Autoimmunity lecture 1

Question 1

Autoimmune disease develops only if enough of the safeguards and checkpoints to an immune response to self are overcome to lead to a ………….. reaction to self that includes the generation of e………. cells and molecules that destroy t……….. Although the mechanisms by which this occurs are not completely known, autoimmunity is thought to result from a combination of ………. susceptibility, breakdown in natural tol………… mechanisms, and environmental tri. su……..ch as infe……., to……… and dr……. Genetic and environmental factors together can overcome tolerance mechanisms and result in autoimmune disease. For example, naive ….. cells with low af………. for a ubiq……… self-antigen can become activated if they encounter an acti……….. de…………. cell presenting that an………. and expressing high levels of co-sti…………….. signals or pr………………………. cytokines as a result of the presence of in………..
The genes identified as predisposing to autoimmunity can be classified as follows:
genes that affect auto…………… availability and cle………….; those that affect apo……….. (Fas …..-cell surface death receptor for …….. ligand); those that affect sig……….. thresholds; those involved in cyto……… gene expression or sign………..; those affecting the ex………… of co-stim……….. mole……….. or their recep………; and those that a……… the development or fu…………. of regu………… …… cells (FoxP3).
Many autoi…………… di………., including SL…., M…, Gr…….. and R…., are more common in females than in males indi…………. a role for eostr……….
Some autoimmune disorders may be triggered by infectious agents that express epi………. resembling self anti……… and that lead to sensi………… of the patient against that tissue. There is, also evidence that many auto………… disorders are caused by internal dysre……….. of the immune system without the apparent pa………….. of infect…….. agents.

Answer 1

Autoimmune disease develops only if enough of the safeguards and checkpoints to an immune response to self are overcome to lead to a sustained reaction to self that includes the generation of effector cells and molecules that destroy tissues. Although the mechanisms by which this occurs are not completely known, autoimmunity is thought to result from a combination of genetic susceptibility, breakdown in natural tolerance mechanisms, and environmental triggers such as infections, toxins and drugs. Genetic and environmental factors together can overcome tolerance mechanisms and result in autoimmune disease. For example, naive T cells with low affinity for a ubiquitous self-antigen can become activated if they encounter an activated dendritic cell presenting that antigen and expressing high levels of co-stimulatory signals or pro-inflammatory cytokines as a result of the presence of infection.
The genes identified as predisposing to autoimmunity can be classified as follows:
genes that affect autoantigen availability and clearance; those that affect apoptosis (Fas T-cell surface death receptor for Fas ligand); those that affect signaling thresholds; those involved in cytokine gene expression or signaling; those affecting the expression of co-stimulatory molecules or their receptors; and those that affect the development or function of regulatory T cells (FoxP3).
Many autoimmune diseases, including SLE, MS, Graves and RA, are more common in females than in males indicating a role for oestrogen.
Some autoimmune disorders may be triggered by infectious agents that express epitopes resembling self antigens and that lead to sensitization of the patient against that tissue. There is, also evidence that many autoimmune disorders are caused by internal dysregulation of the immune system without the apparent participation of infectious agents.

Question 2

Autoimmunde diseases

Systemic

• systemic lu……. erythe………. (SLE)
• Rhe…………. arthritis (RA)

Organ specififc

• Myas……….. gravis
• Gra………. disease
• Goodp………… syndrome
• Type … diabetes
• Multiple scle……… (MS)
• Vitil……….
• Cro………… disease

Although individual autoimmune diseases are u……………., collectively they affect approximately …..% of the populations of Western countries, and their incidence is on the rise. Nevertheless, their relative rarity indicates that the immune system has e………. multiple mechanisms to prevent da……….. to self this……….
The most fundamental principle underlying these disease mechanisms is a failure in the ability of the immune system to re………. and tol……… …….. antigens, and to discri…………. self from ……..self. This discrimination is not easy to achieve and we are going to consider the making and breaking of self toler……….
Autoimmune responses resemble normal immune responses to pathogens in that they are specifically activated by antigens, in this case self antigens or autoanti……….,
and give rise to auto………. effe……….. …..-cells and ……-cells and to an……….., called autoanti…….., against the self ant………
When reactions to self tiss………. do occur and are then impro……….. regul……., they cause a variety of chronic syndromes called autoimmune diseases. These syndromes are quite varied in their severity, in the tissues affected, and in the effector mechanisms that are most important in causing damage.
There are around …… different autoimmune diseases affecting many organs of the body. We will consider a few of them.
SLE and RA are examples of systemic autoimmune diseases.

