Module 8 - Endocrine control of Immune Function Flashcards
1
Q
Insulin secretion by pancreatic beta cells is primarily regulated by the _______ in the extracellular fluid bathing the beta cells
A
Insulin secretion by pancreatic beta cells is primarily regulated by the glucose level in the extracellular fluid bathing the beta cells
2
Q
________ activation triggers increased expression of insulin receptors
A
lymphocyte activation triggers increased expression of insulin receptors
3
Q
Other than glucose level in extracellular fluid, what modulates insulin secretion?
A
Sympathetic nerve stimulation and norepinephrine inhibit insulin production
Parasympathetic activity, growth hormone and prolactin stimulate insulin release
4
Q
What is the purpose of increased expression of insulin receptors following lymphocyte activation in response to exposure to antigen?
A
Helps to augment glucose uptake by these immune cells which supports their metabolic needs
May also directly support growth/differentiation (eg of T-cells in response to antigen)
5
Q
_______ has been shown to have an anti-inflammatory effect
A
Insulin
6
Q
What is the relationship between vitamin D and the immune system?
A
Vit D deficiency is associated with impaired immune responses – increased susceptibility to infection
Vit D promotes early immune response
7
Q
What part of immune response does Vit D contribute to?
(5)
A
Early immune response:
- ↑ differentiation, phagocytic activity and cytotoxicity of macrophages (via ↑IL-1 prod)
- Antibody production and fxn
- ↑Ab receptor expression on lymphocytes
- ↑Inflammatory response
- Inhibits over-activity by inhibiting t-cell proliferation
7
Q
What part of immune response does Vit D contribute to?
A
Early immune response:
- ↑ differentiation, phagocytic activity and cytotoxicity of macrophages (via ↑IL-1 prod)
- Antibody production and fxn
- ↑Ab receptor expression on lymphocytes
- ↑Inflammatory response
- Inhibits over-activity by inhibiting t-cell proliferation
- *
8
Q
The _____ contains the largest population of endocrine cells in the body
A
The GI tract contains the largest population of endocrine cells in the body
9
Q
Endocrine cells in the GIT are located among the _________
A
Endocrine cells in the GIT are located among the epithelial cells of the gut mucosa
10
Q
Endocrine cells in the GIT release:
A
Substances that can act locally or systematically upon entering circulation
11
Q
95% of the _____ in the body is gut-derived
A
95% of the serotonin (5-HT) in the body is gut-derived
12
Q
Serotonin (5-HT) in the gut can induce production of ________ to promote _______
A
Serotonin (5-HT) in the gut can induce production of IL-1beta by macrophages to promote GIT/systemic inflammation
13
Q
IL-1beta vs IL-1?
A
IL-1beta thought to be more potent proinflammatory cytokine than IL-1
14
Q
_______ released by the stomach stimulates appetite and growth hormone release
A
Ghrelin released by the stomach stimulates appetite and growth hormone release
15
Q
How does ghrelin provide a link between the GIT and neuroendocrine regulation of immune function?
A
Ghrelin → ↑GH release
GH has a supportive effect on immune function
16
Q
What contributions does the cardiovascular system make to endocrine regulation?
A
- Peptides released by heart, vascular epithelium serve as endocrine signals capable of influencing immune responses
- (eg ANP (atrial natriuretic peptide) released in response to stretch of atrial muscle has been found in immune tissues (thymus, spleen and lymph nodes)
- receptors for ANP found on leukocytes
- (eg ANP (atrial natriuretic peptide) released in response to stretch of atrial muscle has been found in immune tissues (thymus, spleen and lymph nodes)
17
Q
ANP released by________ in response to _______
Role in Immune function?
A
- Atrial natriuretic peptide released by heart, vascular epithelium in response to stretch of atrial muscle has been found in immune tissues (thymus, spleen and lymph nodes)
- receptors for ANP found on leukocytes
- ANP functions as a vasodilator in response to increased BP
- Enhanced production of reactive oxygen species (ROS) by neutrophils
- augments (↑) NK cells activity
18
Q
- Atrial natriuretic peptide (ANP) has been found in which 3 immune tissues?
- receptors for ANP found on ______
A
- Atrial natriuretic peptide (ANP) has been found in which 3 immune tissues?
- Thymus, spleen, lymph nodes
- receptors for ANP found on leukocytes
- Thymus, spleen, lymph nodes
19
Q
High levels of ANP have _______ effects by blocking __________
A
High levels of ANP have anti-inflammatory effects by blocking pro-inflammatory cytokine effects on vascular permeability
20
Q
ANP modifies ______ production favouring _______ responses
Reduces ______ proliferation
A
ANP modifies cytokine production favouring anti-inflammatory responses
Reduces T-cell proliferation
21
Q
All together, ANP supports _____ of immune responses and also functions to __________
A
All together, ANP supports initial stimulation of immune responses and also functions to contain the extent of these responses as a protective measure
22
Q
Why is adipose tissue considered an endocrine organ?
