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Immunology > Week 9: Autoimmunity > Flashcards

Week 9: Autoimmunity Flashcards

1
Q

What is tolerance?

A

The property that the immune system can distinguish self and non-self

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2
Q

What are the components of self tolerance?

A

Central and peripheral

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3
Q

What is tolerance not?

A

The absence of an immune response but is induced by suppressing the immune response

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4
Q

How do we establish and maintain tolerance?

A
  1. Mechanisms are a life long process
  2. Tolerance to a self-antigen can be induced in the primary lymphoid organs or in the periphery
  3. Mechanism are not perfect
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5
Q

What is self tolerance?

A
  1. Preventing adaptive immune responses against self sntigens
  2. Established by both central and peripheral
  3. Failure leads to autoimmune disease
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6
Q

What is induced tolerance?

A
  1. Manipulating the immune system to protect us from allergic reactions
  2. Manipulating the immune system to enable transplanted organs to survive in their new host
  3. Preventing the immune system from mounting an attack against commensal microbes living in the intestine
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7
Q

What is central tolerance?

A

Deletion of self-reactive lymphocytes before they mature

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8
Q

Where does central tolerance take place?

A
  1. Thymus (T cell)
  2. Bone marrow (B cell)
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9
Q

What occurs during central tolerance?

A
  1. Lymphocytes are remove through negative selection processes
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10
Q

What is the fate of negative selected lymphocytes in central tolerance?

A
  1. Induced to undergo apoptosis
  2. Self-reactive B cells may be rescued from clonal deletion by undergoing receptor editing to produce a less self reactive BCR
  3. Helper T cells can be induced to become TREGs to suppress effector cell activation
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11
Q

What is peripheral tolerance?

A

Either renders self-reactive lymphocytes non responsive or actively generates inhibiting lymphocytes?

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12
Q

What are the mechanisms of peripheral tolerance?

A
  1. Apoptosis
  2. Anergy
  3. Regulation through suppression: T reg releases anti-inflammatory cytokines, IL10, IL35, TGF-b
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13
Q

Where does peripheral tolerance occur?

A

Secondary lymphoid tissues and blood

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14
Q

What is anergy?

A

A state of non-responsiveness

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15
Q

What is an anergic cell?

A

Unable to become activated even upon subsequent exposure to signals 1, 2, and 3

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16
Q

What is the induction of T cell anergy?

A
  1. T cells requires 3 signals for activation
  2. If naive T cell only receives signal 1 and not 1 and 2 then it will become anergic
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17
Q

What are the signals required for T cell activation?

A
  1. MHC and TCR
  2. CD80/86 and CD28
  3. Cytokines
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18
Q

What cell induces tolerance to self-antigens

A

CD4+ T regs

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19
Q

What is a dependent mechanism of suppression?

A

Occur as T reg express high levels of inhibitory CTLA-4
CTLA4 has higher affinity for CD80/86 than CD28

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20
Q

What is independent mechanism of suppression?

A

Rely upon the secretion of anti-inflammatory cytokines into the surrounding area, shutting down the cell response

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21
Q

What are the anti-inflammatory cytokines?

A

IL-10, TGF-β, IL-35

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22
Q

What is the purpose of independent mechanisms?

A
  1. Absorb lots of IL2 preventing IL2 from interacting with other effector T cells
  2. Induces IDO production in DC that inhibit TNF-a and IL6 production
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23
Q

What is the overall cause of autoimmunity?

A

Failure of tolerance mechanism

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24
Q

What is the autoimmune response?

A

Recognition of self antigens via humoral responses (antibodies) or cell mediated immunity (auto reactive T cells)

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25
Q

What is the auto regulative cell?

A

Treg

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26
Q

What is an autoimmune disease?

A

When the last tolerance barriers are broken and the recognition of autoantigens has pathologic consequences

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27
Q

What are examples of autoimmune diseases?

A
  1. Organ dysfunction
  2. Deposition of immune complexes
  3. Activation of complement
  4. Production of autoantibodies
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28
Q

What is the current definition of autoimmunity?

A

Disruption of central and peripheral tolerance barriers thereby allowing activation of self-reactive T cells and B cells which induce tissue destruction and generate pathogenic autoantibodies

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29
Q

What causes autoimmunity?

A

Multifacotral processes?

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30
Q

What are the components of multifactorial induction?

