Inmunomodulacion y

Tolerancia en Alergia
Dr Jhann Arturo MD.MSc.MRes.PhD
Instituto de Medicina Molecular Inmugen
Corporation
Pontificia Universidad Javeriana
Bogota Colombia

inmugen@gmail.com

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS
Resumen de la Conferencia
Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico y Tolerancia Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

Homotoxicology
IMMUNOMODULATION

DETOXIFICATION
AND DRAINAGE

ORGAN REGULATION &

CELLULAR ACTIVATION

Atopia y Alergia

Atopia (del griego a + topos, "sin lugar",

"desubicado") fue acuado por Coca en 1923 para

calicar a aquellas personas con predisposicin
familiar para padecer alergia a sustancias muy
variadas e inocuas para la poblacin general.

Atopia y Alergia

Alergia (de griego allos ergo, reaccin alterada) es un

concepto ms amplio que fue introducido por Von
Pierquet en 1906 para designar la respuesta anormal
que se produca en determinados animales frente a
sustancias concretas (alergenos) tras una exposicin
previa.

Atopia y Alergia

La atopia puede ser causada por factores

hereditarios o por la excesiva canOdad de

Inmunoglobulina E(IgE) en la sangre lo cual hace la
reaccin de glbulos blancos excesiva o ms de lo
necesario.

PoluOon

Epidemiologia Alergica
En las ulOmas decadas las enfermedades alergicas han

alcanzado proporciones epidemicas.

Millones de personas alergicas
15 millones de asmaOcos en USA.
El incremento se atribuye al efecto que ejercen los cambios
producidos en el medio ambiente sobre los individuos que
Oenen predisposicion.
CONTAMINACION

AnOgen Processing and PresentaOon

Paul W.E.. Fundamental Immunology. Lippincott Williams & Wilkins; 4th edition (January 15, 1999)

Th17
TReg

Th1

Th3

Th0

TSup

Th4
Th2

Cytokine Proles and Immune PolarizaOon

More Than Th1/Th2


IgG2a - ADCC

INMUGEN CORPORATION
NKT

Tumores

CD3

CD16+

R/. Inmune
Celular

CD56+

R/. Inmune
Humoral

LTCD4

Th1

IL-4
IL-5 LTCD4
IL-6
IL-10 CD3
IL-13 CD20

NK CD16+

Abortos

CD56+

CD3

CD28-

CD8 TReg
Th-4?

CD3

Th3

TGF- LTCD4 Reg

IFN- FoxP3+
IL-10
IL-4
TGF-

IL-17
IL-10

CD25

IgE

+
Y Y Y

LTCD4
IL-1
IL-23
IRF-4

Th-23
LTCD4

LB1
CD20

+
Y
Y

IL-6

Intolerancia
Alimentaria
IgA
IgG2b/IgG4a

CD19+CD5+

-
Y

CD3

Th-10 ?

Th-17

Lisis Complemento IL-5 Eosinolia

Inmunocomplejos
ADCC
AnU-Receptor
Alergias

Treg
CD8+CD122+

Tsup

Adiponectina

Y
Y

IFN-
IL-10
TGF-

Leptina
Resistina

Y
Y
Y

MS, ELA, mieliUs, GB,

IL-6

HLA-DR CD64

Autoinmunidad T LTCD8s

APC

IgM
IgG
IgA

CD28+

CD10

TNF-
LT
IL-2
IFN-
IFN-

LTCD8c

-
ROS
NO-
Fr

LBCD19

Resultado

GM-CSF
M-CSF

+
Y Y Y

Bacterias
Parsitos
Hongos

NKU
CD16+CD9+

CD3
AcUvacion
Macrofagos TLR-2-4

Virus

IL-5
IL-7
IFN-

Th2

Progresin

Y
Autoinmunidad B

IgG AutoanUcuerpos
ANAS ANCAS -ENAS A-CCP3 DNAds
AnU-Mielina, AnU-rACh
Inmugen Corporation Cra 45 A No. 103B-52. Boota Colombia. Tel: 7049872. inmugen@gmail.com

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS

Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico y Tolerancia Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

