Central Tolerance

Slide 1 · Central Tolerance

Immature lymphocyte selection and protection from autoimmunity

T-cell selection in thymus

B-cell selection in marrow

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Interpret central tolerance as a linked series of developmental checkpoints.

Explain why somatic receptor rearrangement creates self-reactive clones.

Trace thymic deletion, AIRE-dependent self-antigen display and thymic Treg development.

Explain bone-marrow receptor editing versus apoptotic B-cell deletion.

Connect imperfect central selection to peripheral tolerance and autoimmunity.

Slide 3 · Self-tolerance prevents immune injury

Autoreactivity must be controlled before it becomes pathogenic.

Antigen receptors are diverse enough to recognize many molecular structures.

Some newly generated receptors recognize components of the host.

Tolerance prevents these potential responses from damaging normal tissue.

Receptor diversity

Self-reactive clones arise

Tolerance restrains injury

Slide 4 · Immunologic tolerance is antigen-specific unresponsiveness

Exposure to an antigen can establish a state of unresponsiveness.

Immunologic tolerance describes unresponsiveness induced by antigen exposure.

Self-tolerance refers specifically to an individual’s own antigens.

The distinction is the identity of the antigen, not a separate immune system.

Immunologic tolerance

Unresponsiveness to an antigen

Self-tolerance

Unresponsiveness to self antigens

Slide 5 · Central tolerance acts during lymphocyte maturation

Immature clones are tested in primary lymphoid organs.

Developing lymphocytes are assessed before joining the mature repertoire.

The thymus is the central tolerance site for T lymphocytes.

Bone marrow is the corresponding site for B lymphocytes.

Thymus

Developing T cells

Bone marrow

Developing B cells

Slide 6 · Central and peripheral tolerance are complementary

Tolerance has a developmental checkpoint and a later safety net.

Central mechanisms operate during maturation in generative organs.

Peripheral mechanisms restrain mature self-reactive cells after their exit.

The second tier is necessary because central selection is not complete.

Immature lymphocyte

Central checkpoint

Mature lymphocyte: Peripheral control

Slide 7 · Random receptor rearrangement creates the problem

Antigen-receptor diversity is generated without foreknowledge of self.

Somatic gene rearrangements generate distinct antigen receptors.

A subset of receptors acquires high affinity for self antigens by chance.

Tolerance is therefore an essential consequence of normal receptor diversity.

Random somatic rearrangement

Diverse antigen receptors

Some recognize self

Slide 8 · Self-reactivity is initially a property of the receptor

Selection addresses specific developing clones—not all lymphocytes.

The relevant signal depends on recognition by a particular receptor.

Different developing clones can react to different self antigens.

Eliminating or changing a dangerous clone preserves the broader repertoire.

Diverse immature clones

Non-self-reactive clone

Self-reactive clone

Alternative outcomes

Slide 9 · Central tolerance makes cells harmless by different routes

Deletion is not the only possible central outcome.

Self-reactive cells may be removed through apoptosis.

Developing B cells may change receptor specificity by receptor editing.

Some CD4-lineage T cells recognizing self differentiate into regulatory T cells.

Self recognition

Apoptotic deletion

Receptor editing / Treg fate

Alternative outcomes

Slide 10 · A conceptual map of the two central organs

The organ and lineage determine the dominant tolerance options.

Feature

T-cell pathway

B-cell pathway

Central site

Thymus

Bone marrow

Principal mechanism

Clonal deletion

Receptor editing / deletion

Additional fate

Thymic Treg generation

No analogous fate described here

Slide 11 · Central selection is preventive, not a clinical diagnosis

Central tolerance is a developmental mechanism.

The normal process does not require tissue inflammation or visible pathology.

Clinical disease appears when failures permit harmful autoimmune responses.

Its mechanisms are best taught through receptor–antigen interactions.

Developmental recognition

Tolerance outcome

Reduced autoreactive repertoire

Slide 12 · The thymus is the T-cell selection environment

Developing T lymphocytes encounter self antigens within the thymus.

Immature T cells express newly generated T-cell receptors (TCRs).

Autologous antigens are processed and presented by thymic antigen-presenting cells.

