Peripheral Tolerance

Slide 1 · Peripheral Tolerance

Mechanisms of self-tolerance and the pathogenesis of autoimmunity

Mechanism-focused pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain why mature self-reactive lymphocytes need peripheral safeguards.

Distinguish anergy, regulatory suppression, apoptotic deletion and sequestration.

Relate CTLA-4, PD-1, FOXP3, IL-2, Bim and Fas to tolerance.

Connect tolerance defects to illustrative autoimmune syndromes.

Slide 3 · Self-tolerance protects normal tissues

Recognition of self antigen

Tolerance mechanisms restrain the clone

Prevention of self-directed tissue injury

Immunologic tolerance is antigen-induced unresponsiveness; Self-tolerance prevents immune attack on the host.

Slide 4 · Central and peripheral tolerance differ

Central tolerance

During lymphocyte maturation

T cells: Thymus; B cells: Marrow

Deletion or receptor editing; Some Tregs arise

Peripheral tolerance

After mature cells enter tissues

Acts on self-reactive cells that escaped

Silencing, suppression, deletion or ignorance

Slide 5 · Central tolerance is necessarily incomplete

Not all self antigens are displayed centrally

Self-reactive clones may enter the mature pool

Peripheral checks prevent harmful activation

Incomplete central antigen display leaves the need for peripheral tolerance.

Slide 6 · Peripheral tolerance operates on mature cells

T lymphocytes

Best-characterized mechanisms

B lymphocytes

Can become anergic without helper T cells

Peripheral tissues

Self antigen is encountered outside primary lymphoid organs

Peripheral tolerance silences autoreactive T and B cells; Detailed mechanisms are best defined in T cells.

Slide 7 · Four major peripheral safeguards

Anergy

Functionally inactive clone

Regulatory T cells

Active suppression of other immune cells

Deletion / sequestration

Cell death or antigen kept from immune recognition

The source outlines anergy, Treg suppression, apoptosis and antigen sequestration.

Slide 8 · Antigen recognition alone is not enough

T-cell receptor engages peptide–self MHC

APC provides or lacks costimulation

Activation or functional unresponsiveness

T-cell activation normally requires antigen recognition and APC-derived costimulation.

Slide 9 · Signal 1 is antigen specificity

TCR recognizes peptide bound to self MHC on an APC

This is necessary for antigen-specific responses.

It does not, by itself, guarantee full activation.

The fate depends in part on accessory signals.

Slide 10 · Signal 2 is costimulation

B7-1 / B7-2 on an APC

Engage CD28 on the T cell

Support productive T-cell activation

CD28 engages APC B7-1 and B7-2 costimulators.

Slide 11 · Self antigen without signal 2 causes anergy

Autoreactive TCR binds self peptide–MHC

APC supplies inadequate costimulation

T cell becomes functionally unresponsive

Insufficient costimulation during self-antigen recognition can induce anergy.

Slide 12 · Resting dendritic cells favor nonactivation

Resting DCs

B7 expression absent or weak

Normal tissues

Autoreactive cells may encounter self antigen

Consequence

Anergy instead of productive activation

The source links weak costimulation on resting dendritic cells to tolerance.

Slide 13 · Activation and anergy are different fates

Productive T-cell response

Antigen presented with adequate B7

CD28 costimulatory engagement

T-cell activation

Anergy

Self antigen presented with weak B7

Insufficient second signal

No effective T-cell activation

Slide 14 · Anergy is not the same as deletion

Anergy

Clone remains functionally unresponsive

Core event: Impaired response to stimulation

Deletion

Self-reactive clone is eliminated

Core event: Apoptosis

Slide 15 · Inhibitory receptors reinforce tolerance

Self antigen may be recognized

CTLA-4 and PD-1 limit activation

Autoreactive response is restrained

CTLA-4 and PD-1 are inhibitory checkpoints discussed in the source.

Slide 16 · CTLA-4 targets the costimulatory axis

CD28

Binds B7 and supports costimulation

CTLA-4

Also binds B7 molecules

Net effect

Reduced access to the second signal

CTLA-4 binds the same B7 ligands as CD28 and promotes tolerance.