Factores de Riesgo en la Sensibilizacion Inmune

Problema Central de Alergias
Sensibilizacion anOgenica-alergenica
Toxicidad (Contaminacion)
Infeccion (Viral, Bacteriana, MicoOca, Parasitaria (Th2)
EsOmulacion dietaria (malos habitos, mala dieta, exceso productos
animales, toxicidad alimentaria)
Obesidad
Fragilidad Neuropsicologica

Perdida de la tolerancia

GeneOca y Medio El Ambiente

Pathogenic

Gluckman P.D. and Hanson M.A. Living with the Past: Evolution, Development, and Patterns of Disease. Science. VOL 305. 17 September 2004

GeneOca y Medio El Ambiente

Los factores
hereditarios
determinan el riesgo de
desarrollar una
enfermedad alergica.
Los cambios en el
medio ambiente
(Interno y Externo) son
los disparadores de la
alergia.

GeneOca y Medio El Ambiente

GeneOca y Medio El Ambiente

GeneOca Alergica

Genes polimorcos de predisposicion

Cr 2: CD28, CTLA-4, ICOS
Cr 5: CD14, B2-Rptr, Th2 Cluster (IL-3, IL-4, IL-5, IL-9,

IL-13, GM-CSF).
Cr 6: HLA-DR, TNF-alpha
Cr 11: FCeRI B-chain, T-Bet
Cr 12: IFN-gamma, NO sintetasa, STAT-6
Cr 16: IL-4 Rcptr

William W. Busse, Lanny J. Rosenwasser. Mechanisms of asthma. Journal of J Allergy Clin Immunol 2003;111(3):S799-804.)

Enfermedades asociadas a polimorsmo

genOco
Protena

IL-1, ILRA
IL-2

IL-4

IL-5

IL-10

IL-13

IFN-

TNF-

TGF-

Fc-RII b1
Insulina

RANTES

Nramp 1

Nramp 2

ACE 1

CCRX 2 y 5
MHC clase II
IL-12R/Tpm1

Enfermedad

OsteoartriOs, periodonOOs
Diabetes mellitus Insulino dependiente
Asma
Atopia
LES
Asma
Asma y atopia
LES, AR y otras
Rechazo de trasplante
LES
Diabetes mellitus insulino dependiente
DermaOOs Atpica
HIV, TB, ARJ
Anemia
Hipertensin arterial
HIV
Muchas enfermedades

Lehismaniasis cutnea

Polymorphism in regulatory gene sequences. N A Mitchison. Genome Biology 2000, 2:comment2001.1 2001.6.http://genomebiology.com/
2000/2/1/comment/2001

Zytokin Mix
1
IL 1
2
IL 1
3
IL 1
4
IL 1
5
IL 1
6
IL 1
7
IL 1R
8
IL 1R
9
IL 1RA
10
IL 1RA
11
IL 4R
12
IL 4R
13
IL 12
14
IL 12
IFN
15
IFN
16
17
TGF
18
TGF
19
TGF
20
TGF
21
TGF
22
TGF
23
TNF
24
TNF
25
TNF
26
TNF
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48

IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL
IL

2
2
2
2
4
4
4
4
4
4
4
4
6
6
6
6
10
10
10
10
10
10

Allelic specificity
T at pos -889
C at pos -889
C at pos -511
T at pos -511
T at pos +3962
C at pos +3962
C at pos pst1 1970
T at pos pst1 1970
T at pos mspa1 11100
C at pos mspa1 11100
G at pos +1902
A at pos +1902
C at pos -1188
A at pos -1188
A at pos UTR 5644
T at pos UTR 5644
C at Codon 10 ;G at Codon 25
C at Codon 10 ;C at Codon 25
T at Codon 10 ;G at Codon 25
T at Codon 10 ;C at Codon 25
C at Codon 10
T at Codon 10
G at pos 308 ;G at pos -238
A at pos 308 ;G at pos -238
G at pos 308 ;A at pos -238
A at pos 308 ;A at pos -238
T at pos 330; G at pos +166
G at pos 330, G at pos +166
G at pos 330; T at pos +166
T at pos 330; T at pos +166
T at pos1098 ;T at pos -590
T at pos-1098 ;C at pos-590
G at pos-1098 ;T at pos-590
G at pos-1098 ;C at pos-590
T at pos-590 ;T at pos-33
T at pos-590 ;C at pos-33
C at pos-590 ;T at pos-33
C at pos-590 ;C at pos-33
G at pos 174; G at pos nt565
C at pos 174; G at pos nt565
G at pos 174; A at pos nt565
C at pos 174; A at pos nt565
G at pos 1082; C at pos-819
G at pos 1082; C at pos-592
A at pos 1082; C at pos-819
A at pos 1082; T at pos-819
A at pos 1082; C at pos-592
A at pos -1082; A at pos-592

