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MUCOSAL IMMUNITY

SUBIJANTO MARTO SUDARMO

GASTROENTEROLOGY DIVISION
DEPARTMENT OF CHILD HEALTH
DR.SOETOMO HOSPITAL

MEDICAL FACULTY
AIRLANGGA UNIVERSITY
(MALT)
Mucosa-associated
lymphoid
tissue

Lymphoid elements in
GALT
from bone marrow,
thymus

Common mucosal immune


system (CMIS)

2
Nature Immunology 11, 558560 (2010) doi:10.1038/ni0710-558
OUT LINE

Introduction
General organization of the mucosal
immune system
The epithelium
Secretory IgA
Ag sampling in the gut
Initiation adaptive immune response in the
gut
Lymphoid populations in the gut
Host-microbes interaction in the gut
Mucosal tolerance
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,
Your Childs Health Starts in the Gut
Myers SP. The causes of intestinal dysbiosis: a review. Altern Med Rev 9: 180197, 2004.

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 Human Microbiome Project:
Extending the definition of what
constitutes a human
The human genome contains only 20,000 - 25,000 protein-
coding genes
More than 3,000,000 genes provided by our gut
microbiome!

Other sources of genetic material that contribute to


human function. One of these sources was the human
microbiome.
The microbiome is defined as
the collective genomes of the microbes (composed of
bacteria, bacteriophage, fungi, protozoa and viruses) that
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
INTRODUCTION

600 m2

2 m2
INTRODUCTION
INTRODUCTION
INTRODUCTION
General organization of the
mucosal immune system
The gut, nasal, upper respiratory and salivary, mammary, lacrimal, and other

glands consist of a single layered epithelium.


PLOS Biology | www.plosbiology.org
The gut epithelium exhibits several pathways that protect the integrity of

this organ.
PLOS Biology | www.plosbiology.org
The mucosal immune system (MIS) is interconnected, enabling it to protect

vast surface areas. PLOS Biology | www.plosbiology.org


Crosstalk Dendritic cell, T cell, B cell
Nature Reviews Immunology 12, 339-351 (May 2012)
Nature Reviews Immunology 10, 403-414 (June 2010)
Nature Reviews Immunology 2, 116-126 (February 2002)
In T cellDC interactions, semaphorins mediate the reciprocal stimulation of T cells and DCs. The T cellderived semaphorins
Sema4D and Sema6D enhance DC activation and maturation through CD72 and a plexin-A1TREM2DAP12 complex,
respectively. Conversely, Sema4A expressed on DCs directly stimulates T cells through TIM-2. These semaphorin signals might
contribute to the optimal activation of antigen-specific T cells. (b) During the differentiation of CD4+ T cells into cytokine-
producing effector cells, Sema4A is selectively induced in TH1 cells. The TH1 cellderived Sema4A further promotes TH1
differentiation, which might be mediated by cognate cellular interactions between TH1 cells and/or in an autocrine way.

Nature Immunology 9, 17 - 23 (2008) Published online: 17 December 2007


a | Several classes of pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), sense the presence of
viral pathogens, and the triggering of these receptors leads to the activation of antigen-presenting cells (APCs),
including dendritic cells (DCs).
b | Virus-specific memory CD4+ T cells can directly activate DCs through the recognition of antigens presented by
MHC class II molecules, even in the absence of co-stimulation delivered via PRR-mediated signalling.

Nature Reviews Immunology 12, 136-148 (February 2012)


PLOS Biology | www.plosbiology.org
CROSS LINKING
RECEPTOR AND LIGAND
STRUCTURE AND GENETIC CODES
OF IMMUNOGLOBULIN
Monomeric IgA is structurally similar to
monomers of other immunoglobulin
classes.

39
40
Nature 394, 624-625 (13 August 1998) | doi:10.1038/29187
The immunoglobulin genes encode antibodies protective molecules
produced by B cells in the vertebrate immune system.

