MUCOSAL IMMUNE SYSTEM

SUBIJANTO MARTO SUDARMO

GASTROENTEROLOGY DIVISION
DEPARTMENT OF CHILD HEALTH
DR.SOETOMO HOSPITAL

MEDICAL FACULTY
AIRLANGGA UNIVERSITY
INTRODUCTION
 FOOD HUMAN

MARINE ANIMAL

SOIL PLANT

SUMMARIZED BY SUBIJANTO MARTO SUDARMO 2018

THE THEME OF WORLD MICROBIOME DAY
HUMAN CELLS IS 10 TRILLION

GUT
DISEASE/HEALTHY
GUT MICROBIOME

GENETIC CODE
Some facts about gut:
• About 100 trillion bacteria reside in the gut and they
produce metabolites that have health effects

• 70-80% of the body’s immune cells are concentrated

in the gut

• There are 100 million neurons located along the gut

which produce various neurotransmitters that regulate
mood and satiety

• 95% of the body’s total serotonin is located in the gut

You may think of yourself as human,
but 90 percent of the cells in your body are
actually bacterial.

That's 100 trillion microbes living on your skin,

in your gut, up your nostril—any body surface
you can think of.
We have about 10 times as many microbial cells as
human cells.

Human: 10 power 13 human cells

10 power 14 bacterial cells

Human as a "supraorganism," composed of both

non-human and human cells
Mapping the Human Gut Microbiome in Health and Disease Using Sequencing,
Supercomputing, and Data Analysis
https://www.slideshare.net/Calit2LS/ayasdi-oct-2014
The phrase "normal microbiota" refers to the
microorganisms that reside on the surface and
deep layers of skin, in the saliva and oral
mucosa, in the conjunctiva, and in the
gastrointestinal tracts of every human being.
WHY MUCOSAL IMMUNIY IS
IMPORTANT
 HYPOCRATES
Born: c. 460 B.C.E.
Cos, Greece
Died: c. 377 B.C.E.
Larissa, Greece
Greek physician

Read more: http://www.notablebiographies.com/He-

Ho/Hippocrates.html#ixzz4QV9ZpTU4
/www.philrichardsperformance.co.uk/blog/part-3-improving-digestion-for-muscle-gain-fat-loss-health/
 INTRODUCTION
HOW IS IMPORTANT OF GUT
AND MICROBIUM

Hippocrates has been quoted as saying “death sits in the bowels” and

“bad digestion is the root of all evil” in 400 B.C.

Hawrelak JA, Myers SP. The
causes of intestinal dysbiosis: a review. Altern Med Rev 9: 180–197, 2004.
Your Child’s Health Starts in the Gut
All Diseases begin in the Gut
-Hippocrates,460-370 BC
85% of the body's immune system can be found in the gut
The vital functions of gut flora
Gut flora protect and nourish the digestive tract
THE STRUCTURE OF MUCOSA
INTESTINAL MUCOSA
THE STRUCTURE OF MUCOSAL
IMMUNE SYSTEM
PLOS Biology: Inside the Mucosal Immune System
Coordination between inductive and effector sites for the induction and regulation of
antigen-specific mucosal immune responses. Antigens in the lumens of the
gastrointestinal tract, nasal cavity, and tear ducts
The schematic feature of mucosal immune system in the gut.
www.slideshare.net/MBashir17/mucosal-immunity-34531723
Ag processing and induction of immune responses in the intestine.
J Immunol January 1, 2007, 178 (1) 27-32; DOI: https://doi.org/10.4049/jimmunol.178.1.27
Proposed mode of action of SIgA-Ag immune complexes after uptake by Peyer’s
patch in the intestine.
J Immunol January 1, 2007, 178 (1) 27-32; DOI: https://doi.org/10.4049/jimmunol.178.1.27
Role of secretory IgA in infection and maintenance of homeostasis - ScienceDirect
Autoimmunity Reviews Volume 12, Issue 6, April 2013, Pages 661-665
 Characteristics of antigen-sampling M cells located in the follicle-associated epithelium
(FAE) of Peyer’s patches (PPs) and villous epithelium. M cells are preferentially located in
the FAE of mucosa-associated lymphoid tissues
 (MALT)
Mucosa-associated
lymphoid
tissue

Lymphoid elements in
GALT
from bone marrow,
thymus

Common mucosal immune

system (CMIS)