Spezifitt
Size bp
SpezSpec
T
220
C
220
C
215
T
215
T
336
C
336
C
288
T
288
T
297
C
297
G
143
A
143
C
802
A
802
A
277
T
277
CG
80
CC
80
TG
80
TC
80
C
195
T
195
GG
110
AG
110
GA
110
AA
110
TG
562
GG
564
GT
569
TT
569
TT*
557
TC*
557
GT*
557
GC*
557
*TT
610
*TC
610
*CT
610
*CC
610
GG
427
CG
426
GA
428
CA
428
GC*
305
G*C
530
AC*
305
AT*
305
A*C
530
A*A
530

GeneOca y Medio El Ambiente

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

P Value (Log10)

was with a SNP within the IL18R1 gen

15
(P = 3.4109; odds ratio, 0.87). IL18
proximity to IL1RL1, which also con
HLA-DQ
showing significant association w
(Table 1 in the Supplementary App
SNPS were in high linkage disequi
rs3771166 (r2 = 0.96 for the correla
10
ORMDL3/GSDMB
rs3771166 and each of the three mo
IL33
IL18R1
SMAD3
IL2RB
SNPs on the IL1RL1 gene). A locus
rs9273349 in the HLA-DQ region of t
RORA
SLCA22A5 IL13
tocompatibility complex gene (MHC)
strong evidence of association in the
5
ple (P = 71014; odds ratio, 1.18).
significant association between
rs1342326 (on chromosome 9), flan
gene (P = 91010; odds ratio, 1.20) (T
SNPs showing significant associati
0
ease were rs744910 on chromosome 1
1
2
3 4 5 6 7 8 9 10 11 12 13 14 151617
X
22
18
odds ratio, 0.89), within the SMAD
Chromosome
19 21
20
rs2284033, within IL2RB on chro
(P = 1108; odds ratio, 0.89) (Table
Figure 1. Manhattan Plot of Study Results.
The odds ratios for these loci g
The results of genomewide association testing are shown for all subjects.
gested more pronounced effects in
The horizontal line indicates the stringent genomewide significance threshold
8
11
(P7.210 ). Gene names are provided for loci at this level of significance
onset asthma than in later-onset
and are also provided for loci at the less stringent threshold of P510 7
HLA-DQ region was observed to ha
used by the Wellcome Trust Case-Control Consortium.6
stronger association with later-o
(P = 4108; odds ratio, 1.26) than wit
unknown and those with occupational asthma or onset disease (P = 2105; odds ratio
N Engl J Med 363;13 Nejm.Org September 23, 2010
severe asthma) and controls (Fig. 1 and Table 2, ever, none of these differences wer
and Table 1 in the Supplementary Appendix). The (Table 2 and Fig. 2, and Table 2 in
mentary Appendix).

GeneOca y Medio El Ambiente

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 3. Peak Associations with Total Serum IgE Compared with Peak Associations with Asthma.*
Chromosome

