Topic 3 Flashcards

Question

What are Th2 type autoimmune diseases?

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

``` 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+ ```

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

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

Answer 41

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

Answer 42

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

Answer 43

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

Answer 44

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

Answer 45

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

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

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

Answer 51

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

Topic 3 Flashcards

(75 cards)