Immunotolerance and Autoimmunity

Question 1

Immune Tolerance

Answer 1

Immune system doesn’t react to self antigens.

Question 2

Immunogenic Antigens

Answer 2

Antigens that cause lymphocytes to activate, proliferate, and differentiate into effector cells, leading to a productive immune response.

Normally, Microbes are immunogenic and self antigens are tolerogenic.

Question 3

Tolerogenic Antigens

Answer 3

Cause lymphocytes to become functionally Inactivated or Die.

Normally, Microbes are Immunogenic and Self Antigens are Tolerogenic.

Question 4

Immunological Tolerance

Answer 4

Lymphocytes Fail to React to antigen

Question 5

Central Tolerance

Answer 5

Development of immunological tolerance to Self antigen that occurs in the Central (Generative) Lymphoid Organs: Thymus and Bone Marrow.

–*Can Only Be Developed to Self Antigens Present in the Thymus and Bone Marrow.

Question 6

Central T Lymphocyte Tolerance

Answer 6

• T cells First Arrive to Thymus as *Triple Negative for TCR, CD4, CD8.
• Cortical Epithelial Thymic Cells, Bone Marrow-Derived Dendritic Cells, and Medullary Epithelial Thymic Cells present Self Antigen on Self MHC to T cells to ensure Self MHC Restriction and Self Antigen Tolerance.

Thymus Cortex:
*Positive Selection of T cells that Recognize Self MHC on Cortical Thymic Cells.
(otherwise die)

*In the Cortex, they *Rearrange the *TCR and simultaneously acquire Coreceptors, becoming *Double Positive CD4+ and CD8+.

Thymus Medulla:

Once they pass the MHC Restriction test in the Cortex, they *Move to the Medulla where they Become Single Positive, either CD4+ or CD8+ (Not Both).

*Negative Selection (Death) of T cells that Strongly Recognize Self Antigen expressed on Thymic Dendritic Cells or Tissue-Specific Self Antigen expressed on Medullary Epithelial Cells.

They then leave the Thymus as Mature, Naive CD4+ or CD8+ T cells, unlikely to recognize self antigen, but capable of recognizing self MHC with foreign antigen.

Question 7

The Important of CD4+ Helper T Cells

Answer 7

CD4+ Helper T cells **Control ALL Humoral AND Cellular Responses to PROTEIN Antigen.

**If CD4+ Helper T cells Become Unresponsive to Protein antigen, **This may Prevent Both Cellular AND Humoral Responses to that antigen.

Failure of CD4+ Helper T cell Tolerance has the Opposite Effect and leads to Autoimmunity.

Question 8

2 Mechanisms Lead to Central T cell Tolerance

Answer 8

1) **T cell Death of Self-Reactive T cells

–When Immature T cells encounter *Antigen at *High Concentrations, such as Self Antigen in the Thymus, and the T cell has a High Affinity TCR for that Self Antigen, this Strong Recognition Signals **Apoptosis ==> Negative Selection.

–**This Negative Selection is a Major Mechanism of Central Tolerance and affects both CD4+ T cells and CD8+ T cells.

2) **Conversion to Regulatory T cells

–Some Immature *CD4+ T cells that Recognize Self Antigens Develop into **Regulatory T cells
Instead of Dying.

–Regulatory T cells enter Peripheral Tissues and Block Activation of Harmful T cells Reactive to Self Antigens.

Question 9

AIRE

Answer 9

Autoimmune Regulator Protein.

*Controls the Expression in the Thymus of many peripheral *Tissue-Specific *Self Protein Antigens and *HLA Molecules.

–Mutations of AIRE result in Polyendocrine Syndrome, an autoimmune disease.

Question 10

Peripheral T Lymphocyte Tolerance

Answer 10

Peripheral Tolerance is Induced When Mature T cells Recognize Self Antigens in Peripheral Tissues, Leading to

1) Functional Inactivation (Anergy),
2) Death,
3) or Suppression of the Self-Reactive T cells by Regulatory T cells.

Very important in preventing T cell responses to Self antigens Present in Peripheral Tissues but Not Present in the Thymus.

–Peripheral Tolerance also provides a “back-up” mechanism to Prevent Autoimmunity when Central Tolerance is Incomplete or Ineffective.

Question 11

Anergy in T cells

Answer 11

= Long-lived Functional Inactivation of T cells that Recognize Antigen *Without Appropriate Costimulation from APC (Second Signaling).

–In Normal, Uninfected tissues and peripheral lymphoid organs, APCs are Resting APCs.
=> Resting APCs do Not Express Costimulators.

–Activated APCs present microbial antigen with costimulatory second signals.

APCs may constantly present Self antigens while in a Resting State Without Costimulation.

–**TCR that is Chronically Exposed to Self Antigen Without Costimulation Become Unresponsive.

–**Without accompanying Costimulation over time,
1) TCR loses its ability to be activated, and even
2) *Induces Expression of Inhibitory Costimulatory Receptors, such as *CTLA-4
==> which *Shuts Down T cell Response.

–**B7 Binding to CTLA-4 Inactivates Lymphocytes
(whereas B7 binding to CD28 activates lymphocytes).