Gene

Marker

Position

P Value, Random Effects

IgE

Asthma

Loci linked to serum IgE

1

FCER1A

rs2252226

157542777

6.6105

4.7101

IL13

rs20541

132023863

1.0106

2.8107

HLA-DRB1

rs9271300

32689560

8.31015

3.2101

12

STAT6

rs167769

55790042

8.5107

7.2104

16

IL4-R/IL21R

rs1859308

27305499

8.2106

3.5101

IL18R1

rs3771166

102352654

2.0101

3.4109

HLA-DQB1

rs9273349

32733847

5.4105

7.01014

IL33

rs1342326

6180076

6.0101

9.21010

15

SMAD3

rs744910

65233839

1.5101

3.9109

17

GSDMB

rs2305480

35315722

6.0102

9.6108

17

GSDM1

rs3894194

35375519

3.0101

4.6109

22

IL2RB

rs2284033

35863980

3.9101

1.1108

IL13

rs1295686

132023742

2.4106

1.4107

SLC22A5

rs2073643

131751187

2.0102

2.2107

15

RORA

rs11071559

58857280

3.0102

1.1107

Loci linked to asthma

* Two sets of loci are shown: the most significant hits that show association with the total serum IgE level (on the basis of
genomewide-association-study significance in the current study or previously published studies) and those that show association with asthma in the current study.
The nominal gene was taken from the Illumina SNP database.
Position is based on the number of base pairs from the start of the chromosome.
P values are shown for the association of marker with phenotype in a random effects model.

Many loci have been reported to have an assowith the mucosa. RORA encodes a member of the
N Engl J Med 363;13 NR1
Nejm.Org
September
23,hormone
2010 receptors. It ciation with asthma47; most of these associations
subfamily
of nuclear
is expressed at high levels in keratinocytes, to- were not significant in our well-powered study.
gether with a cluster of genes that form the struc- The relative risks observed with our markers will

Factores de Riesgo Prenatales

GenOcos
Desequilibrio en la expresin de
los genes para citoquinas Opo 1
(IFN-, Chr 12) y Opo 2 (IL-4, IL-13,
en Chr 5 )
Ambientales intrauterinos
Predominio de citoquinas Th2
Ausencia de eskmulos infecciosos
que induzcan la sntesis de IL-12
por DC
Factores que esOmulen la sntesis
de PGE2 que suprime
principalmente la sntesis de IFN-
pero no de IL-4 o IL-5

Predominio citoquinas perl Th2 (IL-4

e IL-10) Atena la respuesta
alognica Th1 potencialmente
peligrosa para el feto
Clulas NK uterinas : ConsOtuyen el
mayor porcentaje de linfocitos en el
implante fetal y secretan IFN-gamma
necesario para el desarrollo de la
decidua y remodelacin vascular
uterina
Clulas NKT (NK1.1+ TCR+ CD4-
CD8-) : Reconocen glipolpidos (LPS)
a travs del CD1d Se desarrollan in
situ por eskmulo de las beta 2
microglobulinas expresadas por en el
feto por los alelos HLA paternos

Sugiyama M, Arakawa H, Ozawa K, Mizuno T, Mochizuki H, Tokuyama K, Morikawa A. Early-life risk factors for occurrence
of atopic dermatitis during the first year.Pediatrics. 2007 Mar;119(3):e716-23.

Factores de Riesgo Post-Natales

Factores
ost-Natales
Exposicin materna
a de Riesgo
PTabaco:
El humo esOmula la
aeroalergenos:
sntesis de IL-4 y de IgE y
IgG cordal para alergenos
Eos
inhalantes < desarrollo de
Microora intesOnal:
alergia
Lactancia materna:
300 m 2 de intesOno
Previene infecciones y
colonizados con 1 kg de
sibilancias precoces
bacterias aportan la
Modula selecOvamente la
primera seal
maduracin del SI del RN a
maduraOva para el SI
travs de su contenido en
citoquinas y cidos grasos
Bacterias fagocitosis
insaturados
por macrfagos
Dieta: cidos grasos omega-6
expresin de molculas
son precursores de PGE2
co-esOmulatorias y
IL-4
citoquinas
esOmulacin Th

Factores de Riesgo Post-Natales

Polucin
ambiental: de Riesgo
Endotoxinas:
Factores
P
ost-Natales
Parkculas emanadas de
Derivadas de grmenes
motores diesel esOmulan
Gram (-) inducen IL-12 y
expresin de genes de
respuesta Th1 Los nios
citoquinas niveles de IgE
criados en granjas con alto
especca mayores en los
contenido de bacterias
que viven cerca de las
Oenen una menor
autopistas
prevalencia de alergia
Infecciones: EsOmulacin de Stress: Las catecolaminas y
la maduracin Th1
corOcoides pueden causar
Inmunizaciones (BCG),
una polarizacin de las
Infecciones (hepaOOs A),
respuestas hacia citoquinas
AnObiOcos
Th2
Los nios con hermanos
mayores Oenen < incidencia
de asma

Hipotesis de Higiene
La disminucion de
infecciones por germenes
intracelulares en los
primeros anos de vida es un
factor relevante para la
falta de acOvacion de
mecanismos inmunes Th1
Estos mecanismos Th1
contraregulan los Th2
responsables de la
induccion de los procesos
alergicos.

