17: Immunological Tolerance

Central tolerance

The process of testing maturing lymphocytes for self reactivity; AKA negative selection

Features of organs that are immunologically privileged

• Abnormal lymph drainage

• Blood-Organ barrier

Peripheral tolerance

The process of avoiding self reactivity even if self reactive cells have made it out of the primary lymphoid organs

Peripheral tolerance mechanisms

• Keeps naive cells separate from blood before activation

• Inactivates self reactive cells in peripheral tissues

How are self reactive T cells inactivated in the peripheral tissues

Anergy is induced when only one of the three activating signals is provided

How are self reactive B cells inactivated in the peripheral tissues

• Anergy is induced when no T_H cell comes along to further activate the B cell once it has presented the self Ag on an MHC II

• No thymus-independent activation because self reactive antigens are not usually repetitive, so BCRs don’t get cross linked

What process contributes to the development of autoreactive B cells

Somatic hypermutation

How do T_reg cells prevent autoimmunity

They express CD25, which is a receptor that has a higher affinity for IL-2 than the IL-2 receptor, and interferes with the autocrine proliferation signal

How do T_H cells prevent a mix of responses that may lead to autoimmunity

The cytokines that induce differentiation into one subtype often suppresses the other subtypes

Negative-selection-type process that happens in the periphery

Antigen/activation induced cell death

Antigen/activation induced cell death mechanism

Lymphocytes that react too strongly to self antigens without the presence of inflammation will undergo anergy

Important types of non-self tolerance

• Feto-maternal tolerance

• Oral tolerance

How does the placenta get the immune system to have a blind spot for the fetus

• Anti-infl cytokines

• Expressed FasL

• Lots of T_reg cells

• Expressed non-classical MHC I

Purpose of oral tolerance

Prevents reactions to dietary antigens

Which GIT cells absorb soluble antigens

Enterocytes

Which GIT cells absorb particulate antigens

Microfold cells (M cells)

What does the body do if there is a low amount of antigen

Mounting a response isn’t worth the energy cost, so it does nothing (tolerance)

What does the body do if there is a lot of antigen

The body knows it can’t win, so it does nothing (tolerance)

Risks of immune system overactivation

Increased risk of secondary pathologies and loss of function

Easiest way to stop an immune response

Remove the antigen

What has to happen for autoimmunity to occur

Something is wrong in one of the many regulatory steps and barriers in the immune system

Types and causes of autoimmunity

• Primary: genetics, hormones, age

• Secondary: cancer, exposure, drugs, vaccines, diseases

Genetic defects that can cause autoimmunity

• Changes in MHC and TCR

• Mutations in critical genes (ex: AIRE)

• Cytokine polymorphisms

What happens after an individual reaches clinical autoimmunity the first time

They will never be normal again, and will have to manage symptoms (you can’t make the immune system forget)

Ways an infection trigger autoimmunity

• Molecular mimicry

• Epitope spreading

• Bystander activation

How does molecular mimicry cause autoimmunity

If the Ag epitopes are similar to self-epitopes, then the immune system will produce B and T cells that both fight the foreign Ag and happen to recognize self Ag

How does epitope spreading cause autoimmunity

Inflammation due to an infection brings in T cells and B cells that recognize self antigens

How does bystander activation cause autoimmunity

Lymphocytes presenting self Ag in an area with infection/inflammation accidentally get activated by cytokines that were intended for different lymphocytes

Regions with mucosal immunity

• Resp

• GIT

• Urogenital tract

• Mammary glands

Components of mucosal immunity

• Mucus secretions

• Antimicrobial peptides

• Microbiota

• IgA

• MALT

• Lymphatic drainage

What layer of the mucosa holds most of the lymphocytes

Lamina propria

Specialized epithelial cells that capture particulate antigens

Microfold cells (M cells)

Adaptations to M cells that make them better at their job

• No glycocalyx

• Less mucus

How do M cells get antigens in contact with lymphocytes

Shuttles them to the lamina propria via transcytosis

Peyer’s patch morphoology

Dome shaped structure under the epithelium

GIT cell that captures soluble antigens

Enterocytes

How do enterocytes prevent immune responses to food

Presents food Ag on MHC II, but doesn’t express all the co-stimulatory molecules, so any T cell that binds eventually falls into anergy and dies

Default function of dendritic cells

Anti inflammatory

Default cytokines that DCs secrete when just floating around

• IL-10 and TGFβ (T_reg)

• IL-4 (T_H2)

How do lymphocytes know to stay in the mucosa

Imprinting and homing

Homing mechanism

MALT lymphocytes have integrins that are specific to mucosal epithelial cells, and expression can be induced by mucosal DCs

Function of IgA in mucosal immunity

X-linked IgA dimers neutralize antigens by binding them at the F_ab (variable) portion, but they can’t interact with any immune cells because the F_c (constant) portion is not free

What dictates which lymphocytes are allowed where

• Integrins

• Cytokines

• Receptors

What allows intranasal vaccines to work

Common mucosal system

How do neonates get passive immunity

The homing of lymphocytes to the mammary gland allows lactogenic immunity