A
Releases multitude of bioactive factors
23
Q
White adipose tissue is predominant in adults and is composed of ______ and _______
A
White adipose tissue is predominant in adults and is composed of adipocytes and macrophages
24
White adipose tissue is a major contributor to _______ states and is a source of \_\_\_\_\_\_\_\_
White adipose tissue is a major contributor to low grade _inflammatory_ states (characteristic of obesity) and is a source of _pro-inflammatory cytokines (IL-1, IL-6, TNFalpha)_
24
White adipose tissue is a major contributor to _______ states and is a source of \_\_\_\_\_\_\_\_
White adipose tissue is a major contributor to low grade _inflammatory_ states (characteristic of obesity) and is a source of _pro-inflammatory cytokines (IL-1, IL-6, TNFalpha)_
24
White adipose tissue is a major contributor to _______ states and is a source of \_\_\_\_\_\_\_\_
White adipose tissue is a major contributor to low grade _inflammatory_ states (characteristic of obesity) and is a source of _pro-inflammatory cytokines (IL-1, IL-6, TNFalpha)_
25
What are two hormones that stem from the adipose tissue?
Leptin and Adiponectin
26
Leptin from adipose tissue has what effect on immune response
Leptin is proinflammatory and promotes Th1 predominance
27
Effect of adiponectin from the adipose tissue on immune response?
Anti-inflammatory effects (release of adiponectin is inversely related to circulating IL-6 levels)
28
release of adiponectin from adipose tissue is inversely related to circulating ____ levels
release of adiponectin from adipose tissue is inversely related to circulating _IL-6_ levels
29
6 contributions to immune regulation from increased **glucocorticoid levels**
* Inhibition of cytokine production
* esp pro-inflammatory cytokines
* Inhibition of lymphocyte proliferation
* Death of immune cells
* Lymphoid tissue involution
* down-regulating antibody receptors on phagocytes
* Inhibition of fever
30
Explain inhibition of lymphocyte proliferation by glucocorticoids
* T-cells, NK cells, monocytes, macrophages
* Typically occurs after inhibition of lymphokine production
* Reduction of cell numbers not due solely to cell death
31
Describe lymphoid tissue involution by glucocorticoids?
Death of immune cells BUT NOT stromal cells
32
How do glucocorticoids down-regulate antibody receptors on phagocytes
via diminished release of certain cytokines (eg interferon IFN)
33
How do glucocorticoids mediate inhibition of fever?
via diminished IL-1 production
34
Inflammation can be detrimental:
* ________ released during phagocytosis may damage healthy cells
* Loss of fluid from the \_\_\_\_\_\_\_
* increase ______ slowing blood flow and clogging capillaries with stagnant RBCs
* may result in \_\_\_\_\_\_
Inflammation can be detrimental:
* _lysosomal hydrolases_ released during phagocytosis may damage healthy cells
* Loss of fluid from the _microvasculature_
* increase _blood viscosity_ slowing blood flow and clogging capillaries with stagnant RBCs
* may result in _ischemia_(because of decreased blood flow)
* Compromise CV function
35
\_\_\_\_\_\_\_\_\_ suppress inflammation
_adrenal steroids_ suppress inflammation
36
How do glucocorticoids control the extent of inflammation? (6)
* Inhibition of histamine/serotonin production and release (vasodilators)
* Stabilization of lysosomal membranes
* Maintenance of vascular responsiveness to catecholamines
* Inhibition of arachidonic acid formation and increased arachidonic acid metabolism
* Inhibition of bradykinin release from damaged tissues
* inhibition of enzymes
37
Explain how glucocorticoids inhibit histamine/serotonin production and release and the result of this inhibition
* From granulocytes/mast cells/macrophages
* Thereby preventing vasodilation, diapedesis and damage to tissues and blood vessels
diapedesis=The movement or passage of blood cells, especially white blood cells
38
Explain how glucocorticoids maintain vascular responsiveness to catecholamines
* vasoconstriction counteracts local vasodilation caused by inflammatory mediators
* decreases blood flow
* limiting availability of fluid to form exudates
* Swelling reduced because arterial constriction decreases capillary and venule pressure and facilitates reabsorption of extracellular fluid
39
Describe the glucocorticoid mediated inhibition of arachidonic acid formation and increased arachidonic acid metabolism
Inhibition of phospholipase A2 and **prostaglandin** production - thereby reducing chemotaxis
40
How do glucocorticoids mediate inhibition of bradykinin release from damaged tissue?
bradykinin triggers the complement cascade; blocking bradykinin will impair complement cascade
41
How does glucocorticoids inhibition of enzymes mediate inflammation?
plasmin/collagenase secreted by granulocytes/mast cells/macrophages
By inhibiting plasmin/collagenase prevents damage to tissues and blood vessels
42
What is glucocorticoid resistance?