Type I diabetes, MS, Crohns, myasthenia gravis and vitiligo are examples of organ-specific autoimmune diseases.

Answer 2

Autoimmunde diseases

Systemic

• systemic lupus erythematosus (SLE)
• Rheumatiod arthritis (RA)

Organ specififc

• Myasthenia gravis
• Graves disease
• Goodpastures syndrome
• Type 1 diabetes
• Multiple scleorsis (MS)
• Vitiligo
• Crohns disease

Although individual autoimmune diseases are uncommon, collectively they affect approximately 5% of the populations of Western countries, and their incidence is on the rise. Nevertheless, their relative rarity indicates that the immune system has evolved multiple mechanisms to prevent damage to self tissues.
The most fundamental principle underlying these disease mechanisms is a failure in the ability of the immune system to recognise and tolerate self antigens, and to discriminate self from nonself. This discrimination is not easy to achieve and we are going to consider the making and breaking of self tolerance.
Autoimmune responses resemble normal immune responses to pathogens in that they are specifically activated by antigens, in this case self antigens or autoantigens,
and give rise to autoreactive effector T-cells and B-cells and to antibodies, called autoantibodies, against the self antigen.
When reactions to self tissues do occur and are then improperly regulated, they cause a variety of chronic syndromes called autoimmune diseases. These syndromes are quite varied in their severity, in the tissues affected, and in the effector mechanisms that are most important in causing damage.
There are around 80 different autoimmune diseases affecting many organs of the body. We will consider a few of them.
SLE and RA are examples of systemic autoimmune diseases.

Type I diabetes, MS, Crohns, myasthenia gravis and vitiligo are examples of organ-specific autoimmune diseases.

Question 3

A definition of autoimmunity

The immune responses to self an…….., or anti…….associated with the co………..l micr…….., are called autoimmunity and can lead to autoimmune diseases that are characterized by inflammation and tissue damage,

Commensal bac…… are re……..t, non-path…….., bacteria to which the immune system is normally unresponsive

To generate to……… to self, the immune system must be able to distin……
self-reac……. from nonself-reactive lymp…….. as they develop. The immune system takes adva…….. of markers of self and non-self to identify and delete potentially self-re………. lymph……….
Despite this, some self-rea…….. lymph……. escape elim…….., leave the thymus, and can subs…….. be activated to ca…….. aut………… dise……..
In part, autore………. occurs be……… the recogn……… of self-reactivity is kind……… and other……… imp……. In addition, many lymp……. with some deg……. of self-reactivity can also make an immune response to fo…….. antigens; therefore, if all we………. self-reactive lym……….. were eliminated, the function of the immune system would be I’m………..

Answer 3

A definition of autoimmunity

The immune responses to self antigens, or antigens associated with the commensal microbiota, are called autoimmunity and can lead to autoimmune diseases that are characterized by inflammation and tissue damage,

Commensal bacteria are resident, non-pathogenic, bacteria to which the immune system is normally unresponsive

To generate tolerance to self, the immune system must be able to distinguish
self-reactive from nonself-reactive lymphocytes as they develop. The immune system takes advantage of markers of self and non-self to identify and delete potentially self-reactive lymphocytes.
Despite this, some self-reactive lymphocytes escape elimination, leave the thymus, and can subsequently be activated to cause autoimmune disease.
In part, autoreactivity occurs because the recognition of self-reactivity is indirect and therefore imperfect. In addition, many lymphocytes with some degree of self-reactivity can also make an immune response to foreign antigens; therefore, if all weakly self-reactive lymphocytes were eliminated, the function of the immune system would be impaired.

