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MEDSCI 708 > Topic 3 > Flashcards

Topic 3 Flashcards

1
Q

Why is inflammation a necessary and beneficial immunological defence mechanism?

A

It attempts to limit the extent of damage
It can counteract infection
It can promote healing by facilitating the restoration of tissue structure and function

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2
Q

How can inflammation become pathogenic?

A

This can occur in autoimmune disease and allergies/hypersensitivies as well as inflammation following trauma or infection

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3
Q

What are some examples of inflammation becoming pathogenic through injury?

A

Adult Respiratory Distress syndrome which can occur As a result of injury or infection to the lungs
Systemic inflammatory response syndrome which can affect the whole body and may be the result of an immune reaction to mitochondria which are massively released into the bloodstream from dying cells at the site of injury which activate innate immunity
Multiple Organ dysfunction syndrome

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4
Q

What is the process of inflammation?

A

Innate immunity acts as the first line of defence responding to inflammation-induced traffic signals
The innate immune response may then provide effector cells and molecules relied upon by the adaptive immune system
Naïve lymphocytes will respond poorly to inflammatory signals, but migrate efficiently to secondary lymphoid tissue
Effector and memory lymphocytes adapt their trafficking properties to match their immunologic function
Antigen activated T cells will travel efficiently to onflammed tissues due to their increased levels of adhesion molecules and chemokine receptors

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5
Q

What are the different classes of inflammatory mediators?

A 
Amines
Lipid mediators
Complement
Nucleotides
Adhesion molecules
Cytokines
Cheomokines
Steroid hormones
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6
Q

What are the pro-inflammatory amine mediators?

A

Histamine, Bradykinin

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7
Q

What are the anti-inflammatory amine mediators?

A

Adrenaline, noradrenaline

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8
Q

What are the pro-inflammatory lipid mediators?

A

PGE2, PGI2, LTB4, LTC4

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9
Q

What are the anti-inflammatory lipid mediators?

A

PGJ2, PGA1/2, lipoxins

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10
Q

What are the pro-inflammatory complement mediators?

A

C3a, C5a

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11
Q

What are anti-inflammatory complement mediators?

A

C1q receptor

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12
Q

What are the pro-inflammatory adhesion molecule mediators?

A

cGMP and ATP

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13
Q

What are the anti-inflammatory nucleotide mediators?

A

cAMP, adenosine

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14
Q

What are the pro-inflammatory adhesion molecule mediators?

A

E-selectin, P-Selectin, ICAM1 and VCAM1

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15
Q

What are the anti-inflammatory adhesion molecule mediators?

A

Alpha4beta3 integrin, TSP receptor and PS receptor

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16
Q

What are the pro-inflammatory cytokine mediators?

A

TNF, IL-1Beta and IL-6

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17
Q

What are the anti-inflammatory cytokine mediators?

A

TBFbeta1 and IL-10

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18
Q

What are the pro-inflammatory chemokine mediators?

A

IL-8, GRO/KC, MIP1alpha, MCP1

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19
Q

What are the ant-inflammatory steroid hormone mediators?

A

Glucocorticoids

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20
Q

What are the features of an acute inflammatory response?

A

Immediate and early response to tissue injury
Short duration of minutes to several days
An increase in capillary permeability and blood flow
Accumulation of fluid and plasma components
Leukocyte infiltration which involves predominately neutorphils
Inflammation will terminate when the stimulus is removed and the mediators produced by the inflammatory cells are gone
It is a self-limiting process (unless it progresses to chronic inflammation)

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21
Q

What are the features of a chronic inflammatory resonse?

A

A long duration of days to years
Accumulation of macrophages within 24-48 hours and lymphocytes within 5-7 days
It is often associated with concomitant tissue repair involving proliferation of fibroblasts and angiogenesis. Cytokines are released to stimulate fibroblast proliferation and collagen production
INF-gamma which is secreted by Th1, cytotoxic and NK cells activates macrophages perpetuating the inflammation
TNF-alpha cause tissue damage
Persistant accumulation and activation of leukocytes is a hallmark of chronic inflammation

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22
Q

What is the timing of the inflammatory response?