A
  1. Genetic predisposition (HLA polymorphism): HLA associations reflects the important of T cell tolerance in preventing autoimmunity
  2. Combining a series of triggering events that cross an individual’s systems of tolerance over a threshold
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31
Q

What are environmental factors that cause autoimmunity?

A
  1. Infection or physical trauma
  2. Medications
  3. Chemicals
32
Q

How can infection or trauma cause autoimmunity?

A

Damage in immune priveged sites that lead to release of sequestered self-antigens or cause necrotic cell death exposing intracellular antigens

33
Q

How can medication cause autoimmunity?

A

Induce bY interfering with deletion or suppression of auto reactive lymphocytes

34
Q

How can chemicals cause autoimmunity?

A

Mercury or silica have been implicated in the development of autoimmune disease

35
Q

What are the mechanisms leading to the break down of autoimmunity?

A
  1. Impaired function of suppressor cells (T reg)
  2. Increased numbers of TH17 (pro-inflammatory)
  3. Epitope spreading due to immune response to a pathogen
  4. Release of sequestered auto antigens from immune privileged sites
  5. Structural modification of autoantigens
  6. Infectious agents can induce molecular mimicry
  7. Defective clearance of apoptotic cells
36
Q

What can cause a loss of suppression?

A

Inadequate number or defective function of T regs can result in their inability to suppress the activation of auto reactive lymphocytes

37
Q

What is epitope spreading?

A
  1. Inflammation induced tissue injury exposes self-antigens that were previously not recognized by the immune system
  2. Peripheral mechanisms fail
  3. Prolonged response leads to chronic disease
38
Q

What are immune privileged sites?

A
  1. Brian
  2. Eyes
  3. Testes
  4. Ovaries
  5. Pregnant uterus/placenta
39
Q

What is special about the immune privileged sites?

A

Partially isolated from interacting with the immune system

40
Q

What is antigen sequestration?

A
  1. Protection from self-antigen attacks that are not part of tolerance mechanisms
  2. Damage to privileged sites may expose their antigens to the systems, initiating response
  3. Sequestered antigens become immunogenic
41
Q

What can cause damage to privileged sites?

A

Surgical procedures and trauma to eye

42
Q

Describe the release of sequestered antigens?

A
  1. Trauma released sequestered antigens (immunogenic)
  2. Leads to the activation of lymphocytes against the immune privileged site antigens
43
Q

What is molecular mimicry?

A

Process where an infection by a particular microbe is associated with the subsequent development of a specific autoimmune disease

44
Q

What are some adverse side effects of autoimmune disease?

A
  1. Antigens on the surface of microbes are similar to self-antigens that the immune system response to the infection also causes a response against the self antigen by B and T cells
  2. Antibodies against Streptococcal cell wall antigens cross-react with cardiac muscle antigens (Rheumatic fever)
  3. Peptide fragments of viral infections can cross react with proteins of the pancreatic beta cells.
45
Q

What is a cryptic epitope?

A
  1. Molecules that possess “immune privileged sites”
  2. Hidden epitopes in the interior away from immune system
46
Q

How are cryptic epitopes exposed?

A

Molecule is denatured or altered when IgG binds causing a conformational change the exposes the cryptic epitopes that are recognized by Rheumatoid facotr

47
Q

What Ab is a rheumatoid factor?

A

IgM against IgG

48
Q

How are amino acids modified due to autoimmunity?

A

Citrullinated peptides are recognized as foreign and the immune system mounts a response against these altered proteins.

49
Q

What is defensive clearance of apoptotic cells?

A
  1. Does not induce inflammation
  2. Increased cell death may expose intra and nuclear antigens
  3. Antibodies against nuclear antigens are genrated
  4. IC form between auto-antibody and nuclear antigens form causes inflammation
  5. Some individuals have defects in the mechanisms used to clear apoptotic cells
50
Q

How can normal factors cause autoimmunity?

A
  1. Lymphocytes have an estrogen receptor on their surface
  2. Etrogens promote certain autoimmune diseases by altering the function and levels of auto reactive lymphocytes
  3. Ongoing studies are seeking to determine the mechanism of estrogen in autoimmune diseases
51
Q

Identify the criteria of autoimmune disease?

A
  1. Identify the target auto antigen in humans and reproduce the disease in the animal model by injecting the antigen
  2. Tranferring autoantibody or self-reactive lymphocyte to a new host in order to reproduce the disease
52
Q

What are the types of autoimmune disease?

A
  1. Organ specific
  2. Systemic
53
Q

What is organ specific autoimmunity?

