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Microbiology > 2. Autoimmunity > Flashcards

2. Autoimmunity Flashcards

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1
Q

autoimmunity

A
  • results from failure or breakdown of mechanisms that maintain self-tolerance
  • multiple factors contribute to development of autoimmunity, poorly understood
  • various effector mechanisms are responsible for tissue injury
  • affects 1-2% US population
  • immunity to self antigens
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2
Q

how does autoimmunity arise

A
  • clonal deletion of self-reactive T and B cells is not perfect
  • in normal individuals, self-reactive lymphocytes are suppressed
  • loss of regulation of self-reactive cells leads to immune response to self
  • don’t know etiology of autoimmunity
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3
Q

2 mechanisms of tissue injury

A
  • same as any type of immune response, except to self tissue
    1. immune complex-mediated injury
    2. anti-tissue antibodies
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4
Q

immune complex-mediated tissue injury

A
  1. mechanism of antibody deposition (circulating immune complexes in blood vessel)
  2. complement- and Fc receptor-mediated recruitment and activation of inflammatory cells
  3. effector mechanisms of tissue injury (neutrophil granule enzymes, reactive oxygen intermediates, neutrophils in blood vessel)
  4. vasculitis
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5
Q

injury caused by antitissue antibody

A
  1. mechanism of antibody deposition (antigen in ECM attached to antibody deposition)
  2. complement- and Fc receptor-mediated recruitment and activation of inflammatory cells
  3. effector mechanisms of tissue injury (neutrophils, macrophages, enzymes, reactive oxygen species in ECM)
  4. tissue injury
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6
Q

2 types of autoimmunity

A
  • organ specific
  • systemic
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7
Q

organ-specific autoimmune diseases

A
  • response is to a target antigen whose expression is restricted to a particular organ or tissue (can be antagonist or agonist)
  • two general types:
    • diseases caused by cellular damage, decline in organ function
    • diseases caused by stimulating or blocking autoantibodies
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8
Q

anemia (organ specific disease)

A
  • pernicious anemia: auto-Abs to “intrinsic factor”, a membrane-bound protein on gastric parietal cells. blocks uptake of vitamin B12, which is required for RBC hematopoiesis
  • autoimmune hemolytic anemia: auto-Abs to RBC antigens, triggers C’-mediated lysis of RBC’s, IgG, recognize Rh complex
  • drug-induced hemolytic anemia: penicillin can cause RBC’s to become antigenic
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9
Q

hashimoto’s thyroiditis (organ specific disease)

A
  • thyroid self-antigens, e.g. thyroglobulin and thyroid peroxidase
  • causes goiter, blocks iodine uptake and leads to decreased production of thyroid hormones (hypothyroidism)
  • usual onset in middle-aged women
  • involves CD4+ T cells, DTH response
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10
Q

goodpasteur’s syndrome (organ specific disease)

A
  • auto-Abs to kidney and lung self-antigens located in basement membranes of kidney glomeruli and lung alveoli
  • usually against type IV collagen
  • C’ activation leads to cellular damage and inflammatory response
  • kidney damage and pulmonary hemorrhage
  • deposits of autoantibody along basement membrane
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11
Q

insulin-dependent diabetes mellitus (IDDM)

A
  • auto-abs to pancreatic beta cells in islets of langerhans, affects 0.2% of population
  • beta cells are destroyed, results in decreased production of insulin and increased blood glucose (type I diabetes)
  • metabolic problems result in:
    • ketoacidosis
    • increased urine production
    • atherosclerotic lesions, can cause gangrene, renal failure and blindness
  • CTL’s migrate to islet, secrete inflammatory cytokines (TNF, IL-1, IFNgamma)
  • auto-Abs cause DTH and Ab-dependent cytotoxicity (ADCC)
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12
Q

multiple sclerosis (MS)

