Mucosal Immunity

Question 1

What is the mucosa?

Answer 1

The mucosa is like a multi-tasking barrier that helps protect and support the areas of your body that are exposed to the outside world.

Question 2

Where is the mucosal immune system?

Answer 2

• Respiratory tract
• Urogential tract
• Gastrointestinal tract

Question 3

Definition of mucosal surface

Answer 3

Mucosall surfaces is the largest surface area exposed to outside, thus, the mucosal surfaces are exposed to large #s of pathogens.

Question 4

Function of Mucosal Membranes

Answer 4

• Mucosal membranes of the digestive track must allow for the absorption of nutrients by the hose, so mucosal immune system should remain hyporesponsive and able to discriminate “commensal microbiota” versus “invaded pathogens.

Question 5

What occurs when there is an imbalance in mucosal immunity?

Answer 5

Disease like asthma, allergy, inflammatory bowel disease, crohn’s disease, immune-mediated abortions.

Question 6

What is the Mucosal-Associated Lymphoid Tissue (MALT)?

Answer 6

• MALT is the highly specialized immune system which protects mucosal surfaces.
• They lymphoid elements associated with different mucosal sites share organizational as well as functional similarities.
• It is the largest mammalian lymphoid organ system and in an adult it comprises approximately 80% of all lymphocytes.

Question 7

What are the components of MALT?

Answer 7

• Respiratory tract (BALT: Bronchus-associated)
• NALT: (Nasal-associated lymphoid tissue)
• Intestine (GALT: Gut-associated lymphoid tissue)
• Genitourinary Tract - lymphoid nodules
• Mammary glands associated
• Salivary and lacrimal glands
• Inner ear

Question 8

What are the two components of the lungs?

Answer 8

• Airway
• Alveolus

Question 9

Mechanism of the antigen uptake and immune induction in the lungs

Answer 9

Question 10

What are the characteristics fo the GI Mucosal Immune System?

Answer 10

• The GI tract surface area is LARGE: > 300 m^2
• Gut is colonized with 10^14 commensal organisms
• GI lymphoid tissue = 25% of total lymphoid tissue

Question 11

What some non-immune compartments of the GI mucosal?

Answer 11

Question 12

Which are the immune compartments of the GI mucosal immune system?

Answer 12

• Lamina propia
• Peyer’s Patch
• Epithelium (intraepithelial lymphocytes)
• Mesenteric lymph nodes

Question 13

Describe what is lamina propria

Answer 13

Lamina propria is a loose connective tissue in a mucosa, which supports the delicate mucosal epithelium, allows the epithelium to move freely with respect to deeper structures and provides immune defense.

Question 14

What is the composition of Peyer’s Patch?

Answer 14

• Follicular Associated Epithelium (FAE)
• M cells

Question 15

How does the M cells allow the antigens to pass the gut lumen?

Answer 15

1. M cells are interspersed between enterocytes and in close contact with subepithelial lymphocytes and dendritic cells
2. M cells take up antigens from gut lumen by endocytosis
3. Antigens are released beneath M cells and taken up by antigen-presenting dendritic cells.

Question 16

Which are the components of the Intestinal Epithelium?

Answer 16

• Villi
• Crypts

Question 17

What is the function of the villi?

Answer 17

Villi are projections into the lumen covered predominantly with mature, absorptive enterocytes, along with occasional mucus-secreting goblet cells. These cells live only for a few days, die and are shed into the lumen to become part

Question 18

What is the function of crypts?

Answer 18

• Crypts are most-like invaginations of the epithelium around the villi, and are lined largely with younger epithelial cells whoch are involved primarily in mucus secretion.
• Towards the base of the crypts are stem cells, which continually divide and provide the source of all the epithelial cells in the crypts and on the villi.

Question 19

What are the characteristics of Intraepithelial lymphocytes?

Answer 19

Located between epithelial cells
Attach to Epithelial cells - CD103 on IELs to E-cadherin (epithelial cells)
Large granular morphology
Largely T-cells CD3+, (alpha-beta TCR), CD8+
Produce IL-2, IFN-gamma
Function: Cytoxicity and immunoregulatory.

Question 20

What are the characteristic of mesenteric lymph nodes?

