Chapter 15 Flashcards
(108 cards)
1
Q
Response to self antigens or antigens associated w/ commensal bacteria is called….
A
autoimmunity
2
Q
When immune responses are directed against self antigens, they give rise to auto-reactive effector cells and antibodies (____________) against the self antigen
A
autoantibodies
3
Q
What are some common autoimmune diseases?
A
-psoriasis
-rheumatoid arthritis
-graves disease
-hashimoto’s thyroiditis
-systemic lupus erythematosus
-sjogrens syndrome
-crohns disease
-MS
-type 1 diabetes
4
Q
Multiple tolerance mechanisms normally _______ autoimmunity
A
prevent
5
Q
Immature lymphocytes recognize antigens and lead to negative signal causing lymphocyte death or inactivation. This self tolerance happens when they are developing in thymus and BM (then they can go to secondary lymphoid organs). This is called ________ ______________ (bc its centrally where it happens @ the BM+ thymus)
A
central tolerance
6
Q
Tolerance induced to antigens after they have left primary lymphoid organs is called….
A
peripheral tolerance (away from where tolerance began at the BM/thymus)
7
Q
Mechanisms to prevent autoimmunity goes through a succession of __________. Together all these ___________ ensure immune system still functions and there is no anti-self response
A
checkpoints, checkpoints
8
Q
Autoimmunity results from a combo of different factors. What are they?
A
-genetic susceptibly
-breakdown of natural tolerance mechanism
-environmental triggers such as infection
9
Q
what cells undergo central tolerance?
A
B and T cells
10
Q
Anytime auto-reactive (reacting to self) T cells are generated, what happens?
A
they need to be eliminated
11
Q
What is the first checkpoint of self-tolerance?
A
central deletion or inactivation of newly formed lymphocytes
12
Q
Many tissue specific antigens are expressed in the thymus region by __________ _________ cells or ____________ ____________ cells
A
thymus epithelial, special dendritic
13
Q
A single transcription factor, ___________, is thought to be responsible for turning on expression of many tissue specific proteins in thymic medullary cells
A
AIRE (autoimmune regulator)
14
Q
Peptides are presented to the developing thymocytes as they undergo __________ selection
A
negative
15
Q
Individual organs of the body express tissue specific antigens. In the thymus, T cells arise capable of recognizing tissue specific antigens. Under control of the ______ protein, thymic medullary cells express tissue specific proteins leading to deletion of tissue reactive T cells. In the absence of _______, T cells reactive to tissue specific antigens mature and leave the thymus
A
AIRE, AIRE
16
Q
Elimination of auto-reactive B cells in germinal centers occurs during ________ ___________.
A
somatic hypermutation
17
Q
B cells w/ auto-reactive _____ arises and binds to soluble auto-antigen which induces apoptosis of the auto-reactive B cell
A
BCR
18
Q
Antigens in immunologically privileged sites do not induce immune attacks but can serve as targets. These sites are unique in 4 ways:
A
-communication between privelged site and body extracellular fluid does not pass through conventional lymphatics
-sites are surrounded by tissue barriers that exclude naive lymphocytes (such as BBB)
-anti-inflammatory TGF-beta is produced here, so when antigens are recognized along w/ TGF, then it induces Treg response (NOT TH17 OR OTHERS)
-expression of Fas ligand in theses sites ensures that if Fas-bearing lymphocytes enter, then they will undergo apoptosis
19
Q
If theres an accumulation of antigen in the privileged sites and auto-reactive T lymphocytes are activated elsewhere, then they can come to these sites and do an….
A
autoimmune attack
(ex: myelin basic protein in brain and spinal cord, antigens that become targets for autoimmune attack for MS)
20
Q
What are the immunologically privileged sites (places sterile from immune cells)?
A
-brain
-eye
-testis
-uterus (fetus)
21
Q
In sympathetic opthalmia, trauma to one eye results in the release of sequestered intraocular protein antigens. The released intraocular antigen is carried to lymph nodes and activates T cells. Effector T cells return via ___________ and encounter antigen in both eyes
A
bloodstream
22
Q
In sympathetic opthalmia, trauma to one eye releases sequestered antigen into surrounding tissues and makes it accessible to T cells. The effector T cells can now come to the traumatized eye area and attack but they will also attack the…..
A
healthy eye
23
Q
In sympathetic opthalmia, sequestered antigens do not elicit immune response, but if response is induced elsewhere, then they severe as….