Slide 17 · CTLA-4 removes B7 from antigen-presenting cells

Regulatory T cell expresses CTLA-4

CTLA-4 removes B7 costimulators from APC

Nearby T cells receive less costimulation

The source describes CTLA-4-mediated removal of B7 by regulatory T cells.

Slide 18 · CTLA-4 is prominent on regulatory T cells

Regulatory T cells are a major cellular setting for CTLA-4 activity

Treg CTLA-4 helps prevent costimulation.

Reduced B7 availability can promote anergy.

This links active suppression to passive unresponsiveness.

Slide 19 · CD28 versus CTLA-4: Opposed effects

Feature

CD28

CTLA-4

B7 binding

Yes

Yes

Principal effect

Costimulation

Limitation of costimulation

Tolerance relevance

Activation if signal 2 available

Promotes anergy / Treg suppression

Source emphasis

T-cell activation

Expressed mostly on Tregs

Both bind B7, but are contrasted by their functional effects.

Slide 20 · PD-1 is a second inhibitory receptor

PD-1 expressed on T cell

Engagement by PD-L1 or PD-L2

Inhibition of T-cell activation

PD-1 blocks T-cell activation when engaged by its ligands.

Slide 21 · PD-1 ligands are broadly distributed

PD-1

Coinhibitory receptor

PD-L1

One PD-1 ligand

PD-L2

Another PD-1 ligand; Ligands occur on many cells

PD-L1 and PD-L2 are broadly expressed according to the source.

Slide 22 · CTLA-4 and PD-1 have distinct described actions

CTLA-4

Interacts with B7 on APCs

Treg-associated removal of costimulators

Reduces opportunity for signal 2

PD-1

Engages PD-L1 / PD-L2

Delivers an inhibitory signal

Blocks T-cell activation

Slide 23 · Checkpoint loss produces systemic inflammation

CTLA-4 or PD-1 checkpoint disrupted

Immune restraint diminishes

Systemic inflammatory disease can develop

Knockout mouse and inherited human data support the importance of inhibitory checkpoints.

Slide 24 · Human CTLA4 variants establish clinical relevance

Inherited CTLA4 mutations can cause systemic inflammatory disease

This is human genetic evidence for checkpoint function.

It supports a causal link between faulty inhibition and immune disease.

It does not establish a mechanism for every common autoimmune illness.

Slide 25 · Tumors and viruses can exploit immune brakes

Immune-inhibitory pathways restrain T cells

Some tumors and viruses exploit these pathways

Antitumor or antiviral attack is reduced

The source states that tumors and viruses may use tolerance pathways to evade immune attack.

Slide 26 · Checkpoint blockade releases inhibitory brakes

Antibody targets CTLA-4, PD-1 or PD-L1

Inhibitory signaling is blocked

T-cell response against tumor is enhanced

The source identifies antibody blockade of CTLA-4, PD-1 and PD-L1 as tumor immunotherapy.

Slide 27 · The same checkpoint has opposite contexts

Normal self-tolerance

Checkpoint intact

Autoreactive activity restrained

Protection from inflammation

Cancer immunotherapy

Checkpoint blocked by antibody

Antitumor immunity promoted

Therapeutic release of restraint

Slide 28 · Mature B cells also become anergic

Mature B cell encounters peripheral self antigen

Adequate specific helper T-cell support is absent

Subsequent B-cell response is impaired

Peripheral self antigen can produce B-cell unresponsiveness, especially without helper T cells.

Slide 29 · Absence of T-cell help matters to B cells

Self-antigen recognition

B cell engages a self determinant

Helper-cell context

Specific helper T cells not available

Outcome

An anergic B-cell state may develop

The source highlights missing specific helper T cells in B-cell anergy.

Slide 30 · Anergic B cells may be excluded from follicles

Self-reactive B cell becomes anergic

Cell may be excluded from lymphoid follicle

Its survival declines; Death may follow

The source links anergy to follicular exclusion and eventual B-cell death.

