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Cellular and Molecular Immunology > Mucosal Immunity > Flashcards

Mucosal Immunity Flashcards

1
Q

What is the mucosa?

A

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.

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2
Q

Where is the mucosal immune system?

A
  • Respiratory tract
  • Urogential tract
  • Gastrointestinal tract
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3
Q

Definition of mucosal surface

A

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

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4
Q

Function of Mucosal Membranes

A
  • 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.
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5
Q

What occurs when there is an imbalance in mucosal immunity?

A

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

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6
Q

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

A
  • 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.
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7
Q

What are the components of MALT?

A
  • 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
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8
Q

What are the two components of the lungs?

A
  • Airway
  • Alveolus
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9
Q

Mechanism of the antigen uptake and immune induction in the lungs

A
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10
Q

What are the characteristics fo the GI Mucosal Immune System?

A
  • 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
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11
Q

What some non-immune compartments of the GI mucosal?

A
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12
Q

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

A
  • Lamina propia
  • Peyer’s Patch
  • Epithelium (intraepithelial lymphocytes)
  • Mesenteric lymph nodes
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13
Q

Describe what is lamina propria

A

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.

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14
Q

What is the composition of Peyer’s Patch?

A
  • Follicular Associated Epithelium (FAE)
  • M cells
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15
Q

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

A
  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.
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16
Q

Which are the components of the Intestinal Epithelium?

A
  • Villi
  • Crypts
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17
Q

What is the function of the villi?

A

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

18
Q

What is the function of crypts?

A
  • 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.
19
Q

What are the characteristics of Intraepithelial lymphocytes?

A

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.

20
Q

What are the characteristic of mesenteric lymph nodes?

A
  • 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.
21
Q

Which are the regulatory mechanism of the mucosal immune system?

“Protection against pathogens”

A
  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

22
Q

How does respiratory mucosal immunity works?

IgE and Allergy

A
  • 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.
23
Q

Characteristics of GI mucosal immunity works?

A

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

24
Q

Mechanism of IgA during GI mucosal immunity

A

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

IgA is cleaved and released into lumen

25
Q

Mechanism of protection at mucosa

During GI mucosal immunity

A
  • 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)
26
Q

Antimicrobial peptides
(defensis)

A
  • 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
27
Q

Which are Soluble factors?

A

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

28
Q

What are some of the Microbiota/Intestinal Environment factors?

A
  1. Commensal (barrier)
  2. AMPs
  3. Resident macrophages
  4. DC presents in lamina or driven to LN
29
Q

Clinical Implications
IgA Deficiency

A
  • 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
30
Q

Clinical Implications
Immunopathology in Mucosal Tissues

A

Gastro-instestinal:
* Celiac disease
* Inflammatory bowel disease (Crohn’s disease and Ulcerative colitis)

Respiratory
* Allergies
* Anaphylaxis

31
Q

Characteristics of Celiac Disease

A

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

32
Q

Immunological features of Inflammatory Bowl Disease (IBD)

A

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).

33
Q

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

A

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)

34
Q

What are the emerging therapies for IBD?

A

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

35
Q

What is microbiota?

A
  • 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
36
Q

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

A
  • Inducing Tolerance (Oral Tolerance and Hyposensitization)
  • Mucosal Vaccines (Systemic Immunization = lower mucosal immunity and mucosal vax may enhace systemic immunity)
37
Q

How does oral tolerance works?

Inducing Tolerance

A
  • 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).
38
Q

How does hyposensitization works?

Inducing Tolerance

A
  • 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).
39
Q

Mechanism of Mucosal Vaccines

A
  • 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.
40
Q

What are some of the challenges with Mucosal Vaccines?

A

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

41
Q

Summary

A
  • 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.

Cellular and Molecular Immunology (20 decks)

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