Microbial Conditioning of the Mucosal Immune System

Silbart Lecture – 2/19/14

Nature Reviews ImmunologyNagler-Anderson Vol 1: 59-67 (2003)

Pathogens/toxins oftenenter our bodies acrossmucosal surfaces

Surface Areas: Skin – 2 m2 Lung – 140 m2 G.I. – 200 m2

Thus, a very largecommitment of lymphocytesis needed to protect these surfaces

                                           

                                          

Innate and antibody-mediated mucosal host defense mechanisms. Shown are soluble antimicrobial proteins lactoperoxidase, lactoferrin, and lysozyme, and the peptide defensins. Human neutrophil peptide (HNP) and Paneth cells in crypt regions produce -defensins, whereas epithelial cells secrete -defensins.

© 2003 by LIPPINCOTT WILLIAMS & WILKINSFundamental Immunology

Anti-microbial peptides (AMPs)

Tight junctionsmaintain mucosalintegrity

Fundamentals of Mucosal Immunology

Presence of foreign antigens at a mucosal surface is generally not sufficient to elicit a mucosal immune response - in fact, in the absence of “signal 1 - danger” Ag is often toleragenic (e.g. non-replicating protein antigens).

Regulation of mucosal immune responses is distinct from systemic “humoral” immunity

Stimulation at one mucosal surface often results in mucosal immunity at many, if not all mucosae - “CMIS”

The “Common Mucosal Immune System”

“D-MALT”

“O-MALT”

Cross section of a Peyer’sPatch; epithelial cells (blue)T cells (red) B cells (green)

Separate Inductive and Effector Sites

Antigen uptake occurs at the “follicle associated epithelium” (FAE), a lymphoepithelial structure that has few if any goblet cells (thereby less mucus) and specialized epithelial cells known as “M” cells.

M cells sample the intestinal surface and lumen through phagocytosis, then pass antigens into a sub-epithelial pocket without processing.

Note: Many pathogens exploit Peyer’s patches - e.g. Salmonella sp.

Fagarasan and Honjo; Nature Reviews Immunology: 3: 63-72 (2003)

Nature Reviews ImmunologyNagler-Anderson Vol 1: 59-67 (2003)

Nature Reviews ImmunologyNagler-Anderson Vol 1: 59-67 (2003)

Entry of GFP-labeled Salmonellatyphimurium throughthe FAE, and uptakeby CD11c+ DCs

(DC’s – red, bacteriagreen)

The Germinal Center Microenvironment

In the dome region of a Peyer’s patch, the T helper cell population is heavily biased toward a Th2 response.

This leads to B cell isotype switching from sIgM+/sIgD+ to sIgA, heavily influenced by TGF-beta and IL-5.

Fagarasan and Honjo; Nature Reviews Immunology: 3: 63-72 (2003)

Activation inducedcytidine deaminase

Reciprocaldown-regulation

Lymphocyte traffickingAntigen-specific, IgA-committed lymphoblasts emigrate from the FAE, lodge transiently in the mesenteric lymph nodes, where antigen re-exposure and secondary rounds of proliferation/differentiation can occur.

These cells rejoin circulation via the thoracic duct, then home to effector tissues, generally the lamina propria of the intestine or lung, or a variety of glandular tissues.

Kunkel and ButcherNature Reviews Immunology3: 822-829 (2003)

Brandtzaeg et al. ImmunologyToday: 20:267-277 (1999)

Selectins and integrinsbind to tissue specificcellular addressins (likezip codes).

Differential lymphocyt

e trafficking

Brandtzaeg et al. ImmunologyToday: 20:267-277 (1999)

Kunkel and Butcher; Nature Reviews Immunology3: 822-829 (2003)

Secretory IgA ProductionOnce the IgA-committed lymphoblasts extravasate into the lamina propria, they will proliferate in the presence of antigen, then terminally differentiate into an S-IgA secreting plasma cell.

S-IgA dimers, joined by a “J” chain, bind to the polymeric immunoglobulin receptor (pIgR), and S-IgA is expelled into the lumen with the secretory component attached.

Note: S-IgA is substantially more proteolytically stable than IgG

© 2003 by LIPPINCOTT WILLIAMS & WILKINSFundamental Immunology

Trans-epithelialtransport of dimeric IgA

Molecular dimensions, proteolytic fragments, and domain structure of the human dimeric secretory immunoglobulin A1 molecule.

© 2003 by LIPPINCOTT WILLIAMS & WILKINSFundamental Immunology

Secretory component derived from pIgR (22% sugar)

The Nasal Associated Lymphoid Tissues (NALT)

Recognition of commensals and pathogens - TLRs

Basolateral expression

Defects in NOD2 arefound in 30% of Crohn’sdisease patients

ToleranceMediated by encounter with antigen while T cells are immature, usually within the thymic epitheliumSecondary mechanisms for peripheral tolerance through anergy or apoptosis.“high-zone” tolerance occurs following activation induce apoptosis.Tolerance is a dynamic process, and depends on dose, timing, route of infection and localization of antigen.

Th0

www.scielo.br/scielo.php?pid=S0100-879X200900...

Also Tr1 and Th3

Artis, 20081014

Artis, 2008

Artis, 2008

Artis, 2008

Commensals required for proper development as neonates

Premature birthC-sectionsAntibiotic useC. diff necrotizingenterocolitis (NEC)[colonization resistance]

Bifidobacter andLactobacillus lovebreastmilk oligo-saccharides

Intestinal dysbiosis, pre-biotics and probiotics

Prebiotics are non-digestible carbohydrates, such as oligosaccharides and fructo-oligosaccharides. They remain in the digestive tract where they stimulate the growth of beneficial bacteria.

http://nutrition.about.com/od/therapeuticnutrition1/p/pro_prebiotics.htm