Immuno-endocrinology Flashcards
(112 cards)
1
Q
What happens when there is a loss of tolerance to self antigens?
A
Autoimmune disease
2
Q
What are the two broad categories of auto-immune disease?
A
Organ-specific vs systemic
3
Q
What are the most common organ-specific autoimmune diseases?
A
Autoimmune thyroid diseases
4
Q
What are the two main auto-immune thyroid diseases?
A
Hashimoto’s thyroiditis and Graves disease
5
Q
Describe the normal histological structure of the thyroid
A
Follicles that contain colloid surrounded by follicular cells or thyrocytes
6
Q
What does colloid consist of?
A
Prohormones (thyroglobulin) and hormones
7
Q
What is needed along with thyroglobulin to produce T3 and T4?
A
Iodine
8
Q
What is the function of T4?
A
Regulates metabolism, mood and body temperature
9
Q
What is the function of T3?
A
Regulates metabolism, digestive tract and bone health
10
Q
What happens when serum T3 and T4 are low? Explain the whole feedback loop.
A
Hypothalamus releases TRH, which triggers TSH release by the pituitary gland and later the release of T3 and T4 from the thyroid. This leads to increased basal metabolic rate of cells and a rise in body temperature. High T3 and T4 then inhibits release of TRH and TSH by the hypothalamus and pituitary gland, respectively.
11
Q
What is the main difference in mechanism behind symptoms of Hashimoto’s vs Graves?
A
Hashimoto’s is a generalized decrease in metabolic processes whereas Graves causes an increase in metabolic processes
12
Q
Is there an increase in functional volume in a goiter thyroid?
A
No
13
Q
How is the immunopathophysiology characterized in Hashimoto’s thyroiditis? (3)
A
- Massive T/B-lymphocyte and NK cell infiltration
- Locally activated thyroglobulin (Tg)-specific T-lymphocytes
- Immune cells cause damage to the thyroid tissue
14
Q
What are the implications of having Thyroglobulin specific T-lymphocytes?
A
Thyroglobulin is prohormone for T4 and T3, so a reduction in this due to self-T-cell responses would lead to a decrease in T4 and T3 and a subsequent reduction of metabolism in the body. Destruction of thyroid tissue as a result of the autoimmune responses further enhance this effect.
15
Q
How is the immunopathophysiology characterized in Graves disease? (3)
A
- Limited immune cell infiltration
- Locally activated TSH-receptor specific T-lymphocytes
- Limited thyroid destruction
16
Q
What types of autoantibodies are present in Hashimoto’s vs Graves?
A
Both have autoantibodies directed against Tg and thyroid peroxidase, but Graves also has autoantibodies against the TSH receptor.
17
Q
What is thyroid peroxidase?
A
It is an enzyme involved in iodination of Tg (thyroglobulin)
18
Q
What are the three mechanistic pathways that lead to thyroid injury in hashimoto’s thyroiditis?
A
- T cell-mediated cytotoxicity (CD8+ T cells)
- Thyrocyte injury through macrophages activated by IFNy produced by CD4+ Th1 cells
- Antibody-dependent cell-mediated cytotoxicity
19
Q
How does ADCC work? (4)
A
- Anti-TPO antibodies bind to antigens on thyroid cells
- Fc receptors on NK cells recognize the antibodies
- Cross-linking of Fc receptors leads to NK cell activation and degranulation
- Thyroid cells undergo apoptosis
20
Q
Describe pathogenesis of Grave’s disease
A
Stimulating auto-antibodies against TSH receptors expressed in the thyroid gland cause activation of the thyroid and an excess of thyroid hormone (hyperthyroidism)
21
Q
When can a patient with Hasimoto’s present with hyperthyroidism, and why?
A
Initially there is a release of thyroid hormones due to destruction of the thyroid tissue.
22
Q
How does peripheral tolerance prevent auto-immunity? (3)
A
Ignorance, anergy and regulation. Lymphocytes that escape the central tolerance system (delection of anti-self lymphocytes) do not necessarily cause autoimmunity due to the need for antigen presence, co-stimulation, etc.
23
Q
What are environmental risk factors for autoimmune thyroid disease? (4)
A
Dietary iodine intake, smoking (only Graves), infection (molecular mimicry) and stressful life events
24
Q
How can stress lead to increased risk for autoimmune thyroid disease? (2)
A
Activation of the hypothalamic-pituitar-adrenal axis leads to:
1. Th2 skewing -> (auto)-antibody production
2. Steroid-induced immune supression -> recovery -> immune rebound (hypersensitivity to stimuli) -> hyperactivation (cytokine storm and disrupted tolerance)
25
What happens in the pituitary when testosterone is high?
Supression of pituitary-stimulating hormones (measured by serum LH)
26
What is substance P?