In response to chronically elevated glucocorticoid concentrations, some immune cells (particularly those involved in inflammation) exhibit down regulation of glucocorticoid receptors (alters responses)
= **decrease in sensitivity of some immune cell populations to glucocorticoid hormones that would normally terminate an inflammatory response**
43
Inappropriate inflammation linked to onset or progression of _________ or ________ diseases
Inappropriate inflammation linked to onset or progression of _autoimmune_ or _chronic_ diseases
44
Increased sympathetic nervous system activity independently stimulates \_\_\_\_\_
Increased sympathetic nervous system activity independently stimulates _inflammation_
45
Control of **stress responses** and in turn **sympathetic** **NS** activity and **glucocorticoid** **levels** can help preserve _____ and help maintain the _____ of glucocorticoids in controlling inflammation
Control of **stress responses** and in turn **sympathetic** **NS** activity and **glucocorticoid** **levels** can help preserve _cellular glucocorticoid sensitivity_ and help maintain the _protective effects_ of glucocorticoids in controlling inflammation
46
How does the inhibition of histamine/serotonin production and release by glucocorticoids control inflammation?
* typically released by granulocytes (like neutrophils) as well as mast cells and macrophages
* Histamine and serotonin are vasodilators = vasodilation is a **hallmark of inflammation**
* preventing his/serotonin = limit extent of vasodilation → limit the stretching of capillary walls → helps prevent diapedesis of immune cells into tissue → prevent damage to tissues and blood vessels
47
How does stabilization of lysosomal membranes help in glucocorticoid-mediated control of inflammation?
* Prevents release of hydrolytic enzymes from lysosomes that can damage healthy tissues
48
Glucocorticoids maintain vascular responsiveness to catecholamines; how does this control inflammation?
* critical
* elicits **vasoconstriction** to counter local vasodilation induced by mediators like histamine and serotonin
* vasoconstriction of arterioles reduces blood flow to downstream capillaries which reduces availability of fluid to *leave the capillaries* and enter the tissues as an exudate
* Vasoconstriction - added effect of promoting *fluid reabsorption from the tissues into the vasculature* = relieves tissue swelling and protects Blood volume and cardiovascular function
49
Glucocorticoid-mediated control of inflammation:
Inhibition of arachidonic acid formation and increased arachidonic acid metabolism:
* Inhibition of Phospholipase A2 by coritsol
* Phospholipase A2 enzyme which converts Phospholipids to Arachidonic acid
* Arachidonic acid is converted to prostaglandins
* **Prostaglandins are notoriously involved in perpetuating inflammatory response** and have variety of actions including **vasodilations** and participate in pain
* THUS BY INHIBITING ARACHIDONIC ACID PRODUCTION, GLUCOCORTICOIDS INHIBIT PROSTAGLANDIN PRODUCTION
50
How do aspirin-like drugs mediate inflammation?
These drugs block action of cyclooxygenase which is required to convert arachidonic acid to endoperoxides which are converted to prostaglandins
ie aspirin-like drugs prevent prostaglandin production
51
Prostaglandins have ______ properties; reducing prostaglandin production by inhibiting arachidonic acid formation will reduce _____ migration of immune cells (hallmark of inflammation)
Prostaglandins have _chemotactic_ properties; reducing prostaglandin production by inhibiting arachidonic acid formation will reduce _chemotactic_ migration of immune cells (hallmark of inflammation)
52
Glucocorticoid-mediated control of inflammation:
Bradykinin
* Glucocorticoids inhibit release of **bradykinin** from damaged tissues
* Bradykinin is big contributor to inflammation and pain and is a trigger for the **complement cascade**
* inhibiting bradykinin → contains inflammatory response
53
Glucocorticoid-mediated control of inflammation:
Inhibition of enzymes
* Glucocorticoids inhibit release of certain enzymes such as **plasmin and collagenase** which are released by **granulocytes/mast cells/macrophages**
* These enzymes have the potential to damage healthy tissues and blood vessels
54
What is the main goal of glucocorticoid-mediated control of inflammation?
To allow the healing benefits while preventing “collatoral damage”
55
In chronic stress, inflammation is heightened but glucocorticoids are also increased, why isnt inflammation suppressed?
