• The Mucosal Immune System (Ch. 12)

1. The organization of the mucosal system.

2. The mucosal response to infection and regulation of mucosal immune responses.

◆ Lymphocytes are originated from BM, but mature in the bone marrow (B) or the thymus (T).

◆ Lymphocyte resides in lymphoidtissues or organs where mature naïve lymphocytes are maintained and adaptive Immune response are initiated.

◆ Lymphoid organs: central (primary) or peripheral (secondary)

Central: bone marrow and ThymusPeripheral: lymph nodes, spleen mucosal lymphoid tissues of the gut, the nasal and respiratory tract and the urogenital tract and other mucosa

1. The organization of the mucosal immune system

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Mucosa-associated lymphoid tissue:Lymphocytes, Macrophages and Dendritic cells in the intestine (as an example):1. Scattered throughout the surface epithelium of the mucosa2. Underlying layer of connective tissue (called the lamina propria)3. In organized tissues such as gut-associated lymphoid tissues (GALT).

GALT:i) Peyer’s pathcesii) Isolated lymphoid follicleiii) Appendixiv) Mesenteric lymph node

Peyer’s patch

- B cell follicles with germinal Center- Subepithelial dome (Area between the surface epithelium and

the follicles): DC, T, B cells- Microfold (M) cell: No digestive enzymes or mucus, No thick

surface glycocalyx, the route by which antigen enters the Peyer’s patch.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Mucosa-associated lymphoid tissue (MALT):

-GALT-Bronchus-associated lymphoid tissue (BALT): upper respiratory tract-Nasal-Associated lymphoid tissue (NALT)

Tonsils and Adenoids: BALT, NALT

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Waldeyer’s ring:

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Transcytosis by the M cells:

The M cells i) take up antigens by endocytosis or phagocytosisii) transfer antigens to the basal cell membrane iii) and release antigens into extracellular space.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

DCs are also abundant in the wall of the intestine to acquire antigens without the M cells.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Cells in the mucosal immune system:

- The intestinal mucosa displays many characteristics of a chronic inflammatory response because of the myriad of innocuous antigens.

- But no diseases due to powerful regulatory mechanisms.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

The circulation of lymphocytes within the mucosal immune system is controlled by tissue–specific adhesion molecules and chemokine receptors

Once T cells encounter antigens in the GALT, they become activated and lose expression of CCR7 (receptor for CCL21 and CCL19) and L-selectin.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

GALT DCs specifically induce lymphocytes to express gut-specific homing receptors and integrins.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Secretory IgA is the class of antibody associated with the mucosal immune system.

IgA: -form dimer (monomer in the blood) -function in secretions -present in intestinal and respiratory tract-Non-inflammatory antibody (tolerance)

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Proteolytic clevage of the extracellular domain of the poly-Ig receptor

Transcytosis of IgA:

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Functions of secretory IgA:

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

2. The mucosal response to infection and regulation of mucosal immune responses.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Epithelial cells play a critical role in innate defense against pathogens.

- Epithelial cells have no TLR4 (unable to sense bacteria in the intestinal lumen).

- Epithelial cells have TLR5 which recognizes bacterial flagellin ontheir basal membrane.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Salmonella tryphimurium

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Innate immune response by intestinal epithelial cells.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Immune priming vs oral tolerance (mucosal tolearance)

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

The mechanisms of oral tolerance?

1. anergy?

2. Deletion of antigen-specific T cells?

3. Generation of regulatory T cell (TGFβ)?

4. TGFβ also stimulates B cells to switch to IgA.

1. Commensal bacteria induce TGFβ, thymic stromal lymphopoietin (TSLP) and prostaglandin E2 (PGE2) expression by gut epithelial cells to keep local DCs in a quienscent state with low level of co-stimulatory molecules.

2. Commensal bacteria cannot penetrate the intact epithelium.

3. Commensal bacteria inhibit NF-κB activation

Commensal bacteria:

- The failure of these regulatory mechanisms induces unrestricted immune response to commensal bacteria: inflammatory bowel diseases such as Crohn’s disease

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

PPARγ: Proliferator activated receptor-γ

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.

Side effects of antibiotics:

JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.