Nature 407, 31-33(7 September 2000)


Most genes that code for a protein consist of many exons that are at the RNA level
assembled in one intronless RNA and will serve as the input for the ribosomes that
geberates a protein based on the RNA template. Based on single exon genes at the start
of evolution, variety could be afterwards generated by assembling exons into genes.

http://www.design4evolution.net/efficient-genome-building
The organization of Immunoglobulin heavy chains constant region genes in
human and mice

46
Protein post-translational modification (PTM) increases the functional diversity of the proteome by the covalent
addition of functional groups or proteins, proteolytic cleavage of regulatory subunits or degradation of entire
proteins. These modifications include phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation,
acetylation, lipidation and proteolysis and influence almost all aspects of normal cell biology and pathogenesis.

http://www.design4evolution.net/efficient-genome-building
http://www.design4evolution.net/efficient-genome-building
TRANSCRIPTION DNA
1 RNA is transcribed
from a DNA template.
3

5 RNA RNA
transcript polymerase
RNA PROCESSING Exon
2
In eukaryotes, the RNA transcript
RNA transcript (pre- (pre-mRNA)
mRNA) is spliced and Intron
modified to produce
mRNA, which moves Aminoacyl-tRNA
from the nucleus to the synthetase
cytoplasm. NUCLEUS

Amino
FORMATION OF acid
INITIATION COMPLEX AMINO ACID ACTIVATION
CYTOPLASM tRNA
3 After leaving the 4
Each amino acid
nucleus, mRNA attaches attaches to its proper tRNA
to the ribosome. with the help of a specific
enzyme and ATP.
mRNA Growing
polypeptide
Activated
amino acid

Ribosomal
subunits

5
TRANSLATION
5
A succession of tRNAs
E A add their amino acids to
Anticodon the polypeptide chain
A A A
as the mRNA is moved
U G G U U U A U G
through the ribosome
one codon at a time.
Codon (When completed, the
polypeptide is released
Ribosome from the ribosome.)
Figure 17.26
Making Proteins
How are such a diverse range of proteins possible? The code for making a protein is
found in your genes (on your DNA). This genetic code is copied onto a messenger
RNA molecule. The mRNA code is read in multiples of 3 (a codon) by ribosomes
which join amino acids together to form a polypeptide. This is known as gene
expression.

Source: http://genetics.nbii.gov/Basic1.html 50
Fab
papain

Fc

51
Dimeric IgA consists of two IgA monomers bound by J
chain. Individual B cells are committed to secretion of
either monomeric or dimeric IgA.

52
The Y shaped of Ig
molecule can be
dissected by partial
digestion with
protease

53
http://www.arthritis.co.za/immunologyupdate.html
http://www.arthritis.co.za/immunologyupdate.html
STRUCTURE AND GENETIC CODES
OF TCR
T cell co-receptor molecules
Lck PTK TcR Lck PTK TcR

CD8 3 CD4 2

MHC Class I MHC Class II

CD4 and CD8 can increase the sensitivity of T cells to peptide antigen MHC
complexes by ~100 fold
TcR
TcR-CD3 complex
CD3 CD3

The intracytoplasmic region
of the TcR chain is too short
to transduce a signal


The CD3or (zeta)chains
are required for cell surface
expression of the TcR-CD3
complex and signalling
through the TcR

Signalling is initiated by aggregation of TcR by MHC-peptide complexes on APC


Transduction of signals by the TcR
CD3

ITAMs

The cytoplasmic domains of the CD3 complex contain 10 Immunoreceptor


Tyrosine -based Activation Motifs (ITAMS) - 2 tyrosine residues separated
by 9-12 amino acids - YXX[L/V]X6-9YXX[L/V]
As with B cell receptors, immunoreceptor tyrosine-based
activation motifs (ITAMs) are involved in the transmission of the
signals from the receptor and require clustering of TcR/CD3 and the CD4 or
CD8 co-receptors
Early T cell activation
CD4
CD45
MHC II
MHC II
Receptor associated kinases accumulate
under the membrane in close proximity
to the cytoplasmic domains of the TcR
-CD3 complex
As the T cell antigen receptor binds
the MHC-peptide antigen, the
phosphatase CD45 activates kinases
such as Fyn
P
This mechanism of activation is
Fyn similar to the used to activate Syk in
Lck
B cells

Zap-70
CD4
CD45
MHC II
T cell activation

Fyn phosphorylates the ITAMs of


CD3, , and ITAMS

The tyrosine kinase ZAP-70 binds


to the phosphorylated ITAMs of
P CD3 - further activation requires
ligation of the co-receptor, CD4
Fyn Lck

Zap-70
T cell activation
Binding of CD4 co-receptor to MHC
MHC II class II brings Lck into the complex,
which then phosphorylates and
activates ZAP-70
ZAP-70 phosphorylates LAT and
SLP-76