Question 4

A definition of self tolerance

Self tolerance is the lack of an immune response, particularly by …… and ……. lym……….., to antigens that are normal constit……. of the organism

Self to……… is a normal process whereby a………… disease are av…………

The immune response most distinguishes self from non-self and any aut…………. ly.,……….. ….- cells and … cells, must be elim……. before they can be activated to cause autoi………. disease

Answer 4

A definition of self tolerance

Self tolerance is the lack of an immune response, particularly by T and B lymphocytes, to antigens that are normal constituents of the organism

Self tolerance is a normal process whereby autoimmune disease are avoided

The immune response most distinguishes self from non-self and any autoreactive lymphocytes, T- cells and B0cells, must be eliminated before they can be activated to cause autoimmune disease

Question 5

The making or normal self-tolerance

Three key mechanisms;
1. …..mature ….-cells, or …..-cells, recognise self-………. that bind to newly formed sp…….. antigen receptors when the lym…….. is in the the………, or ……. m…….., are acti…….. and d….. (ce……. tole…….)

2. A high and con…….. conce………. of self-ligand

3, Binding the ligand in the absence of pro infl………….. or cos………….. molecules results in T-cell activation (anergy) or development of reg………… T-cells (tregs) that suppress the immune response (per…………… tolerance)

Three mechanisms are proposed for distinguishing between self and nonself ;
1. Rec…………. of antigen by an immature lymp…………. leads to a neg………. signal that causes lymphocyte death or inact……….. Thus, ‘self’ was thought to comprise those molecules recognized by a lymphocyte sh…….. after it has begun to ex……… its antigen …………. This is an important mechanism of inducing self-tol………..in lymph…….. developing in the thy……… and bone ma……… The tolerance induced at this stage is known as central tolerance. Newly formed lymphocytes are especially sensitive to inac………… by strong signals through their an……. receptors, whereas the same signals would activate a ma……… lym………….
2. Sustained high concentration of the antigen cor………. with self. Many self pr……….. are expressed by multiple cell types in the body or are abundant in c…………. tissues. These can provide strong signals to lymphocytes, and even mature lym………… can be made to………. to an antigen, or tolerized, by strong and co……….. signals through their antigen receptors. In contrast, path………. and other foreign antigens are intro………. to the immune system suddenly, and the concern……… of their anti……… increase rapidly and exp………. as the path…….. replicate in the early stages of an infection. Naive mature l…………. are tuned to respond by activation to a sudden increase in antigen-receptor sig………
3. Disc………….. between self and nonself relies on the innate immune system, which provides signals that are cr……….. in ena……….. the active……… of an ad……… immune response to infection.
In the absence of infection, these signals, which include pro-inflammatory cytokines (for example IL-.. or IL-…..) and co-stim……….. molecules (for example B7.l) that are expressed by activated antigen-presenting cells, are not generated. In these circumstances, the encounter of a naive lymphocyte with a self an……… tends to lead to a negative ina……….. signal, rather than no signal at all, or can promote the development of reg……….. lymp……… that suppress the development of effector responses that might injure tissues. This tolera……. mechanism is particularly important for antigens that are encountered outside the the………. and bo…….. marrow. Tolerance induced in the mature lym……….. repe……….. once cells have left the central lymphoid org…….. is known as peri………. tolerance.

Answer 5

The making or normal self-tolerance

Three key mechanisms;
1. Immature t-cells, or B-cells, recognise self0ligands that bind to newly formed specific antigen receptors when the lymphocyte is in the thymus, or bone marrow, are activated and die (central tolerance)

2. A high and constant concentration of self-ligand

3, Binding the ligand in the absence of pro inflammatory or costimulatory molecules results in T-cell activation (energy) or development of regulatory T-cells (tregs) that suppress the immune response (peripheral tolerance)

