Cytokines & Peripheral Tolerance

What is central tolerance?

Removal of B-cells and cytotoxic T-cells that recognize ‘self’ antigens

What is peripheral tolerance?

Immune system doesn’t attack antigens that are not ‘self’, but are part of the normal environment

When does peripheral tolerance develop?

After maturation of B-cells and T-cells

What is the mechanism of peripheral tolerance most likely related to?

Treg cells

What is a surgical example of peripheral tolerance?

Allograft acceptance

What is the typical location of the first inoculation of graft tissue?

An area with low immune surveillance

How is tolerance induced with grafts?

Long-term exposure to tissue

Functions of IL6

Induce release of CRP by hepatocytes

Which cell releases IL6?

Macrophages

What cells does IL6 inhibit?

Treg cells

Functions of IL18, IL15, and IL12?

Increase NK cells and neutrophils

Functions of IL1

Hematopoiesis, fever

What cells does IL1 bind to?

Stem cells in the bone marrow

Which cells secrete IL18, IL15, and IL12?

Macrophages

Which cells secrete IL1?

Macrophages

Function of IL8

Attract neutrophils and immune cells

Where does IL8 bind?

Endothelial cells and neutrophils

Where does IL1 bind?

Hypothalamus

Function of TNF alpha

Promote inflammation

Function of GM-CSF

Activates macrophages and eosinophils

Function of interferon alpha

Induce antiviral response in cells

Which cells secrete inferferon alpha?

Plasmacytoid dendritic cells

Functions of IL7

Stimulate pre-B-cells and ILCs

Which cells secrete IL7?

Bone marrow cells

Function of IL11

Induce hematopoiesis

Which cells secrete IL11?

Bone marrow cells

Functions of IL13, IL25, IL33

Activate mast cells and eosinophils

Which cells secrete IL13, IL25, IL33?

ILC2

Functions of IL17, IL22

Induce production of antimicrobial proteins and defensins by skin and gut mucosa

Which cells produce IL17 and IL22?

ILC3

Which cells secrete IL8 for the activation of helper T-cells?

Conventional dendritic cells

Function of IL4

Activate B-cells and IgE synthesis

Which cells produce IL4?

Eosinophils

Function of IL5

Increase eosinophils

Which cells secrete IL5?

Eosinophils

Functions of IL13

Airway inflammation and mucus secretion

Which cells secrete IL13?

Eosinophils

Th1 infection

Intracellular

Th2 infection

Eukaryotic

Tfh infection

Bacteria

Th17 infection

Mucosal

Th22 infection

Skin

Through which protein do CDC and macrophages present viruses?

MHCII

Which cytokine do CDCs and macrophages release after viral antigen presentation?

IL12

Which cytokines do Th1 cells release during a viral infection?

IL2, interferon gamma, TNF alpha, GM-CSF

What is the function of interferon gamma?

Increase MHCI and MHCII expression, IgG production by B-cells

Through which protein does viral cross-presentation occur?

MHCI

What is the major cytokine that creates feelings of malaise/fatigue/general unwell during illness?

TNF-alpha

Which cytokines do CDCs and macrophages release during bacterial antigen presentation?

IL16, IL23, TGF-beta

Which cytokines do Tfh cells release after viral antigen presentation?

IL21, IL6

What are the major antigen-presenting cells during eukaryotic infections?

Basophils

Which cytokine do basophils secrete during eukaryotic infections?

IL4

Which cytokines do Th2 cells release after eukaryotic antigen presentation?

IL4, IL5, IL13, IL31

What are the major functions of IL31?

Binds to skin receptors to induce itching

What is the first cell to detect a mucosal infection?

Microfold cells on intestinal lining

Which cells do CDCs release in response to a gut infection?

IL23, TGF-beta, IL6

Which cytokine do Th17 cells release after mucosal antigen presentation?

IL17

What are the main two helper-T-cells involved in skin infections?

Th22 and Th17

What are the two cytokines secreted by Th17 and Th22 in response to skin infections?

IL17 and IL22

What is the effect of IL22 on epithelial cells?

Produce anti-microbial proteins and stimulate wound healing

What are major clinical associations with elevated IL17?

Crohn’s disease, intestinal cancer, IBD

What are major clinical considerations with elevated IL17 and IL22 in the skin?

Psoriasis, autoimmune conditions

If a good bacteria is presented to a Th0 cell in the gut, what does it become?

Treg cell

Which cytokine is secreted when a normal bacteria is presented?

TGF-beta

Which cytokines are secreted when a bad bacteria is presented in the gut?

IL23, TGF-beta, IL6

Which cytokines are secreted by Treg cells in response to good gut bacteria?

IL10, TGF-beta, IL35

When Th17 cells secrete IL17 in the gut, which cells are recruited?

Macrophages and neutrophils

What is the major function of IL10?

Inhibit cytokine production, downregulates Th1 cells

What is the major function of IL35 and TGF-beta?

Immune suppression

Where is the vitamin D receptor expressed?

B-cells, T-cells, antigen-presenting cells

How does vitamin D modulate the immune response?

Inhibits B-cell proliferation, suppresses Th1 cell proliferation, induces Th2 response, reduces Th17 phenotype, induces Treg cells

How does vitamin D influence inflammatory cytokines?

Decreased production of inflammatory cytokines

What do M-cells do, and where do they reside?

Sample microbiome to DCs, Peyer’s patches

What is the typical progression of a microbiome sample, cell-wise?

M-cell to DC to helper T-cell

What occurs during a response to a normal microbiome?

Treg cells block immune response

What occurs during a response to a pathogen in the microbiome?

Th17/Th1 induce immune response

What can occur if tolerance to a normal microbiome is compromised?

IBD or Crohn’s

Which helper T-cell and cytokine are not properly regulated during chronic inflammation of the gut?

Th17, IL17

What happens during the last trimester with regard to the fetal microbiome?

Lactobacillus in the vaginal tract increases for transfer to fetus

What time period is most critical for establishing the fetal microbiome?

First few days of life

Which cells are ‘taught’ to tolerate Lactobacillus in the fetus?

Treg cells

Birth via C-section establishes a ___ microbiome

Poor

Which types of bacteria are more likely to be introduced when a baby is born via C-section?

Staphylococcus and enterococcus

What is a poor fetal microbiome associated with?

Increased allergies or asthma

Is breast milk sterile?

No

___ pick up ___ in the gut and deposit in ___

Macrophages, bacteria, breast milk

Which bacteria is most prevalent in breast milk?

Bifidobacteria

When does bacterial deposition into breast milk most often occur?

Last trimester and while lactating

Does baby formula contain bacteria?

No

___ were historically part of the microbiome

Helminths

In the past, which helper T-cells did helminths typically activate in the microbiome?

Treg, occasionally Th2

Which helper T-cells did helminths historically inhibit? (leads to ___)

Th1 and Th17 (leads to autoimmune disease)

Where are diseases like IBS and Crohn’s less common?

Underdeveloped countries

What is helminth therapy?

Treatment of autoimmune disease via reintroduction of helminths