42
The mucosal immune system consists of organized and
dispersed lymphoid tissues that are closely associated
with mucosal epithelial surfaces,
and mucosal immune responses generated in one
location are transferred throughout the mucosal
immune system by lymphocytes programmed to home
to regional effector sites.
THE IMPORTANT OF MICROBIOME
IN OUR LIVE
 BRAIN
LUNG OBESITY HEART

GUT MICROBIOTA
CANCER
MICROBIOME KIDNEY
DYSBIOSIS

ORAL CAVITY
PANCREAS LIVER
GUT
 Researchers are only beginning to understand how the gut microbiome—the vital
community of microorganisms that lives in our intestines—interacts with our bodies and
the food we eat.
Scientific Reports (2018). DOI: 10.1038/s41598-018-30783-1
Microbiome and Cardiac Health
Integrative Cardiology pp 67-97 | Cite as
Signals from the gut microbiota to distant organs in physiology and disease
Nature Medicine volume 22, pages 1079–1089 (2016)
 IMMUNE SYSTEM

SUMMARIZED BY SUBIJANTO MS 2017

GUT MICROBIOME IS DYNAMIC AND UNSTABLE
How does the human microbiota change
with age?

Our human microbiota evolves with the different stages of

life, and is very influenced by
Genetics
Mode of delivery
Antibiotics
Nutrition, diet
Geography
Hygiene
Medications
Stress
"Flavonoids, Inflammation and Immune System"
A special issue of Nutrients (ISSN 2072-6643).
Frontiers | Interactions between Intestinal Microbiota and Host ...
Regulation of mucosal barrier functions by gut microbes and host immune cells. Mucosal
barrier function is modulated by gut microbes and host immune cells.
Ryu Okumura, Kiyoshi TakedaPublished in Inflammation and regeneration 2018 DOI:10.1186/s41232-018-0063-z
New insights in gut microbiota and mucosal immunity of the small intestine
New insights in gut microbiota and mucosal immunity of the small intestine -
ScienceDirect
 GUT MICROBIOME AND
MUCOSAL IMMUNE SYSTEM
Link between Innate immunity and Adaptive immunity
https://geekymedics.com/immune-response/
Immunity-diagram
/mykosan.com/how-can-medicinal-mushrooms-fight-infections/immunity-diagram/
Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems.
Prosper N BoyakaPublished in Journal of immunology 2017
Immunity in the Gut: Mechanisms and Functions
Immunology of the gut and oral tolerance
Diagram Of Plant Cell Easy Adaptive Immune Response Flow
Effects of probiotic bacteria and yeast on intestinal epithelial barrier function.
www.researchgate.net/publication/42345184_Probiotic_bacteria_and_intestinal_epithelial_barrier_function/figures?lo=1
Multi-Faceted Functions of Secretory IgA at Mucosal Surfaces
Blaise CorthésyPublished in Front. Immunol. 2013 DOI:10.3389/fimmu.2013.00185
 Commensal bacteria
IgA

Tight junction

Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut
Nicholas J Mantis, Nicolas Rol, Blaise CorthésyPublished in Mucosal Immunology 2011 DOI:10.1038/mi.2011.41
Microbiota-associated metabolites shape mucosal immunity. Metabolites participate in a
complex host-microbiome network of communications orchestrating immune responses.
J Immunol January 15, 2017, 198 (2) 572-580; DOI: https://doi.org/10.4049/jimmunol.1601247
What Role Does the Route of Immunization Play in the Generation of Protective
Immunity against Mucosal Pathogens?
J Immunol December 1, 2009, 183 (11) 6883-6892; DOI: https://doi.org/10.4049/jimmunol.0901466
Mucosal Immune Response - an overview
www.sciencedirect.com/topics/immunology-and-microbiology/mucosal-immune-response
Mechanistic links between gut microbial community dynamics, microbial functions and
metabolic health
November 2014World Journal of Gastroenterology 20(44):16498-16517 DOI: 10.3748/wjg.v20.i44.16498
Immune mechanisms of probiotics.
September 2013Korean Journal of Pediatrics 56(9):369-376 DOI: 10.3345/kjp.2013.56.9.369
Effect of probiotics on the intestinal microbiota. SCFA, short chain fatty acid.
September 2013Korean Journal of Pediatrics 56(9):369-376 DOI: 10.3345/kjp.2013.56.9.369
 Gut Epub ahead of print: 27/06/2018. doi: 10.1136/gutjnl-2018-
316723.