Three mechanisms are proposed for distinguishing between self and nonself ;
1. Recognition of antigen by an immature lymphocyte leads to a negative signal that causes lymphocyte death or inactivation. Thus, ‘self’ was thought to comprise those molecules recognized by a lymphocyte shortly after it has begun to express its antigen receptor. This is an important mechanism of inducing self-tolerance in lymphocytes developing in the thymus and bone marrow. The tolerance induced at this stage is known as central tolerance. Newly formed lymphocytes are especially sensitive to inactivation by strong signals through their antigen receptors, whereas the same signals would activate a mature lymphocyte.
2. Sustained high concentration of the antigen correlates with self. Many self proteins are expressed by multiple cell types in the body or are abundant in connective tissues. These can provide strong signals to lymphocytes, and even mature lymphocytes can be made tolerant to an antigen, or tolerized, by strong and constant signals through their antigen receptors. In contrast, pathogens and other foreign antigens are introduced to the immune system suddenly, and the concentrations of their antigens increase rapidly and exponentially as the pathogens replicate in the early stages of an infection. Naive mature lymphocytes are tuned to respond by activation to a sudden increase in antigen-receptor signals.
3. Discriminating between self and nonself relies on the innate immune system, which provides signals that are crucial in enabling the activation of an adaptive immune response to infection.
In the absence of infection, these signals, which include pro-inflammatory cytokines (for example IL-6 or IL-12) and co-stimulatory molecules (for example B7.l) that are expressed by activated antigen-presenting cells, are not generated. In these circumstances, the encounter of a naive lymphocyte with a self antigen tends to lead to a negative inactivating signal, rather than no signal at all, or can promote the development of regulatory lymphocytes that suppress the development of effector responses that might injure tissues. This tolerance mechanism is particularly important for antigens that are encountered outside the thymus and bone marrow. Tolerance induced in the mature lymphocyte repertoire once cells have left the central lymphoid organs is known as peripheral tolerance.

Question 6

Central tolerance
Development and se……….. of T cells in the the…………

Central deletion or in…………. of newly formed lymphocytes is the first checkpoint of self-tolerance Normally; In the thy………, pre……….. thymo……. from the bone marrow initially develop as ‘double-positive’ cells expressing both CD.. and CD…., and low levels of the αβ TC…. These undergo po……. selection for weak, low aff…….., inte……… with self MHC class … or class …… molecules on c……… epith……, ie the cells are selected for their usefulness. Unselected cells (the majority) undergo progr……… cell death by apopt…….
Cells undergoing positive selection lose one or the other of their co-rece…….. molecules (CD… or CD…). Cells that interact with MHC class .. on the thy….. epithelium become CD…. cells, and those that interact with MHC class ….. on the thymic epit……… become CD…….. cells.
Finally, self-reactive cells that react strongly and with high affi…… to s…….. antigens presented on cells (den……… cells and macrophages) in the thy……. are eliminated by ap……… (neg……… selection). Newly formed lympho……… are especially sensitive to intact………. by strong signals through their antigen receptors.
The mature T-cell pool contains T-ce…… able to react to fo……….. prot…….. and also the….. that are able to react we…….. to self anti…… or react strongly to self anti…….. that they have not seen, for exam…… antigens in peri………. tissues, including the joints. The tole…. induced at this stage is known as central toler………
Defective pos……… and ne………. selection in the thymus are reported in models of autoimmunity. Defects in negative selection would bias the TC……. repertoire towards autoreactivity. Defects in positive selection may cause lym………. (a ………… in the number of circulating ….-cells), which has been shown to be a risk factor for autoim……..
Lymp………. due to a decreased output from the thym…..is followed by a cycle of peripheral homeostatic proliferation, or self-replication, of naïve T-cells to restore T-cell numbers. This process of expansion in the per………… favours T-cells with autoreactive potential, ie those that recognise and have a higher affinity to self a……. and have lower threshold for activation.

