Organ-Specific Autoimmune Diseases Flashcards
1
Q
organ specific autoimmune diseases, symptoms are confined to
A
single organ
2
Q
why are there organ specific autoimune disease
A
Cells of target organ are damaged directly, or
Autoantibodies may overstimulate or block the normal function of the target organ
3
Q
there are no type ____ HSR for organ specific autoimmune disease
A
III
4
Q
organ specific autoimmune disease are mediated by what HSR
A
type II or IV
5
Q
autoimmune hemolytic anemia caused by
A
autoantibody against antigens on RBC
6
Q
what are most susceptible to complement mediated lysis
A
RBC
7
Q
Autoimmune Hemolytic Anemia antigen is on surface of
A
RBC
8
Q
why do we have antibodies against RBC?
A
we don’t know 100%, think they might be cross reactive antibodies (molecular mimicry)
9
Q
what are other forms of hemolytic anemia
A
anti-RhD (alloantigen incompatibility)
drugs that alter RBC glycoprotein structure (drug induced)
10
Q
draw out mechanism of anti-RBC autoantibodies
A
pg 5
11
Q
RBC are removed by what in spleen and liver
A
phagocytes
12
Q
clincal features of autoimmune hemolytic anemia
A
Anemia, thrombocytopenia, hepatosplenomegaly
either Cold agglutinins (IgM) or Warm agglutinins (IgG)
13
Q
IgM is referred to as what in hemolytic anemia
A
cold
14
Q
IgG are referred toa s what in hemolytic anemia
A
warm agglutinin
15
Q
how do you diagnose autoimmune hemolytic anemia
A
spherocytes in blood smear
coombs test
16
Q
if individual has the autoimmune hemolytic anemia RBC will be coated with
A
autoantibody
17
Q
if you take RBC from pts with what wil already be bound to RBC
A
autoantibody
18
Q
to do coombs test:
A
use coombs reagant and if there is autoantibody it will bind, agglutination.
19
Q
what is coombs reagant
A
anti human Ig
20
Q
look at results of direct coombs test
A
pg 8
21
Q
what test is used to see if mom has antibody against Rh
A
indirect coombs test
22
Q
why don’t you use direct coombs test to see if mom has antibody for Rh
A
b/c then you would need to take blood from baby :(
23
Q
indirect coombs test:
A
take serum from mom, add to RBC with recess G antigen, add mom’s serum, if mother has antibody against it, it will bind to the positive RBC so when you come back with coombs reagant, it will lead to agglutination of the RBC if the mother has antibody that has bound
24
Q
direct coombs test for Rh
A
just need fetal RBC and add anti human antibody
25
indirect coombs test for Rh
maternal serum Abs, add Rh+ then add anti-human antibody (so one extra setep)
26
if there is antibody bound to antigen on surface of RBC you will do what to clls with coombs reagant
agglutiante
27
exxample of drug to induce hemolytic anemia
penicillin
28
how do drugs cause autoimmune response
they modifiy RBC platelet and induce antibody production
29
once you stop taking drug, what happens to antibodies against blood
they will no longer bind, it is jsust b/c they are modified by the drug
30
Goodpasture’s Syndrome isn't exclusively organ specific b/c epitope is shared b/w
glomerular basmenet membrane of kidney and alveolar basement membrane (lung)
31
autoantibody in lung with Goodpasture’s Syndrome are pretty much
not accessible in lungs - until there is infection, once ther is infection the autoantibody will get access to the thing in lungs
32
what happens in Goodpasture’s Syndrome
phagocyte/complement activation, neutrophils undergo frustrated phagocytosis, to attempt to engulf, but they can't b/c it's too big so they release their stuff at glomerular basement membrane resulting in tissue damage
33
Goodpasture’s Syndrome is it direct or indirect immunofluorescence (pg 12) take biopsy and add immunofluorescent IgG
direct
34
Goodpasture’s Syndrome is unusual b/c it is more common in
males
35
two forms of Pemphigus
Pemphigus folaceous
| Pemphigus vulgaris
36
Pemphigus folaceus
mild
37
Pemphigus vulgaris
severe, can be fatal if not treated
38
Pemphigus folaceus, autoantigen is
demolglein 1
39
Pemphigus vulgaris, autoantigen is
desmoglein 3 (& 1)
40
autoantibodies of Pemphigus are usually
IgG1 and IgG4
41
what do the autoantibodies of Pemphigus do
unqipping - blisters
| splitting of keratonicyte sheets
42
why is Pemphigus vulgaris so severe
can get lots of fluid loss through the blisters
43
HOW DO YOU DIAGNOSE Pemphigus VULGARIS
Immunohistological demonstration of anti-desmoglein; detection of acantholysis
SHOULD BE ABLE TO DETECT AUTOANTIBODY HIGHLIGHTING THE DESMOSOMES
44
Myasthenia Gravis what kind of HSR
non-cytotoxic type II HSR
45
non-cytotxic tyep II HSR mean
do not destroy the tissue
46
Myasthenia Gravis ?
