Mucosal Immunity and Eukaryotic Pathogens L13-15

Question 1

What is a mucosal surface?

Answer 1

A mucus-secreting membrane lining all body cavities or passages that communicate with the exterior.

Question 2

What 2 conflicting functions do mucosal surfaces have?

Answer 2

Facilitate exchanges between the inside of the body and the outside world:

• Food processing and nutrient uptake - digestive tract
• Gas exchanges - respiratory tract
• Reproduction and elimination of metabolic waste - urogenital tract

Form an efficient barriers to biological and chemical insults: requires complex and specific defense systems

Question 3

Name the 3 levels of mucosal defence.

Answer 3

• Immediate innate immunity
• Induced innate immunity
• Adaptive immunity

Question 4

Continuous ___1___ of epithelial cells release infected and other damaged cells contributing to maintaining healthy epithelium
Muscle contractions also induce mucus movements along ___2___ surfaces (respiratory tract – sneezing and coughing, digestive tract - peristalsis) contributing to the elimination of ___3___ and other harmful material.

Answer 4

1. Shedding
2. Mucosal
3. Pathogens

Question 5

Describe ‘Epithelial cells are polarized’.

Describe Apical membrane.

Describe Basolateral membrane.

Answer 5

• Epithelial cells have distinct inner and outer surfaces, they are highly polarized - essential for their functions
• The outer surfaces are called the apical membranes. They face the air (lungs) or a fluid-filled organ cavities (the lumen of the gut)
• Apical surfaces may have cilia (movement) or be highly folded forming microvilli to increase surface area
• The inner surfaces are called the basolateral membranes; they mediate cell-cell interactions and cell-extracellular matrix interactions

Question 6

Epithelial cells have complex membrane trafficking routes including trancytosis.
Define Trancytosis.

Answer 6

Vesicular mediated transport of internalized endogenous or exogenous material.

Question 7

Describe the barrier functions of epithelial cells.

3

Answer 7

• Stratified epithelium: not involved in large scale selective transport activity of material necessary for life
• Simple columnar epithelium: transport of solutes, ions, water or gas
• Secretions of innate (e.g. mucins) and adaptive defense molecules (e.g. SIgA)

Question 8

Describe the antigen recognition, uptake and presentation functions of epithelial cells.

Answer 8

• Innate functions: e.g. TLR and NOD receptors regulate antimicrobials secretions
• Antigen uptake and processing: regulation of adaptive immune responses

Question 9

Describe the regulation of immune responses function of epithelial cells.

Answer 9

• Integrate signals from the microbiota (lumen), pathogens and immune cells
• Secretions of mucosal immunoglobulins (e.g. SIgA)

Question 10

What are the two arms of the mucosal immune system?

Answer 10

• The mucosal innate immune system

- The mucosal adaptive immune system

Question 11

Describe what structures are part of the mucosal innate immune system.

Answer 11

• Epithelial cells lining the mucosal surfaces

- Various innate immune cells dispersed within the lamina propria and/or squeezed between epithelial cells

Question 12

Describe what structures are part of the mucosal adaptive immune system.
(2)

Answer 12

• Inductive sites are where antigen capture and presentation to naïve B and T cells takes place. Organized in some mucosa into Mucosal Associated Lyphoide Tissues (MALT).
• Effector sites are where effector lymphocytes migrate to carry their functions. Include the lamina propria, exocrine glands and surface epithelia.

Question 13

How does the mucosal adaptive immune system differ from its systemic counterpart.
(4)

Answer 13

1. Specialized antigen sampling strategies
2. Distinct homing program allowing immune effector cells to return to mucosal sites
3. Specialized immune effectors including the secretory IgA (SIgA)
4. A variety of suppressive mechanisms:
   - To maintain tolerance to environmental antigens (food, pollen, etc.)
   - To avoid inflammations against mucosal microbiota (regulated by epithelial cells, DC and macrophages)

Question 14

What are the mucosal inductive sites?

Give examples.