Hipotesis de la Higiene y Desarrollo Inmune

Nacimiento
predominio TH2
Hermanos mayores
Numerosas infecciones
Ambiente rural

Alergenos

Estimulacin
TH1

Busse WW, Lemanske RF. Advances in Immunology. NEJM. 2001; 344:350-362.

Hijo nico
Escasas infecciones
Ambiente urbano
Persistencia
TH2

NEWSFOCUS

Bacteria and Asthma:

Untangling the Links
Our guts and airways are awash in bacteriabut people with asthma
have a different balance of microbes. Could this be a cause of disease?
SIX YEARS AGO, GARY HUFFNAGLE, AN
immunologist at the University of Michigan,
Ann Arbor, conducted an experiment that
reflects what happens to many of us early in
life. He exposed mice to a triple whammy:
yeast in their intestines, mold spores up their

ean section, who experience a more sterile

entry into the world than those born vaginally, are more likely to get asthma. So are
young children treated with many courses of
antibiotics. Along with animal studies, these
observations suggest that the balance of bac-

SCIENCE VOL 330 26 NOVEMBER 2010

who stay healthy. Its really coming down

to the bacterial community structure, whos
there, and in what numbers, and where,
Huffnagle says. Cataloging these inhabitants is a new frontier.

.sciencemag.org on April 8, 2013

Bugs galore. We all harbor bacteria,

but asthmatics host different species,
including Staphylococcus aureus.

one of the first

gsaw puzzle of
elusive even as
g. Researchers
examuch less
A rich
ldhood
William
ian and
e Lonre now
nvironploring
t influ-

sound,
at baccesar-

play host to bacterial residents. But children

who develop asthma, researchers are learning, are home to different bacteriaand
sometimes a less diverse mixthan those

SCIENCE VOL 330 26 NOVEMBER 2010

26 NOVEMBER 2010

chance to assuag
colleagues were r
nant women with
of disease in their
swabs
were 4
certai
their g
harbor
airwa
influen
Th
and so
years
had h
Sterile birth. C-sections, which
early
expose babies to fewer bacteria
pared
than vaginal births, are linked
out th
to a higher risk of asthma.
publis

VOL 330 SCIENCE www.sciencemag.org

geneticist Miriam Moffatt, leaders.

for limited gene sequencing
own variation of Bisgaards
So far, the evidence linking asthma and is inhaled, and because wer
They had at their disposal bacteria are associations, not proof that an young children, a lot of this
sequencing techniques that imbalance of bacteria causes the disease. The ingested, says von Mutius.
h more comprehensive cen- big question, says Martinez, is, Do asthmatAlthough researchers a
flourishing
childs m
anuary, the
affected by
colleagues
ment, they
ONE that
this for su
ced more
ing definiti
ent species
teria help c
including
remarkably
ma and othonly proof li
althy.
ized control
al balance
you someho
rent in the
exposure a
ected chilsick, says B
e proteoResearch
h include
menting wit
influenza.
in the gu
Hay protects. Youngsters on farms
bacteria
microorgan
are less prone to asthma and alleretes, found
tobacillus fo
gies, but its not clear why.
r, the gut,
could in th
SCIENCE VOL 330 26 NOVEMBER 2010
more comful, but sma
asthmatics.
whether the
offatt are now collaborating ics have an immune system that makes them gic disease havent been defi
o conduct gene sequencing be colonized by different things? Or is it the University of California,
in Bisgaards Copenhagen because they were colonized by different began recruiting about 200 b

