Download risk by hla in relatives

HLA ASSOCIATED RISK
General population
General population
General population
First Degree Relatives
First Degree Relatives
First Degree Relatives
DQ
Any
DQ2/8+
DQ2/8Any
DQ2/8DQ2/8
Risk%
1%
2%
0%
12%
0%
24%
RISK BY HLA IN RELATIVES
DQ
DR
2 3/3-3/7
2
5/7
2
3/X
8 4/4-4/7-7/7
x Other (1-5)
TOTAL
Mean
Group Freq cases
G1
0,26
G2
0,37
G3
0,24
G4
0,06
G5
0,08
1,01
Risk Cases Weigh Risk RR24%
1
33
0,26
56,73
0,68
47
0,2516
54,89
0,23
30
0,0552
12,04
0,27
8
0,0162
3,53
0,02
10
0,0016
0,35
2,2
127
2,2
0,733333
0,11692
25,51
Weighed Risk = (Risk * cases)/127
RR24% = (Weighed Risk *24)/Mean Weighed Risk
R ISC H IO D I C E L IA C H IA IN F A M IL IA R I D I C E L IA C O = 12%
6 SONO DQ2 E DQ8 POS
4 S O N O D Q 2 E D Q 8 N E G = R IS C H IO = 0
R IS C H IO = 2 4 %
DR3/3
Rischio = 55%
DR3/7
Rischio = 55%
DR5/7
Rischio = 55%
DR3/X
Rischio = 12%
DR4/4-7
Rischio = 0,4%
Not all DQ2 are identical !
• DQ2.5 = DQA1*0501 /DQB1*0201
• DQ2.2 = DQA1*0501/DQB1*0202
•
•
•
•
and combinations Homo/Heterozygotes
DQ2.5/DQ2.5 = DR3/DR3
DQ2.5/DQ2.2 = DR3/DR7
DQ2.5/DQX = DR3/DRX
DQ2.5 AND DQ2.2
very similar but not identical
!
• Peptide binding properties are almost
identical, but :
• a PROLINE in position P3 has an adverse
effect on binding on DQ2.5 but not on
DQ2.5
• Gluten is the protein richest in PROLINE,
hence a subtle difference become GREAT
PEPTIDE BINDING BY HLA DQ2
Peptide
Glia-a2
Glia-a9
Glu-5
Glia-g1
Glia-g30
Glut-17
Position 3 DQ2.5 B. DQ2.2 B T-cell 2.5 T-cell 2.2
P
P
P
Q
Q
S
15
8
30
14
10
25
130
>500
>500
35
50
12
+
+
+
+
+
+
+
+
+
WE NEED A GENE THRESHOLD TO
START ADVERSE GLUTEN RESPONSE
• Individuals with two copies of αβ
heterodimer (DR3/3 DR3/7) recognize more
gluten peptides , may be too much : they
stimulate a lot of T-cells!
• Individuals with one copy or with a minute
(P3) pouch difference recognize less gluten
peptides and stimulate less T-cells
Many genes, but NOT ONLY GENES ???
• When an high HLA
gene dose is present
(DR3/3 DR3/7)
• and another gene
lower the control to Tcells (CTLA4)
• The infection/nutrition
may well trigger CD !!
T-CELL STIMULATORY
PEPTIDES
30
DR3/3
25
DR3/7
DR3/X
20
15
Threshold
10
5
0
1
2
3
4
5
6
N. of stimulatory peptides
GENOTYPE, AND THE PHENOTYPE ?
• The expression on the cells of HLA DQ2.5
is controlled by
• Coactivator CIITA
»
» IFN-γ
»
result of
which is stimulated by
which is produced as
»INFECTION
WP4: Novel HLA risk locus
• a) Partner 9, UOSLO: A pooled analysis was conducted on
data from Italy, Scandinavia and France by the Homozigous
Parents TDT in DR3 informative trios:
• 1. TNF2 showed an Odds Ratio of 2.40 (1,26-4,48)
• 2. TNF2 associated with MICB*10 showed an OR of 2,32
(1,264,22)
• 3. D62223*3 showed a risk of 4.24
The association of nine loci in the HLA region
telomeric of HLA-A, in CD families
• MICA-A5.1,
MICB-CA24
and
MIB-350,
characteristic alleles of the B8-DR3 extended
haplotype, showed a significantly increased
frequency in DR3 transmitted haplotypes in the
Italian families
• DR3 haplotypes carrying the combination of these
alleles conferred an about 4 fold increased CD risk
(p=0.022; OR=3.83).
WATH IS MCH Class I Chainrelated Gene A/B MIC-A/B?
• A family of highly polymorphic proteins
that match Vδ-1γ/δ T-Cell Receptors
distributed in the Intestinal Epithelium
• Are ‘sentinels’ that respond to ‘self’
antigens
• Are independent of antigen processing
• May regulate protective T-cell response in
the intestinal tract
RISK ASSOCIATED TO MIC
Simplex
T
NT
MICA5.1
22/47
MIB350
Multiplex
p
TT
NTNT
4/14
44/70
22/45
2/13
MICB15
1/47
4/13
MIB348
2/45
3/13
0.006
Simplex+Multiplex
p
p
O.R.
5/15
0.02
2.88
35/68
3/14
0.005
4.48
1/71
1/15
0.003
0.08
3/68
4/14
0.002
0.13
0.001
THE CTLA4 COSTIMULATORY
MOLECULE
COMBINED ANALYSIS OF CTLA4/CD28
LINKAGE
LINKAGE
ASSOCIATION
NPL
TDT
TDT
(AFF. SIB(ALL AFFECTEDS)
(1 AFF. SIB/FAMILY)
PAIRS)
Marker
Best p
Population Fa NPL Best Fam Marker Best p
m
p
Finland
wed/Nor
100
2,70
0,004
104
0,71
0,24
France
UK
Italy
(5)
113
1,24
Combined
322
2,31
-
100
D2S116
104
D2S2214
(329)
136 CTLA4(at)n
0,05
D2S2237
0,013
0,005
D2S2214
0,023
0,002
CTLA4(at)n
0,002
166
D2S2214
0,002
D2S2214
0,002
0,11
113
D2S72
0,022
D2S2237
0,016
0,01
844
D2S2214
0,002
D2S2214
0,002
WHO IS THIS C.D. MAN ?
• A strong warrior, survivor to many battles
against bugs : parasites, bacteria, viruses !
• His weapons are :
• a very efficient HLA DQ2 system capable of
recognizing many antigens + coadjuvants
• a wide system of antigen handling in the cell
• a considerable lack of suppression of T-Cells
(CTLA4)