Recognition can trigger deletion or, in a subset, a regulatory lineage.

Immature T cell: TCR

Self antigen on thymic APC

Selection of cell fate

Slide 13 · TCR recognition is directed at antigen on self MHC

Presentation determines which self determinants can be seen.

Thymic antigen-presenting cells display processed protein antigens.

These are presented in association with self MHC molecules.

An immature TCR can therefore encounter host-derived peptide–MHC complexes.

Self protein

APC: Processing and MHC display

TCR recognition

Slide 14 · Negative selection deletes dangerous T-cell clones

Self-antigen recognition may induce apoptosis in the thymus.

A self-specific immature TCR receives signals upon antigen encounter.

Those signals may culminate in programmed cell death.

The mechanism is termed negative selection, or clonal deletion.

Self-reactive immature T cell

Self-antigen recognition

Apoptosis / deletion

Slide 15 · Negative selection is a clone-level filter

Specificity, rather than wholesale T-cell loss, is the central principle.

Cells bearing receptors for encountered self determinants can be eliminated.

Cells without that problematic recognition are not the target of that signal.

The resulting mature pool is depleted of potentially injurious specificities.

Immature T-cell repertoire

Self recognition → deletion

No such recognition → not deleted by this signal

Alternative outcomes

Slide 16 · Apoptosis removes the receptor-bearing cell

Deletion differs from reversible loss of responsiveness.

The autoreactive lymphocyte is physically eliminated by apoptosis.

Its particular antigen receptor is consequently absent from surviving cells.

Peripheral anergy, by contrast, can silence a mature cell without initial removal.

Clonal deletion

Cell eliminated by apoptosis

Anergy (peripheral)

Cell remains functionally unresponsive

Slide 17 · Thymic antigen display is unusually broad

Selection requires more than thymus-specific antigens.

Many different autologous proteins are processed in the thymus.

The displayed antigen set includes some proteins usually associated with peripheral tissues.

This broad representation allows deletion of clones threatening distant organs.

Autologous proteins

Thymic presentation

Tolerance to represented antigens

Slide 18 · Tissue-restricted antigens create a sampling challenge

An endocrine or other peripheral antigen may rarely occur locally.

A developing T cell can be selected only against antigen it encounters.

Proteins ordinarily restricted to nonthymic tissues require thymic representation.

Specialized expression mechanisms help bridge this anatomical separation.

Peripheral tissue

Normally expresses restricted antigen

Thymus

Must display a relevant self determinant

Slide 19 · AIRE broadens thymic self-antigen representation

AIRE is a key link between thymic selection and distant organs.

AIRE means autoimmune regulator.

It stimulates expression of some peripheral tissue–restricted self antigens within the thymus.

The antigens can then contribute to elimination of self-specific immature T cells.

AIRE activity

Some tissue-restricted self antigens

Deletion of recognizing T cells

Slide 20 · AIRE also influences thymic epithelial differentiation

AIRE is not limited to turning on a list of antigens.

AIRE also promotes differentiation of thymic epithelial cells.

Some resulting cells mimic cells normally found in peripheral tissues.

This increases the repertoire of host proteins encountered in thymic selection.

AIRE

Thymic epithelial cell differentiation

Peripheral tissue-like programs

Slide 21 · AIRE connects antigen availability to deletion

Central tolerance depends on both display and clone recognition.

AIRE-associated tissue antigens become available for thymic presentation.

The matching self-reactive TCR can encounter these determinants.

Deletion prevents that specificity from entering the mature pool.

AIRE-linked antigen display

Matching immature TCR

Apoptosis

Slide 22 · AIRE does not imply universal thymic antigen display

Only some tissue-restricted antigens are induced.

AIRE-dependent expression broadens but does not encompass every self antigen.

Thymic antigen representation remains incomplete.

AIRE therefore improves, but does not perfect, central tolerance.

Self-antigen repertoire

Represented in thymus

Not represented in thymus

Alternative outcomes

Slide 23 · AIRE loss disrupts a specific tolerance pathway

A genetic defect can remove a protective thymic mechanism.

Germline loss-of-function variants of AIRE impair the relevant pathway.