P SLP-76 LAT
P P P P
Fyn Lck
Tyrosine rich cell membrane
associated Linker of
Zap-70 Activation in T cells (LAT) and
SLP-76 associate with
Activated ZAP-70 phosphorylates LAT & SLP-76 cholesterol-rich lipid rafts
T cell activation
MHC II
Activated ZAP-70 phosphorylates
Guanine-nucleotide exchange factors
(GEFS) that in turn activate the small GTP
binding protein Ras

Ras activates the MAP


kinase cascade

P SLP-76 LAT
P P P P
Fyn Lck Tec Tec SLP76 binds Tec kinases
and activates
phospholipase C- (PLC-)
Zap-70
PLC- cleaves phosphotidylinositol
bisphosphate (PIP2) to yield diacylglycerol
(DAG) and inositol trisphosphate (IP3)
Transmission of signals from the cell
surface to the nucleus
Almost identical to transmission in B cells

T cell-specific parts of the signalling cascade are associated with receptors


unique to T cells - TcR, CD3 etc.
Subsequent signals that transmit signals to the nucleus are common to
many different types of cell.
The ultimate goal is to activate the transcription of genes, the products of
which mediate host defence, proliferation, differentiation etc.

Once the T cell-specific parts of the cascade are complete, signalling to


the nucleus continues via three common signalling pathways via:

1.The mitogen-activated protein kinase (MAP kinase) pathway


2.An increase in intracellular calcium ion concentration mediated by IP3
3.The activation of Protein Kinase C mediated by DAG
TcR gene rearrangement RESCUE PATHWAY
There is a 1:3 chance of productive D-J rearrangement and a 1:3 chance of
productive D-J rearrangement
(i.e only a 1:9 chance of a productive chain rearrangement)
V D1 J C1 D2 J C2

Germline TcR

D-J Joining

V-DJ joining

2nd chance at
V-DJ joining

Need to remove Use (DJC)2


non productive elements
rearrangement
Organisation of TcR genes
L&V
x70-80 J x 61 C

TcR
L&V
x52 D1 J1 x 6 C1 D2 J2 x 7 C2

TcR
TcR genes segmented into V, (D), J & C elements
(VARIABLE, DIVERSITY, JOINING & CONSTANT)
Closely resemble Ig genes (~IgL and ~IgH)

This example shows the mouse TcR locus


TcR gene rearrangement by
SOMATIC RECOMBINATION

Vn V2 V1 J C
Germline TcR

Rearranged TcR
1 transcript

Spliced TcR mRNA

Rearrangement very similar to the IgL chains


TcR gene rearrangement RESCUE PATHWAY
There is only a 1:3 chance of the join between the V and J region being in frame

Vn+1 Vn V2 V1 J C

chain tries for a second time to make a productive join using new V and J elements

Productively
rearranged TcR
1 transcript
TcR gene rearrangement
SOMATIC RECOMBINATION
L & V
x52 D1 J C1 D2 J C2

Germline TcR

D-J Joining

V-DJ joining

Rearranged TcR 1 transcript

C-VDJ joining Spliced TcR mRNA


TcR gene rearrangement RESCUE PATHWAY
There is a 1:3 chance of productive D-J rearrangement and a 1:3 chance of
productive D-J rearrangement
(i.e only a 1:9 chance of a productive chain rearrangement)
V D1 J C1 D2 J C2

Germline TcR

D-J Joining

V-DJ joining

2nd chance at
V-DJ joining

Need to remove Use (DJC)2


non productive elements
rearrangement
Junctional diversity: P nucleotide additions

V
TC CACAGTG
7 23 9
V 7 23 9 AG GTGTCAC

J D
DJ AT GTGACAC
9 12 7
TA CACTGTG
7 12 9

The recombinase complex makes single


stranded nicks at random sites close to the
U U ends of the V and D region DNA.