Microorganismos y Prevencion de Alergias

En varios estudios nios que viven en granjas o en el

campo, tienen menos prevalencia de asma y atopia y

estan expuestos a una variedad de microorganismos
The

n e w e ng l a n d j o u r na l

Children on farms

Asthma

Prevalence (%)

50

m e dic i n e

Reference group

Atopy

50

40

40

30

30

20

P<0.001

P<0.001

20
P<0.001

P<0.001

10
0

of

10

PARSIFAL

GABRIELA

PARSIFAL

GABRIELA

Figure 1. Prevalence of Asthma and Atopy among Children Living on Farms as Compared with Reference Groups.
The PARSIFAL study population included 6843 school-age children 6 to 13 years of age, and the GABRIELA study
population included 9668 children between 6 and 12 years of age. Calculations of prevalence in GABRIELA were
weighted on the basis of the total number of children who were eligible for inclusion in the study (34,491 children).

For the assessment of microbial diversity, scores

were generated by summing up all detectable
bands (PARSIFAL) and all fungal taxa (GABRIELA).
This approach was not feasible for bacterial taxa
in GABRIELA, however, since they were classi-

in the reference groups inNboth

EngltheJ PARSIFAL
Med 2011;364:701-9.
study (adjusted odds ratio, 0.49; 95% confidence
interval [CI], 0.35 to 0.69) and GABRIELA (adjusted odds ratio, 0.76; 95% CI, 0.65 to 0.89). In
both studies, the differences between the two

P<0.001

positive
510
494
474
466
452
442

nisms and Childhood Asthma

430

P<0.001

Undetermined
grams staining

P<0.001

Mesophilic
streptomyces

P<0.001

Cocci, gram
negative

P=0.007

Microorganismos y Prevencion de Alergias

Band Position on Gel

ren on farms

Rods, gram
negative

422

100

Positive Samples (%)

394
Reference group
379

C Fungi (GABRIELA)

B Bacteria (GABRIELA)
365

Cocci, gram
positive
345

P<0.001

Rods, gram
327
positive

P<0.001

Rods, gram
296
negative

P<0.001

279
Undetermined
grams staining

P<0.001

Mesophilic
248
streptomyces

P<0.001

230
Cocci, gram
negative
211

P=0.007

310

265

181

50

155
0
C Fungi (GABRIELA)

50

100

Positive Samples (%)

50

100

Penicillium
species
Cladosporium
sphaerospermum
Aspergillus
versicolor
Eurotium
amstelodami
Aspergillus
fumigatus

P=0.02
P<0.001
P<0.001
P<0.001
P=0.003

Wallemia sebi

P<0.001

Eurotium species

P<0.001

Trichoderma
species

P=0.95

White yeast

P<0.001

50

100

Percentage of Positive Samples

Positive Samples (%)
Penicillium
P=0.02
species
Figure
2. Detection of Environmental Microorganisms in Dust Samples in the PARSIFAL Study and GABRIELA.
Cladosporium
P<0.001
sphaerospermum
In the PARSIFAL study (Panel A), samples of mattress dust were screened for bacterial origin
the use
of single-strand conformation
N Englwith
J Med
2011;364:701-9.
Aspergillus
polymorphism
(SSCP) analysis, with positive samples defined
as those with detectable SSCP bands. In GABRIELA (Panels B and C), setP<0.001
versicolor
tled dust from childrens rooms was evaluated for bacterial and fungal taxa with the use of culture techniques. The listed microbes were
Eurotium
present
in at least 10% of all samples.
P<0.001
amstelodami

Microorganismos y Prevencion de Alergias

The

n e w e ng l a n d j o u r na l

A Bacteria (PARSIFAL)

of

m e dic i n e

B Fungi (GABRIELA)

1.0

1.0
Living on a farm
Living on a farm

0.6

0.8

Probability

Probability

0.8

0.4

0.2

0.6

0.4

0.2
Asthma

Asthma
0.0

20

40

60

0.0

No. of Detectable Bands

No. of Detectable Taxa

Figure 3. Relationship between Microbial Exposure and the Probability of Asthma.

In both the PARSIFAL study and GABRIELA, the range of microbial exposure was inversely associated with the probability of asthma.