Question 12

Immuno-Regulatory T cells

Answer 12

• Develop in the Thymus Upon Recognition of Self Antigen.
• Know as nTregs (naturally occcurring T regulators)
• These are CD4+ T cells that Express High Levels of Alpha Chain IL-2 Receptor **(CD25).
• Foxp3 signals their Development.
• IL-2 is Required for their survival.
• They Produce TGF-Beta, which neutralizes Self-Reactive T cells that Recognize the Same Antigen as the nTregs.

Question 13

Foxp3

Answer 13

Transcription Factor that Signals the Development of nTregs (ImmunoRegulatory T cells)

Question 14

CD25

Answer 14

Alpha chain IL-2 Receptor, expressed in High Levels on nTregs (ImmunoRegulatory T cells)

Question 15

TGF-Beta

Answer 15

Produced by nTregs (Regulatory T cells) to Neutralize Self-Reactive T cells that Recognize the Same Antigen as the nTregs.

–Some nTregs produce this immunosuppressive cytokine to also Block Activation of Macrophages and Dendritic cells.

Question 16

Activation-Induced T cell Death

Answer 16

Recognition of Self Antigen may trigger Apoptosis of Self Reactive T cells if there is Permanent, Ongoing, Chronic Restimulation Because

• -Antigen Stimulation Induces Pro-Apoptotic Signals through Mitochondrial Proteins and Caspases.
• -Permanently Stimulated Lymphocytes Express Death Receptors, such as *Fas.

–Fas mutations are seen in children with autoimmune diseases.

Question 17

Self Antigens in Thymus and in Peripheral Lymphoid Tissue

Answer 17

Self Antigens in *Thymus:
–Induce *Deletion or *Differentiation to Immuno-Regulatory T cells Reactive to Self Antigen.

Self Antigens in *Peripheral Lymphoid Tissue:
–Are Presented by Resting APCs or Epithelial cells, causing TCR Stimulation Without Costimulators and *T cell Anergy.

Question 18

B cell Tolerance

Answer 18

–Self Polysaccharides, Lipids, and Nucleic Acids are
T-Independent Antigens.

–These Self Antigens must Induce Tolerance Directly on B cells.

–There is evidence that Some Protein Antigens may induce Tolerance Directly on B cell too.

–Autoimmune diseases associated with Autoantibody production, such as Systemic Lupus, may be caused by Defective Tolerance of
Both B cells and CD4+ T cells.

Question 19

Central B cell Tolerance

Answer 19

Immature B cells Strongly Reactive to Bone Marrow Self Antigen *Change Specificity by *Reactivating Ig Gene Rearrangement, called
**Receptor Editing
(second chance).

If Editing Fails, **B cells Reactive to Self Antigen Undergo *Apoptosis by *Negative Selection
–which Eliminates High Affinity Receptors for Widely Abundant Self Antigen
(very similar to same process in Thymus).

Question 20

Peripheral B cell Tolerance

Answer 20

• *Mature B cells Reactive to High Concentration Self Antigens in Peripheral Tissue Become Anergic
• -and Fail to Respond.

This is because Mature B cells Reactive to Self Antigen **Do Not Receive CD4+ Helper T cell support, causing these Self Reactive B cells to, thus, become Anergic.
–(Because helper T cells have either been eliminated or are tolerant.)

Anergic B cells leave Lymphoid Follicles and undergo Apoptosis (due to lack of necessary survival stimuli). (They also become excluded from the follicles once they leave.)

• *T-Independent Self Antigens, even if abundant, Don’t Have Repetitive Epitopes.
• -**Thus, they Fail to Activate B cells because of the Weak Cross-Linking.

(Microbial lipids and carbs have Highly Repetitive epitopes, while mammalian ones do not.)

Question 21

Autoimmunity

Answer 21

Immune response against self/autologous antigens.

*Affects about 1-2% of population in developed countries.

Question 22

Principal Factors in the Development of Autoimmunity

Answer 22

1) Inheritance of *Susceptibility Genes

2) *Environmental Factors that *Trigger Autoimmunity:
- -Infections
- -Trauma

Question 23

Genetic Factors

Answer 23

**Autoimmune Diseases in humans are often linked to Specific Alleles or types of the MHC Genes.

1) **Such Alleles may not function as well as other alleles when Displaying Self Antigens, Leading to Defective Negative Selection of T cells in Thymus.
2) –Or the peptide antigens presented by these MHC alleles may Fail to Stimulate Regulatory T cells.

Question 24

Infection

Answer 24

1) **Infection can induce Innate Immune Response, Leading to **Increased Production of Costimulators.

–This **May Push Self-Reactive T cells Beyond the Barrier of T cell Anergy.

–**Many Autoimmune diseases have an Onset Following an Infection.

2) **Infectious Microbes may Produce Peptide Antigen Similar or Cross-Reactive to Self Antigen.

–This may result in **Molecular Mimicry = immune attacking self tissue antigen.

–Example: **Rheumatic Fever:
Antibody to Streptococci cross-react with myocardial antigen, causing cardiac damage and disease.

Question 25

Trauma

Answer 25

**Sequestered Antigen, such as those in the *Eye or *Testicle, are not seen or recognized by the immune system.

**Infection or Trauma may release those Antigen into immune view.

–After trauma to one eye, T cell Activation and Autoimmune Tissue Damage may occur in Opposite eye.

–Damage to one eye leads to immune attack on the other eye.