Immunotolerance and Autoimmunity Flashcards
Immune Tolerance
Immune system doesn’t react to self antigens.
Immunogenic Antigens
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.
Tolerogenic Antigens
Cause lymphocytes to become functionally Inactivated or Die.
Normally, Microbes are Immunogenic and Self Antigens are Tolerogenic.
Immunological Tolerance
Lymphocytes Fail to React to antigen
Central Tolerance
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.
Central T Lymphocyte Tolerance
- 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.
The Important of CD4+ Helper T Cells
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.
2 Mechanisms Lead to Central T cell Tolerance
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.
AIRE
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.
Peripheral T Lymphocyte Tolerance
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.
Anergy in T cells
= 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).
Immuno-Regulatory T cells
- 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.
Foxp3
Transcription Factor that Signals the Development of nTregs (ImmunoRegulatory T cells)
CD25
Alpha chain IL-2 Receptor, expressed in High Levels on nTregs (ImmunoRegulatory T cells)
TGF-Beta
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.
Activation-Induced T cell Death
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.
Self Antigens in Thymus and in Peripheral Lymphoid Tissue
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.
B cell Tolerance
–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.
Central B cell Tolerance
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).
Peripheral B cell Tolerance
- *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.)
Autoimmunity
Immune response against self/autologous antigens.
*Affects about 1-2% of population in developed countries.
Principal Factors in the Development of Autoimmunity
1) Inheritance of *Susceptibility Genes
2) *Environmental Factors that *Trigger Autoimmunity:
- -Infections
- -Trauma
Genetic Factors
**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.
Infection
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.
Trauma
**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.