A

Following the initial injury there are vascular changes like vasodilatation which allows fluid to leave the blood vessels causing exudation and edema
Within a few minutes to hours neutrophils will roll along the walls of blood vessels, adhering to endothelials cells, extravasate, migrate to the site of inflammation, where they will destroy pathogens and release chemoattractants for monocytes and macrophages which will arrive 5-6 hours later become activated and secrete IL-1, IL-6 and TNFalpha to further activate neutrophils, monocytes and lymphocytes. TNFalpha also stimulates vascular endothelium and macrophages to secrete colony-stimulating factors M-CSF, G-CSF and GM-CSF stimulating hematopoiesis leading to a transient increase in leukocyte production

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23
Q

What is the role of TGF-beta in the tming of inflammation?

A

It can limit the response by inhibiting leukocyte proliferation as well as promoting healing through accumulation and proliferation of fibroblasts and the laying down of extracellular matrix. It can also help to generate iTregs

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24
Q

What are Th1 type autoimmune diseases?

A

These affect 35% of the population and are when the immune system attacks itself and includes diseases such as atherosclerosis, Multiple sclerosis, Chron’s disease, Arthritis and type 1 diabetes

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25
Q

What are Th2 type autoimmune diseases?

A

These are allergies where the immune system over reacts to innocuous environmental allergens and includes conditions like asthma, dermatitis, hayfever, hives, food allergies and ulcerative colitis

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26
Q

What is positive selection with regards to T lymphocyte generation?

A

Lymphocytes are positively selected based on their affinity of interaction with the MCH complex expressed on the cortical epithelium of the thymus, Cells which do not recognize self at all will undergo death by neglect

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27
Q

What is negative selection with regards to T lymphocyte generation?

A

This is when lymphocytes are negatively selected based on their affinity of interaction with self antigen-MHC complexes presented by dendritic cells at the cortical/meduallary junction of the thymus, and by thymic cells which express extra thymic antigens due to the promiscuous transcription factor AIRE

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28
Q

What are the possible outcomes of negative selection in the generation of a T cell?

A

A T cell which receives very strong signals is considered autoreactive and will undergo apoptotic death
A T cell which receives a weak signal will survive and become an effector cell
A T cell which interacts with self-antigen-MHC complexes expressed on medullary epithelial cells will receive an intermediate signal to become a natural T reg

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29
Q

Do autoreactive lymphocytes escape the selection process?

A

Some do with autoreactive lymphocytes being shown to exist in the body
These cells may be needed to extend the immune repertoire to fight infection and may become activated and induced to proliferate via adjuvants like bacterial extracts

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30
Q

What are the subpopulations of immune cells which can suppress the immune cell?

A 
IL-10 producing Tr1 cells
TGF-Beta producing T helper type 3 cells
CD8+ T suppressor cells
Natural Killer T cells
CD4-CD8- T cells
Gamma-delta T cells
CD4+CD25+FoxP3+
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31
Q

What is the difference between nTregs and iTregs?

A

nTregs are natural regulatory cells formed in the thymus while iTregs are cells which are given a regulatory phenotype by signals they experienced in the periphery
In terms of function nTregs prevent autoimmunity caused by self-antigens while itregs prevent immunity due to environmental allergens

32
Q

How can iTregs be produced in the gut?

A

The gut is a tolerogenic and contains specialized CD103+ dendritic cells in the intestine which secrete both TGF-Beta and retinoic acid which can switch naïve T cells to become iTregs
The expression of IL-33 can also stimulate the production, stability and function of intestinal Tregs

33
Q

What occurs if there is blockade or deletion of iTregs in mice?

A

This does not lead to multi-organ autoimmunity as would be seen with nTregs, instead they develop Th2 type pathologies at mucosal sites reminiscent of allergies including colitis and asthma

34
Q

What is the evidence that Tregs are protective against autoimmunity?

A

Tregs are defective in patients with multiple sclerosis, type 1 diabetes, psoriasis and rheumatoid arthritis
Additionally humans with mutations in Foxp3 (an important gene in Tregs) suffer from a severe and rapidly fatal autoimmune disorder, Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX)syndrome

35
Q

What are the two core mechanisms through which Tregs prevent autoimmunity?