N Engl J Med 2011;364:701-9.

asthma (Table 2), although the associations be- 22% of the effect of the farming environment
came nonsignificant. In turn, the diversity scores on the prevalence of asthma. The bands with the
shifted the point estimates for the effect of farm highest loadings on factor 5 contained the se-

NUTRICION E INMUNIDAD

La nutricion y la
inmunidad estan
ligadas
La desnutricin
aumenta riesgo de
infecciones
La obesidad el riesgo
de complicaciones
inamatorias

Obesidad, Inamacion y Alergia

Importante Factor de
Riesgo Actual
Obesidad induce
fenomenos inamatorios
persistentes Th2
Dependiente de
Adipocitoquinas
Factor de Riesgo para:
Asma, DermaOOs, Alergia
Alimentaria, RiniOs

Tilg H. and Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews in Immunology . Vol. 6. October 2006. 772-780

Complement Factors
Factor D/Adipsin

Adipocyte

Hormones
Leptin
Adiponectin
Resistin

Adipocyte
Others
PAI-1
Angiotensinogen

Enzymes
Aromatase
11-B-HSD-1

Cytokines
TNF-alpha
IL-6

Substrates
Free fatty acids
Glycerol

Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in
adipocytes. J. Biol. Chem. 270, 2674626749.1995.
La Cava, A. & Matarese, G. The weight of leptin in immunity. Nature Rev. Immunol. 4, 371379 .2004.

Tilg H. and Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews in Immunology . Vol. 6. October 2006. 772-780

Tilg H. and Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews in Immunology . Vol. 6. October 2006. 772-780

Statins

Genetic Background

PCR

Cancer
IL-6
TNF-

GH

Neural
System
ACTH
TSH
Gn-RH

LT3

Osteoarthritis
IBD

Crhonic Inflammation
Th0
Th2 = ALERGIA

Immune
System

Leptin

Autoimmune

Fatty Cells
Adipocytes

Adiponectin
Resistin

Esophagus
Colon
Rectum
Pancreas
Liver
prostate

NAC

Fed State
Fatty Cells
Adipocytes

Fasted state

Leptin

Insulin
IGF-1
IGF-2

DHEA

Endocrine
System
Gout

Women
Mestrual Abnormalities
PCOS
High Androgen
DHEA-Es- Uterine Cancer

Reproductive
System
Men
Low Testosterone
High Strogen

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS

Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico y Tolerancia Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

SISTEMA INMUNE

KATZ DH. Allergic breakthrough: consequence of disturbance in normal damping of IgE antibody production. Monogr Allergy 1979;14:5773.
en Bousquet J. y colbs. Epigenetic inheritance of fetal genes in allergic asthma. Allergy.Volume 59(2)February 2004 p 138147

Bousquet J. y colbs. Epigenetic inheritance of fetal genes in allergic asthma. Allergy.Volume 59(2)February 2004 p 138147

Exposicion a Alergenos

Exposicion a Alergenos

Nombre

Acaros

Perros
Gatos

Exposicion a Alergenos
Nombre Cientifico

Area de Alta
Concentracion

Fuente Alergeno

Dermatophagoides pteronyssinus (Der p 1),

Dermatophagoides farinae (Der f 1)

Bedding
Upholstered furnitu
re
Carpeting

Mite body
Mite feces

Felis domesticus (Fel d 1), Canis familiaris

(Can f 1)

Bedding
Upholstered furnitu
re
Carpeting

Sebaceous glands
Salivary glands

Esporas

Blattella germanica (Bla g 1),

Periplaneta americana (Per a 1)

Kitchen

Saliva
Fecal material
Secretions
Dead cockroach bodies

Hongos

Alternaria alternata (Alt a 1),

Cladosporium herbarium
(Cla h 1),
Aspergillus fumigatus (Asp f 1)

Variable

Spores

Exposicion a Alergenos
Nombre

Acaros

Perros
Gatos

Nombre Cientifico

Area de Alta
Concentracion

Fuente Alergeno

Dermatophagoides pteronyssinus (Der p 1),

Dermatophagoides farinae (Der f 1)