Slide 31 · T- and B-cell anergy share a result

T-cell anergy

Recognition with deficient costimulation

CD28–B7 context central to explanation

Functional T-cell unresponsiveness

B-cell anergy

Self antigen without helper T-cell support

Possible exclusion from follicles

Unresponsiveness and possible death

Slide 32 · Tregs actively suppress immune reactions

Regulatory T cell recognizes a tolerogenic context

CTLA-4 and suppressive cytokines act

Response to self antigen is restrained

Tregs are a central peripheral suppression mechanism.

Slide 33 · Regulatory T cells have two origins

Thymic development

Many arise during recognition of self antigens

Connects central selection with peripheral tolerance

Peripheral induction

Tregs may also develop in peripheral lymphoid tissues

Expands suppression outside the thymus

Slide 34 · Best-defined Tregs are CD4⁺CD25highFOXP3⁺

CD4

T-helper lineage phenotype

CD25

High IL-2 receptor α-chain expression

FOXP3

Forkhead-family transcription factor

The source defines the canonical Treg phenotype.

Slide 35 · CD25 identifies the IL-2 receptor α chain

CD25 on regulatory T cells

IL-2 receptor signaling supports Tregs

Development and maintenance of functional Tregs

IL-2 and its receptor are required for functioning Treg populations.

Slide 36 · IL-2 sustains regulatory T cells

IL-2 is essential for maintenance of regulatory T cells

Reduced IL-2 signaling can compromise immune regulation.

The relevant receptor includes α- and β-chain components.

This explains multiorgan autoimmunity in pathway defects.

Slide 37 · FOXP3 is required for functional Tregs

FOXP3 transcription factor is functional

Regulatory T-cell development and function maintained

Immune reactions against self are restrained

FOXP3 is necessary for regulatory T-cell development and maintenance.

Slide 38 · Tregs use CTLA-4 to limit costimulation

Treg with CTLA-4

B7 removed from APC

Costimulation of other T cells is reduced

Regulatory T cells use CTLA-4 to inhibit T-cell costimulation.

Slide 39 · Suppressive cytokines provide another pathway

IL-10

Immunosuppressive cytokine

TGF-β

Immunosuppressive cytokine

Consequences

Lymphocyte activation and effector functions inhibited

The source describes IL-10 and TGF-β as possible mediators of Treg inhibition.

Slide 40 · Treg suppression is multifactorial

Regulatory element

Described contribution

CTLA-4

Depletes APC B7 costimulators

IL-10

Inhibits immune activation / effectors

TGF-β

Inhibits immune activation / effectors

FOXP3 / IL-2

Required for regulatory-cell integrity

The suppressive phenotype is supported by distinct mechanisms.

Slide 41 · FOXP3 loss causes IPEX

Inherited FOXP3 mutation

Severe Treg dysfunction

IPEX: Systemic autoimmune disease

FOXP3 mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Slide 42 · IPEX is a mechanism-linked syndrome

Immune dysregulation

Failure of immunologic restraint

Polyendocrinopathy / enteropathy

Multi-organ autoimmune involvement

X-linked

Included in the established IPEX name

IPEX nomenclature and FOXP3 mechanism are explicitly given in the source.

Slide 43 · IL-2 signaling defects can cause autoimmunity

Mutation in IL2 or IL-2 receptor α / β

Regulatory T-cell maintenance compromised

Rare multiorgan autoimmune disease

The source identifies mutations in IL-2 or IL-2 receptor α/β as causes of autoimmune disease.

Slide 44 · CD25 promoter associations are not causation

Observed association

CD25 promoter polymorphisms

Type 1 diabetes; Multiple sclerosis; Other autoimmune diseases

Interpretive limit

Possible contribution of a Treg defect

Association does not prove the pathway in every patient

Slide 45 · Tregs protect tolerance beyond self antigens

Self antigens

Limit harmful autoreactivity

Fetal paternal antigens

May help sustain maternal–fetal tolerance

Commensal microbes

Help restrain responses to resident microbes

The source identifies self, fetus and commensals as targets of Treg regulation.