A

This occurs through two core mechanisms, bystander suppression Tregs create a regulatory immunosuppressive milieu that suppresses in a non-antigen-specific fashion promoting the bystander effect
Infectious tolerance where Tregs create a regulatory milieu that generates a new population of Treg cells with antigen specificities that are distinct from the original Treg population. The new antigen recognized has to be expressed on the same tissue as that containing the original antigen

36
Q

What are the features of nTregs?

A

ExpressFoxP3 (a transcription factor which controls their development and function)
Mostly CD4+ helper T cell population, expressing IL-2 receptor alpha chain (CD25) and constitute 10-15% of peripheral CD4+ cells
Suppress the activation of the immune system and maintain tolerance to self
Their antigen repertoire is skewed towards recognition of self antigens
Protect against autoimmune disease, graft-versus host disease, transplant rejection and overwhelming tissue destruction during infections
They are established in the thymus
Neonatal thymectomy at 3 days of age in mice results in autoimmunity

37
Q

What are the mechanisms exerted by Tregs?

A

Supressing the proliferation of effector T cells this can occur through direct contact where Tregs have large amounts of cAMP which could be delivered through gap junctions or via scooping up IL-2 due to the constiuitive expression of CD25 (a high affinity IL-2 receptor) by Tregs
Control of initial T cell activation, expansion and differentiation during lymph node priming, through things like interactions with dendritic cells and other antigen presenting cells to cause them to upregulate IDO whch suppresses T cell function
Prevent CD8+ T cells from differentiating into cytolytic effector cells
Kill effector cells directly via granzymes amd perforin
Can cause CD4+ effector cells to differentiate into IL-10 or TGF-Beta producing cells
Expression of IL-10, TGFBeta, CTLA-4, granzyme B, perforin, IFN-gamma, IL-9, heme oxygenase-1, cAMP, CD39, galectins, IL-35
Control of Tcell trafficking to tissues as well as their reactivation and effector function development at the site of inflammation

38
Q

How does Treg activity exist in homeostatic control?

A

The main function of Tregs in a normal person is to maintain homeostasis in secondary lymphoid organs and prevent the outgrowth of autoreactive Tcells through sop-uping IL-2 preventing greater activation of effector T cells, Treg showing greater sensitivity to antigens than effector T cells
Probably make use of TGFbeta and CTLA4, and while they may also use IL-10, IDO and CD39 these molecules are likely not essential

39
Q

What is the role of Tregs in damage control?

A

If steady state tolerance is breached the Tregs become activated, shed L-selectin and upregulate chemokine receptors and cell adhesion molecules required to exit lymphoid organs and gain entry into inflamed tissues where they upregulate CD25 to better compete with effector T cells for IL-2 as well as causing the Tregs to express more IL-10, CTLA4, IL-35, TGF-Beta and HO-1 and CD39 making them more potent immune suppressors
Chornically activated Tregs have cytotoxic granules like granzyme B enabling T cells to kill APCs and effector T cells enabling resolution of the immune response

40
Q

What is the role of Tregs in infectious tolerance?

A

This is established at the final stage of an immune response and is required to stabilize the tolerant state. Tissue destruction leads to the presentation of newly exposed tissue antigens on Treg-silenced Dcs
This occurs via the mechanisms where Treg-Silenced DCs act in concert with TGFBeta to transform effector cells to Tregs

41
Q

How do mouse studies reveal the importance of Tregs in preventing autoimmunity?

A

Gene Knockout of FoxP3 results in fatal autoimmune pathology beginning at an early age an affecting multiple organs
Purging of FoxP3 Treg in newborn and adult mice results in autoimmune disease of similar severity with leukocyte infiltration of liver, lungs and skin and other organs
Autoreactive T cells are continually being targeted and suppressed by Tregs
Gene Knockout of alphaVbeta8 on DCs prevents presentation of active TGFBeta to T cells leading to colitis as there is a failure to produce peripheral Tregs
Gene knockout of CTLA-4 leads to fatal T cell autoimmunity
Tregs control the development of atherosclerosis with mice deficient in CD80 and CD86 (required for Treg development) show accelerated atherogenesis as does antibody mediated depletion of CD25 cells

42
Q

What are the mechanisms responsible for the breakdown of immune tolerance?