A
targets
24
Q
In sympathetic opthalmia, T cells can enter area if the site gets infected. The activated effector T cells can enter ___________ _______ after producing cytokines that alter tissue barriers
A
privileged areas
25
What are the 2 classifications of autoimmunity?
1) organ specific
2) systemic disease
26
What are some examples of organ specific autoimmune diseases
-type 1 diabetes
-MS
-crohns disease
-psoriasis
-graves disease
-hashimotos thyroiditis
-autoimmune hemoltyic anemia
-autoimmune Addison's disease
-vitiligo
MG
27
What are some examples of systemic autoimmune diseases?
-rheumatoid arthritis
-scleroderma
-systemic lupus erythematous
-primary sjogrens syndrome
28
What are the 3 main ways autoimmunity happens?
1) autoantibodies produced against ACh receptor blocks receptor function at NMJ and results in muscle weakness (MG)
2) In other cases, Abs in the form of immune complexes are deposited into tissues and cause tissue damage from inflammation
3) effector cells are the main destructive agents in these cases and T cells recognize self peptides or those from self bacteria in complex w/ MHC. Local inflammation and direct damage from T cells (more common) or NK cells can lead to diabetes, psoriasis IBD, MS, etc
29
Autoantibodies can cross the placenta and leads to disease in the fetus. The symptoms of disease disappear fast as the maternal IgG Ab is catabolized approx 6 months after birth. Sometimes however, the Ab can cause ________ _________
organ injury
30
What are some autoimmune diseases that are transferred across the placenta to the fetus/newborn infant?
31
A pt w/ Graves disease makes _________ antibodies. This is caused primarily from the Abs passed on from mom that were transferred across placenta into the fetus. Newborn infant will then also suffer from Graves disease. Plasmapheresis can remove maternal _________ antibodies and cure the disease
anti-TSHR, anti-TSHR
32
Maternal IgG crosses the placenta. If the mother has IgG mediated autoimmune disease then the infant will most likely show symptoms in the first few weeks of life. Symptoms will disappear when maternal Abs disappear. Children born to such mothers have ______________ and this can be corrected by replacing plasma and removing maternal Abs
hyperthyroidism
33
In Graves disease, symptoms caused by antibodies against...
thyroid stimulating hormone receptor (TSHR)
34
What are the 3 mechanisms of tissue damage in autoimmune diseases?
1) antibody against cell-surface or matrix antigens
2) immune complex disease
3) T cell mediated disease
35
In type 1 diabetes and RA, both T cell and Ab mediated pathways cause....
tissue injury
36
Autoantibodies IgM and IgG against the blood cells promotes their destruction and causes _________ ___________
auto-hemolytic anemia (Abs made on surface of RBCs)
37
Autoantibodies IgM and IgG against the blood cells promotes their destruction and causes auto-hemolytic anemia. RBCs w/ IgG/IgM Ab bound, are cleared from circulation by interaction w/ Fc receptor on ____________ or complement
phagocytes
38
What is the treatment for auto-hemolytic anemia?
-put in new RBCs
-try not to get rid of the RBCs that pt already has/prevent Abs from being produced
-remove spleen (stop RBC destruction)
-large quantities of nonspecific IgG (IVIG) which inhibits Fc receptor mediated uptake of Ab coated cells and suppresses inflammation
39
What is the immunological function of the spleen?
organ where there is the main clearance of RBCs, platelets, and leukocytes
40
Binding of IgG and IgM Abs to cells in tissues causes....
inflammatory response
41
Binding of IgG and IgM Abs to cells in tissues causes inflammatory response. Complement is unleashed, MAC is formed on cell surface, and cytokines are released. Nucleated cells are resistant to lysis by complement, but MAC accumulation on surface can be a stimulus for action. Depending on cell type interaction, it can result in cytokine release, respiratory burst, or membrane phospholipids mobilize to generate arachidonic acid. ____ is released and other inflammatory leukocytes arrive and cause tissue damage
C5a
42
In Graves disease, the pituitary gland secretes _____ which acts on the thyroid to induce the release of thyroid hormones. Thyroid hormones act on the hypothalamus and the pituitary gland to shut down production of TSH, suppressing further thyroid hormone synthesis (_________ ___________). Autoimmune B cells make Abs against TSH receptor that also stimulates thyroid hormone production. Thyroid hormones shuts down TSH production but has no effect on autoantibody production, which continues to cause excessive thyroid hormone production
TSH, feedback suppression
43
Thyroid hormone is produced in response to...