It is produced by neurons and plays a role in several inflammatory diseases
27
What is 111-Indium used for?
It can bind to small peptides such as substance P. Binding of the peptide to its receptor leads to an accumulation of gamma-radioactivity, which can be detected via imaging
28
What happens with substance P during certain inflammatory diseases?
It binds to receptors in the thymus, which is detectable through injection of 111-Indium and imaging
29
What is somatostatin?
A neuropeptide produced throughout the body that excited the brain and inhibits the release of hormones systemically
30
Can the thymus produce hormones?
Yes, thymic hormones such as thymulin.
31
How does thymalfasin decrease CMV viral load? What cells are involved?
It does it in susceptible and resistant mice. It is dependent on the TLR9 pathway. Effects such as IFN and cytokine production are seen in dendritic cells, NK function increases and IFNy+ CD4 T cells are increased in the spleen
32
What type of tumors are thymomas?
Lymphocytic, epithelial, or mixed. Mixed is most common in humans. In mice, usually lymphocytic.
33
What is a big difference between the thymus of a mouse and a human?
Contrary to humans, the thymus of a mouse does not decrease in size as the mouse ages
34
When does thymus hyperplasia occur?
In about 50% of Graves patients.
35
What is good syndrome and what is it characterized by?
An immune dysregulation disease, characterized by thymomas, hypogammaglobulinemia (low serum antibodies), few or absent B cells, abnormal T cell ratio, and CD4 lymphopenia. It makes patients very susceptible to infections
36
How does thyroid stimulating factor affect the immune system?
It is a growth factor involved in T cell development. It stimulateds differentiation.
37
Where is TSH receptor expressed?
The thyroid and selectively in the thymus, on thymocytes
38
Describe the feedback mechanism in the endocrine system and its parallels in the immune system
In the endocrine system, hormone levels are regulatied via negative feedback loops (e.g. testosterone supressed pituitary hormone production). Similarly, the immune system uses feedback mechanisms such as cytokine signalling to regulate immune responses and prevent overactivation.
39
How does the endocrine system interact with the immune system?
Hormones like prolactin and growth hormone influence immune activity, including T cell production and regulation
40
What is the role of thymomas in endocrine and immune dysfunction, and why is it clinically significant?
They produce abnormal hormones and disrupt normal immune regulation, potentially leading to endocrine imbalances and autoimmune conditions.
41
What happens when there are mutations in AIRE?
It can lead to polyendocrine autoimmune diseases, where the immune system attacks multiple endocrine organs due to AIREs disrupted ability to express self-antigens to promote peripheral tolerance
42
Can a thymectomy help in autoimmune conditions?
Yes, it can remove the source of aberrant immune signalling and prevent auto-reactive T cell activity in certain conditions.
43
What can older people potentially benefit from as therapy against immune decline?
Growth hormone to promote thymic growth and enhance T cell production
44
Why is pregancy a challenge for the immune system?
Tolerance of the mother towards genetically different fetal tissue is required
45
What HLA is especially interesting in pregnancy?
non-classic HLA-G
46
Why is egg donation pregancy especially challenging for the immune system?
The child is totally genetically different from the mother as opposed to only half in a spontaneously conceived pregnancy. Egg donation pregnancies are associated with a higher incidence of pregnancy-induced hypertension and placental pathology.
47
What do trohoblasts do during the onset of pregnancy?
They invade the decidua (uterine lining during pregnancy), after which they differentiate into extravillous trophoblasts, leading to penetration and remodelling of uterine arteries.
48
What are decidual NK cells?
NK cells present in the uterine wall during pregnancy (decidua)
49
Is there a Th2 bias in pregnancy? Back up your answer as to why. (5)
Yes, but it seems to be a secondary effect.
1. It was based on studies involving cytokine measurements in the blood, so systemic.
2. A lot of these cytokines come from NK cells, which are increased in early gestation.
3. There is no evidence for T-cell mediated rejection.
4. Th1 is also found to be raised.
5. Deficiency of IL-4 and IL-10 seems to have no effect on pregnancy
50
During what phases of pregancy do what trophoblasts interact with maternal immune cells?
Early phase: Fetal extravillous trophoblasts interact with maternal immune cells in the decidua
Late phase: Placental trophoblasts interact with circulating maternal immune cells
51
What happens when there is inadequate trophoblast invasion?
Fetal growth restriction and pre-eclampsia (high blood pressure and protein in urine)
52
What are trophoblasts characterized by? (5)
They are:
1. Fetal cells in the placenta
2. They secrete hormones like hCG (hormone used for pregnancy tests)
3. Transfer maternal immunoglobulins to the fetus
4. Lack of MHC II
5. Variable expression of MHC I (depends on type)
53
Who expresses HLA-G?
