmunity Flashcards

1
Q

What is tissue injury mediated by in autoimmunity?

A

Tissue injury types II, III, and IV

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2
Q

What patients do autoimmune diseases disproportionally affect?

A

Women

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3
Q

3 genetic factors affecting autoimmunity?

A
  1. HLA alleles
  2. TCR repertoire
  3. Cytokine polymorphisms
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4
Q

Example of an environmental trigger that can cause autoimmunity?

A

Infection

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5
Q

What are the 6 layers of immune tolerance?

A
  1. Central tolerance
  2. Antigen segregation
  3. Peripheral anergy
  4. Regulatory cells
  5. Cytokine deviation
  6. Clonal exhaustion
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6
Q

Central tolerance:

  1. Mechanism?
  2. Site of action?
A
  1. Deletion and editing

2. Thymus and bone marrow

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7
Q

Antigen segregation:

  1. Mechanism?
  2. Site of action?
A
  1. Physical barrier to self-antigen accessing the lymphoid system
  2. Some peripheral organs (e.g. pancreas, thyroid)
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8
Q

Peripheral anergy:

  1. Mechanism?
  2. Site of action?
A
  1. Signal without co-stimulus

2. Secondary lymphoid tissue

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9
Q

Regulatory cells:

  1. Mechanism?
  2. Site of action?
A
  1. Suppression by cytokines and intercellular signaks

2. Secondary lymphoid tissue and sites of inflammation

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10
Q

Cytokine deviation:

  1. Mechanism?
  2. Site of action?
A
  1. Differentiation into TH2 to limit inflammatory cytokine secretion
  2. Secondary lymphoid tissue and sites of inflammation
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11
Q

Clonal exhaustion:

  1. Mechanism?
  2. Site of action?
A
  1. Apoptosis of T cells post-activation (if they have been activated for a long period of time)
  2. Secondary lymphoid tissue and sites of inflammation
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12
Q

How can Treg cells suppress self-reactive T cells? What is this called?

A

Treg cells can suppress self-reactive lymphocytes that recognize peptides different from those recognized by the Treg cell itself provided that the antigens are from the same tissue or presented by the same APC as it inhibits all surrounding auto-reactive T cells, regardless of their precise auto-antigen specificity

=> Regulatory or infectious tolerance

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13
Q

Describe the mechanism through which T cells become activated by low affinity binding to self antigens.

A

A naïve T cell with low affinity for self-antigen meets APC presenting self peptides and expressing high levels of co-stimulatory molecules as a result of concomitant infection i.e. proinflammatory cytokines

Release of sequestered antigens by massive cell death or inflammation

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14
Q

Describe the mechanism through which B cells become activated by low affinity binding to self antigens. What to note?

A
  1. B cells with specificity for DNA bind soluble fragments of DNA through BCR
  2. Cross-linked BCR is internalized with the bound DNA fragment
  3. GC-rich fragments from the internalized DNA bind to TLR-9 in an endosome = SIGNAL 1 (mistaken for prokaryotic DNA) => sends co-stimulatory signal = SIGNAL 2

Note: similarly, viral RNA can be recognized and bound by TLR-7 or 8

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15
Q

10 organ-specific autoimmune diseases?

A
  1. Type 1 DM
  2. Goodpasture’s syndrome (lungs and kidneys)
  3. MS (CNS)
  4. Grave’s disease

THYROID:

  1. *Grave’s disease
  2. *Hashimoto’s thyroiditis
  3. *Autoimmune pernicious anemia (stomach)
  4. *Autoimmune addison’s disease (adrenals)
  5. *Vitiligo (skin)
  6. *Myasthenia gravis (muscles)
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16
Q

5 systemic autoimmune diseases? Which ones tend to occur in clusters?

A
  1. Rheumatoid arthritis
  2. Scleroderma
  3. *Systemic lupus
  4. *Primary Sjogren’s syndrome
  5. *Polymyositis
17
Q

6 mechanisms of the induction of autoimmune diseases?

A
  1. Molecular mimicry
  2. Release of sequestered antigens
  3. Gell and Coombs type 2 with cell membrane self antigen as target
  4. Inappropriate expression of Class II MHC
  5. Polyclonal B and T cell activation by mitogens/superantigens
  6. Chronic infection/inflammation
18
Q

Describe the mechanism of molecular mimicry. 3 examples?