Slide 46 · The fetus presents a distinct tolerance challenge

Fetus expresses paternal antigens

Some antigens are foreign to mother

Maternal immune responses must be restrained

Maternal–fetal tolerance is discussed as a physiological challenge.

Slide 47 · Mouse experiments support fetal-antigen Tregs

Fetal antigens induce long-lived FOXP3⁺ Tregs in mice

Experimental depletion of these cells

Fetal loss occurs

The source attributes fetal-antigen Treg causality to experimental mouse studies.

Slide 48 · Human pregnancy relevance remains unsettled

Established in cited experiments

Mouse fetal-antigen FOXP3⁺ Tregs form

Their depletion can cause fetal loss

Open in humans

Contribution to normal pregnancy

Whether Treg defects explain recurrent miscarriage

Slide 49 · Deletion eliminates mature self-reactive T cells

T cell recognizes peripheral self antigen

Pro-apoptotic pathways are engaged

Autoreactive clone is eliminated

Peripheral apoptotic deletion can remove self-reactive mature T cells.

Slide 50 · Two apoptotic routes are proposed

Mitochondrial pathway

Bim becomes unopposed

Intrinsic apoptosis occurs

Death receptor pathway

Fas engages FasL

Extrinsic apoptosis occurs

Slide 51 · Bim promotes mitochondrial apoptosis

Self-antigen recognition increases Bim

Opposing survival proteins are insufficient

Mitochondrial apoptosis deletes T cell

Unopposed Bim may induce deletion via the mitochondrial pathway.

Slide 52 · BCL-2 and BCL-X counteract Bim

Bim

Pro-apoptotic BCL-family member

BCL-2 / BCL-X

Anti-apoptotic family members

Balance

Without full activation, Bim may dominate

The source contrasts Bim with BCL-2 and BCL-X induction during full lymphocyte activation.

Slide 53 · Full activation favors survival signaling

Full activation signals

Anti-apoptotic BCL proteins can be induced

Survival of responding T cells supported

Self recognition without full support

Bim activity may remain unopposed

Clonal deletion becomes possible

Slide 54 · Fas and FasL form a death receptor pathway

T cell expresses Fas (CD95)

FasL on activated T cells binds Fas

Death-receptor apoptosis is initiated

The source names Fas/CD95 as TNF-family death receptor and FasL as its ligand.

Slide 55 · Fas-mediated deletion can be self-directed

Self antigen engages an autoreactive T cell

Fas and FasL can be coexpressed

Fas-driven death removes the cell

Self-antigen engagement can produce Fas/FasL coexpression and apoptotic elimination.

Slide 56 · Fas and Bim are not interchangeable

Feature

Bim pathway

Fas pathway

Trigger described

Unopposed pro-apoptotic Bim

Fas–FasL engagement

Route

Mitochondrial (intrinsic)

Death receptor (extrinsic)

Important members

Bim, BCL-2, BCL-X

Fas/CD95, FasL

Teaching context

Peripheral T-cell deletion

Peripheral T-cell deletion

Both pathways contribute to proposed apoptotic elimination.

Slide 57 · Fas pathway defects cause ALPS

Fas or FasL mutation

Impaired apoptotic removal of lymphocytes

Autoimmune lymphoproliferative syndrome

ALPS, with lupus-like features, is described following Fas / FasL mutations.

Slide 58 · ALPS links failed deletion to disease

Molecular defect

Fas or FasL

Cellular consequence

Deletion pathway is compromised

Clinical phenotype

Autoimmune lymphoproliferative disorder resembling lupus

The source illustrates loss of peripheral death-receptor deletion through ALPS.

Slide 59 · Antigen sequestration prevents encounter

Certain tissue antigens are physically sequestered

They avoid normal blood / lymph communication

Immune system may ignore these self antigens

The source describes immune ignorance through sequestration rather than active silencing.

Slide 60 · Immune-privileged sites in the source

Testis

Example of an immune-privileged site

Eye

Example of an immune-privileged site

Brain

Example of an immune-privileged site

Testis, eye and brain are named as immune-privileged sites.

