Documente Academic
Documente Profesional
Documente Cultură
NIH
JDRF
Alexander V. Chervonsky
The University of Chicago
KleinandFlanagan
Rubtsova etal.,JCI,2015
physical and
chemical
insults
biological
insults
CSHpress,2013
Wheelotella sp.
Reyniers germfreesystem1
massproductionIsolator
Diabetes
Sialitis
% incidence
80
70
60
Male
50
Female
40
30
20
10
0
1
Center
Yurkovetskiy etal.,Immunity2013
Institution
SPF Facilities
U of Chicago
Yale 2008
Taconic 2009*
Harvard
T1DR** Jax
2002
2003
2004
2005
2006
2007
2008
2009
Germ-Free
Facilities
Taconic 2008
U of Chicago 2012
Gnotobiotic
Facilities
Taconic ASF 2008
Female
(F)
Male
(M)
Ratio F/M
60%
90%
80%
50-60%
--75%
85%
90%
80%
65%
100%
90%
90%
25%
70%
50%
10-15%
--50%
60%
45%
40%
35%
65%
85%
65%
2.4
1.3
1.6
4.4
--1.5
1.4
2.0
2.0
1.9
1.5
1.1
1.4
100%
95%
85%
84%
1.2
1.1
ND
75%
*CumulativeincidenceofdiabetesinNODmiceat
30weeksofage.
T1DR T1DrepositoryatTheJacksonLaboratory
regulatory
step 1
A
hormonesmicrobes
autoimmunity
microbialcontrol
B
hormonesmicrobes
autoimmunity
C
hormonesmicrobes
autoimmunity
effector
step 2
A
hormonesmicrobes
microbialcontrol
autoimmunity
microbialcontrol
autoimmunity
Experiment 1
Experiment 2
Experiment 4
Experiment 3
Proportion of seqquences
belonging to a listed family, %
Phylum Bacteroidetes Actinobacteria Firmicutes Proteobacteria Firmicutes Firmicutes Bacteroidetes Firmicutes Bacteroidetes
Family Porphyromonadceae Kineosporiaceae
Veillonellaceae Enterobacteriaceae
LactobacillaceaeCytophagaceae
Peptococcaceae
Bacteroidaceae
Peptostreptococcaceae
Kineosporiaceae
80
p<0.004
60
0.12
p<0.016
Veillonellaceae
p<0.05
0.8
Enterobacteriaceae
0.4
p<0.04
Peptococcaceae
0.6
p<0.04
p>0.57
0.6
0.08
40
0.3
0.4
0.4
0.2
0.2
M F
Prepubescent
0.00
Postpubescent
0.0
50
p<0.03
p<0.005
40
30 p>0.34
20
10
p<0.0003
q=0.02
p<0.0008
q=0.05
3 p<0.001
q=0.05
0.2
0.04
20
Lactobacillaceae
0.1
0.0
0.0
FF
M
M
FF
M
M
F
F
M
M
conclusions
Input microbiota affects gender differences in postpubescent animals
Hormones affect gender differences
Gender bias in NOD T1D does not depend on a
specific microbial lineage
Incidence of T1D, %
GF F (n=81)
SFB F (n=10)
GF M (n=25)
SFB M (n=18)
75
50
25
0
10
20
Wks
30
autoimmunity
male
GFNOD
ASFNOD
DiabetesIncidence,%
100
80
60
40
20
0
10
20
30
Wks
micewithnoprotectivemicrobiota
micewithprotectivemicrobiota
Since
a. protective bacteria protect at a wide range of
androgen concentration in blood, and
b. ASF that elicits reasonable levels of androgens
does not protect males from T1D,
it is likely that linear hypothesis B is also incomplete
single mom
traditional
family
T1D incidence, %
100
traditional family
single mom
80
60
40
20
0
10
20
Age (weeks)
30
20 mice/group
amplification
regulatory loop
hormones
microbes
Block of
autoimmunity
M
GF
SPF
3
P=0.001
Control Castrated
P=0.025
P=0.02
% IF N
10
2
1
CD4
CD8
% IF N
% IFN+ cells
CD8
IFN (pg/ml)
3000
2000
1000
M Gender
SECS
M
WT
-
F
WT
-
M
M
IFNKO WT
+
F
WT
+
M
IFNKO
+
Female MF
9.6
PI
Male MF
17.6
Male MF+anti-IFNg
11.5