Produce blocking autoantibodies against subunit of the nicotinic acetylcholine receptor (AchR), which is found at neuromuscular junctions in skeletal muscle
47
in most common form of Myasthenia Gravis the Ach receptors are blocked by
antagonistic IgG autoantibody that prevents binding of Ach to AchR
48
regardless of form of Myasthenia Gravis, they all have the same phenotype:
failure to transmit neoronal signal at neuromusclar junction: POOR MUSCLE CONTRACTION
49
similar to Myasthenia Gravis in presentation, but autoantiobody involved doesn't block Ach binding, it prevents release of Ach at other side of junction
Lambert-Eaton Syndrome:
50
Lambert-Eaton Syndrome:
| most common autoAbs
direct against voltage gated Ca2+ on neuron block release of Ach
51
clinical features of Myasthenia Gravis
Progressive weakening of muscles
Facial muscles – drooping eyelids (ptosis), tongue, mouth
Chest muscles - impaired breathing, respiratory infections
52
Myasthenia Gravis treated with
Acetylcholinesterase inhibitor, allows Ach to stay long enough to bind to residual receptors
53
how do you diagnose Myasthenia Gravis
Anti-AchR antibodies in serum
54
most common form of hyperthyroidism
Graves’ Disease
55
Graves’ Disease:
Produce stimulating autoantibodies against thyroid-stimulating hormone receptor (TSH-R)
56
what normall y happens in Graves’ Disease
release of thyroid hormones is strictly controled (levels of T3 and T4 shut down production of TSH, negative feedback), in this disaese stimulation fo TSH-R is independent of TSH, it doesn't prevent stimulation through TSH-R, so:
Anti-TSH-R autoAbs bind to and activate TSH-R on thyroid cells, leading to overproduction of T3/T4
57
what is overproduced in grave's disease
T3 and T4
58
symptoms of grave's disease
Enlarged thyroid gland (goiter), heat intolerance, irritability, nervousness, warm moist skin, weight loss
Bulging eyes, stare (exophthalmos)
59
enhanced appetite but still weight loss, what disease
grave's disease
60
at initial presentation, ppl with graves disease don't always present with
exophthalmos
61
what is exophthalmos?
bulging eyes, stare
62
how do you diagnose graves disease
High T3/T4 levels in patient plasma, with no TSH
| detection f antibody against TSH receptor
63
how do you treat grave's diseases?
Anti-thyroid drugs that inhibit thyroid function
Thyroid removal or destruction by radioiodine (131I), with synthetic thyroid hormone daily
64
Plasmapheresis what is it
remove blood cells and filter to remove immunoglobulin and then reinfuse back into individual, to get rid of pathogenic autoantibody
65
unlike passive immunization, Intravenous immunoglobulins dose is much
higher than you'd give for passive
66
Intravenous immunoglobulins such high does b/c
injected high dose Intravenous immunoglobulins bind to low affinty Fc receptor on B clls (fc gamma recptor on b cells is negative co-receptor_ so you can force the injected IgG to bindt o the low affinity Fc receptor and shut down production of autoantibodies
67
type II HSR are mediated by
IgG
68
what can IgG do?
cross placenta
69
if women suffering from type II HSR it can be
transferred to child by crossing plaecnta
70
list diseases that can be transferred to mother through IgG in placenta
Myasthenia gravis
graves
thrombocytopenic purpura
pemphigus vulgaris
71
pernicious anemia is what type of HSR
type IV
72
Pernicious Anemia is characterized by presecens of
autoantibody
73
we don't think autoantibody in Pernicious Anemia is
pathogenic antibody
74
why do we think autoantibodies in Pernicious Anemia are not pathogenic
unless parietal cell si damaged, there is no way the autoantibody can get ti autoantigen, b/c parietal cel autoantigen is proton potassium ATPase which exclusivelly localized in luminal side of cell, not availble on basal lateral surface of cell so antibody can't get to it
75
IF is entirely ____ until secreted into lumen
intracellular
76
what do they think happens in pernicious anemia
some inflammatory process damges parietal cell which reveals ATPas and IF to B cells so autoantibody is useful for diagnosis but not pathogenic
77
what deficiency is in pernicious anemia
vitamin B12
78
what is not accessible to autoantibody in Pernicious Anemia
IF and ATPase
79
what do they think causes pernicious anemia
Evidence for Type IV HSR response against H+/K+-ATPase leading to parietal cell destruction (by Th1 cells and macrophages) and release of autoantigens.