A

Molecular mimicry, Protein changes or Cryptic antigens, super antigens/adjuvants, bystander effect

43
Q

What role does the gut microbiome play in regulating tolerance and autoimmunity?

A

Sex differences in the gut microbiome drive hormone dependent regulation of auto-immunity with female NOD mice developing type 1 diabetes being protected by the transfer of gut microbiota from male mice which resulted in elevated testosterone levels
The gut microbiota produces short chain fatty acids which increase the size and enhance the function of the colonic pool of Tregs and administration of short chain fatty acids protected mice against adoptively transferred colitis

44
Q

What is Asthma?

A

This is a chronic inflammatory disease of the small airways characterized by mononuclear, eosinophil and mast cell infiltration of the bronchial fluid and submucosa along with mucus gland hyperplasia and subepithelial fibrosis
It affects 25% of the developed world
Often suffered by those with a predisposition to produce IgE against common environmental allergens, and produce Th2 cytokines rather than Th1 cytokines which would typify the response

45
Q

What is the hygiene hypothesis?

A

This states that there is an increase in world-wide allergic disease due to a lack of viral and bacterial infections which used to occur in the first 2 years of life
This reduced exposure causes reduced immune stimulation to trigger the release of IL-12 and IFN-gamma which are required to stimulate a Th1 response and suppress a Th2 response, causing this response to remain predominant and predispose to allergy development
Th2 responses evolved to fight parasitic infections, the modern day reduction of these infections results in less drive to produce iTregs leading to an impairment of peripheral tolerance

46
Q

What are the Dendritic cell subsets in the lung?

A

CD8alpha-beta- plasmacytoid DCs which are immunogenic
CD11Beta+ conventional DCs which are also immunogenic
CD8alpha+beta- and CD8alpha+beta+ which are tolerogenic, converting naïve CD4 cells to iTregs through the expression of RALDH and the production of retinoic acid promoting tolerance to inhaled antigens

47
Q

What are Asthma Markers and symptoms?

A 
Variable degree of airflow obstruction
Bronchial hyper responsiveness
Bronchiole constriction
Mucus hypersecretion
Airway epithelial hypertrophy
Leukocyte infiltration
Allergen-specific Ig
48
Q

What can be the stimuli for asthma?

A

Allergic agents such as mites, cockroaches, cat dander etc and non-allergic agents such as viral infections
Note many allergens are proteases this is possibly due to their ability to disrupt the epithelial barrier allowing access of allergens

49
Q

What occurs during the induction of asthma?

A

Inhaled antigens are processed by dendritic cells which line the airway and migrate to draining lymph nodes to present the allergen to T lymphocytes via an engagement of the B cell MHC II presented allergen to the TCR complex causing rapid expression of CD40 on the T cells allowing co-stimulation of B cells and T cells via CD80/86 interactions with CD28
T cell produced IL-4 and 13 provide the first signal to B cells to produce the IgE isotype with alphaLbeta2 and ICAM-1 and CD40 and its ligands providing the second signal
IgE then circulates, binds allergens and activates receptors on mast cells triggering the release of mediators which will cause the clinical symptoms of asthma

50
Q

What are the two phases of asthma?

A

Early Phase reaction which typically resolves within an hour and occurs when inhaled allergen precipitates acute airway obstruction through the release of inflammatory mediators which cause airway constriction
Late Phase reactions which develop 4-6 hours later as a result of cytokines and chemokines generated by both resident and recruited inflammatory cells

51
Q

What is the role of adhesion molecules in leukocyte infiltration into the inflamed lung?

A

Cell rolling is mediated by P-selectin on the surface of eosinophils which express alpha4beta1, which binds to the ligand VCAM-1
Interactions between Btea2 integrins and ICAM-1 on vascular tissue are important for transendothelial migration of eosinophils
VCAM-1 and ICAM-1 are expressed on lung tissue from asthmatic animals and patient bronchial biopsies
The levels of soluble ICAM-1 and E-selectin in the blood and bronchoalveolar lavage fluid are elevated in asthma subjects
Anti-alpha4 integrin and anti-VCAM1 mAbs reduce pulmonary eosinophilia, mucin levels and bronchial hyper responsiveness to methacholine in animal models of asthma

52
Q

What is the evidence for the role of chemokines in asthma?