Answer 20

• Similar to other peripherial lymph nodes - contains a mixture of T, B, plasma cells, macrophages, DCs, etc.
• They are drain from the thoracic duct and into systemic circulation.
• Thought to be important in tolerance induction
• Pathogens/microbes taken up –> traffic to MLN
• Cytokines and chemokines influence trafficking to MLN.
• Age-related differences in inflammatory potential of MLN cells.

Question 21

Which are the regulatory mechanism of the mucosal immune system?

“Protection against pathogens”

Answer 21

1. Immunoglobulins; secreted into the lumen
2. Antimicrobial peptides (e.g. defensins)
3. Soluble factors:
   * Retinoic acid (RA) - metabolite of vitamin A
   * Local cytokines (TGF-beta, IL-10, IL-6)

4.Microbiota/intestinal environment

Question 22

How does respiratory mucosal immunity works?

IgE and Allergy

Answer 22

• Occurs in respiratory tract, skin primarily
• Produced by plasma cells and B cells in response to allergens, helminths, foods.
• Binds/coats FcERI on mast cells, eosinophils and basophils
• Degranualtion –> Histamine, cytokines, mucous secretion, airway constriction.

Question 23

Characteristics of GI mucosal immunity works?

Answer 23

Throught IgA
* Rate of production - Exceeds all other Ig classes
* Monomeric IgA - Main from in serum
* Polymeric IgA - Binds J chain
* Secretory IgA - Covalently bound to polymeric Ig receptor (secretory component) synthesized by epithelial cells.

• Subclasses - Products of two different genes
• IgA1 - Main from in serum from M, B cells
• IgA2 - Main form in secretions; from mucosal B-cells

M cells cannot produce IgA

Question 24

Mechanism of IgA during GI mucosal immunity

Answer 24

Polymeric Ig receptor:
* Sythesized by epithelial cells
* Binds IgA, transports across ECs

IgA is cleaved and released into lumen

Question 25

Mechanism of protection at mucosa | During GI mucosal immunity

Answer 25

* Relatively resistant to proteolysis (IgA2>IgA1) * Poor activation of complement * Inhibits bacterial adhesion, macromolecules/antigen absorption, inflammatory effects of other immunoglobulins * Neutralizes viruses, toxins * Enhances non-specific defense mechanism (lactoperoxidase, lactoferrin) * Mediates antibody dependent cytotoxicity (ADCC)

Question 26

Antimicrobial peptides (defensis)

Answer 26

* Broadly defines as a family of 2-5 kDA, cationic and Cys-roch antimicrobial peptides, are found in plants, insects, and mammals. * Defensin family consists of three distinct members: alpha, beta, and omega-defensins. While alpha and beta-defensins are expressed in humans and other mamals, omega-defensis are only present in non-human primates such as rhesus macaques and Olive baboons

Question 27

Which are Soluble factors?

Answer 27

Regulatory cytokines: * IL-10 and TGF-Beta Retinoic acid: * Regulate Th17/Treg balance * Influence local immune cells * Promotes a regulatory environment Microbiota influence local immunity

Question 28

What are some of the Microbiota/Intestinal Environment factors?

Answer 28

1. Commensal (barrier) 2. AMPs 3. Resident macrophages 4. DC presents in lamina or driven to LN

Question 29

Clinical Implications IgA Deficiency

Answer 29

* Most common primary immunodeficienty, defined by a serum IgA concentration of less than 50mg/ml * IgA deficient individuals often appear perfectly healthy and are identified * Increased incidence of infections * Higher incidence of autoimmune diseases, allergic diseases and celiac disease

Question 30

Clinical Implications Immunopathology in Mucosal Tissues

Answer 30

Gastro-instestinal: * Celiac disease * Inflammatory bowel disease (Crohn's disease and Ulcerative colitis) Respiratory * Allergies * Anaphylaxis

Question 31

Characteristics of Celiac Disease

Answer 31

T-cell mediated immune disease of the small intestine Triggered by ingesting proteins of wheat, rye, or barley in susceptible persons - protein called gliadin/glutenin. Major Clinical features: * Villus atrophy with a lymphocytic infiltrate (mainly CD8+ T-cells) * Increased epithelial proliferation with crypt hyperplasia * Malabsorption Alleviated by gluted-free diet