Answer 6

Central tolerance
Development and selection of T cells in the thymus

Central deletion or inactivation of newly formed lymphocytes is the first checkpoint of self-tolerance Normally; In the thymus, precursor thymocytes from the bone marrow initially develop as 'double-positive' cells expressing both CD4 and CD8, and low levels of the αβ TCR. These undergo positive selection for weak, low affinity, interaction with self MHC class I or class II molecules on cortical epithelium, ie the cells are selected for their usefulness. Unselected cells (the majority) undergo programmed cell death by apoptosis. 
Cells undergoing positive selection lose one or the other of their co-receptor molecules (CD4 or CD8). Cells that interact with MHC class I on the thymic epithelium become CD8+ cells, and those that interact with MHC class II on the thymic epithelium become CD4+ cells. 
Finally, self-reactive cells that react strongly and with high affinity to self antigens presented on cells (dendritic cells and macrophages) in the thymus are eliminated by apoptosis (negative selection). Newly formed lymphocytes are especially sensitive to inactivation by strong signals through their antigen receptors.
The mature T-cell pool contains T-cells able to react to foreign proteins and also those that are able to react weakly to self antigens or react strongly to self antigens that they have not seen, for example antigens in peripheral tissues, including the joints. The tolerance induced at this stage is known as central tolerance.
Defective positive and negative selection in the thymus are reported in models of autoimmunity. Defects in negative selection would bias the TCR repertoire towards autoreactivity.  Defects in positive selection may cause lymphopenia (a decrease in the number of circulating T-cells), which has been shown to be a risk factor for autoimmunity. 
Lymphopenia due to a decreased output from the thymus is followed by a cycle of peripheral homeostatic proliferation, or self-replication, of naïve T-cells to restore T-cell numbers. This process of expansion in the periphery favours T-cells with autoreactive potential, ie those that recognise and have a higher affinity to self antigens and have lower threshold for activation.

Question 7

Self-tolerance generated in the central lym……… organs is effective. Many (but not all) tissue-specific antigens, such as in……. for example, are actually expressed in the thy……. by a subset of den…….-like cells, and thus self-tolerance against these antigens can be generated centrally. These ‘peripheral’ g…….. are turned on ec………. in the thymus by a single train……….. factor, AIRE (for aut………… regu…….) in the thy…….
The ‘autoimmune regulator’ gene AIRE promotes the expression of some tissue-specific antigens in thymic med……… cells, causing the del……. of immature thym………s that can react to these antigens. Although the thymus expresses many genes, and thus self proteins, common to all cells, it is not obvious how antigens that are specific to specialized tissues, such as ret…… or ……. (fir…… panel), gain access to the thy…….. to promote the neg……….. selection of immature auto reactive thy……… It is now known that a gene called AIRE promotes the expression of many tissue-specific proteins in the……… medu……cells. Some developing thymo……. will be able to recognize these ti……….-specific antigens (s………. panel). Peptides from these proteins are presented to the developing thy………. as they un…….. ne……… selection in the thymus (the…….. panel), causing de……. of these cells.
In the absence of AIRE, this deletion does not occur; instead, the autoreactive thy…….. mature and are exp…… to the peri……. (fourth panel), where they could cause autoimmune disease. Indeed, people that lac.. ex………… of AIRE develop an autoimmune syndrome called APECED, or autoimmune polyendocrinopathy-candidi…………… dystrophy, leading to the destruction of multiple end….. tissues incl……. the insulin-producing cells of the pancreas.

Answer 7

Self-tolerance generated in the central lymphoid organs is effective. Many (but not all) tissue-specific antigens, such as insulin for example, are actually expressed in the thymus by a subset of dendritic-like cells, and thus self-tolerance against these antigens can be generated centrally. These ‘peripheral’ genes are turned on ectopically in the thymus by a single transcription factor, AIRE (for autoimmune regulator) in the thymus.
The ‘autoimmune regulator’ gene AIRE promotes the expression of some tissue-specific antigens in thymic medullary cells, causing the deletion of immature thymocytes that can react to these antigens. Although the thymus expresses many genes, and thus self proteins, common to all cells, it is not obvious how antigens that are specific to specialized tissues, such as retina or ovary (first panel), gain access to the thymus to promote the negative selection of immature auto reactive thymocytes. It is now known that a gene called AIRE promotes the expression of many tissue-specific proteins in thymic medullary cells. Some developing thymocytes will be able to recognize these tissue-specific antigens (second panel). Peptides from these proteins are presented to the developing thymocytes as they undergo negative selection in the thymus (third panel), causing deletion of these cells.
In the absence of AIRE, this deletion does not occur; instead, the autoreactive thymocytes mature and are exported to the periphery (fourth panel), where they could cause autoimmune disease. Indeed, people that lack expression of AIRE develop an autoimmune syndrome called APECED, or autoimmune polyendocrinopathy-candidiasisectodermal dystrophy, leading to the destruction of multiple endocrine tissues including the insulin-producing cells of the pancreas.