TSH (thyroid stimulating hormone)
44
In Graves disease, thyroid hormone works as a feedback suppression to stop release of TSH and that stops thyroid hormone production. Autoantibodies against the TSH receptor activates the pituitary gland to produce thyroid hormone. Thyroid hormone shuts down TSH production but Abs continue to be made so thyroid keeps getting made. The excessive thyroid hormone production causes....
hyperthyroidism
45
In normal situations, Ach is released from stimulated neurons and bind to AChR on skeletal muscles and triggers muscle contraction. In MG, however, autoantibodies against the AChR is present on the NMJ in the skeletal muscle cells. The system internalizes the AChR bound to ACh and degrades it, so AChR is gone. ACh will still be released but it doesn't bind to anything because there is no longer a receptor, and so there will be no response from muscle cells. As the number of receptors decrease, muscles become __________
unresponsive
46
Autoantibodies against cell surface receptors cause disease by __________ or __________ receptor function
stimulating, blocking
47
Define an agonist
stimulates the receptor
48
Define an antagonist
inhibits the receptor
49
In streptococcal glomerulonephritis, there is immune complex deposition in the glomerulus of the kidneys. The kidneys are unable to filter like they should and this is bc Abs showed up there because _____ was made against the strep infection prior. Abs can also be made against the basement membrane of the renal glomeruli and cause rapidly fatal disease if not treated (secondary). The autoantibodies bound to the basement membrane ligate to Fc receptor on ___________ and _____________ activating them. Chemokines are released and call more cells to show up and cause tissue injury
IgG, monocytes, neutrophils
50
In systemic lupus erythematosus (SLE), there is a defective clearance of nucleic acids bound immune complexes. This comes from dying cells. ssRNA or dsDNA from dead cells are bound by Fc receptors on ____________ cells. This is internalized and TLRs are activated which causes the cell to release ________. This in tern asks monocytes and other cells to produce BAFF (B cell activating factor, a part of TNF family). BAFF interacts w/ B cells and it can increase auto-reactivity of B cells and increased Ab production. More and more immune complexes form and T cells get activated which will result in tissue damage
dendritic, IFN-alpha
51
Inherited impairment of mechanisms that contribute to clearance of immune complexes from reduced expression or defects in compliment/its receptors, or Fc receptors leads to.....
systemic lupus erythematosus (SLE)
52
In diabetes, the cytotoxic T cell response is against insulin producing cells, which are the __________ cells
b-islet
53
MS is a T cell mediated neurological disease caused by a destructive immune response against ______ NS myelin antigens including myelin basic protein (MBP). MS is called this because of the hard/sclerotic lesions or plaques in the white matter of the CNS and dissolution of the myelin sheath
central
54
Rheumatoid arthritis (RA) is the inflammation of the synovium over time with damage to the cartilage and bone erosion. It is thought to be autoimmune and driven by B cells making anti-IgG autoantibodies called ____________ __________. T helper cells are activated. Auto-reactive T cells provide help to the B cells to make arthritogenic antibodies. They also produce cytokines that recruit neutrophils, monocytes, and macrophages which will produce more inflammatory cytokines and matrix metalloproteinases which cause tissue destruction
rheumatoid factor
55
The islets of langerhans contain several cell types secreting distinct hormones. Each cell expresses different tissue specific proteins. In type 1 diabetes, an effector T cell recognizes peptides from a beta cell specific protein and kills the beta cell. Glucagon and somatostatin are still produced by the alpha and delta cells but no ________ can be made
insulin
56
In diabetes, there is selective destruction of pancreatic ______ cells
beta
57
In diabetes, CTLs recognize peptides from the _____ cells producing insulin and spare the other cell types
beta
58
In MS, there is an unknown trigger that sets up initial focus of inflammation in the brain and BBB and becomes locally permeable to leukocytes and blood proteins. T cells are specific for CNS antigen and are activated in the peripheral lymphoid tissues that reencounter antigen presented on the _________ or DCs in the brain. An inflammatory reaction occurs in the brain due to mast cell activation, complement activation, antibodies, and cytokines. Demyelination of neurons occurs.
microglia
59
In MS, at the sites of inflammation, there are activated T cells that are auto-reactive for brain antigens and can cross the BBB. Here, they encounter their antigens again on microglial cells and secrete cytokines such as _________. This results in more blood cells, macrophages, DCs, B cells, and complement all show up into the affected site. This results in demyelination and loss of neuronal function.