V V
TC TC CACAGTG
AG AG GTGTCAC
7 23 9

J J DTA DTA
AT AT GTGACAC
CACTGTG
7 12 9

The 2nd strand is cleaved and hairpins form between


the complimentary bases at ends of the V and D
region.
STRUCTURE AND GENETIC CODES
OF MHC
MHC molecules

MHC class I MHC class II


Peptide

Peptide
binding groove

Cell Membrane
Overall structure of MHC class I molecules

MHC-encoded -chain of 43kDa

2 1 -chain anchored to the cell membrane

Peptide antigen in a groove formed


3 2m from a pair of -helicies on a floor of
anti-parallel strands

2-microglobulin, 12kDa, non-MHC encoded, non-


transmembrane, non covalently bound to -chain

3 domain & 2m have structural & amino acid


sequence homology with Ig C domains Ig GENE
SUPERFAMILY
Overall structure of MHC class II molecules

MHC-encoded, -chain of 34kDa


and a -chain of 29kDa
and chains anchored to the cell membrane
1 1
No -2 microglobulin

Peptide antigen in a groove formed from a pair of -


2 2 helicies on a floor of anti-parallel strands

2 & 2 domains have structural & amino acid


sequence homology with Ig C domains Ig GENE
SUPERFAMILY
Simplified map of the HLA region
DP DM LMP/TAP DQ DR B C A
1 3 4 5

MHC Class II MHC Class I


Class III

Polygeny
CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia genes)
CLASS II: 3 types HLA-DP HLA-DQ HLA-DR.
3 extra DR genes in some individuals can allow 3 extra HLA-DR molecules
Maximum of 9 types of antigen presenting molecule allow interaction with
a wide range of peptides.
Simplified map of the mouse MHC

Chromosome 17

K M LMP/TAP A E D L

Class I Class II Class III Class I

Similar organisation to the human MHC except:

one class I gene is translocated relative to human MHC


2 pairs of genes encoding class II molecules
no alternative class II chains
Antigen sampling in the Gut
Innitiation of adaptive immune response
In the GUT
Cooperation between Innate and Adaptive Immune Response

http://2008.igem.org/Team:Slovenia/Background/Immune_re.
Lectin-glycan interactions in the control of immune cell homeostasis.
Nature Immunology 9, 593 - 601 (2008)
Host Microbe interaction in the Gut
Interaction Microbiota and Mucosal
Epithelial cells
Trends in Immunology Volume 34, Issue 5, May 2013, Pages 208215
Trends in Microbiology Volume 20, Issue 10, October 2012, Pages 467476
Diabetes Metab J. 2015 Aug;39(4):291-303. English.
Nature Immunology 14, 668675 (2013 doi:10.1038/ni.2635
B) Healthy humans and other animals have enormous numbers of bacteria and other microorganisms in the lower intestine.

http://www.mucosalimmunology.ch/de/The-lab-University-of Bern Switzerland


Mucosal Tolerance
Mechanisms of induction of mucosal tolerance.
Front. Microbiol., 13 January 2015
TRANSCRIPTION TRANSLATION
PROCESS
CENTRAL DOGMA
https://www.studyblue.com/notes/note/n/ch-17-gene-to-
protein/deck/6947214
http://sphweb.bumc.bu.edu/otlt/MPH-Modules/PH/PH709_DNA-Genetics/PH709_DNA-
info@tritechresearch.com
ABERRANT OF MUCOSAL
IMMUNE STATUS AND RESPONSE
IN ALLERGY
The genetic glitch of Allergy

CHROMOSOME 5

CHROMOSOME 6

CHROMOSOME 11q

CHROMOSOME 12

CHROMOSOME 13q14
Factors that promote Allergic reaction in mucosa
Allergic enterocyte
1. Genetic glitch of intestinal cells and immunocompetent cells
http://www.foodallergysleuth.com/2013/07/genetic-glitch-at-root-of-food-
2. Intestinal Epithelial Barrier Dysfunction
allergies Journal of Allergy Volume 2012 (2012),

Eur J Gastroenterol Hepatol 2005 Dec;17(12):1279-85

2. Defect of tight junction J. Nutr. 141: 769776, 2011


3. Enhance Trans epithelial Antigen transport, role of IgE/CD23
4. Intestinal dysbiosis www.intechopen.com
5. Lack of microbiota stimulation Immunological Reviews 2005 Vol. 206: 204218
6. Aberrant of intestinal epithelial cells response to
allergens
8. Defect or weakness of T reg-TGF
9. Lack of Tolerance
10. Propensity to Th2 differentiation
11. Allergenicity of protein
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
instead. Immunol Res. 2012 December ;
54(0)
Intestinal Epithelial Barrier
Dysfunction in Food Hypersensitivity
Linda Chia-Hui Yu