* After prolonged exposure to high [glucocorticoid], immune cells lose sensitivity to this hormone
* Glucocorticoid receptor **downregulation**
* Glucocorticoid resistance
56
What is glucocorticoid resistance?
Chronically high [glucocorticoid] leads to downregulation of glucocorticoid receptors on immune cells → reduced sensitivity to glucocorticoids
ie *decrease in sensitivity of some immune cell populations to glucocorticoid hormones that would normally terminate an inflammatory response*
57
What is the effect of aging on endocrine and immune systems?
↑age → ↓efficiency of endocrine and immune systems
58
In some cases, with aging, **basal levels** of some hormones may NOT decline but _______ responses do decline and receptors may be \_\_\_\_\_\_\_
In some cases, with aging, **basal levels** of some hormones may NOT decline but _secretory_ responses do decline; receptors may be _downregulated_
59
\_\_\_\_\_\_ and _____ cell function are not impaired by age
_B-cell_ and _macrophage_ cell function are not impaired by age
60
All _____ and _____ cells exhibit reduced efficiency with respect to aging
All _T-cells_ and _NK_ cells exhibit reduced efficiency with respect to aging
61
Effect of aging on the thymus?
During aging, the thymus undergoes progressive *involution*
62
During aging, the thymus undergoes progressive *involution*
Leads to:
Increased incidence of infectious and neoplastic diseases in the elderly
63
The thymus is a ________ gland located in the ________ above the \_\_\_\_\_
The thymus is a _two-lobed_ gland located in the _chest_ above the _heart_
64
What are the roles of the two regions of the thymus
* One in which the t-cells mature
* one containing epithelial cells which secrete the thymus hormones
65
Why is the thymus gland called the master gland of the immune system?
thymic hormones are essential for both **cell-mediated** and **humoral** immune responses
Facilitate production of T-cell precursors in the bone marrow
Regulated differentiation of T-cell precursors into helper, cytotoxic, or suppressor t-cells in the thymus gland
activate mature t-cells in the spleen and lymph nodes
66
Five functions of thymic hormones:
* Facilitate production of T-cell precursors in the bone marrow
* Regulated differentiation of T-cell precursors into helper, cytotoxic, or suppressor t-cells in the thymus gland
* activate mature t-cells in the spleen and lymph nodes
* Mobilize NK cells
* Stimulate release of cytokines
67
What happens if the thymus gland is absent at birth?
T-cells fail to develop and the infant lacks the ability to cope with viral/bacterial infections
68
How does the thymus gland change with age
* Size increases until puberty
* After puberty the thymus begins to decline in size and function
69
What might be the cause of the decline in size and activity of the thymus gland after puberty?
The decline in size and activity of the thymus gland might be due to the **immunosuppressive** actions of **glucocorticoids** which increase with time and age
70
What is thymic involution?
The decline of the size of the thymus gland
71
How can thymic involution be reversed?
Can be restored by neuroendocrine manipulation such as treatment with GH or PRL
* GH and prolactin (PRL) stimulate thymus growth and function to the point that these hormones have been referred to as “the fountain of youth”
72
With advancing age, **thymic involution** occurs which is accompanied by:
With advancing age, **thymic involution** occurs which is accompanied by: _reduction in the circulating thymic hormones_
_Causes gradual decline in cell-mediated immunity_
_Linked to increase in age-related diseases_
73
Explain the image:
* As we move from left to right we see gradual thymic involution (top)
* Accompanied by reduction in circulating thymic hormones (serum thymus factor)
* Causes gradual decline in cell mediated immunity (thymus dependent immunity)
* Linked to increase in age-related diseases (cancer and infectious disease)
* normally low in early years save for a small blip accounting for incidence of childhood diseases
74
Which three major hormones are reduced with age?
* ↑age → :
* ↓efficiency of cortisol feedback
* ↓GH
* ↓Gonadal steroids
75
What does the decreased efficiency of cortisol feedback with aging cause?
Leads to:
Characterized by:
* Leads to hypersecretion of glucocorticoid and the glucocorticoid cascade
* Characterized by altered immune function and heightened inflammation
76
Which hormone(s) are increases as age increases?
↑age → ↑LH/FSH
(↓immune stimulation in aging females int he absence of estrogen; increased inflammation in males)
77
↑age → ↑LH/FSH
Effect?
* ↓immune stimulation in aging females in the absence of estrogen
* increased inflammation in males
78
Why is there an increase in LH/FSH with age?
↑age → ↓gonadal steroids
* Gonadal steroids (estrogen/testosterone) releases negative feedback of the gonadotropins (LH/FSH)
* Low estrogen/testosterone → high LH/FSH (because reduced negative fb)