Answer 14

Inductive sites are where antigens are sampled and processed and then presented to naïve T and B cells that then become activated

Mucosal inductive sites include:

• Mucosal-associated lymphoid tissues (MALT)
• Local mucosal-drained lymph nodes - involving intra or sub-epithelial dendritic cells

Question 15

Which structures make up the GALT?

Answer 15

• Peyer’s patches
• Isolated lymphoid follicles
• Appendix

Question 16

Which structures make up the NALT?

Answer 16

• Adenoids
• Tonsils
• Isolated lymphoid follicles

Question 17

“There is a physical barrier between the mucosal antigens and the immune effector cells/molecules.”

In what 2 ways does the body circumnavigate this?

Answer 17

1. Antigens can be sampled by specialized cells
   - Microfold cells (M-cells), specialized epithelial cells - antigen uptake via endocytosis or phagocytosis followed by trancytosis
   - Cross-epithelial dendritic cells (DC) can sample antigen from the lumen of the mucosa via cellular extensions
   - Macrophage in alveoli also sample antigens
2. IgA and IgM are transcytosed into the lumen of mucosa where they contribute to pathogen/toxins elimination

Question 18

What are CD8 IEL’s (inter-epithelial lymphocytes) active against?

Answer 18

Virus and other intracellular pathogen infected cells.

Question 19

What are Type b IEL’s (inter-epithelial lymphocytes) active against?

Answer 19

Infected and stressed cells and cells with altered growth.

Question 20

The polymeric immunoglobulin receptor is produced by ______ cells
Two abreviations are used:
- pIgR
- SC: secretory component

Answer 20

Epithelial

Question 21

Most mucosal surfaces secrete large amount of what?

Answer 21

Secretory immunoglobulins IgA (SIgA).

Question 22

Name the 2 types of polio vaccine?

Answer 22

• Inactivated poliovirus vaccine (IPV) - Salk, 1954 (injection)
• Oral polio vaccine (OPV) live, attenuated - Sabin, 1957

Question 23

List the advantages and disadvantages of the OPV (polio) vaccine?

Answer 23

Advantages:

• Cheap; orally administered - ideal for mass immunization
• Promotes antibody formation in the gut; this protects more effectively against wild polio infection and reduces transmission of the wild virus. Also prevents viremia and protects motor neurons (systemic IgG)
• Provides community benefit because the vaccine virus is excreted; therefore the contacts of recently immunized children may, in effect, get a second-hand dose of the vaccine.
• It is therefore used to contain outbreaks, and for eradication where polio is endemic.

Disadvantage:

• Small risk of vaccine-related paralytic polio (VAPP) and vaccine-derived polioviruses (VDPVs).
• The VAPP risk is higher for immunocompromised patients.

Question 24

List the advantages and disadvantages of the IPV (polio) vaccine?

Answer 24

Advantage:

• No risk of vaccine-related polio (VAPP and VDPVs).
• Prevents polio infection from progressing to viremia and protects the motor neurons (systemic IgG)

Disadvantage:

• Does not stimulate antibody in the gut, so less effective against wild poliovirus.
• Protects only the immunized person; no community benefits.
• More expensive then OVP, requires sterile syringe

Question 25

Upon the balance of which risks is the decision to use a particular polio vaccine over another made?
(3)

Answer 25

• The risks of wild polio virus being imported - if this is high, favours OPV.
• The risks of VAPP and VDPVs from OPV.
• The efficacy of IPV.

Question 26

List some key characteristics of the NALT.

Answer 26

• Involved in the digestive, respiratory and urogenital tract mucosal immune responses
• Intranasal immunization induces antigen specific protection in both mucosa and systemic immune compartments - relevant for both the respiratory and urogenital tract where IgG derived from serum can play important functions (transudation, difusion)
• Induces both cytotoxic T lymphocytes (CTL) and immunoglobulin responses (SIgA, IgG)
• M-cells are important for antigen sampling

Question 27

List some key characteristics of the GALT.