A

Pathogen displays antigens on its surface that are structurally similar to self-antigens => T-cells activated to respond to self molecules

Examples: acute rheumatic fever (group A strep), GBS, Type 1 DM

Infections can lead to autoimmune disease as a result of cross-reactive antibodies or T cells.

19
Q

Describe GBS.

A

It’s the most frequent cause of acute paralysis in the western world

Infections causing molecular mimicry: campylobacter jejuni, cytomegalovirus, EBV, and mycoplasma pneumoniae (e.g. swine flue vaccine) => similar LPS to ganglioside in nerve cell membranes

The immune attack consists of deposition of antibodies and complement on the axon and Schwann cell surface => infiltration of the nerve with macrophages and T cells

  • The antibodies are IgM, IgA, IgG1 and IgG3
  • T cells are CD4+, CD8+, and express αβ or γδ TCR
  • The gangliosides are GM1, GM1b, GD1a and Gal-NAc-GD1a
20
Q

Other name for molecular mimicry?

A

Antigenic cross-reactivity

21
Q

Example of how the release of sequestered antigens can cause autoimmunity? Treatments?

A

Sympathetic ophthalmia: trauma to one eye releases the sequestered eye antigens into the surrounding tissues, making them accessible to T cells => effector cells that are elicited attack the traumatized eye, and also infiltrate and attack the healthy eye

Treatment: remove damaged eye before it illicits immune response OR suppress immune system (preferable)

22
Q

2 example of how the Gell and Coombs type 2 with cell membrane self antigen as target can cause autoimmunity?

A
  1. Graves’ disease: autoantibodies specific for the receptor for TSH are agonists for the TSH receptor and therefore stimulate the production of thyroid hormones => these inhibit TSH production in the normal way but do not affect production of the autoantibody => excessive thyroid hormone production => hyperthyroidism
  2. Myasthenia gravis: in normal circumstances, acetylcholine released from stimulated motor neurons at the NMJ binds to AChR on skeletal muscle cells, triggering muscle contraction, but in this disease there are autoantibodies against the α subunit of the receptor for acetylcholine => they bind to the receptor without activating it and also cause receptor internalization and degradation => number of receptors on the muscle is decreased => muscle becomes less responsive to acetylcholine
23
Q

Explain how the inappropriate expression of Class II MHC can induce autoimmunity. Example? What do molecules are implicated?

A

In autoimmunity, cells other than APCs may express MHC II and higher levels of MHC I

e.g., pancreatic β cells in insulin-dependent diabetes mellitus (IDDM) and thyroid acinar cells in Graves’ disease

Interferon γ and mitogens have been implicated

24
Q

Describe how polyclonal B and T cell activation by mitogens/superantigens can induce autoimmunity.

A

Superantigens can activate sub-sets of CD4 T cells some of which may be auto-reactive

Mitogens (e.g. LPS from gram-negative bacteria, CMV and EBV) are polyclonal B cell activators that can induce auto-reactive IgM antibodies

25
Q

How can chronic inflammation lead to autoimmunity? What can this lead to? Example?

A

Tissue injury releases autoantigens that are not normally presented during development in bone marrow or thymus

Can lead to epitope spreading: further damage caused by the immune response releases more autoantigens

Example: systemic lupus

26
Q

What is linked recognition?

A

For isotype switching: B cell and follicular helper T cell MUST recognize epitopes of the same antigen in order to interact BUT the B cell receptor doesn’t have to have that same peptide specificity as long as the MHC loaded peptide is the same as the one the DC presented to the TFH cell = linked recognition

27
Q

How are epitope spreading and linked recognition related?

A

B cell autoreactive to H1 (histone) in nucleosome

T cell specific for the H1 histone protein of the nucleosome can activate both a B cell specific for H1 and a B cell specific for double-stranded DNA to become a plasma cell

=> broadening of the autoimmune response

28
Q

Overall what is necessary in autoimmune responses?

A

Both autoreactive B and T cells => low occurrence

SMP - MIM Part 1 (14 decks)

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