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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
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
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
this organ.
PLOS Biology | www.plosbiology.org
The mucosal immune system (MIS) is interconnected, enabling it to protect
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.
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
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
ITAMs
Zap-70
CD4
CD45
MHC II
T cell activation
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
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
Germline TcR
D-J Joining
V-DJ joining
2nd chance at
V-DJ joining
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)
Vn V2 V1 J C
Germline TcR
Rearranged TcR
1 transcript
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
Germline TcR
D-J Joining
V-DJ joining
2nd chance at
V-DJ joining
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
V V
TC TC CACAGTG
AG AG GTGTCAC
7 23 9
J J DTA DTA
AT AT GTGACAC
CACTGTG
7 12 9
Peptide
binding groove
Cell Membrane
Overall structure of MHC class I molecules
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
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.
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),
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
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.
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
INTRODUCTION
HOST DEFENCE
STRUCTURE
IMMUNOCOMPETENCE CELLS
INDUCTIVE SIDE
EFFECTOR SIDE
CMIS
INNATE IMMUNITY
ADAPTIVE IMMUNITY
Steps of TcR gene recombination
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