Answer 27

• Represent the largest and best understood MALT
• Is made of different inductive and effector sites
• M-cells and DC are important for antigen sampling
• The gut hosts the largest fraction of the human microbioata, which affects virtually all aspects of human development and homeostasis
• Complex interactions between the GALT and the microbiota take place - homeostasis
• Mediates oral tolerance

Question 28

The majority of lymphocytes in the human body are located in the ___1___.
Lymphocytes can leave the gut via ___2___ lymph nodes or via portal vein - reaching the liver where important immune regulation take place including oral tolerance.

Answer 28

1. GALT

2. Mesenteric

Question 29

The great majority of microbial ___1___ encountered by the GALT are not derived by pathogens but from the members of the beneficial ___2___.
The mucosal immune system has developed sophisticated means the differentiate the innocuous ___1___ from those derived from pathogens.
There is a complex balancing act between maintaining a thriving ___2___ and keeping it under control.

Answer 29

1. Antigens

2. Microbiota

Question 30

True or false? Macrophages are present in high numbers in the intestinal lamina propria.

Answer 30

True.

Question 31

The great majority of antigens encountered by the GALT are not derived by pathogens but from food and the microbiota.
Those derived from food are typically harmless in themselves and benefit us - nutrition.
The mucosal immune system has developed sophisticated means the differentiate the innocuous antigens from those derived from pathogens.
The default response to food antigens is to develop a state of un-responsiveness - CALLED WHAT?

Answer 31

Oral Tolerance.

Question 32

Describe Primary pathogens.

Answer 32

• Typically cause disease upon infection, adapted to their human host

Question 33

Describe Opportunistic pathogens.

Answer 33

• Cause disease under some circumstances, are sometime members of normal flora (e.g. Candida sp.)
• Can be derived from the environment and are not specifically adapted to live on/in humans (e.g. Aspergillus sp.)
• Typically thrive in immunocompromised hosts (e.g. HIV, AIDS) and cause damage (e.g. Microsporidia, Aspergillus sp., Pneumocystis)

Question 34

Describe a Rotavirus?

Answer 34

Rotaviruses are the leading cause of life-threatening diarrhoeal disease among infants and young children.

Question 35

Describe Microsporidia.

Answer 35

• Strict obligate intracellular parasites, no “active” extracellular forms
• Depend on one or more host to proceed through their life cycle
• Mostly animal hosts, a few example of protists
• Multiple examples of host switching
• Zoonotic origins of most, if not all, microsporidia infecting humans

Question 36

Which disease?

• Invades different cell types and targets T-cells, eventually destroying the immunological defence system of the carrier
• No vaccine is currently available. Various strategies are being investigated in different labs with both systemic and mucosal vaccination approaches
• Is essentially transmitted through mucosal surfaces - STI

Answer 36

HIV.

Question 37

Which pathogen?

• Ca. 270 million new infections per year (WHO estimates)
• Its prevalence is higher then the combined prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae put together
• Up to 60% of a given population can be positive
• Linked with an increase in HIV susceptibility and cervical cancer as well as aggressive prostate cancer
• Usually efficiently treated with metronidazole or tinidazole but ~5% of infections are resistant to treatment

Answer 37

Trichomonas vaginalis.

Question 38

Why do Trichomonas vaginalis infections result in increased susceptibility to HIV infections?

Answer 38

• They directly damage mucosa surfaces
• They induce an inflammatory response and recruit immune cells
• They disturb the microbiota – loss of the Lactobacilli species

Question 39

Why do Trichomonas vaginalis infections result in increased potential for HIV transmission?

Answer 39

Infections increase HIV mucosa shedding of dually infected patients.

Question 40

Describe the filtration and clearance mechanisms that remove particles and pathogens in the respiratory system.

Answer 40

• Filtration in nasal cavity removes large particles
• Muco-ciliary clearance along the trachea
• Macrophages ingesting particles in the alveoli

Question 41

Describe the mucosal immune system in the respiratory system.

Answer 41

• Innate responses (epithelial cells, macrophages, dendritic cells, neutrophils, mast cells, others…)
• Adaptive responses (T- and B-cells, SIgA, IgG)
• Some lung bacterial pathogens have developed SIgA specific proteases - SIgA1: Salmonella pneumonia (most common bacterial cause of pneumonia). Haemophilus influenzae.