A

Many chemokines have been detected in the airways of patients with asthma including RANTES, MIP-1alpha, MCP-1 and eotaxin
There is a positive correlation with the levels of RANTES and number of eosinophils that have infiltrated into the airspace 4 hours after airway challenge
Immunohistochemistry shows epithelial cells, endothelial cells and macrophages as the primary sources of RANTES, MCP-3, MCP-4, eotaxin and eotaxin-2
Antibody blocking of MCP-5, eotaxin, RANTES and MCP-1 contribute in a non-redundant fashion to airway responsiveness and cellular emigration
Mucosa-infiltrating eosinophils express the eotaxin receptor CCR3 with chemoskines for this recpeotr important in attraction of eosinophils to the airways
CCR3 deficient mice have defects in eosinophil migration, however Th2 trafficking is left intact and can still mount allergic responses
CCR1 and CCR5 antagonist Met-RANTES blocks lung inflammation in mice
Th2 cell trafficking is mostly mediated and maintained by CCR4 and CCR8
Chemokines may act as histamine-releasing factors in the absence of antigen and IgE antibody.
MCPs, RANTES, MIP-1alpha and eotaxin are all able to cause IgE independent degranulation of basophils and directly contribute to local inflammatory processes

53
Q

What is the role of lipid mediators in asthma?

A

These mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2) ar synthesized de novo from arachidonic acid by the lipoxygenase and cyclooxygenase pathways respectively and bind to the BLT1 and DP2 receptors which are highly expressed by specific T cell subsets, PGD2 can also bind DP1 on lung epithelial cells
Classically LTG4 contributes to asthma development through neutrophil recruitment and activation while PGD2 contributes via oedema formation, mucus production and bronchoconstriction

54
Q

What has been noted in BLT1-deifienct mice with regards to asthma development?

A

This identified an unexpected function of LTB4 in T cell trafficking early in pulmonary allergic inflammation. This compound, probably produced in the airways of immunized animals following mast cell and/or alveolar macrophage activation via aerosolized allergen is the main chemoattractant directing effector T cells to the airways immediately after allergen challenge

55
Q

What has generation of DP1 deficient mice revealed with regards to asthma development?

A

An unexpected role for PDG2 in T cell early trafficking for allergic pulmonary inflammation. PDG2 is produced in the airways following mast cell/alveolar macrophage activation inducing expression of CCL2 which augments Th2 recruitment to the airways

56
Q

How are Th2 cells attracted to the airways in allergic inflammation in asthma/

A

The initial T cell recruitment to the airways in allergic immune responses is directed by LTB4 and PGD2 while subsequent T cell recruitment is required to amplify or maintain allergic pulmonary inflammation and this is directed by cytokines

57
Q

What are the three waves of T cell chemoatrractants in asthma?

A

LTB4 and PGD2 have cooperative roles to provide the first wave with LTB4 directing the earliest phase by interacting with BLT1 on effector T cells, PGD2 may also participate in this through interaction with DP2 found on effector Th2 cells
PGD2 participates in the second wave of attraction through inducing respiratory epithelial cell expression of CCL22 via interaction with DP1 on respiratory epithelium, CCL22 can then recruit Th2 cells via CCR4 binding
Production of IL-4 and IL-13 by recruited Th2 cells initiates the third wave of recruitment by inducing CCR3 agonists such as CCL11, CCL24 (eotaxin 1 and 2) and the CCR4 agonists CCL22, CCL17 and the CCR8 agonist CCL1

58
Q

What are the current therapies for asthma?

A

The conventional therapy involves inhaled corticosteroidswhich may have potential side effects, other options include beta adrenergic receptor agonists or bronchodilators, leukotriene antagonists and antibodies against IgE (like Omalizumab) which can be helpful in some patients

59
Q

What are the cell-adhesion based asthma therapies which have not yet reached the clinic?