Current insights and challenges when studying the human gut microbiome
Gut Epub ahead of print: 27/06/2018. doi: 10.1136/gutjnl-2018-
Nutrients Mediate Intestinal Bacteria–
Mucosal Immune Crosstalk
Front. Immunol., 24 January 2018 | https://doi.org/10.3389/fimmu.2018.00005
 Mucosal barriers in the gut. Chemical barriers including AMPs and Reg3γ secreted by
Paneth cells mainly contribute to the separation between intestinal bacteria and IECs in the
small intestine.
Okumura and TakedaInflammation and Regeneration (2018) 38:5
Host-microbial load under health and dysbiosis.
Front. Immunol., 09 October 2015 | https://doi.org/10.3389/fimmu.2015.00512
Mechanisms of immunomodulation by beneficial microbes. Probiotics can modulate the
immune system in the intestine through the luminal conversion process.
December 2012Therapeutic Advances in Gastroenterology 6(1)
Specific colonizing bacteria elicit innate immune responses and development of T
cells and IgA-producing cells in the intestine.
https://www.researchgate.net/figure/228065582_fig1_Fig-1-Specific-colonizing-bacteria-elicit-innate-immune-
responses-and-development-of-T
Main groups of adjuvants and vaccine delivery systems
for induction of mucosal IgA
Prosper N BoyakaPublished in Journal of immunology 2017
MUCOSAL IMMUNE RESPONSE
TO BACTERIAL PATHOGEN
General overview of mucosal immunity to intestinal pathogens and commensal
microorganisms.
 Classification of Toll-like receptors (TLRs). All TLRs recognize bacteria pathogen-
associated molecular patterns (PAMPs) of protein, lipid or nucleotide composition.
https://jeb.biologists.org/content/216/1/84/F2
Routes of invasion by enteric pathogens in the human small intestine.
Influenced by the microbiota, intestinal epithelial cells (IECs) elaborate cytokines, including
thymic stromal lymphoprotein (TSLP), transforming growth factor (TGF), and interleukin-10
(IL-10), that can influence pro-inflammatory cytokine production by dendritic cells (DC) and
macrophages present in the lamina propria (GALT) and Peyer’s patches.
NeoReviews Vol.10 No.4 2009 e166, with permission).
Figure 2. PRR and Th17-Based Immunity to Candida albicans (A) PRRs including CLRs (dectin-1, dectin-2, mincle), TLRs (TLR2, TLR4) and
inflammasomes (NLRP3, NLRC4, Caspase-8) respond to Candida PAMPs by inducing the NF-kB and MAPK pathways. (B) PRRs in turn trigger
expression and secretion of IL-6, IL-23, and IL-1b, which induce Th17 differentiation via the transcription factors STAT3 and RORgt. (C) IL-17A
and IL-17F produced by Th17 cells act on epithelial and mesenchymal cells to induce expression of neutrophil attracting chemokines (IL-8,
CXCL1, CXCL5) and G-CSF, as well as AMPs such as defensins and S100 proteins.
Nydiaris Hernández-Santos, Sarah L GaffenPublished in Cell host & microbe 2012 DOI:10.1016/j.chom.2012.04.008
 Alterations in the gastric microbiota following
Helicobacter pylori infection and gastric
disease progression.

The gastric microbiome, its interaction with Helicobacter pylori, and its potential role in the
progression to stomach cancer
PLOSPathogens| https://doi.org/10.1371/journal.ppat.1006573October5, 2017
MUCOSAL IMMUNE RESPONSE
TO VIRAL INFECTION
Viral infections of mucosal surfaces are a
frequent threat to human health. Mucosal
immunity to viruses relies mainly on early,
innate responses (interferons, natural killer
cells) and on specific cellular (cytotoxic T cells)
and humoral (secretory IgA, transudated IgG)
immune responses.
The innate mucosal immune response to
respiratory viruses is made up of natural killer
cells and B cells producing low-affinity natural
antibodies. Dendritic cells are the sentinels of
the immune system linking sensing by ancient
innate immune system receptors to activation
of adaptive immunity to respiratory viruses.