A
  • relapsing neurologic disorder, affects young adults
  • progressive demyelination of nerves, breakdown of blood brain barrier
  • evidence for autoimmunity is circumstantial:
    • inflammatory cells in CSF, brain, spinal cord
    • autoantigens not known, but CD4+ T cells reactive to myelin basic protein elevated in MS patients
  • treatment with interferon-1beta somewhat successful, mechanism unknown
  • 12 viruses involved:
    • HTLV-I-like retrovirus
    • increased titer of measles virus in CSF
    • herpesviruses: EBV, herpes simplex I, HHV-6
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13
Q

MS animal model

A
  • experimental allergic encephalomyelitis (EAE)
  • immunization of mice with myelin basic protein (MBP) in complete Freund’s adjuvant
  • mediated by CD4+ T cells, can be transferred
  • response is not always the same
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14
Q

EAE mouse model

A
  • mice injected with myelin basic protein and complete Freud’s adjuvant develop EAE and are paralyzed
  • the disease is mediated by myelin basic protein-specific Th1 cells
  • disease can be transmitted by transfer of T cells from affected animal and lead to paralysis i
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15
Q

2 types of diseases caused by antibodies

A
  • stimulating auto-antibodies
  • blocking auto-antibodies
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16
Q

grave’s disease

A
  • antibodies against TSH receptor
  • Abs mimic hormone, but are not regulated (Ab bind to TSH receptors and make the receptors think they’re hormones)
  • antibodies are agonists (stimulate function)
  • hyperthyroid syndrome, heat intolerance, nervousness, weight loss, enlarged thyroid
  • CD4+ T cells, Th2 response implicated
17
Q

stimulating auto-antibodies in grave’s disease

A
  • autoantibody to TSH receptor stimulates hormone synthesis in the thyroid cell
  • leads to unregulated overproduction of thyroid hormones
  • this is an ex of stimulating/agonistic antibodies
  • no feedback mechanism to stop producing thyroid hormones
18
Q

myasthenia gravis

A
  • Abs to acetylcholine receptor
  • blocks normal binding to ACh and induces C’-mediated lysis
  • anti-ACh receptor antibody is antagonist (inhibit function)
  • progressive muscle weakening, esp facial and respiratory muscles
19
Q

blocking auto-antibodies in myasthenia gravis

A
  • ACh cannot bind to AChR because Ab are there
  • auto-antibodies bind to AChR, which inhibits muscle activation
  • nerve is firing ACh but there is no response
20
Q

inflammatory bowel diseases

A
  • chronic, presumably noninfectious inflammation of bowel
  • presumed to be autoimmune in origin
  • ulcerative colitis (limited to large bowel, fairly superficial inflammation)
  • chrohn’s disease (occurs anywhere along GI tract)
21
Q

sjogren’s syndrome

A
  • autoimmune disease of exocrine tissue
  • lymphocyte infiltration in salivary tissue and lachrymal (tear) ducts
  • can become systemic, involving musculoskeletal, pulmonary, renal systems
  • often associated with other autoimmune diseases
  • females 9:1
  • dry mouth and eyes, “crocodile skin”
22
Q

systemic autoimmune diseases

A
  • response directed to a broad range of target Ags, numerous tissues and organs
  • variable course among afflicted individuals
  • increased susceptibility in women
  • overlap: an individual may have symptoms of multiple diseases, confounds diagnosis
  • usually respond poorly to exogenous Ags
23
Q

systemic lupus erythmatosus (SLE)

A
  • 10x higher in women
  • fever, weakness, skin rashes, kidney dysfunction
  • antibodies to DNA, histones, nucleolar RNA, RBC’s, platelets and clotting factors
  • high levels of complement proteins, esp C5a and C3a (anaphylotoxins)
  • renal disease associated with immune complexes and DNA-Ab complexes trapped in glomerular epithelium, triggers C’-mediated injury
  • inflammatory skin disease is T cell-mediated (butterfly rash)
24
Q