Question 8

Peripheral tolerance

• Antigen segragation at immunologicaslly priveled sites (brain, eye, testis, thyroid gland) do not undice immune responses
• On exposure to self antigens, peripheral anery (unresponsiveness) or act……….-induced T-cell death occurs, in the ab………. of inf………..
• sustained high concentration of self a……….. induce T=cell tolerance

induction of reg……….. Treg … cells (functional deviation) and suppression of immune responses by Treg cyto…….

Lym…….. that encounter sufficient quantities of self anti…….. for the first time in the per……. are eliminated or ina………. Large numbers of aut……..lymphocytes have been up…….. from the population of new lymphocytes in the central lym……… organs; however, this only involves lymphocytes specific for autoa……… that are expressed in or can reach these organs. Not all potential self antigens are expressed in the central lymphoid organs. Some, like the thyroid product thyro………., are highly tissue specific, or are compare……….. so that little if any is available in the circulation. Therefore, newly emi…….. self-reactive lymp……… that encounter their specific autoantigen for the first time in the periphery must be elim……… or inactivated. This tolerance ……… is known as peripheral tolerance. Like self-reactive lymphocytes in the central lymphoid organs, lymphocytes that encounter self ant……. de novo in the periphery can have several fates: deletion, anergy, or survival.
In some cases, T cells reacting to self antigens in the periphery are eliminated. This usually follows a brief period of acti……… and cell d……….., and so is known as activation-induced cell death. In other cases, the self-reactive cells may be rendered anergic (unresponsive).
Sus…….. high concentration of the antigen co……… with self. Many self proteins are expressed by multiple cell types in the body or are abu…….. in connective tissues. These can provide strong signals to lymphocytes, and even mature lymp…….. can be made to………. to an antigen, or tolerized, by strong and constant signals through their antigen receptors. In contrast, pathogens and other foreign antigens are introduced to the immune system suddenly, and the conc……….. of their antigens increase ra……. and exp………… as the pathogens replicate in the early stages of an infection. Naive mature lymphocytes are tuned to respond by activation to a sudden increase in antigen-receptor signals.
The encounter of a mature naive ly………. with a self antigen leads to cell death or anergy, but a mature lymp…….. that reco……. a pathogen-derived antigen is activated. The answer is that infection sets up inflammation, which find……. the exp……. of co-stimulatory mol……… on the antigen-pres……….dendritic cells and the production of cytokines promoting lym………. activation. The outcome of an encounter with antigen in these conditions is the activation, prolif………, and differ……… of the lym…….. to effector-cell status. In the a………. of infection or inflam……., de…….. cells still process and present self anti……., but in the ab………. of co-stim…… and other signals, any interaction of a mature lymp……… with its specific antigen seems to result in a tole…….-inducing (tolerogenic) signal from the antigen receptor.

