Lecture 20 - Autoimmunity and immune tolerance

What is autoimmunity?

Immune response to self antigens mediated by adaptive immune system

What is immune tolerance?

Failure of the immune system to mount a response against self antigens

What are the two types of immune tolerance? Give a brief description of each

-Central tolerance - established during B and T cell development

-Peripheral tolerance - additional mechanisms to prevent autoimmunity

What is positive selection in T-cells?

Selects for double positive T-cells with receptors that recognize a specific antigen

What is MHC restriction in T-cell positive selection?

-Determines CD4 or CD8 cell

-TCR recognizes antigen when bound to a specific MHC

What are cortical thymic epithelial cells (cTECs)

Cells that express both MCH class I and II

What is negative selection in T-cells?

-Eliminated T-cells that are potentially autoreactive

-Only T-cells that survive this will enter peripheral circulation

What are the cells that assist with T-cell negative selection?

-Dendritic cells

-Macrophages

-Medullary thymic epithelial cells (mTECs)

What are the two methods for T-cell central tolerance?

-Positive selection

-Negative selection

What four things are included in T-cell peripheral tolerance?

1. Immunological ignorance (physical barrier

2. Deletion (apoptosis)

3. Inhibition (anergy)

4. Suppression (Treg cells)

What are the two things that can cause T-cell inhibition?

1. No CD28 signaling = cannot be fully activated

2. Induced inhibition with inhibition molecule

What are two types of Treg cells? Where do they develop and what do they do?

1. Natural Tregs (nTregs) - develop in thymus and recognize self-antigens with weak affinity

2. Induced Tregs (iTregs) - develop in periphery and require T-cell activation with TGF-b

What is the function of the AIRE (autoimmune regulator) gene? What is it expressed in?

-Assists with T-cell negative selection (produces hundreds of tissue specific self-Ags)

-Essential for induction of T-cell central tolerance

-Expressed in mTECs

What is APECED (Autoimmune polyendocrinophathy-candidiasis-ectodermal dystrophy)? What does it cause?

-Mutation in AIRE gene causing loss of central tolerance

-Endocrine issues and chronic fungal infections

What is IPEX (immune dysregulation polyendocrinopathy, enteropathy, X-linked disease)? What does it cause?

-X-linked mutation in FOXP3 (critical for Treg function)

-Causes progressive multi-organ autoimmunity and failure to thrive

Where does B-cell central tolerance occur? What two things are involved? Which one is more predominant?

-Bone marrow

-Receptor editing (predominant) and apoptosis

What is receptor editing in B-cell central tolerance?

-Replaces light/heavy chain of self reactive antigen with newly rearranged chain

-Continues until non-reactive receptor is generated

What happens if receptor editing in B-cells cannot form a non-autoreactive receptor?

Apoptosis (clonal deletion)

How do B-cells undergo peripheral tolerance?

Not fully mature after leaving bone marrow and can undergo apoptosis if self-reactive (no receptor editing)

Which types of hypersensitivity reactions involve an autoimmune component?

Types II-IV

How is hypersensitivity determined in reactions that involve T-cells and antibodies?

Determined by most important immune mediator (ex. in SLE, T-cells play a supportive role)