Intestinal epithelial barrier plays a critical role in the maintenance of


gut homeostasis by limiting the penetration of luminal bacteria and
dietary allergens, yet allowing antigen sampling for the generation of
tolerance. Undigested proteins normally do not gain access to the
lamina propria due to physical exclusion by tight junctions at the cell-
cell contact sites and intracellular degradation by lysosomal enzymes
in enterocytes.
The sensitization phase of allergy is characterized by antigen-induced
cross-linking of IgE bound to high affinity FcRI on mast cell surface,
leading to anaphylactic responses. Recent studies have demonstrated
that prior to mast cell activation, food allergens are transported in
large quantity across the epithelium and are protected from
lysosomal degradation by binding to cell surface IgE and low-affinity
receptor CD23/FcRII. Improved immunotherapies are currently
under study including anti-IgE and anti-CD23 antibodies for the
management of atopic disorders.
Journal of Allergy Volume 2012
(2012)
Abstract
The epithelial barrier dysfunction is an important pathogenic feature in a number of diseases.
The underlying mechanism is to be further investigated. The present study aims to investigate
the role of tight junction protein claudin-2 (Cldn2) in the compromising epithelial barrier
function. In this study, the expression of Cldn2 in the epithelial layer of mice and patients with
food allergy was observed by immunohistochemistry. The induction of Cldn2 was carried out
with a cell culture model.
The Cldn2-facilitated antigen internalization was observed by confocal microscopy. The
epithelial barrier function in the gut epithelial monolayer was assessed by recording the
transepithelial resistance and assessing the permeability to a macromolecular tracer. The
results showed that the positive immune staining of Cldn2 was observed in the epithelial layer
of the small intestine that was weakly stained in nave control mice, and strongly stained in
sensitized mice as well as patients with food allergy. Exposure to cholera toxin or
Staphylococcal enterotoxin B induced the expression of Cldn2 in HT-29 or T84 cells. Cldn2
could bind protein antigen to form complexes to facilitate the antigen transport across the
epithelial barrier. Blocking Cldn2 prevented the allergen-related hypersensitivity the intestine.
We conclude that the tight junction protein Cldn2 is involved in the epithelial barrier
dysfunction. E | www.plosone.org August 2013 | Volume 8 | Issue 8 |
e68547
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 ve T cells by anti- gen-presenting cells, mainly dendritic cells (DCs).
Immunological Reviews 2005 Vol. 206: 204218
IgE/CD23-mediated transepithelial antigen transport in allergic
intestines. http://www.hindawi.com/journals/ja/2012/596081/fi
FcRII

Nature Reviews Immunology 8, 205-217 (March


FcRII
FcRII

Actions of IgE in food allergic reactions


Immunol Rev. 2011 July ; 242(1): 128143.
http://www.foodallergysleuth.com/2013/07/genetic-glitch-at-root-of-food-
allergies
Classical mechanisms of atopy in asthma and atopic
dermatitis.
Nature Reviews Immunology 4, 978-988 (December
2004)
http://blogs.yahoo.co.jp/janeway_tlr2/65556708.ht
ml
HOW TO REGULATE ABERRANT
OF MUCOSAL IMMUNE RESPONSE
IN ALLERGY
Role of Treg and Breg cells in the suppression of allergic inflammation.
https://aaaai.confex.com/aaaai/2014/.../Handout/.../Akdis2101Hando
ut.
The healthy microbiota.Asymbiotic relationship exists between the intestinal microflora and the

host. The nature of this relationship depends on the type of bacterial species present.
THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Immunomodulatory effects of the microbiota in the gut have the potential to decrease allergic inflammatory responses.

THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY


http://www.ncbi.nlm.nih.gov/books/NBK27145/
Comparison of VDJ recombination and germline transcription of
TCR-Vbeta genes.
http://www.nature.com/icb/journal/v86/n2/fig_tab/7100120f4.html
http://www.arthritis.co.za/immunologyupdate.html
Lactobacillus GG acts on different mechanisms of
CMA. Pharmaceuticals 2012, 5(6), 655-664;
Schematic representation of the potential mechanisms of action of
probiotics in children with cows milk allergy.

