Fischer HLA und Krankheit ÖGTB 2013

HLA und Krankheit
ÖGBT Jahrestagung
Parkhotel Schönbrunn, Wien
06.06.2013
15 min
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Allgemeines
Historisches
Beispielhaftes
Mechanistisches
Wozu?
HLA Assoziationen
• Case Control
• OR/RR – mäßig (Bestätigung) bis sehr hoch
• Kein krankheits-spezifisches Allel
• Funktionelle Kausalität oft nicht bekannt
(„auto-immun“)
Table 1. Some HLA associated autoimmune diseases (Thorsby & Li, 2005)
a
Ctrls
a
b
Disease
HLA
Pts
RR
Ankylosing spondylitis
B27
> 95
9
> 150
Subacute thyroiditis
B35
70
14
14
Psoriasis vulgaris
Cw6
87
33
7
Graves disease
DR3
65
27
4
Myasthenia gravis
DR3
50
27
2
Addisons disease
DR3
69
27
5
Rheumatoid arthritis
DR4(some)
81
33
9
Juvenile idiopathic
arthiritis
DR8
38
7
8
Celiac disease
DQ2 (+DQ8)
92
28
30
Narcolepsy
DQ6(02)
> 95
33
> 40
Multiple sclerosis
DQ6(02)
86
33
12
Type 1 diabetes
DQ8(+)
81
23
14
Type 1 diabetes
DQ6(02)
< 0.01
33
0.02
Linkage Disequilibrium
• Definition
– Non random association of alleles at two or more
loci (A1 B8 DR3 DQ2)
• Refinement
– Narcolepsy
– Celiac disease
HLA-DR2->DQ6
HLA-B8 -> DQ2/DQ8
• Genetic marker or culprit?
GWAS-Schizophrenia
• We found significant association with
several markers spanning the
– major histocompatibility complex (MHC) region on
chromosome 6p21.3-22.1,
– a marker located upstream of the neuro- granin
gene (NRGN) on 11q24.2 and
– a marker in intron four of transcription factor 4
(TCF4) on 18q21.2.
Vol 460 | 2009 | doi:10.1038/nature08186
GWAS-Schizophrenia
• Our findings implicating the MHC region are
consistent with an immune component to
schizophrenia risk, whereas the association
with NRGN and TCF4 points to perturbation of
pathways involved in brain development,
memory and cognition.
Vol 460 | 2009 | doi:10.1038/nature08186
HLA Assoziationen
• Infektionskrankheiten???
• Abacavir
HLA und HIV
S. Mallal et al., Lancet 359:727 (2002)
… the presence of HLA-B*5701, HLA-DR7, and HLADQ3 alleles had a positive predictive value … of
100%, and the absence of this combination of
alleles had a negative predictive value of 97% …
Current Opinion in Immunology Volume 25, Issue 1 2013 81 - 89
Current Opinion in Immunology Volume 25, Issue 1 2013 81 - 89
Current Opinion in Immunology Volume 25, Issue 1 2013 81 - 89
Andere Mechanismen
• Interaktionen mit
– TCR
• Shared epitope, shared peptides
– KIR
• HIV
– anderen NK Zellrezeptoren
• ?
– nichtklassisches HLA in LD
• MICA
– Epistasis
• HIV
Wozu?
Abacavir Starters per Year
HLA-B*5701
Prescreening
120
N° of ABC Starter
100
80
60
40
20
0
97/98
98/99
99/00
00/01
01/02
02/03
03/04
04/05
05/06
ABC Terminations per Year
100
90
80
% of ABC Starter
70
60
50
40
30
HLA-B*5701
Prescreening
20
10
0
97/98
98/99
99/00
00/01
01/02
02/03
03/04
04/05
05/06
Hypersensitivity Reactions
14
% of ABC Starters with HSR
12
10
8
6
HLA-B*5701
Prescreening
4
2
0
98/99
99/00
00/01
01/02
02/03
03/04
04/05
05/06