80
some evidence that what two diseases might be involved in development of pernicious anemia
Autoimmune Gastritis
| Role of Helicobacter pylori infection??
81
destruction of parietal cell leads to decreased production of
intrinsic factor
82
less intrinsic factor means there is less absorption of
vitamin B12
83
Type 1 Diabetes mediated by what HSR
type IV
84
describe Type 1 Diabetes
specific destruction f insulin producing beta cells in panreatic islets by autoreactive T cells
85
what is killed in Type 1 Diabetes
insulin producing beta cells in pancreas
86
Type 1 Diabetes can be associated with prior infections of
coxsackie virus proteins
87
most important players in destruction of beta cells in Type 1 Diabetes
Th1 cells and macrophages
88
Th1 cells make what that harm beta cells
IFN gamma
89
clinical features of Type 1 Diabetes
Symptoms due to disruption of glucose metabolism
Atherosclerotic vascular lesions; gangrene in extremities; renal failure; blindness
beta-cell damage precedes symptoms
Increased appetite, increased urinary frequency/micturition
90
diagnoseis of type 1 diabetes
Increased blood glucose levels
| Autoantibodies against GAD65 and insulin
91
type 1 diabetes treatment
daily insulin jections
| beta cell transplantation
92
downside of beta ell transplanataion
need two pancreas to get enough beta cells for transplantation
93
Hashimoto’s Thyroiditis
| is example of
hypothyroidism
94
hypothyroidism:
decreased thrydoif fucntion
95
goiter of Hashimoto’s Thyroiditis is result of
infiltration f CD4, CD8 and B cells
96
Hashimoto’s Thyroiditis get malignancy in
thyroid
97
Hashimoto’s Thyroiditis more common in
women
98
autoantibodies in Hashimoto’s Thyroiditis are against
products, they are not pathogenic
99
Th1 cells in individuals with Hashimoto’s Thyroiditis are against
thyroglobulin
100
what is treatment for Hashimoto’s Thyroiditis
synthetic thyroid hormone daily
101
diagnosis of Hashimoto’s Thyroiditis
Thyroid histology (well-developed germinal centers) antibodies to TPO & thyroglobulin are epiphenomena and not pathogenic
can detect inappropriate expression of MHC II
102
what disease can you detect inappropriate expression of MHC II
Hashimotos's thyroiditis (can detect them on thyroid cells)
103
MHC II expression is usually limited to
APC & epithelial cells in thymus for positive and negative selection
104
autoreactive Th1 cells promote differentiation into
cytotoxic t cells
105
evidence that what is actually killing the thyroid cells in Hashimoto’s Thyroiditis
cytotoxic t cells
106
Addison’s Disease like type I diabetes and celiac is associated with what
HLADQ2 and HLADQ8
107
Addison’s Disease is risk for developing
type I diabetes & celiac disease
108
Addison’s Disease mediated by what HSR
IV
109
primary pathogenic cells of Addison’s Disease
CD8 T cells specific from peptide 21 hydroxylase
110
Addison’s Disease following destruction of cells in adrenal cortex get production of
autoantibodies
111
autoantibodies against 21 hydroxylase in Addison’s Disease are, they are useful for diagnsis
not pathogenic
112
main mechanism of destruction of Addison’s Disease
killing of adrenocorticol cells by autoreactive cytotoxic t cells and macrophages
113
review pg 38
38
114
symptoms of Addison’s Disease
Tiredness, extreme weakness, weight loss, nausea/vomiting, abdominal pain
115
treatments of addison's disease mostly due to lack of
cortisol
116
how to treat addison's disease
Cortisone acetate
Hydrocortisone tablets
Fludrocortisone acetate
117
MS is caused by destruction of
myelin sheath of nerve fibers in brain and spinal cord
118
what causes destruction of myelin sheath in MS
autoreactive T cells
119
MS is more common in women or men
women
120
areas of demyelination seen in MS are often referred to as
plaques
121
edge of plaques in MS contain:
CD4 and CD8 t cells, b cells, plasma cells
122
cells responsible for destroying myelin sheath are
resident macrphages in brain - microglial cells activated by infiltrating Th1 cellse
123
symptoms of MS
Muscle wasting - weakness
Progressive visual failure
Epilepsy
Disarthria (speech impairment)
124
describe relapsing-remitting MS
unpredictable relapses followed by periods of months to years of remission
125
describe secondary progressive MS
initially relapsing-remitting MS changing to progressive neurologic decline without remission
126
describe primary progressive MS
Steady neurological decline with little or no remission
127
describe progressive relapsing MS
Steady neurological decline with additional acute attacks of MS
combination of primary progressive and relapsing-remitting
128
what form of MS never has relapsing phase to it
primary progressive
129
progressive forms of MS can lead to total loss of mobility within
8-10 years of onset
130
what cells do they think are activating the microglial cells that start MS
autoreactive Th1 cells
131
Th17 are highly
inflammatory
132
Th17 implicated in pathogenesis of
MS and rheumatoid arthritis
133
candidate antigens in pathogenesis of MS
myelin basic protein (MBP)
| myelin oligodendrocyte glycoprotein (MOG)
134
can find cells reactive against what in MS
MBP nd MOG
135
you can find autoreactive cells against MBP and MOG in ppl who do not have
MS - so something else is going on
136
what happens to allow the autoreactive T cells to reach BBB and get into CNS and attack the demyelinated axons?