Pharmaceuticals 2012, 5(6), 655-664;


Immunoregulatory circuits in the gut mucosa

triggered by food components.


www.frontiersin.org May 2013 | Volume 4 | Article 102 |
THANK VERY YOU MUCH
HARTELIJK BEDANKT
DANKE SEHR
ARIGATOGOZAIMASHITA
FEICHANG GANXIE
Intestinal epithelial cells: regulators of barrier
function and immune homeostasis
Nature Reviews Immunology 14,141153 (2014)
Epithelial-cell recognition of commensal
bacteria and maintenance of immune
homeostasis in the gut
Nature Reviews Immunology 8, 411-420 (June 2008)
IgE/CD23-mediated transepithelial antigen transport in allergic
intestines.
Intestinal Epithelial Barrier Dysfunction in Food
Hypersensitivity
Journal of Allergy 2012(1687-9783):596081
IgE/CD23-mediated transepithelial antigen transport in allergic intestines. In
food allergy, Th2-skewing and IL-4 synthesis induce isotype switching in B cells
to produce a large amount of IgE that is secreted into serum and gut lumen, or
bound to high affinity receptor FcRI on mast cell surface. IL-4 also acts on
intestinal epithelial cells to upregulate the expression of low-affinity IgE
receptor, CD23/FcRII. Following exposure to dietary allergens, enhanced
luminal-to-serosal transepithelial antigen transport is mediated by IgE/CD23
prior to mast cell activation during phase I. Transcytosed allergens reach the
subepithelial lamina propria and cause IgE cross-linking on mast cells, resulting
in cell degranulation and anaphylactic responses. The release of mast cell
mediators, such as histamine, prostaglandin, serotonin and proteases, are
known to induce epithelial ion secretion and to increase paracellular epithelial
permeability in phase II.
Overview of therapeutic strategies to limit Th2 activity in allergic diseases, including
asthma. Drugs can directly inhibit Th2 effector function or modulate APC function.
Otherwise, drugs may act to promote Th1 or Treg cell activities. See text for further
details
Pharmacology & Therapeutics 112 (2006) 489 500
Mechanisms of induction of mucosal tolerance.
Frontier in immunologyJanuary 2015 | Volume 5 | Article 781
A multistep model of oral tolerance to soluble antigens.

Mucosal Immunology VOLUME 5 NUMBER 3 | MAY 2012


Step-wise induction of oral tolerance.
Frontiers in Immunology |
August 2015 | Volume 6 | Article 415
MATUR NUWUN
Mucosal immune responses involved in interacting with fungi at different
body sites.
Nature Reviews Immunology 14, 405416 (2014)
T cell distribution following parenteral and respiratory mucosal tuberculosis
(TB) immunization.
Trends in Immunology 31 (2010) 247252
http://www.dept-med.pitt.edu/paccm/faculty/raya.html
http://www.dept-med.pitt.edu/paccm/faculty/raya.html
The mechanisms that contribute to ocular immune privilege are multiple and overlapping.

http://www.streilein-foundation.org/ocular_immunology.html
Immunoregulation on the ocular surface:
http://www.nature.com/mi/journal/v3/n5/fig_tab/mi201026f1
Homing properties of human mucosal memory/effector B cells.
http://www.journaloforalmicrobiology.net/index.php/jom/artic
This diagram, resembling the oriental symbol for yin and yang, represents microenvironmental factors that stimulate T-cells to

express either T-helper 1(Th1) or


Thelper 2 (Th2) cytokines which are associated with "cellular and "humoral"
immunity, respectively.
Liu et al. Trends in Immunol v34 p120-128, 2012
Human gut microbiota: repertoire and variations
Front. Cell. Infect. Microbiol., 02 November 2012
OUTLINE

INTRODUCTION
HOST DEFENCE
STRUCTURE
IMMUNOCOMPETENCE CELLS
INDUCTIVE SIDE
EFFECTOR SIDE
CMIS
INNATE IMMUNITY
ADAPTIVE IMMUNITY
Steps of TcR gene recombination

V 7 23 9 A number of other proteins, (Ku70:Ku80,


XRCC4 and DNA dependent protein
D J 9 12 7 kinases) bind to the hairpins and the
heptamer ends.

The hairpins at the end of the V and D


regions are opened, and exonucleases
V D J and transferases remove or add random
nucleotides to the gap between the V
and D region

DNA ligase IV joins the ends of the V


9

and D region to form the coding joint


7 23

V D J and the two heptamers to form the


7 12 9

signal joint.
V3
V2
V4
CACAGTG
GTGTCAC
7 23 9
GTGACAC
7 12 9 V5
CACTGTG
V9
V8
Heptamers are ligated by V6
DNA ligase IV V7
U U

V
TC

D J
AG AT
V
U
TC

U
TA
J D
AT AG
TA

V and D regions juxtaposed