C’ means

A

complement

25
Q

rheumatoid arthritis

A
  • chronic inflammation of synovial joints, also affects CV system
  • intense inflammation of synovial joints, leads to bone erosion (deformation of joints due to bone erosion)
  • 3x more common in women
  • Abs to the Fc region of IgG are often found (usually IgM), termed “rheumatoid factor”
    • causes immune complexes, C’ activation, chronic inflammation
26
Q

RA-involvement of cytokines

A
  • synovial fluid contains inflammatory cytokines, usually of monocyte origin (TNGFalpha, IL-1,6) (exceptions: IL-17, T cell-derived)
  • therapies aimed at blocking TNFalpha and IL-1 have had some success (fake TNF will bind to receptors instead of real TNF)
  • conflicting evidence for infection as underlying cause
27
Q

mechanisms that cause autoimmunity

A
  • failure of self-tolerance
    • central tolerance: not much evidence
    • peripheral tolerance
  • genetic factors
  • infection
  • gender (hormonal/gender components)
28
Q

central tolerance

A
  • all pro-thymocytes migrate from blood marrow, enter thymus
    1. positive selection - must recognize self-MHC
    2. negative selection - must not recognize self Ags
29
Q

failure of peripheral tolerance

A
  • defects in molecules that inactivate T cells can cause autoimmunity
    ex:
  • CTLA-4 is inhibitory receptor on T cells that downregulates T cell signaling response (binds B7-1 and B7-2)
  • CTLA-4 KO mouse results in severe, fatal autoimmunity
  • turning off the response is as important as turning it on
30
Q

defective T-cell mediated suppression contributes to autoimmunity due to

A

loss of T regulatory (suppressor) cells and their inhibitory cytokines
- IL-10 KO and TGF-beta KO mice experience autoimmune syndromes

31
Q

failure of B cell tolerance

A

exposure of B cells to polyclonal activators such as LPS or EBV infection may nonspecifically activate B cells that recognize self

32
Q

genetic factors predispose to autoimmunity

A
  • MHC loci are frequently linked to certain autoimmune diseases
  • presumably a self Ag is particularly well presented by this MHC haplotype
  • ex: HLA-DQbeta1 gene, position 57
    • most people have aspartic acid
    • patients with IDDM more often have valine, serine, or alanine
    • disruption of salt bridge may disrupt stability
33
Q

MHC connection to disease in IDDM

A

position 57 of DQbeta chain affects susceptibility to insulin-dependent diabetes mellitus (IDDM)

34
Q

__ is linked to risk for autoimmunity

A

HLA (human leukocyte antigen)
- composition/MHC can affect your autoimmunity risk

35
Q

environmental factors

A
  • smoking increases severity of diseases in many cases
    • goodpasteur’s disease fatalities due to kidney failure and/or pulmonary hemorrhage. pH only seen in smokers
  • physical trauma/release of sequestered Ags
    • sympathetic opthalmia: anterior chamber of eye is “privileged site”. physical damage to eye can release sequestered Ags that trigger autoimmune response
36
Q

molecular mimicry

A

microbial Ags sometimes cross-react with self-Ags
- streptococcal infections cause development of Abs that also recognize heart muscle Ags, can cause severe cardiac damage

37
Q

which gender is more severely affected by autoimmune diseases

A

women - over 90% of AI diseases are in women

38
Q

hormonal influences in autoimmune diseases

A
  • castrated males become more susceptible to autoimmunity (in mice)
  • androgen treatment of female mice reduces incidence
  • females tend to develop more vigorous Th1 responses
  • estrogen may stimulate immune responses
39
Q

therapeutic approaches to AI disease

A

aimed at reducing symptoms:
- generalized immunosuppressants (corticosteroids, cyclophosphamide)
- plasmapheresis (plasma removed, RBC returned, helps with disease involving immune complexes)
- targeted therapies (cyclosporin A kills activated T cells only, cytokine therapies target anti TNFR Abs for RA)

Microbiology (7 decks)

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