they don't know what the trigger is
| they can do it in animals with neurotrpic viruses
137
describe cells involved in MS
Th1 activate microglial cells and microglial cells are responsible for the demyelination
in add'n to Th1 cells will also detect B cells and sometimes will see what looks like secondary lymphoid tissue in the CNS
138
treatment of MS
IFN beta - they dn't know why really but many pts benefit
139
downside of IFN beta treatmen tof MS
need to give a strong dose
140
about 40% of ppl who take IFN beta for MS develop
antibodies against the IFN beta
141
where is crohn's disease
any part alng GI tract
142
where is ulcerative colitis
usually just in colon/rectum
143
NOD1 and NOD2 detect
bacterial products in cytoplasm of cells
144
IL 23 binding to IL23-R promotes
proliferation and stabilizes phenotype of Th17 cells
145
result of polymorphsm in IL23 receptor in crohns and ulcerative colitis it may promote
generation fo Th17 cells at expense of Treg cells
146
essential balance b/w Th17 and
Treg in gut
147
Th17 role in inflammation
highly pro-inflammatory cytokine
148
review pg 50
50
149
IL 22 is important for maintaining barrier in
gut
150
IL 22 induces production of
antimicrobial petpdies and prmotes colonization of gut by microflora at expense of pathogenic flora
151
in inflammatory bowel diseases balance b/w what is thrown off
Th17 and Treg
| too any Th17 abd nt enough Treg
152
experimental evidence that restoration of Treg/Th7 balacne can resolve IBD:
inflammatory lesions entirely clear up
153
celiac disease is associated with
MHC II
| HLA-DQ2 and HLA-D8
154
what HSR is celiac disease
IV
155
80% of individuals with celiac disease is
undiagnosed
156
many people with celiac disease have silent celiac disease:
no real symptoms, but intestine still looks bad
157
symptoms of celiac disease
Symptoms associated with malabsorption due to villus atrophy
Iron-deficiency anemia
Osteoporosis (Calcium, Vitamins D and K)
Stunted growth
Fatigue
Silent celiac disease
Overtly asymtomatic but have mucosal damage
Can present with other autoimmune diseases
1:20 celiacs have Type I diabetes (HLA-DQ2/DQ8)
158
co-presentations of ppl with celiac disease
dental enamel defects & dermatitis herpetiformis
159
dental enamel defects may be the only symptom of
celiac disease
160
dermatitis herpetiformis with celiac disease, will find what if you look at contents
lots of IgA anti-epidermal translutaminase
161
what gives rise to rash and blister in skin for celiac disease
tissue transtaminase in gut is one recgnized in gut, they cross react with epidermal form
162
describe mechanism of celiac (also on pg 57)
enterocytes in gut become stressed and induce stress response and the stressed eneerocytes release zonulin which acts on enterocytes to make epithelial barrier more leaky. that allows stuff to penetrate. stressed enterocytes express MICA and MICB which are recognized by intraepithelial lymphocytes which kill the enterocytes. when the enterocytes are killed get released of tissue transcataminase (one substrate is alpha gliadin itself) and modifies the apha gliadin, you get t cell response against this and get antibodies against it. so get alpha glidin specific Th1 cells. some evidence for enterocyte lysis by actiated CTL. T cells help B cells make antibodies and main antigen they rcognize are antigens releaed from enterocytes including tissue transcaatminase as wella s alpha gliadin. IgA against the tissue transcataminase that cross reats with epiderm and gives rise to rashes.
163
diagnosis for celiac disease
Serological tests
Antiendomysial antibodies
Anti tissue transglutaminase antibodies
Tissue biopsy of symptomatic seropositive individuals
164
treatment for celiac disease
strict gluten-free diet for life