Immature T cells specific for affected tissue antigens may fail to be deleted.

The causal chain links defective thymic education with organ-directed autoimmunity.

AIRE loss of function

Reduced effective self-antigen display

Risk of autoreactive escape

Slide 24 · AIRE deficiency has a human disease correlate

Endocrine autoimmunity illustrates failed central education.

Rare patients with AIRE deficiency develop autoimmune polyglandular syndrome.

Multiple endocrine organs may undergo immune-mediated destruction.

The phenotype supports the physiological importance of thymic self-antigen display.

Inherited AIRE defect

Defective thymic tolerance

Multiple endocrine organs injured

Slide 25 · Autoimmune polyglandular syndrome is mechanistic evidence

A single tolerance pathway can influence several organs.

The defect is in immune tolerance, not necessarily within each targeted gland.

The affected endocrine organs provide a systemic readout of a central selection defect.

This example is not evidence that all autoimmune diseases arise from AIRE mutations.

Primary defect

AIRE-dependent thymic selection

Downstream phenotype

Autoimmunity involving several endocrine organs

Slide 26 · An alternative thymic fate is regulatory T-cell development

Not every CD4-lineage self-recognizing cell undergoes deletion.

Some developing CD4 T cells recognizing self antigens become regulatory T cells.

This lineage later suppresses immune responses, including responses to self.

Thymic Treg generation is a productive outcome of selected self recognition.

Self-reactive CD4-lineage thymocyte

Clonal deletion

Regulatory T-cell development

Alternative outcomes

Slide 27 · Thymic Tregs complement clonal deletion

Deletion and regulation prevent injury by different mechanisms.

Deletion eliminates a developing clone that might otherwise be harmful.

Regulatory T cells persist to restrain activity of other immune cells.

Both outcomes can arise in connection with self-antigen recognition in the thymus.

Deletion

Remove a potentially dangerous clone

Treg development

Produce an immunosuppressive cell

Slide 28 · The deletion-versus-Treg decision remains unresolved

The source does not establish a deterministic selection rule.

The determinants of this thymic fate choice are not established.

TCR affinity for thymic self antigens may contribute.

It would be inaccurate to present a fixed affinity cutoff as an established rule.

Self-antigen recognition

Deletion (one possible fate)

Treg fate (another possible fate)

Alternative outcomes

Slide 29 · Affinity is a proposed influence, not a sole explanation

Avoid converting a hypothesis into an absolute pathway.

The discussion identifies receptor affinity as a possible contributor.

It does not state numerical affinity thresholds or exclusive determinants.

The scientifically sound model leaves the fate decision conditional.

Established

Self recognition can cause deletion or Treg fate

Unresolved

Exact rules governing the choice

Slide 30 · Thymic regulatory cells provide peripheral protection

A central developmental event can yield a peripheral safeguard.

Many regulatory T cells arise in the thymus after self-antigen recognition.

Once mature, these cells suppress potentially harmful immune responses.

Their origin is central; Their suppressive activity largely concerns peripheral responses.

Thymic self recognition

Regulatory T-cell development

Suppression of peripheral responses

Slide 31 · FOXP3 and CD25 help identify the regulatory lineage

The regulatory lineage has a recognizable protein-expression profile.

A well-defined regulatory population is CD4-positive and highly expresses CD25.

FOXP3 is a transcription factor required for functional regulatory T-cell development.

This phenotype describes the regulatory lineage, not the mechanism of thymic deletion.

CD4 Treg lineage

High CD25; FOXP3

Immune regulation

Slide 32 · Regulatory-cell deficiency offers a distinct failure mode

A regulatory defect is not synonymous with AIRE deficiency.

Feature

AIRE defect

FOXP3 defect

Primary pathway

Thymic antigen display

Regulatory T-cell function

Source-linked syndrome

Autoimmune polyglandular syndrome

IPEX

Teaching point

Deletion checkpoint impaired

Regulatory restraint impaired

Slide 33 · Bone marrow is the B-cell checkpoint

Developing B lymphocytes are tested before entering the mature pool.

Immature B cells express newly rearranged antigen receptors.