Answer 8

Peripheral tolerance

• Antigen segragation at immunologicaslly priveled sites (brain, eye, testis, thyroid gland) do not induce immune responses
• On exposure to self antigens, peripheral anery (unresponsiveness) or activation-induced T-cell death occurs, in the absence of infection
• sustained high concentration of self antigen induce T=cell tolerance

induction of regulatory Treg t cells (functional deviation) and suppression of immune responses by Treg cytokines

Lymphocytes that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated. Large numbers of autoreactive lymphocytes have been purged from the population of new lymphocytes in the central lymphoid organs; however, this only involves lymphocytes specific for autoantigens that are expressed in or can reach these organs. Not all potential self antigens are expressed in the central lymphoid organs. Some, like the thyroid product thyroglobulin, are highly tissue specific, or are compartmentalized so that little if any is available in the circulation. Therefore, newly emigrated self-reactive lymphocytes that encounter their specific autoantigen for the first time in the periphery must be eliminated or inactivated. This tolerance mechanism is known as peripheral tolerance. Like self-reactive lymphocytes in the central lymphoid organs, lymphocytes that encounter self antigens de novo in the periphery can have several fates: deletion, anergy, or survival.
In some cases, T cells reacting to self antigens in the periphery are eliminated. This usually follows a brief period of activation and cell division, and so is known as activation-induced cell death. In other cases, the self-reactive cells may be rendered anergic (unresponsive).
Sustained high concentration of the antigen correlates with self. Many self proteins are expressed by multiple cell types in the body or are abundant in connective tissues. These can provide strong signals to lymphocytes, and even mature lymphocytes can be made tolerant to an antigen, or tolerized, by strong and constant signals through their antigen receptors. In contrast, pathogens and other foreign antigens are introduced to the immune system suddenly, and the concentrations of their antigens increase rapidly and exponentially as the pathogens replicate in the early stages of an infection. Naive mature lymphocytes are tuned to respond by activation to a sudden increase in antigen-receptor signals.
The encounter of a mature naive lymphocyte with a self antigen leads to cell death or anergy, but a mature lymphocyte that recognizes a pathogen-derived antigen is activated. The answer is that infection sets up inflammation, which induces the expression of co-stimulatory molecules on the antigen-presenting dendritic cells and the production of cytokines promoting lymphocyte activation. The outcome of an encounter with antigen in these conditions is the activation, proliferation, and differentiation of the lymphocyte to effector-cell status. In the absence of infection or inflammation, dendritic cells still process and present self antigens, but in the absence of co-stimulatory and other signals, any interaction of a mature lymphocyte with its specific antigen seems to result in a tolerance-inducing (tolerogenic) signal from the antigen receptor.

Question 9

Tolerance mediated by regulatory T cells.

Specialized autoreactive natural reg……… T (Treg) cells develop in the thymus in response to w…… stimulation by self-an……… that are not suf……… to cause del……….. (upper left panel)
Regulatory T cells can also be induced from naive see……. reactive T cell reco………. its an……… and is activated in the presence of the cytokine TGF-…. (upper right panel)

Regulatory T cells, both nat……… or find……. can in……. other self reactive T cells. If regulatory T cells encounter their self ant…… on an antigen press……… cell, they sec…….. inhib…… cytokines such as IL-…. and TGF-…., that in…….. all surround….. autore…….. T cells, rega…….. of their prec…….. autoantigen specif…..

Auto reactive cells that have escaped the tolerance-inducing mecha……… described previously can still be regulated so that they do not cause clinical disease. This reg……….. takes two forms: the first is ex…………, coming from specific regulatory T cells that exert effects on activated ……. cells and on antigen-pre………… cells.
The second is I…….. and has to do with limits on the size and duration of immune responses that are programmed into the lym………. themselves.
T………… due to regulatory lymphocytes is distinguished from other forms of self-tolerance by the fact that a regulatoryT (Treg ) cell has the potential to suppress self-reactive lymph……… that recognize antigens different from those re…….. by the Treg cell (see Fig). This type of tol……….. is therefore known as regulatory tolerance. The key feature of regu…… tolerance is that regulatory cells can suppress auto reactive lymphocytes that reco……. a variety of different self antigens, as long as the antigens are from the same tissue or are presented by the same antigen-pres………. cell.
In addition to the extrin…….. regulation of autoreactive T and B cells by regul……… cells, lymph……… have intrinsic limits to prolif…….. and survival that can help to restrict autoi…….. responses as well as normal immune responses.
This is illustrated by the effects of mutations in the pathways that control apo………., that lead to spontaneous autoim…….. This form of autoimmunity provides evidence that auto……….. cells are normally gen………. but are then controlled by ap……….. This seems to be an imp………t mechanism for both ……- and …..-cell tol………….