Mucosal Immunology (Fourth Edition) Volume 2, 2015, Pages 1805-1815

 Concerted action of iFN-λ and iFN-α promotes mucosal immunity and viral protection.
After the interaction of the epithelium surface of the mucosa with viruses, epithelial cells
release IFN-λ.
Frontiers in Immunology 7(8) DOI: 10.3389/fimmu.2016.00598
Production of iFN-λ and establishment of the antiviral state. After virus attack, IFN-λ genes
are induced.
When viral particle ligands (VPL) are sensed by pattern recognition receptors (PRRs),
particular transcription factors, mainly IRF-3 and NF-κB, are induced to allow IFN-λ gene
expression and subsequent release of IFN-λ proteins outside the infected cell.
Frontiers in Immunology 7(8) DOI: 10.3389/fimmu.2016.00598
Innate Immune Responses to Rotavirus Infection
Molecular Epidemiology and Pathogenesis 2016, Pages 243-263
Innate immune response against rotavirus in intestinal mucosa.
Front. Immunol., 05 December 2016 | https://doi.org/10.3389/fimmu.2016.00563
Innate immune response against rotavirus in intestinal epithelial cells (IECs).
Front. Immunol., 05 December 2016 | https://doi.org/10.3389/fimmu.2016.00563
Inflammatory damage of the intestinal mucosa induced by rotavirus in a toll-like receptor
3-deppendent manner.
Front. Immunol., 05 December 2016 | https://doi.org/10.3389/fimmu.2016.00563
 Frontiers | Transcriptomic Analysis of the Innate Antiviral Immune Response in Porcine
Intestinal Epithelial Cells: Influence of Immunobiotic Lactobacilli | Immunology
Global overview of the signaling pathways and immune genes differentially regulated in
porcine intestinal epithelial (PIE) cells after the challenge with the viral molecular associated
pattern poly(I:C)
Front. Immunol., 02 February 2017 |
 Possible modifiers of rotaviruses protection in
resource-poor settings.

From Correlates of protection against human rotavirus disease and the factors influencing
protection in low-income settings
Possible modifiers of rotaviruses protection in
resource-poor settings. Mucosal Immunology 2015 DOI:10.1038/mi.2014.114
Innate immune response to HIV

Download Human Immunodeficiency Virus.pdf (652.04 KB)