Self-antigen recognition can reveal potentially autoreactive receptors.

The bone marrow allows a response before those cells reach peripheral tissues.

Immature B cell

Strong recognition of self

Receptor editing or deletion

Slide 34 · Strong self recognition can reactivate rearrangement

Immature B cells have an additional corrective option.

Recognition of self antigen can restart antigen-receptor gene rearrangement.

The cell can consequently express a different receptor.

This is a defining feature of receptor editing.

Self-reactive B-cell receptor

Rearrangement machinery reactivated

New receptor generated

Slide 35 · Receptor editing changes specificity rather than cell identity

The same developing B cell can escape autoreactivity.

The initial receptor recognizes a host antigen strongly.

A subsequent rearrangement creates a new antigen receptor.

If it is no longer specific for self, the cell need not be discarded for that reason.

Original receptor: Self-reactive

Rearranged receptor

New specificity: Not self-reactive

Slide 36 · Editing is a second chance for an immature B cell

Receptor revision preserves a useful developing cell.

B-cell deletion eliminates a cell together with its receptor.

Editing instead attempts to replace the dangerous specificity.

The outcome is functional tolerance without obligatory loss of the clone.

Deletion

Discard cell carrying self-reactive receptor

Editing

Replace receptor specificity within the cell

Slide 37 · Successful editing requires loss of self specificity

A new receptor is valuable only if it corrects autoreactivity.

Rearrangement must generate specificity different from the original self-reactive receptor.

The edited receptor is described as no longer specific for self antigens.

The tolerance outcome depends on changed recognition, not merely rearrangement itself.

Receptor rearrangement

Altered antigen recognition

Self specificity removed

Slide 38 · Failure of editing results in deletion

Apoptosis is the fallback when autoreactivity remains.

Some developing self-reactive B cells do not successfully edit their receptors.

If receptor editing does not occur, the self-reactive cells undergo apoptosis.

This removes potentially dangerous specificities from the mature B-cell pool.

Strong self recognition

Effective editing → altered receptor

No editing → apoptosis

Alternative outcomes

Slide 39 · The B-cell pathway is a sequence of decisions

Receptor revision precedes elimination in the described pathway.

First, self antigen is recognized by an immature B cell.

Second, receptor rearrangement may be reactivated.

Third, the repertoire is shaped by successful editing or cell death.

Self recognition

Receptor editing attempt

New specificity or deletion

Slide 40 · Receptor editing is common during B-cell maturation

Editing is estimated to affect a substantial proportion of B cells.

An estimated one-quarter to one-half of B cells may have been edited.

This is a broad textbook estimate, not a universal rate for each B-cell subset.

The point is that editing is a major physiological mechanism, not a rare anomaly.

Textbook estimate

About one-quarter to one-half of B cells

Interpretation

Editing contributes substantially to the normal repertoire

Slide 41 · Receptor editing and T-cell deletion solve related problems

Both remove hazardous receptor specificity by different routes.

Aspect

Immature T cell

Immature B cell

Site

Thymus

Bone marrow

Response to self

Deletion; sometimes Treg fate

Editing; deletion if no editing

Mechanistic emphasis

Remove dangerous clone

Replace receptor when possible

Slide 42 · Editing is not peripheral anergy

Three tolerance terms describe distinct mechanisms.

Mechanism

What changes?

Where emphasized?

Receptor editing

Antigen-receptor specificity

Immature B cells, marrow

Clonal deletion

Cell survival

Central T and B checkpoints

Anergy

Functional responsiveness

Peripheral tolerance

Slide 43 · Receptor diversity requires both generation and correction

Immune competence and self-protection are coupled processes.

Random rearrangement creates recognition breadth and the risk of autoreactivity.

Editing provides a second rearrangement in selected self-reactive B cells.

Apoptotic deletion prevents unsuccessful cells from contributing to mature immunity.

Diverse receptors generated

Self-reactive receptors identified

Edit or eliminate

Slide 44 · Central tolerance cannot test unseen antigens

Selection is constrained by which self antigens are represented.

Not every self antigen is available in the thymus and bone marrow.

A cell can carry a receptor for a self antigen absent during its maturation.