Answer 9

Tolerance mediated by regulatory T cells.

Specialized autoreactive natural regulatory T (Treg) cells develop in the thymus in response to wak stimulation by self antigens that is not sufficient to cause deletion (upper left panel)
Regulatory T cells can also be induced from naive self reactive T cell recognizes its antigen and is activated in the presence of the cytokine TGF-B (upper right panel)

Regulatory T cells, both natural or induced can inhibit other self reactive T cells. If regulatory T cells encounter their self antigen on an antigen presenting cell, they secrete inhibitory cytokines such as IL-10 and TGF-B, that inhinity all surrounding autoreactive T cells, regardless of their precise autoantigen specificity

Auto reactive cells that have escaped the tolerance-inducing mechanisms described previously can still be regulated so that they do not cause clinical disease. This regulation takes two forms: the first is extrinsic, coming from specific regulatory T cells that exert effects on activated T cells and on antigen-presenting cells.
The second is intrinsic and has to do with limits on the size and duration of immune responses that are programmed into the lymphocytes themselves.
Tolerance due to regulatory lymphocytes is distinguished from other forms of self-tolerance by the fact that a regulatoryT (Treg ) cell has the potential to suppress self-reactive lymphocytes that recognize antigens different from those recognized by the Treg cell (see Fig). This type of tolerance is therefore known as regulatory tolerance. The key feature of regulatory tolerance is that regulatory cells can suppress auto reactive lymphocytes that recognize a variety of different self antigens, as long as the antigens are from the same tissue or are presented by the same antigen-presenting cell.
In addition to the extrinsic regulation of autoreactive T and B cells by regulatory cells, lymphocytes have intrinsic limits to proliferation and survival that can help to restrict autoimmune responses as well as normal immune responses.
This is illustrated by the effects of mutations in the pathways that control apoptosis, that lead to spontaneous autoimmunity. This form of autoimmunity provides evidence that autoreactive cells are normally generated but are then controlled by apoptosis. This seems to be an important mechanism for both T- and B-cell tolerance

Question 10

….- cell induction of self tolerance

Negative selection of autoreactive I’m………. B cells in the bone marrow. Clonal d…….. of immature B- cells binding to self- ………… (c………. tolerance)

In the absence of infection …….-cells that encounter strongly cross-li……….. an……. in the periphery undergo ap……… and dele……… #

Both ma…….. and I’m…….. B-cells are ina……..(anergic) when they are chr……… exp….. to soluble self anti…..

At the I……….. B cell stage, the antigen receptor is first tested for reactivity to self ant……., or autoreactivity, in the bone ma……. The elimination or inac………. of autoreactive B cells ensures that the B-cell population as a whole will be too……..of self antigens. The t………. produced at this stage of…-cell development is known as c……. tolerance because it arises in a central lymphoid organ, the bone marrow.
Self-reactive B cells that esc…… this test and go on to mature may still be rem…….. from the repertoire after they have left the bone marrow, a process that pro…………peripheral tolerance.

Answer 10

B- cell induction of self tolerance

Negative selection of autoreactive immature B cells in the bone marrow. Clonal deletion of immature B- cells binding to self- antigen (central tolerance)

In the absence of infection B-cells that encounter strongly cross-linking antigen in the periphery undergo apoptosis and deletion #

Both mature and immature B-cells are inactivated (anergic) when they are chronically exposed to sluble self antigen

At the immature B cell stage, the antigen receptor is first tested for reactivity to self antigens, or autoreactivity, in the bone marrow. The elimination or inactivation of autoreactive B cells ensures that the B-cell population as a whole will be tolerant of self antigens. The tolerance produced at this stage of B-cell development is known as central tolerance because it arises in a central lymphoid organ, the bone marrow.
Self-reactive B cells that escape this test and go on to mature may still be removed from the repertoire after they have left the bone marrow, a process that produces peripheral tolerance.