Adaptive immune response to HIV
Download Human Immunodeficiency Virus.pdf (652.04 KB)
Immune Response to HIV
T Cell Dysfunction in HIV Infection
www.stemcell.com/immunology-features/immune-response-to-hiv
 HIV Replication
HIV/AIDS: Replication, pathogenesis, clinical manifestation and lab diagnosis
www.onlinebiologynotes.com/hiv-aids-replication-pathogenesis-clinical-manifestation-lab-diagnosis/
HIV infection and T cell differentiation during primary and memory antiviral
immune responses.
July 2013Frontiers in Microbiology 4:178 DOI: 10.3389/fmicb.2013.00178
 GUT MICROBIOME AND
INTESTINAL MUCOSAL BARRIER
Mechanisms of action of the intestinal microbiome on the gastrointestinal barrier.
www.researchgate.net/publication/50394128_'Gut_health'_A_new_objective_in_medicine/figures?lo=1
Effects of probiotic bacteria and yeast on intestinal epithelial barrier function.
www.researchgate.net/publication/42345184_Probiotic_bacteria_and_intestinal_epithelial_barrier_function/figures?lo=1
Intestinal crypt-villus axis and formation of intestinal barriers for luminal
confinement of commensal bacteria
World J Gastrointest Pathophysiol. Feb 15, 2012; 3(1): 27-43 Published online Feb 15, 2012. doi: 10.4291/wjgp.v3.i1.27
Heat Shock Proteins: Intestinal Gatekeepers that Are Influenced by Dietary
Components and the Gut Microbiota
Pathogens 2014, 3(1), 187-210; https://doi.org/10.3390/pathogens3010187
 Intestinal epithelial intercellular junctions.
World J Gastroenterol. Jan 21, 2008; 14(3): 401-407 Published online Jan 21, 2008. doi: 10.3748/wjg.14.401
Intestinal barrier function elements and mast cell interactions in the intestinal mucosa
Wouters MM,et al.Gut2016;65:155–168. doi:10.1136/gutjnl-2015-309151
Schematic diagram for the disruption of intestinal mucosal barrier functions induced by
simulated weightlessness.
International Journal of Biological Macromolecules 94(Pt A) DOI: 10.1016/j.ijbiomac.2016.09.099
 Probiotics as Complementary Treatment for Metabolic Disorders
Potential direct effects of probiotics to protect gut microbiota and intestinal barrier
integrity.
August 2015Diabetes & metabolism journal 39(4):291-303 DOI: 10.4093/dmj.2015.39.4.291
Intestinal epithelial cells: regulators of barrier function
and immune homeostasis
Nature Reviews Immunology 14,141–153 (2014)
MUCOSAL IMMUNE RESPONSE TO
HELMINTHS INVESTATION
 Cellular interactions in the immune response against helminths. Helminth-secreted
excretory/secretory (ES) products are capable of inhibiting in vitro generated dendritic cells
(DCs).
Journal of Biomedicine and Biotechnology 2014:964350 DOI: 10.1155/2014/964350
Helminth excretory/secretory (ES) products effect on host immune cells.
Front. Immunol., 24 April 2017 | https://doi.org/10.3389/fimmu.2017.00453
Acuteness and chronicity of helminth infection drive distinct immune profiles.
F1000Research 2018, 7(F1000 Faculty Rev):1685 Last updated: 17 JUL 2019
MUCOSAL IMMUNE RESPONSE
IN ALLERGY
Intestinal Epithelial Barrier Dysfunction in Food Hypersensitivity
Linda Chia-Hui YuPublished in Journal of allergy 2012 DOI:10.1155/2012/596081
Intestinal barrier functions. Tight junctional complexes located at the most apical portion
of the lateral plasma membrane between two cells excludes the influx of antigenic
proteins and bacteria through paracellular routes.
Linda Chia-Hui YuPublished in Journal of allergy 2012 DOI:10.1155/2012/596081
 Intestinal Epithelial Barrier Dysfunction in Food Hypersensitivity
IgE/CD23-mediated transepithelial antigen transport in allergic intestines
Linda Chia-Hui YuPublished in Journal of allergy 2012 DOI:10.1155/2012/596081
The Epithelial Gatekeeper Against Food Allergy
Intestinal epithelial barrier defects in food allergy.
December 2009 Pediatrics & Neonatology 50(6):247-54 DOI: 10.1016/S1875-9572(09)60072-3
 Beyond Hygiene: Commensal Microbiota and Allergic Diseases
Interplay between intestinal microbiota and immune cells in the context of IgE-mediated
food allergy. pTreg cells are abundant in the small intestine.
February 2017Immune Network 17(1):48 DOI: 10.4110/in.2017.17.1.48
The genetic glitch of Allergy

CHROMOSOME 5

CHROMOSOME 6

CHROMOSOME 11q

CHROMOSOME 12

CHROMOSOME 13q14
 HOW IS MUCOSAL IMMUNE SYSTEM IN ALLERGY

The mucosal immune system typically exists in a state of

active tolerance to food antigens and
commensal bacteria.

Tolerance to food proteins is induced in part by dendritic

cells residing in the intestinal mucosa and implemented by
regulatory T cells.

Food allergy occurs when immune tolerance is

disrupted and a sensitizing immune response
characterized by food-specific IgE production occurs
Immunol Res. 2012 December ; 54(0)
instead.
 Cellular mechanisms of allergic responses to food.
In healthy individuals, ingestion of innocuous antigens leads to sys- temic non-responsiveness (oral tolerance). In allergic patients, oral tolerance is not

induced. In the T helper 2 cell (Th2)-biased mucosal cytokine microenvironment, antigen-specific Th2 cells are generated when antigen frag- ments are

presented to na ̈ıve T cells by anti- gen-presenting cells, mainly dendritic cells (DCs).
Immunological Reviews 2005 Vol. 206: 204–218
FcεRII

Nature Reviews Immunology 8, 205-217 (March 2008)

FcεRII
FcεRII

Actions of IgE in food allergic reactions

Immunol Rev. 2011 July ; 242(1): 128–143.
Role of Treg and Breg cells in the suppression of allergic inflammation.
https://aaaai.confex.com/aaaai/2014/.../Handout/.../Akdis2101Handout.
Immunomodulatory effects of the microbiota in the gut have the potential to decrease allergic inflammatory responses.

THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY · MARCH 2011

 CINTAILAH YANG INI

MATUR NUWUN
THANK VERY YOU MUCH
HARTELIJK BEDANKT
DANKE SEHR
ARIGATOGOZAIMASHITA
FEICHANG GANXIE