A

Antibody blockade of alpha4integrin expression prevents transmigration of eosinophils into the lung and the development of bronchial hyperresponsiveness to agonists in sensitiized and challenged animals
Small molecule aplha4beta1 antagonists may be useful as aerosol for asthma treatment as they can inhibit both early and late phases of asthma and blocke hypersensitivity with the small peptides Ro 27-2441, TR14035 and BIO1211 of alpha4beta1 and alpha4beta7 are currently being tested in clinical trials
Targeting T lymphocyte chemokine receptors in asthma may be a reasonable therapeutic strategy so CCR4 and CCR8 may prove useful therapeutic targets

60
Q

What is atherogenesis?

A

This is the process which typically starts in childhood and begins with the build up of deposits of fatty acids, cholesterol, cellular waste products, calcium and other substances in the inner lining of an artery with mononuclear infiltrate being detectable even in babies
A protective response ensues, which depending on the nature and duration of the insult to the endothelium may become excessive and create a plaque
Arteries affected by this process harden as people age and plaques can grow to the point fo causing sever pathological damage

61
Q

What are the steps in the developemtn of an atherosclerotic plaque?

A

Deposition of lipid leads to formation of a fatty streak with a lipid rich core, if this core becomes inflamed it can grow and proteases secreted by activated leukocytes will degrade the extracellular matrix. The fatty streak will then progress, forming a fibrous plaque- the result of an accumulation of lipid and migration and proliferation of smooth muscle cells which deposit an extracellular connective tissue matrix which forms a fibrous cap which overlies a core of lipid-laden foam cells, extracellular and necrotic cellular debris. Growth of the fibrous plaque results in vascular remodelling, progressive luminal narrowing, blood-flow abnormalities and compromised oxygen supply to the heart. Inflammatory cells contribute to plaque rupture as they localize in the shoulder region of the plaque where IFN-gamma inhibits smooth muscle cell proliferation and collagen synthesis
Activated macrophages produce MMPs which degrade collagen, the cap thins and weakens as a consequence and can rupture leading to thrombus formation and potentially myocardial infarction

62
Q

What are the risk factors for atherosclerosis?

A

Elevated levels of cholesterol and triglyceride in the blood]
High blood pressure
Tobacco smoke
Diabetes
Metabolic syndrome which leads to type 2 diabetes, hypertension, elevated triglyceride and cholesterol levels

63
Q

What is the role of monocytes in atherosclerosis?

A

Activation of the endothelium leads to upregulation of VCAM-1 and monocyte diapedeses, monocytes enter the intima along a chemokine gradient of MCP-1 and differentiate into tissue macrophages which ingest lipid via scavenger receptors and turn into foam cells which secrete proinflammatory cytokines as well as producing MMPs which degrade the extracellular matrix potentially leading to plaque rupture. Some of these macrophages will die within the plaque to produce a necrotic core

64
Q

What is the role of lymphocytes in atherosclerosis?

A

Lymphocytes bind VCAM-1 on the endothelia, transmigrate to the intima, being recruited by IFN-Gamma inducible cytokines like IP-10, Mig and I-TAC which binds the CXCR3 expressed by T cells in the plaque
In the arterial intima the T cells encounter antigens such as oxidised low density lipoprotein and heatshock proteins of endogenous or microbial origin. Binding of CD40L on T cells to CD40 on macrophages induces the expression of tissue factor, MMPs and proinflammatory cytokines by macrophages.
Th1 cells predominate in the atheroma

65
Q

What is the role of mast cells in atherosclerosis?

A

A small number of mast cells infiltrate the lesions, recruited by eotaxin binding to CCR3, In the intima mast cells release TNF-alpha and the serine proteases tryptases and chymase. The latter proteases activate MMPs

66
Q

What is the evidence for the roles of chemokines?

A

Chemokines have been detected in lesions from animal models including IL-8, SDF-1, IP-10, I-309 and the CXCR2 chemokine receptor
MCP-1, RANTES, LD78 and eotaxin have been found in human atherosclerotic lesions
Blocking of CCR2 attenuates disease in the preclinical models, suggesting a role for the MCP-1 and CCR2 ligand-receptor pair

67
Q

What are the current therapies for atherosclerosis?