IFN-gamma
60
MS disease has acute attacks (________) followed by reduction in disease activity (____________)
relapse, remission
61
After decades, most MS patients go into _____________ _____________ MS. This is a steady neuro decline w/o remission and is less responsive to therapy. It is likely that long term disease exhausts CNS regenerative capacity
secondary progressive
62
What is the inflammatory cascade of MS?
63
In RA, there is an unknown trigger that sets up initial focus of inflammation in the synovial membrane attracting leukocytes into the tissue. Auto-reactive _________ cells activate macrophages, resulting in the production of pro-inflammatory cytokines and sustained inflammation. Cytokines induce production of MMP and RANK ligand by fibroblasts. MMPs attack tissues. Activation of bone-destroying osteoclasts by RANK ligand results in joint destruction
CD4 T
64
In RA, there is inflammation of the synovial membrane which is initiated by an unknown trigger that attracts auto-reactive lymphocytes and macrophages to inflamed tissue. Auto-reactive T cells also activate B cells to produce Abs which are _______ Abs called rheumatoid factor. Abs are against joint proteins. IgG is present in large quantities in the blood. B cells are specific for IgG and are not activated usually, but when immune complexes are not cleared properly, then ignorant B cells will end up responding and making anti-IgG autoantibodies called Rheumatoid factor (since present in RA pts). Pro-inflammtory cytokines are produced. Fibroblasts are activated by matrix metalloproteins (MMPs) that cause tissue destruction. TNF family cytokine, RANK (receptor activator of NFkB) ligand expressed by T cells and fibroblasts stimulates differentiation of osteoclast precursors into mature osteoclasts that reabsorb bone in affected joints
anti-IgG
65
RA is associated w/ MHC class ____ HLA-DR gene of MHC
2
66
Not sure how RA starts, but B/T cells are needed to initiate...
the disease
67
RA is treated w/ therapeutic Abs targeting many cytokines and ____ cell activation
B/T
68
What is rheumatoid factor?
Abs against other Abs
69
Autoimmune diseases have a strong _______ component
genetic
70
Autoimmune diseases have a strong genetic component but environmental factors are also involved. Some microbiota may predispose genetically susceptible individuals to develop diseases like....
IBD or Crohn's disease
71
Multiple components of the _____ and ______ receptors response pathways show genome wide association in a broad range of diseases
IL12, IL23
72
Crohn's disease is an abnormal hyperresponsiveness of CD4 T cells to antigens of the...
commensal microbiota
73
Crohn's disease is a failure of the innate ________ immunity to shield liminal bacteria from the adaptive immune response
mucosal
74
For Crohn's disease, there have been identified genetic predispositions like ______ aka ________ expressed on monocytes, DCs, and Paneth cells. The job is to recognize microbial antigens from peptidoglycan as part of the innate immune system. It is a receptor for peptidoglycan peptides and activates transcription factor NFkB and pro-inflammatory cytokines
NOD2, CARD15
75
Crohn's disease has Paneth cells that activate _______ to release peptides which sequester bacteria and keep them away from the adaptive immune system. Mutations in the gene are associated w/ CD. Also an accumulation of neutrophils leads to heightened response to the commensal microbiota
NOD2
76
Crohns disease results from the breakdown of normal ___________ mechanisms
homeostatic
77
Innate and adaptive immune systems cooperate to limit inflammatory responses of intestinal bacteria in crohns disease by.....
hint: theres 4 bullet points
-mucus from goblet cells
-tight junctions between epithelial cells
-Paneth cells release antimicrobial peptides
-induction of t reg cells which promote IgA production and inhibit CD4 T cell development
78
External events can initiate autoimmunity by:
-incidence of disease in northern hemisphere decreases as we move from north to south (especially for _____ and _____________ in Europe), could potentially be related to vitamin D levels. Vitamin D active form is made in the skin in response to sunlight and plays a role in suppressing T helper 17 cell development
-diversity of commensal microbiota
-exposure to infections/environmental toxins (hygiene hypothesis)
MS, type 1 diabetes
79
Cross-reactivity between foreign molecules on pathogens and self molecules can lead to __________ responses and autoimmune disease
antiself
80
Autoimmune syndromes involve molecular mimicry, for example, ________ ___________ following step infection will have antibodies against bacterial cell surface and can cross react w/ heart valves
rheumatic fever
81
Rejection is caused by immune responses to ____________ (antigens present on some individuals bit not on others) on the graft and proteins that vary from individual to individual within a species, so its seen as foreign
alloantigens
82
When tissues w/ nucleated cells are transplanted, T cell responses to the highly polymorphic MHC molecules triggers the response. Matching the MHC type increases the _________ of the grafts and is typically within related individuals
success
83
For blood transfusions, MHC matching is _______ ___________. RBCs and platelets carry few MHC class 1 and NO MHC class 2. So there is no T cell targets. Blood is only matched for ABO and Rh antigens since there are only 4 major blood types and 2 Rh types, it makes blood easier to match than organs
not necessary
84
Graft rejection is an immunological response mediated primarily by.....