Extravillous trophoblasts, no other trophoblasts
54
What is a prerequisite for pregnancy?
Expression of HLA-G in embryos
55
What is an important function of soluble HLA-G? What happens when it interacts with NK cells?
Apoptosis of activated T cells.
It interacts with uterine NK cells leading to secretion of cytokines and proangiogenic (blood vessels) factors
56
What are ligands of NK cells in pregnancy?
HLA-C, HLA-G and HLA-E
57
How do NK cells get to the decidua? (2)
Selective recruitment by chemokines and local generation from hematopoetic stem cells induced by TGFß and IL-15 produced by decidual cells and trophoblasts
58
What is the phenotype of dNKs?
Non-cytotoxic. They produce anti-inflammatory mediators like IL-10
59
What is the most important function of dNKs?
Contribution to transformation of endometrial vessels into spiral arteries
60
What happens when HLA-C interacts with dNK cells?
Induction of inhibitory receptors
61
What is granulysin?
Produced by dNK cells. It selectively kills bacteria in trophoblasts without killing the trophoblasts.
62
When during pregnancy do dendritic cells play a role?
During implantation. They are required for a healthy pregnancy.
63
What is the phenotype of decidual DCs during pregnancy?
Tolerogenic. High IL-10, low IL-12. Reduced APC capacity. HLA-G expression. Macrophage inhibiting cytokines.
64
What is the role of HLA-G in DCs? (3)
It induced maturation arrest, disruption of MHC II presentation and leads to anergic and immunosupressive effector T cells
65
What is the role of CD200 in local DCs? What happens when it is blocked?
Induction of Tregs. Blocking leads to fetal rejection.
66
What does the three-stage pregnancy concept entail?
Different immunological concepts are playing a role at different phases during pregnancy.
1st trimester: Inflammation
2nd: anti-inflammatory and Th2 microenvironment
3rd: Switch to inflammatory and Th1 immune state (induces labor)
67
What happens during the 1st trimester?
pro-inflammatory cytokine and chemokine abundance produced by endometrial cells and infiltrating immune cells
68
Summarize the role or trophoblasts in pregnancy (3)
1. Immune cell recruitment
2. Immune cell education (reduced cytotoxicity, skew to tissue remodelling and tolerogenic cytokines)
3. Environmental sensing: TLRs and NODLRs to sense DAMPs and PAMPs to react to infections as quickly as possible
69
Why is environmental sensing an important function of trophoblasts?
To sense infection, microbiota and cell damage in the uterus and uterus wall during pregnancy to react as quickly as possible
70
When is IFN induced during pregnancy?
When TLR4 is stimulated by LPS.
71
What does IFN type 1 do? (3)
1. Induces an antimicrobial state
2. modulates the innate immune response
3. activates the adaptive immune response
72
What are the 5 main players in the teamwork that occurs during pregnancy?
Tregs, uNKs, DCs and macrophages, trophoblasts and soluble factors such as IL-10 and hormones
73
What is the main producer of IFN type 1?
Plasmacytoid DCs, which are bone marrow derived and released in the blood. They are present in small numbers in the spleen, lymph nodes and mucosal-associated tissuese the small numbers, they produce high levels of IFN type 1
74
Why is IFN type 1 difficult to assess?
There are different subtypes, so there is no simple protein assay to measure activation
74
What types of receptors are the plasmacytoid DC receptors that lead to IFN type 1 production? (1(2))
Endoplasmic: TLR9 for dsDNA and TLR7 for ssRNA
75
How is IFN type 1 expression assessed?
Via gene expression in IFN type 1 -producing cells, since measuring IFN directly is not simple due to the high number of subsets
76
What was found regarding IFN type 1 in Sjogrens syndrome?
Though the syndrome is heterogeniec, there is a correlation between an IFN type 1 gene expression signature and disease activity and the presence of autoantibodies in patients with Sjogrens compared to healthy controls
77
In what types of diseases are disturbances of IFN type 1 homeostasis detected?
Several systemic autoimmune diseases such as Sjogrens, SLE, systemic sclerosis, and a subset of RA patients
78
What is BAFF and what is its relation to IFN type 1?
B cell activating factor. It is present in serum of patients with systemic sclerosis and, when IFN is blocked, is reduced, suggesting IFN leads to higher expression of BAFF in these patients
79
What is the mechanism loop of IFN induction in autoimmunity? (6 steps)
1. Plasmacytoid DCs produce IFN type 1
2. Upregulation of IFN-inducible genes in monocytes
3. Production of BAFF by monocytes
4. Induction of B cells to differentiate into plasma cells
5. Production of immune complexes of auto-antibodies by plasma cells
6. Induction of IFN in plasmacytoid DCs by auto-antibodies
80
Why do trials blocking IFN type 1 in systemic autoimmune diseases fail?