A

Directed toward a target antigen unique to a single organ or gland

54
Q

What mediates organ specific autoimmunity?

A
  1. Direct cellular damage (induced by effector T cells, macrophages, complement, inflammatory cytokines)
  2. Stimulating or blocking autoantibodies
55
Q

Describe Grave’s disease in pregnant females?

A
  1. Production of IgG autoantibodies against the TSH receptor in the thyroid
  2. Antibodies can cross placenta to the fetal blood and the baby develops symptoms of the disease
  3. Once maternal IgG antibodies are removed the disease symptoms go away
56
Q

What is the function of TSHR autoantibodies?

A

Agonists that mimic the natural ligand of the receptor

Causes activating signals in the absence of the ligand leading to hyperthroidism

57
Q

What is myasthenia gravis?

A

autoantibodies are produced that bind ACh receptors on motor end plates

58
Q

Describe the mechanism of myasthenia gravis?

A
  1. Autoantibodies block the normal binding of acetylcholine, induce complement-mediated lysis of muscle cells (antagonist)
  2. Ach receptor bearing cells are destroyed
59
Q

What are the symptoms of myasthenia gravis?

A
  1. Progressive weakening of skeletal muscles
  2. Early signs are dropping eyes and inability to retract the corners of the mouth
60
Q

What are the treatments for myasthenia gravis?

A

Aimed at increasing acetylcholine levels, decreasing Ab productions, and removing Ab

61
Q

What is Hashimoto thyroiditis?

A
  1. Common in women
  2. Autoantibodies and sensitized TH1 cells specific for thyroid Ag are produced
  3. Lymphocytes infiltrate and form structures mimicking secondary lymphoid tissue
62
Q

What cause the infiltration of lymphocytes in patients with hashimotos?

A
  1. Ab produced interfered with iodine uptake: decreasing thyroid function leading to hyperthyroidism
  2. Induces DTH response in the thyroid: Inflammation results in goiter
63
Q

What is a goiter?

A

Visible enlargement of the thyroid gland

64
Q

What is type 1 diabetes?

A

Caused by autoimmune attack against insulin-producing beta cells in pancrease leading to decreased insulin production

65
Q

What is the mechanism of type 1 diabetes mellitus?

A
  1. CTLs infiltrate the pancreas and activate macrophages
  2. Production of anti-bet cell autoantibodies leads to activation of CDC or ADCC
  3. DTH response relates destructive lytic enzymes
66
Q

What is systemic autoimmunity?

A
  1. Broad range of target antigens
  2. Involves a number of organs and tissues
  3. Defect in immune regulation that results in hyperactivity of auto reactive B and T cells
  4. Widespread tissue damage caused by auto reactive T cells, complement proteins, autoantibodies, or accumulation of immune complexes
67
Q

What are the common features of systemic autoimmunity?

A
  1. Anti-nuclear Ab: non pathogenic unless with IC
  2. Systemic involvement of kidneys, lungs, heart, skin
  3. Joint pain and destruction
  4. Accumulation of auto reactive T and B cells
68
Q

What is systemic lupus erythematous (SLE)?

A
  1. Auto-Ab against DNA, histones, RBCs, clotting factors, platelets, etc
  2. Anti-nuclear antibodies are very common
  3. Auto-Ab form immune complexes
69
Q

What are the symptoms for SLE?

A
  1. Fever, weakness, arthritis, skin rashes, and kidney dysfunction
    2.Type III hypersensitivity reactions often induce damage due to the immune complexes depositing in the walls of the small vessels
70
Q

Who is most likely to acquire SLE?

A

9:1more common in women
Symptom onset 20-40 YO

71
Q

Who is most likely to acquire rheumatoid arthritis?

A

Diagnosed at 40-60 YO
More freq

72
Q

Who is most likely to acquire rheumatoid arthritis?

A

Diagnosed at 40-60 YO
More frequent in women (2.5:1)

73
Q

What is the common symptom of rhematiod arthritis?

A

Chronic joint inflammation

74
Q

What are the mechanism of rheumatoid arthritis?

A
  1. Produce auto-ab against: CCP, RF, joint structural proteins
  2. Forms IC and activate complement cascades
75
Q

What is the treatment for rheumatoid arthritis?

A
  1. Disease Modifying anti-Rheumatic Drugs (DMARDs)
  2. Nonspecific anti-inflammatory drugs
  3. Corticosteroids
  4. Specific anti-cytokine Abs

Immunology (17 decks)

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