A

Statins which lower blood cholesterol is the mainstay treatment
Lifestyle changes recommended eg healthy eating, exercise etc
There are also novel anti-inflammatory treatments still to reach the clinic like cleavage signal 1 peptide which blocks alpha4beta1 on the leucocyte surface is effective at reducing leucocyte recruitment and lipid accumulation in the aortic sinus of atherosclerotic mice suggesting a potential therapeutic strategy for atherosclerosis

68
Q

What is the autoimmune concept of atherosclerosis?

A

All healthy humans develop protective immunity against microbial heat shock protein 60 and autoimmunity against autologous hsp60 released from stressed cells
Bacterial and human hsp60 share 50% similarity and stressed endothelial cells express hsp60. Patients with atherosclerosis produce anti-hsp60 antibodies, animals injected with mycobacterial hsp60 develop atherosclerosis
Autoantibodies and T cells against oxLDL are present. Tolerance to hsp60 and LDL appears to have been broken with plaques containing few Tregs in comparison to normal arterial tissue
Tregs control the development of atherosclerosis, mice deficient in CD80 and CD86 which are needed for Treg development show accelerated atherogenesis. Anti-body mediated depeletion of CD25+ cells enhances angiogenesis

69
Q

What is multiple sclerosis?

A

This is a chronic disease of the brain and spinal cord which prevents the brain from controlling functions such as seeing, walking and talking
It is an autoimmune disorder of the central nervous system of an unknown cause in which the body’s immune system attacks the myelin sheath which coats nerve fibres in the brain and spinal cord
The immune system sees a particular component of the sheath as foreign and blood lymphocytes from patients show increased responsiveness to sheath proteins including myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein
This disease manifests itself as repeated episodes of acute inflammation or as a chronic progressive condition which results in multiple scars or scleroses on the myelin sheath leading to the impairment or loss of function of the nerve as well as blindness, paralysis and loss of some cognitive function

70
Q

What is the current hypothesis as to why multiple sclerosis arises?

A

It is believed to be likely caised by a molecular mimicry event wehere exposure to some infectious agent- implicated agensts include Epstein barr viruses, influenza virus, paramyxoviruses (measles) and picornaviruses with the cerebrospinal fluid of MS patients containing antibodies to epstien barr, rubella and measles
Endogenous retrovirus RNA and protein is present in blood and tissue of MS patients but not healthy controls, this HERV retrovirus composes 8% of the human genome, and EBV has been shown to activate it in blood cells and astrocytes
The immune system reacts to components shared by viruses and the nervous system in particular the proteins of the myelin sheath which surround nerve fibres. Autoreactive T cells are activated outside the CNS and then infiltrate into the brain and spinal cord
Alternatively MS is initiated by a viral or toxic insult to oligodendrocytes which myelinate axons leading to tissue damage, release of autoantigen, activation of autoreactive T cells, inflammation and autoimmunity leading to epitope spreading
CD4 T cells outnumber CD8 cells in lesions and those autoreactive cells react against self myelin proteins as well as microbial peptides, this suggests microbial mimicry or CD8 T cells bearing more than one TCR are responsible
This is approximately 30% of peripheral human T cells and it is hypothesized that autoreactive T cells generated following viral infection express more than one TCR which may allow autoreactive cells to escape thymic selection
Theilers murine encephalomyelitis virus generates autoreactive cells in mice with more than one TCR capable of detecting both virus and self and capable of causing paralysis in mice