Too many subsets
81
What is currently the most effective treatment of IFN type 1-induced auto-immune diseases and why?
Blocking of IFN type 1 receptors, since all subsets bind to it
82
What molecules are important in the induction of IFN type 1?
TLR7, TLR9, cytosolic RIG-like receptors (TLR-independent) and DNA-sensing receptors
83
What do RIG-like receptors detect?
cytosolic viral replication
84
what pathway is hyperresponsive in sjogrens patients and how does that work?
STING. This is due to a self-amplifying loop due to TBK1, a common factor in multiple IFN induction pathways. This leads to continuous IFN type 1 production
85
What is trained immunity?
Innate immune antigen non-specific memory after exposure to an inflammatory stimulus, leading to a hyperresponsive phenotype after a second stimulation that is unrelated to the first stimulus
86
What are the mechanisms behind trained immunity? (2)
1. Metabolic changes in the glucose/cholesterol pathways of cells
2. Epigenetic regulation (histones)
87
What molecule is a trainer and how does that work?
Type 1 IFN: it can induce changes in cell glucose metabolism
88
What concept can clarify the mechanism of action of Type 1 IFN in systemic autoimmunity?
Trained immunity
89
What are mesenchymal stem cells (MSCs)?
Progenitors of osteoblasts, adipocytes, chondrocytes and fibroblasts, depending on the microenvironment/niche
90
What is the difference in origin between osteoclasts and osteoblasts?
Osteoclasts have mesenchymal stem cells as progenitors, while osteoclasts are derived from hematopoetic precursor cells
91
What are the critical transcription factors involved in osteoblastogenesis?
SOX9 and RUNX2. They can lead to differentiation into osteoblasts or chondrocytes. This is influenced by different signalling pathways.
92
What are the critical transcription factors involved in osteoclastogenesis?
NFATc1 is the master transcription factos. It activates genes that drive osteoclast fusion and bone resorption
93
What is osteoimmunology?
The study of the interaxtions betwen the immune system and bone metabolism, particularly in processes like osteoclastogenesis.
94
What do osteoblats look like?
Depends on the functional state. They are cuboidal in the active bone-forming state, but have a spindle-like shape when they line the bone in their inactive state
95
What causes osteoporosis?
Unbalanced differentiation from mesenchymal stem cells into adipocytes instead of osteoblasts
96
What do osteoblasts differentiate into?
Osteocytes that sit in the middle of the bone.
97
What osteocyte function was recently found?
They form a sort of neural network with a mechanosensor function and are involved in controlling the action of osteoblasts and osteoclasts
98
How is osteoclastogenesis regulated?
Through RANK ligand and RANK (receptor activators of NF-kB) and OPG (soluble decoy receptor, binds to RANKL)
99
What is the immunological mechanism involved in bone resorption/destruction? (3)
1 Interaction between osteoblasts and (pre-) osteoclasts via RANKL/RANK system
2. Activation of osteoclasts by T cells via RANKL/RANK pathway
3. Activation of osteoclasts by pro-inflammatory cytokines (osteoblast independent)
100
Which cell expresses RANK?
Pre-osteoclasts. They interact with RANKL on osteoclasts to further differentiate into active osteoclasts
101
What is the main pathway regulating osteoclastogenesis and bone resoprtion?
The RANK/RANKL/OPG pathway
102
What does RANKL stand for, and where is it expressed?
RANKL stands for receptor activator of NF-kB ligand. It is expressed by osteoblasts, fibroblasts, T cells and synovial fibroblasts
103
What is the role of RANK in osteoclastogenesis?
RANK is the receptor on osteoclast precursors that binds to RANKL, triggering differentiation into mature osetoclasts
104
What is OPG and what role does it play in bone resoprtion?
It is a decoy receptor that binds RANKL, preventing it from binding to RANK and inhibiting osteoclastogenesis
105
What happens when RANKL binds to RANK?
It activated pathways that lead to the acitvation of NF-kB, promoting osteoclast formation and bone resorption
106
What are two pro-osteoclastogenic cytokines?
TNF-α and IL-17. Also IL-1 and TGF-ß
107
What are two anti-osteoclastogenic cytokines?
IL-4 and IL-10, also IFNy
108
How does the RANKL-RANK-OPG balance affect bone health?
If RANKL is increased and OPG is decreased, it leads to more osteoclast activity and bone resorption, potentiall causing conditions like osteoporosis
109
What happens when RANKL is inhibited?
It prevents RANK activation and thereby inhibits osteoclast formation and bone resorption
110
What happens to osteoclastogenesis in inflammatory conditions like RA?
Inflammatory cytokines like TNF-α and IL-17 increase RANKL expression, leading to excessive osteoclast activaty and bone erosion in the joint.
111
