Mucosal immunology

What is a mucosal surface?

a membrane that lines various cavities in the body and covers the surface of internal organs.

It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue.

Mucosal immunity’s responsabilities

• Protects against infection

• Determines relative risk

• Limits harmful immune responses

What are the inductive and effector sites of the mucosal immune system?

Inductive sites: NALT, tonsils/adenoids, BALT, GALT, Peyer’s patches, solitary nodules, appendix.
Effector sites: nasal mucosa, upper respiratory tract, lacrimal & salivary glands, mammary glands, intestines, genitourinary tract.

What challenge must mucosal immunity balance?

• Immune Surveillance = detect & eliminate pathogens

• Oral tolerance = avoid reacting to harmless food/self antigens

What are key structural components of the small intestine mucosal system?

• Mucous Gel Layer (MGL)

• Glycocalyx

• Epithelium

• Lamina propria

• Draining mesenteric lymph nodes

What are the components & functions of the Mucous Gel Layer (MGL)?

Components:

1. Water

2. Secreted mucins

3. Tethered mucins

4. Trefoil factors

Functions:

1. Protective barrier

2. Molecular sieve

3. Lubrication

What is the glycocalyx and what are its functions?

A carbohydrate-rich coating on epithelial cells.

Functions:

1. Recognises luminal antigens

2. Protective coating for bacteria

3. Supports epithelial adhesion

What are the five epithelial cell types of the gut?

• Absorptive enterocytes

• Goblet cells

• Enteroendocrine cells

• Paneth cells

• Stem cells

Absorptive enterocytes

- Absorb water/nutrients/fat micelles/vitamins

- Secrete water as part of Enteric Tear Mechanism

Enteroendrocrine cells

Secrete digestive hormones e.g. CCK (cholecystokinin) which regulate digestive processes and coordinate gut function.

What is the Enteric Tear Mechanism?

Enterocytes secrete water via CFTR- mediated chloride efflux; this “tear” flushes microbes away.
Loss of this mechanism predisposes to disease.

CFTR - Cystic fibrosis transmembrane conductance regulator

What are the three main antigen classes in the gut?

• Microbiome-derived antigens

• Dietary antigens

• Self antigens (e.g., anoikic epithelial cells)

What are the five mechanisms of antigen sampling?

1. Tissue-resident phagocytes expressing CCR CX3CR1 extend dendrites into the lumen.

2. CX3CR1+ LPCs cross the epithelium.

3. Soluble antigens diffuse across the epithelium.

4. Goblet-cell-associated antigen passages (GAPs) deliver Ag

5.DC acquisition via apoptotic phagocytic cell uptake or membrane fragment handover

What is oral tolerance?

Induction of regulatory immune responses in Peyer’s patches and mesenteric nodes to prevent activation against harmless dietary or commensal antigens.

Describe the three steps towards neutrophil degranulation (NETosis)

1. Immune trigger (DAMPs/PAMPs)

2. Chemoattractant signalling (e.g., Leukotriene B4, complement derived C5a)

3. Degranulation → NET release

What are common mucosal immune diseases?

• Gastric ulcer

• Cystic fibrosis

• Coeliac disease

• Crohn’s disease

Name the six causes of gastric ulcer

• H. pylori

• NSAIDs (Non-steroidal Anti-Inflammatories)

• Stress

• Smoking

• Alcohol

• Genetics

What is “triple therapy” for gastric ulcers?

• Proton-pump inhibitor (omeprazole/lansoprazole)

• Clarithromycin

• Amoxicillin

Gastric ulcer mechanism

Cystic fibrosis transmembrane conductance regulator (CFTR)

Membrane protein and chloride channel in vertebrates that is encoded by the CFTR gene.

The CFTR gene codes for an ABC transporter-class ion channel protein that conducts chloride ions across epithelial cell membranes

List 10 common symptoms of cystic fibrosis

Respiratory Symptoms

• A persistent cough that produces thick mucus (sputum)

•Wheezing

•Breathlessness

•Exercise intolerance

•Repeated lung infections

•Inflamed nasal passages or a stuffy nose

Digestive Symptoms (GI)

•Steatorrhea (foul smelling greasy stool)

•Failure to thrive

•Intestinal blockage (newborns)

•Severe constipation

List three treatment options for cystic fibrosis

mucolytics, antibiotics, gene therapy

What are the main symptoms of coeliac disease?

Mouth ulcers, enamel loss, joint pain, skin rashes, diarrhoea, bloating, (in women) infertility, miscarriage, etc.

what 2 components make up gluten?

Gliadin and glutenin.

List the 7 steps of Celiac Disease progression

1. Gliadin exposure

2. Deamidation by tissue transglutaminase

3. Activation of antigen-specific T cells i.e. CD4+ by APC that detect - charged gliadin peptide

4. Cytokine release i.e. IL-15

5. Anti-gliadin Ab formation

6. Production of autoantibodies against transglutaminase

7. Intestinal mucosal damage and villous atrophy

What are the four susceptibility factors for IBD?

1. Genetics Susceptibility

2. Barrier disruption

3. Excessive Neutrophilia

4. T cell miseducation

What are the four steps of IBD pathogenesis?

1. Epithelial barrier disruption

2. Bacterial translocation + recognition

3. Naïve T-cell recruitment in blood vessels

4. Cytokine storm by MP + expansion of pathogenic T cells

Therapeutic Targeting for IBD

1. Genetics: Bone marrow transplant effective in very early onset IBD

2. Microbiome: Use of Antibiotics /FMT

3. Immune System: Cytokine blockade/Leukocyte Trafficking/Cytokine Production

4. Environment: Dietary restriction

What are the 3 anti-TNF therapies + how do they differ?

Drug	Type	Notes

Remicade

Humanized antibody

IV infusion; 12-mo loss of efficacy

Humira

Fully human

Injectable

Cimzia

PEGylated Fab

No Fc region → lower clearance

What integrin-based therapies block leukocyte recruitment?

• Vedolizumab (α4β7)

• Etrolizumab (β7)

• Natalizumab (α4 )

• Anti-MAdCAM-1

How does cytokine milieu determine T-cell fate?

• IL-12 → Th1 (via STAT4)

• IL-23 → Th17

• Antibodies blocking these pathways include Ustekinumab (IL-12) , Risankizumab, Guselkumab (IL-23)