Fun. I - Tolerance & Autoimmunity

Immune Tolerance

Unresponsiveness to antigen, particularly self-antigen

What happens when Tolerance breaks down?

Autoimmune Disease

What are the 2 types of Tolerance?

- Central

- Peripheral

Central Tolerance

Cells that bind to "self" antigen are eliminated in Primary Lymphoid Tissue during development

Peripheral Tolerance

Suppression/Deletion of self-reactive cells in tissues outside of the Primary Lymphoid Tissues

How are TCRs regulated by Central Tolerance?

Negative Selection during the Single Positive Phase

What enzyme is used during Negative Selection of TCRs?

AIRE

How are BCRs regulated by Central Tolerance?

BCRs that react to self-antigen undergo apoptosis

BCRs can be altered once they leave the Bone Marrow (T/F)

True; They can undergo Somatic Hypermutation, Affinity Maturation, and Isotype Switching in Germinal Centers

What are 4 methods of Peripheral Tolerance?

- Trafficking of Naive Cells

- Lack of Costimulation (Anergy)

- Downregulation (AICD)

- Suppression via Treg-Cells

Naive T-Cells can only travel to ____.

Secondary Lymphoid Tissue

What molecules regulate Lymphocyte Trafficking?

- Adhesion Molecules

- Chemokine Receptors

A lack of Costimulation will cause ____.

Anergy

What Costimulatory Molecule can suppress T-Cell activity?

CTLA-4

Activation-Induced Cell Death (AICD)

Induced apoptosis of B/T-Cells via...

- Death Receptors (Fas/FasL)

- Loss of survival signals at the end of infection

Treg-Cells

Regulatory T-Cells

- CD4+/CD25+/FoxP3+

What are the 4 functions of Treg-Cells?

- Cytokine Deprivation

- Release of Inhibitory Cytokines

- Inhibit APCs

- Cytotoxicity

What 2 Factors can lead to the breakdown of Tolerance?

- Environmental Factors

- Genetic Factors

Environmental Factors

Infection can lead to activation of B/T-Cells that might cross-react with Host Epitopes

- Molecular Mimicry/Antibody Cross-Reactivity

- Epitope Spreading

Molecular Mimicry

- Close resemblance between foreign and self-antigen that can lead to the Immune System attacking self-antigen

- Can lead to Antibody Cross-Reactivity

Epitope Spreading

Progression of the Immune Response to target more epitopes of an Antigen; Can lead to the Immune Response mistaking a self-antigen for foreign

Cryptic Antigens

- Exposure of antigens that were previously "hidden"

- These antigens were never tested for self-reactivity, therefore, they are recognized as foreign

Acute Rheumatic Fever

Systemic illness of streptococci generates antibodies that cross-react with myocardial proteins, causing autoimmune disease

Genetic Factors

Expression of genes that influence Immune Function (MHC Expression)

Immune Responsiveness depends on ____.

strength of interaction between an MHC allele and the peptide

Expression of certain MHC alleles can cause stronger immune responses that can lead to Autoimmunity

Where do Peptides bind the MHC?

The MHC Binding Groove

Ankylosing Spondylitis

Systemic Inflammatory Arthritis that causes enthesis and the vertebrae to fuse

What proteins are most likely presented to T-Cells in cases of Ankylosing Spondylitis?

Proteins of the Entheseal Fibrocartillage

Enthesis

Sites where ligaments, tendons, and the joint capsule are inserted into bone

Rheumatoid Arthritis (RA)

- Chronic joint inflammation

- Autoantibodies (RF) that react with altered self-protein are deposited into joints

____ of Peptides causes them to be more readily presented on MHC Molecules.

Citrullination

Citrullination

- Conversion of Arginine to Citrulline via Peptidyl Arginine Deiminases (PADs)

- Normal process during cell death that would cause increased immune response

Citrullination of several molecules within RA Joints have been found (T/F)

True

Immune Privileged Sites

Areas that do not elicit an inflammatory immune response upon antigen presentation because these areas cannot tolerate swelling

- Brain

- Eyes

- Testes

- Uterus

Immune Privilege is a suppression of Immune Responses (T/F)

False; It is more so a selective downregulation of certain responses that would cause harmful effects

What are the 3 Characteristics of Immune Privileged Sites?

- Surrounded by a barrier that excludes Naive Lymphocytes

- High level of Immunosuppressive Cytokines (TGFβ)

- High expression of Fas/FasL

Fas/FasL causes apoptosis of ____.

T-Cells