Such cells may escape into the mature repertoire despite normal selection.

Self antigen not encountered

No effective central deletion

Autoreactive cell reaches periphery

Slide 45 · Escape does not automatically produce autoimmune disease

A self-reactive cell is a risk, not synonymous with tissue injury.

Cells escaping central tolerance retain the potential to cause tissue injury.

Other peripheral tolerance mechanisms may delete or silence them.

Disease requires failure of sufficient protection against harmful responses.

Central escape

Peripheral safeguards

Injury if safeguards fail

Slide 46 · Peripheral tolerance provides a second checkpoint

Mature self-reactive cells can still be restrained.

Peripheral tolerance acts after lymphocytes reach peripheral tissues.

Major safeguards include anergy, regulatory T-cell suppression, and apoptosis.

These processes complement rather than replace thymic and marrow selection.

Mature self-reactive cell

Peripheral control

No harmful activation

Slide 47 · Anergy is functional silencing of a mature lymphocyte

Failure to receive adequate activation signals can prevent response.

Antigen recognition alone may be insufficient to activate a mature T cell.

If antigen is presented without appropriate costimulation, the cell may become anergic.

This is a peripheral mechanism, distinct from deletion during development.

Mature T cell sees antigen

Inadequate costimulation

Anergy

Slide 48 · Regulatory T cells suppress responses after thymic education

Developmental selection can generate a protective regulatory population.

Thymic self-antigen recognition contributes to regulatory T-cell generation.

Mature regulatory T cells restrain activation of other lymphocytes.

Their suppressive role addresses potentially self-reactive cells in the periphery.

Thymic Treg origin

Mature regulatory T cell

Suppression of other responses

Slide 49 · Peripheral deletion is not central negative selection

Similar endpoint; Different phase of lymphocyte life.

Both processes may involve apoptosis of self-reactive cells.

Central deletion takes place during immature lymphocyte selection.

Peripheral deletion acts after maturation, when autoreactive cells encounter self.

Central deletion

Developing clone in thymus or marrow

Peripheral deletion

Mature clone outside primary organs

Slide 50 · Autoimmunity emerges when tolerance mechanisms fail

Breakdown can involve selection and/or later regulation.

Autoimmune disease reflects immune attack on self antigens.

Genetic susceptibility may disrupt distinct tolerance pathways.

Infections or tissue injury can also favor exposure of self antigens and immune activation.

Tolerance defect / trigger

Self-reactive immune response

Tissue injury

Slide 51 · The mechanism of autoimmunity shapes its phenotype

Organ specificity depends on what the immune system targets.

Responses directed at one organ yield organ-focused manifestations.

Responses against widespread antigens can produce systemic disease.

Central-tolerance defects contribute to risk but do not alone identify a target organ.

Organ-focused autoreactivity

Disease concentrated in a tissue

Widespread antigen targeting

Multi-organ disease

Slide 52 · Mechanistic boundaries matter in slide interpretation

Do not transfer facts between stages without justification.

Concept

Central assignment

Do not conflate with

AIRE

Thymic antigen representation

All peripheral antigen display

Receptor editing

Immature B-cell receptor revision

T-cell deletion

Anergy

Peripheral functional silencing

Central apoptotic deletion

Slide 53 · Clinical vignette: An inherited AIRE defect

A defined gene defect predicts a particular mechanism of tolerance failure.

A patient has a germline AIRE loss-of-function mutation.

The source associates this defect with autoimmune polyglandular syndrome.

Question: Which checkpoint fails first—antigen representation or peripheral anergy?

Given

Germline AIRE loss of function

Reasoning

Impaired thymic presentation of some tissue antigens

Inference

Self-reactive T cells may escape deletion

Slide 54 · AIRE vignette: The mechanistic answer

The primary defect is inadequate central education.

AIRE supports thymic expression of some tissue-restricted self antigens.

Without this function, relevant thymic deletion becomes less effective.

The clinical consequence can include immune injury to multiple endocrine organs.

AIRE loss

Missed thymic self-specificity

Endocrine autoimmunity

Slide 55 · Clinical vignette: A self-reactive immature B cell

Choose a developmental tolerance outcome from the cell type.