T cells
85
Define autograft
different site on same person with 100% success
86
What is a synergic graft?
between genetically identical animals with 100% success
87
What is an allogenic graft?
unrelated individuals (allograft), pt survives bit acute rejection may occur
88
Transplant rejection is caused primarily by the strong immune response to non-self....
MHC molecules
89
In MHC identical grafts, rejection is caused by ______ from other alloantigens bound to graft MHC molecules
peptides
90
When MHC is identical but offers different genetic loci, then rejection can still occur, but....
its way slower
91
MHC class 1 and 2 process and present many self antigens. If these self peptides that are process in individuals are polymorphic and such polymorphic proteins elicit a response during tissue grafts, then these antigens are called _______ antigens
minor H
92
Self proteins are routinely digested by the proteasome and loaded onto MHC class ___. If the proteins are polymorphic then the peptides made will be different in the donor and recipient of graft. These are called minor H antigens. There is a large fraction of cells in grafts that express minor H. Additionally, there is virtual certainty of mismatches in minor H
1
93
There are 2 ways of presenting alloantigens on the transplanted donor organ to the recipients T lymphocytes. What are they?
1) direct allorejection
2) indirect allorejection
94
Direct allorejection is when organ grafts carry w/ them APCs of the donors origin. These leave the graft and go to secondary lymphoid organs in the recipient and activates host T cells. Then, they move through the circulatory system since lymphatic drainage is interrupted in transplantation. The T cells can now directly attack the....
graft!
95
Indirect allorejection is where there is an uptake of allogenic proteins by the hosts own _______ and their presentation to T cells by self MHC
APCs
96
What are some immunosuppressive drugs that are used before/after graft transplant?
-alemtuxmab
-anti-CD3 mAB
-cyclosporin & tacrolimus
-belatecept
-basiliximab
-sirolimus
-azathioprine
97
Alemtuxmab depletes T cells and other __________ before graft transplant
leukocytes
98
Anti-CD3 mAB is a monoclonal Ab that prevents....
T cell signaling before/after graft transplant
99
Cyclosporin and tacrolimus interfere w/ translocation of nuclear factor os activated T cells and prevents....
T cell signaling before/after graft transplant (this is also interfering w/ pro-inflammatory cytokines from being transcribed)
100
CTLA4 fusion protein Belatecept prevents....
costimulation of T cell before/after graft transplant
101
Basiliximab prevents _____ from binding and signaling activation of T cells before/after transplants
IL2
102
Sirolimus interferes w/ the ____________ of T cells before/after transplant
differentiation
103
Azathioprine prevents _____________ and ____________ of T cells before/after transplant
replication, proliferation
104
The fetus is an allograft that is tolerated repeatedly. Why? How?
Fetus has paternal MHC and minor HC that are different from mother. Abs are made by the mother against the fathers MHC and RBC antigens
also, the placenta sequesters fetus from mom T cells
105
The fetus has an outer-layer called the _______________. It is the interface between the fetus and maternal. There is no MHC 2 there, low restricted subset of MHC class 1 and is SO resistant to direct alloantigen recognition by maternal T cells. The trophoblast expresses nonclassical HLA class molecule called _________ which inhibits NK cell killing
trophoblast, HLAG
106
The placenta does nutrient depletion w/ the enzyme __________ expressed at high levels. It depletes Trp at the site and T cells are starved of Trp so there is reduced responsiveness. This enzyme suppresses T cell proliferation
indoleamine 2,3-dioxygenase (IDO)
107
Uterine epithelium and trophoblast secrete _______ and _________. This suppresses the development of effector T cells in favor of T reg cells. These are increased in pregnancies and seen only in placental mammals. It has a role in maternal fetal tolerance
TGF beta, IL10
108
_________ cells of uterine tissue directly interface w/ the placenta and represses expression of key T cell attracting chemokines
Stromal