Slide 61 · Injury can expose previously hidden self antigen

Trauma or infection disrupts tissue isolation

Previously sequestered antigens are released

Prolonged inflammation / tissue injury may follow

The text proposes exposure after injury as a cause of immune responses.

Slide 62 · Posttraumatic orchitis is a proposed example

Testicular antigen release may trigger prolonged tissue inflammation

The source presents this as a postulated mechanism.

It is an example of loss of antigen sequestration.

It should not be presented as universal for all orchitis.

Slide 63 · Uveitis illustrates the same proposed principle

Ocular antigen exposure may provoke a damaging immune response

Eye is listed as an immune-privileged site.

Trauma or infection can reveal hidden antigens.

This remains the source’s proposed explanation, not a full uveitis taxonomy.

Slide 64 · Silencing and sequestration are distinct

Anergy / suppression / deletion

An immune cell has encountered antigen

Response is impaired or cell removed

Sequestration

Antigen may remain inaccessible

Lack of antigen encounter limits response

Slide 65 · Autoimmunity reflects failure of restraint

Normal balance: Lymphocyte activation ↔ tolerance

Loss of tolerance permits anti-self responses

Inflammatory injury can result

The adjacent general-principles section frames autoimmunity as failure of self-tolerance.

Slide 66 · Susceptibility and environment both contribute

Inherited susceptibility factors

Infections or tissue injury as triggers

Activation of self-reactive lymphocytes

The source describes interactions between inherited risk and environmental stimuli.

Slide 67 · Abnormal self-antigen display is another hypothesis

Persistence, increased expression or modification of self antigen

New or abnormal epitope display

An autoreactive response may emerge

Altered display or neoepitopes are proposed contributors to autoimmunity.

Slide 68 · Innate inflammation can initiate adaptive responses

Microbes or tissue injury provoke local innate inflammation

Innate immune signals activate lymphocytes

Adaptive autoreactivity may be facilitated

Innate responses can serve as initiating conditions for adaptive responses.

Slide 69 · Evidence strength varies among explanations

Strong illustrative mechanisms

FOXP3 mutations → IPEX

Fas/FasL mutations → ALPS

CTLA4 variants → inflammatory disease

Less certain generalization

Why tolerance fails in most common autoimmune disease

Relative importance of altered antigen display or inflammation

Slide 70 · Case: Antigen presented without costimulation

Hypothetical teaching vignette

A mature T cell recognizes a self peptide on a resting dendritic cell with weak B7 expression.

What is the likely functional fate of that T cell?

Reasoned answer

Anergy: Signal 1 without adequate CD28–B7 signal 2 does not fully activate the cell.

Slide 71 · Case: Early multisystem autoimmunity with FOXP3 defect

Hypothetical teaching vignette

A hypothetical child with severe multisystem autoimmunity is found to have a pathogenic FOXP3 mutation.

Which peripheral safeguard is primarily impaired?

Reasoned answer

Treg-mediated suppression; The source identifies FOXP3-associated IPEX.

Slide 72 · Case: Fas-pathway defect

Hypothetical teaching vignette

A hypothetical patient with autoimmune lymphoproliferation carries a pathogenic Fas-pathway mutation.

Which tolerance step is disrupted?

Reasoned answer

Death-receptor-mediated apoptotic deletion of self-reactive lymphocytes; ALPS is the linked syndrome.

Slide 73 · Integrative map of peripheral tolerance

Prevent activation

Low costimulation / CTLA-4 / PD-1

Suppress responses

FOXP3⁺ Tregs, IL-10, TGF-β

Remove or avoid antigen

Bim/Fas apoptosis; Sequestration

Summary across all source mechanisms.

Slide 74 · Mechanistic distinctions to retain

Safeguard

Primary proximal event

Principal outcome

Anergy

Self recognition without enough help

Functional unresponsiveness

Treg suppression

CTLA-4 and inhibitory cytokines

Inhibited immune response

Deletion

Intrinsic / extrinsic apoptosis

Loss of autoreactive clone

Sequestration

Antigen inaccessible

Immune ignorance

An editable synthesis of the four sources of peripheral tolerance.