71
Q

What are the mechanisms of leading to MS/

A

Autoreactive T cells specific for myelin antigens are activated in the peripheral lymphoid organs and circulate in the blood. They enter the perivascular space in the CNS as part of the normal immune surveillance
If these myelin specific T cells come into contact with their target antigens, they will remain in the perivascular space and produce proinflammatory cytokines inducing IL-12, TNF-alpha and IFN-gamma which induces chemokine expression by leukocytes and resident glial cells in the CNS adjacent to the perivascular space, especially astrocytes and microglia
Chemokines recruit further leukocytes into the CNS
Activated T cells generate a Th1 mediated immune response leading to immune-mediated injury to myelin and oligodendrocytes, expression of adhesion molecules including ICAM1, VCAM1 and E-selectin is upregulated on the vascular endothelium
Large scale leukocyte migfration causes loss of integrity of the blood brain barrier, due in part to release by inflammatory cells of matrix metalloproteases which degrade basement membranes
Activated T cells and secondary leukocytes and resident CNS cells further stimulate the production of cytokines, cehomikines and receptors promoting the inflammation as well secreting glutamate in amounts which are toxic to olgodendrogcytes and neurons
IL-12 and 23 are released from microglia and provoke T cells to release IFN-gamma and IL-17 respectively
B cells enter the CNS express antibodies against autoantigens
Macrophages engulf myelin internodes exposing axonal surfaces and releasing injury effector agents such as NO, free radicals and glutamate
Ca entry can provoke a series of deleterious processes resulting in further damage to the axon and eventually transection and neurodegeneration

72
Q

What does immune mediated injury of myelin involve?

A

Cytokine mediated injury of oligodendrocytes and myelin
Digestion of surface myelin antigens by macrophages
Bindng of antibodies against myelin and oligodendrocytes
Complement mediated injury
Direct injury of oligodendrocytes by CD4 and CD8 T cells
Injury of oligodendrocytes by toxic amounts of glutamate released by infiltrating leukocytes and activated parenchymal cells
Oligodendrocytes are required to remyelinate naked axons, hence once damaged or killed denuded axons cannot be remyelinated limited the nervous systems ability to effectively transmit action potentials

73
Q

What is the evidence for the role of cell adhesion molecules in MS?

A

Alpha4 and beta7 integrins play a key role in allowing encephalitogenic leukocytes to gain access to the CNS
MAdCAM-1, VCAM-1 and ICAM-1 are expressed on brain microvessels during disease but disappear during remission
Anti-MAdCAM-1 mAbs block the induction or progression of EAE in rodents
Anti-alpha4 integrin mAb treatment is effective at blocking and binding of lymphocytes to brain tissue in vitro and also effectively prevents the development of EAE, and siginificantly decreases the number of lymphocytes accumulating in the brains of antibody treated mice
Small molecule inhibitors of alpha4beta1 reverse the clinical signs of EAE
Expression of VCAM-1 but neither the CS-1 containing form of fibronectin nor ICAM-1, correlates with the level of leukocyte infiltration into the spinal cord
Alpha4 integrins but not beta7 integrins are involved in the development of the relapsing-remitting EAE
Both alpha4beta1 and alpha4beta7 mediate a chronic progressive form of EAE in mice as blockade with mAbs recognizing the alpha4 ad beta7 subunits can prevent disease progression
Blocking alphaLbeta2 and its ligands does not consistently alleviate EAE
Simultaneous treatment with a MAdCAM1 mAb and neuroprotectors- which protect against glutamate mediated damage- resulted in reversal of the clinicalsigns of EAE in advanced EAE showing that the brain can repair itself if the inflammation is limited

74
Q

What are the new treatments for multiple sclerosis?

A

Humanized anti-alpha4integrin-antibody prevents the development of new lesions in human MS patients. 28 patients have developed progressive multifocal leukoencephalopathy involving activation of the latent JC virus causing the FDA to grant only approved restriction for this drug
Dimethyl fumarate is the latest breakthrough discovery and can be used to treat MS due to its inhibition of inflammation and ability to shift the immune response towards a Th2 response
Sphingosine-1-phosphate receptor modulator has reduced the rate of relapses in relapsing-remittent multiple sclerosis by approximately one half over a two year period by preventing lymphocytes from leaving lymph nodes

75
Q

What are the potential future therapies for inflammatory disease?

A

A challenge for the future is to identify the minimal number of cells and molecules to inhibit in order to prevent inhibiting other immune response pathways such as anti-infection pathways
Exploiting Treg technology to prevent the development of autoimmune disease or to inhibit established disease without becoming too tolerant

MEDSCI 708 (7 decks)

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