Question 32

Immunological features of Inflammatory Bowl Disease (IBD)

Answer 32

Cell - Mediated Immunity: * Increased number of activated mucosal T-cells secreting IFN-gamma (Th1) * Increased mucosal production of cytokines that cativate Th1 cells (IL-12 and IL-18) * Defects in regulatory (IL-10 producing) T-cells Humoral Immunity: * Massive increase in the number of plasma cells and in IgG production (IgG2 in CD and IgG1 in UC) * Imbalance of pro-inflammatory (TNF-alpha, IL-1, IL-8, IL-12) and anti-inflammatory cytokines (IL-10, IL-4, IL-13).

Question 33

Which are the two types of Inflammatory Bowel Disease (IBD)?

Answer 33

Ulceractive Colitis (UC) = colon * Multifactorial (genetics, environment, dysbiosis) * Considered as an autoimmune disease * Antigen tha cause UC is now know or identified Crohn's disease = Any part of GI tract * Cause unknown (~not considered autoimmune) * Multifactorial (genetic, environmental)

Question 34

What are the emerging therapies for IBD?

Answer 34

Inhibitors of proinflammatory cytokines * Anti-TNF therapies: i.e. Infliximab Anti-inflammatory cytokines * IL-10 * IL-11 Anti-leukocyte adhesion therapies * anti-alpha 4 integrin therapy - i.e. Natalizumab Inhibitors of Th1 polarization * Anti-IL-12 * Anti-IL-18 * Anti-IFN-gamma

Question 35

What is microbiota?

Answer 35

* Microbiota refers to the collection of microorganisms that live in or on a specific environment, organism, or habitat. These microorganisms include bacteria, archaea, viruses, fungi, and protozoa. * It is well-established that the microbiota plays a critical role in shaping the mucosal and peripherial immune response. * It also contributes to inflammatory balance

Question 36

What are some of the important clinical/therapeutic aspects of Mucosal Immunology?

Answer 36

* Inducing Tolerance (Oral Tolerance and Hyposensitization) * Mucosal Vaccines (Systemic Immunization = lower mucosal immunity and mucosal vax may enhace systemic immunity)

Question 37

How does oral tolerance works? | Inducing Tolerance

Answer 37

* Oral administration of a protein antigen may lead to suppresion of systemic humoral and cell-mediated immune response to immunization with the same antigen. * There are possible mechanism like induction of anergy of antigen-specific T-cells, clonal deletion of antigen-specific T-cells, selective expansion of cells producing immunosuppresive cytokines (IL-4, IL-10, TGF-beta).

Question 38

How does hyposensitization works? | Inducing Tolerance

Answer 38

* Is a form of immunotherapy where the patient is gradually vaccinated against progressively larger doses of the allergen, so that the severity of their hypersensitive response is reduced or even abolished (Allergy shots - current theory is that escalating doses induce increased Tregs to dimish IgE responses). * Sublingual drop therapy: routinely used in Europe, increasing use in U.S. (Grazax - immuneotherapy for grass pollen alergy).

Question 39

Mechanism of Mucosal Vaccines

Answer 39

* Vaccines delivered via mucosal route (oral polio vaccine, cholera vaccine, rotavirus, inhaled influeza vaccine) * Can be used to induce either mucosa-specific or systemic immune response. * Ideally can generate immune response at the site of highest pathogen exposure.

Question 40

What are some of the challenges with Mucosal Vaccines?

Answer 40

Mucosal sites are often "tolerogenic" * Retionoic acid, TGF-beta, IL-10 all present (Tregs, regulatory APCs) * Immunosuppresive effects is of short duration * Difficult to induce robust immune response (Cellular and humoral responses) Few effective mucosal adjuvants available with side effects: * Cholera toxin: diarrhea if given orally * Bell's palsy if intranasally

Question 41

Summary

Answer 41

* Mucosal surfaces are the largest surface area in our body that get exposed to environment. * Mucus and mucosal immune system provide the protection against all invaded pathogens, allergens, and antigens. * Unique anatomical structure, cell types, soluble factors and microbiota regulate the MIS. * Dysregulation of mucosal immune system contribute to the pathogenesis of various diseases. * Various therapies are available to enhance the mucosal immune system to prevent the disease.