An immature marrow B cell strongly recognizes a self antigen.

Antigen-receptor rearrangement machinery is reactivated.

Question: What result permits this cell to avoid self reactivity?

Cell

Immature B lymphocyte

Event

Strong self recognition

Required outcome

A different receptor not specific for self

Slide 56 · B-cell vignette: Editing is the rescue mechanism

Changing the receptor removes the original problematic specificity.

The developing B cell can generate a new receptor through editing.

If the new receptor lacks self specificity, the dangerous recognition is removed.

If editing does not occur, apoptosis as the alternative.

Self-reactive immature B cell

Editing → new receptor

No editing → deletion

Alternative outcomes

Slide 57 · Clinical vignette: Missing thymic self antigen

A normal receptor may evade deletion because the antigen is absent.

An immature T cell can respond to a protein expressed in a distant tissue.

Suppose that protein is not represented during thymic selection.

Question: Can a clone specific for this antigen be guaranteed to be deleted?

Thymic presentation

Antigen absent

Central outcome

Relevant deletion cannot be assured

Next safeguard

Peripheral tolerance

Slide 58 · Missing-antigen vignette: Peripheral backup is essential

Central tolerance cannot delete cells against unseen targets.

The thymic selection process cannot respond to an antigen not encountered.

A mature autoreactive clone can therefore enter peripheral tissues.

Anergy, regulation, and deletion help prevent progression to injury.

Unrepresented antigen

Autoreactive escape

Peripheral restraint

Slide 59 · Distinguish AIRE loss from FOXP3 loss

Both promote autoimmunity, but disrupt different steps.

Question

AIRE loss

FOXP3 loss

Primary biology

Thymic antigen display

Regulatory T-cell development/function

Central lesson

Defective clonal education

Defective immune restraint

Syndrome in source

Autoimmune polyglandular syndrome

IPEX

Slide 60 · Assessment: Identify the developmental checkpoint

Three observations reveal three different tolerance outcomes.

Observation

Correct interpretation

Apoptotic immature T cell

Central negative selection

New B-cell receptor after rearrangement

Receptor editing

Self-recognizing CD4 cell becomes Treg

Thymic regulatory lineage

Slide 61 · Assessment: Identify the statement that exceeds evidence

Mechanistic conclusions require correct qualification.

Supported: AIRE promotes expression of some tissue-restricted antigens.

Supported: Affinity may contribute to deletion-versus-Treg fate.

Unsupported: All self antigens are displayed, or an exact TCR-affinity threshold is known.

Supported statement

Self presentation is broad but incomplete

Overclaim to avoid

Central tolerance eliminates every self-reactive lymphocyte

Slide 62 · The central-tolerance pathway in one view

The major branch points differ between T and B maturation.

Checkpoint

Trigger

Major outcome

Thymus

TCR recognizes self peptide–MHC

Apoptosis; some CD4 Treg fate

Bone marrow

Immature BCR strongly recognizes self

Receptor editing or apoptosis

Periphery

Autoreactive mature cell escapes

Anergy / regulation / deletion

Slide 63 · Five mechanistic conclusions

Central tolerance is a selective developmental safeguard.

Receptor diversity inevitably creates potentially autoreactive specificity.

Antigen representation and receptor recognition jointly determine selection.

AIRE, thymic regulatory fates, and B-cell editing provide distinct protections.

The system is incomplete and must be reinforced after maturation.

Diversify

Test against self

Delete, edit or regulate

Slide 64 · Learning check: Three discriminating questions

A correct explanation identifies lineage, site and cellular outcome.

Which organ deletes many immature T cells recognizing self antigen?

How can a strongly self-reactive immature B cell change specificity?

Why can a self-reactive clone still reach peripheral tissues?

Model answers

Thymus; Receptor editing; Incomplete antigen representation

Clinical significance

Peripheral safeguards are needed to prevent injury

Slide 65 · Primary reference

The diagrams and explanations are original teaching adaptations of the supplied chapter.

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) · Chapter 6, “Diseases of the Immune System”

Central Tolerance and adjoining Immunologic / Peripheral Tolerance sections