2. Autoimmunity Flashcards
(39 cards)
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
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
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
4
Q
immune complex-mediated tissue injury
A
- mechanism of antibody deposition (circulating immune complexes in blood vessel)
- complement- and Fc receptor-mediated recruitment and activation of inflammatory cells
- effector mechanisms of tissue injury (neutrophil granule enzymes, reactive oxygen intermediates, neutrophils in blood vessel)
- vasculitis
5
Q
injury caused by antitissue antibody
A
- mechanism of antibody deposition (antigen in ECM attached to antibody deposition)
- complement- and Fc receptor-mediated recruitment and activation of inflammatory cells
- effector mechanisms of tissue injury (neutrophils, macrophages, enzymes, reactive oxygen species in ECM)
- tissue injury
6
Q
2 types of autoimmunity
A
- organ specific
- systemic
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
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
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
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
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)
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
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
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
15
Q
2 types of diseases caused by antibodies
A
- stimulating auto-antibodies
- blocking auto-antibodies
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
rheumatoid arthritis
- 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
RA-involvement of cytokines
- 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
mechanisms that cause autoimmunity
- failure of self-tolerance
- central tolerance: not much evidence
- peripheral tolerance
- genetic factors
- infection
- gender (hormonal/gender components)
28
central tolerance
- 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
failure of peripheral tolerance
- 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
defective T-cell mediated suppression contributes to autoimmunity due to
loss of T regulatory (suppressor) cells and their inhibitory cytokines
- IL-10 KO and TGF-beta KO mice experience autoimmune syndromes
31
failure of B cell tolerance
exposure of B cells to polyclonal activators such as LPS or EBV infection may nonspecifically activate B cells that recognize self
32
genetic factors predispose to autoimmunity
- 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
MHC connection to disease in IDDM
position 57 of DQbeta chain affects susceptibility to insulin-dependent diabetes mellitus (IDDM)
34
__ is linked to risk for autoimmunity
HLA (human leukocyte antigen)
- composition/MHC can affect your autoimmunity risk
35
environmental factors
- 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
molecular mimicry
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
which gender is more severely affected by autoimmune diseases
women - over 90% of AI diseases are in women
38
hormonal influences in autoimmune diseases
- 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
therapeutic approaches to AI disease
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)