Bedding
Upholstered furnitu
re
Carpeting

Mite body
Mite feces

Felis domesticus (Fel d 1), Canis familiaris

(Can f 1)

Bedding
Upholstered furnitu
re
Carpeting

Sebaceous glands
Salivary glands

Esporas

Blattella germanica (Bla g 1),

Periplaneta americana (Per a 1)

Kitchen

Saliva
Fecal material
Secretions
Dead cockroach bodies

Hongos

Alternaria alternata (Alt a 1),

Cladosporium herbarium
(Cla h 1),
Aspergillus fumigatus (Asp f 1)

Variable

Sporas

inducch se, IL-5,

ell recretion
gE imrecepeading
l cytohistafactors
racter-

rkes NaAtlanta,
Institute
ersity of

E-mail:
du (D.A.)

T cells that produce IL-4, IL-5, IL-13, IL-9, and

IL-10 and express the transcription factors GATAbinding protein 3 (GATA-3), signal transducer
and activator of transcription5 (STAT-5), and

Alum, MF59

Download

and asthma. Other TH subsets include TH17 cells,

which contribute to immunity against extracellular bacteria and fungi and the pathogenesis
of multiple chronic inflammatory diseases (3, 4);

Helminths

Venoms
(e.g. bee)
Helminth
products

Food allergens
(e.g. peanuts, shellfish)
Interior allergens
(e.g. house dust mite)

Lipopolysaccharides

Pollen allergens

Peptidoglycans

Type 2 responses
Fig. 1. Diversity of stimuli that induce type 2 immune responses. Such stimuli range from nanometersized allergens to 20-m-long helminthic parasites. Despite marked differences in size, shape, structure,
and physical and chemical properties, all of these stimuli induce type 2 immune responses.

www.sciencemag.org

SCIENCE

VOL 337

27 JULY 2012

SCIENCE VOL 337 27 JULY 2012

CREDIT: K. SUTLIFF/SCIENCE

moleconses,
type 2
ologic
ry set-

431

cytokine tumor necrosis kine profiles of individual T cells within the TH2 mal dander, insects, mol
cause IL-10 is a cytokine compartment are dependent on the number of adjuvants) stimuli that pr
s allergic inflammation, cell divisions and the tissue microenvironment in it may be necessary to l
oinflammatory cytokines which the T cells reside. If the TH2 cell variants PRR-DC paradigm whe
type 2 respo
matory TH2
the known s
m from the
Protease activity
account for
y TH2 cells
(e.g. papain,
or do we
Consistent
bromelain)
covered fam
inflammaPattern recognition
innate sens
een isolated
via innate receptor
responses? A
er biopsies
(e.g. certain TLR
in inducing
ibute to an
ligands)
Th2
t promotes
appreciated
responses
Tissue damage
Whether the
examples in
(e.g. caused by
TLRs (e.g.,
gic disease
adjuvants
such as alum)
thetic TLR2
matory phelow doses
. Moreover,
Metabolic changes
signal DCs
an stimulate
in environment
sponses (6).
be pigeon(e.g. amino acid,
oxygen changes
of bacterial p
TH2 phenocaused by
and NOD2
phyromonas
pathogen growth)
DC-SIGN i
ysaccharide
elllike re- Fig. 2. Diverse mechanisms by which the innate immune system senses type in some sce
In the c
ls produce 2inducing stimuli. The host appears to have evolved
multiple
SCIENCE
VOL 337mechanisms
27 JULY 2012
ut not IL-4 to sense a bewildering array of stimuli that induce type 2 immune responses. evidence th
as certain Many pathogens and allergens can be sensed by pattern recognition receptors. PRRs. For

REVIEW

antigen presentation to T cells

the initiation of TH2 cell respo
Allergen
er
allergens and helminths (5355)
sistent with this notion, althoug
were required for TH2 cell resp
depletion of basophils using a
TLR
TLR,
e immune
im
mmune
mune
Innate
NLR,
body against basophils resulted
receptor
ceptto
or
C
LR,RLR
, RLR
LR
R
CLR,
paired TH2 responses to Trichuris
(55). New genetic tools that h
lowed the deletion of the majo
Signaling
ignalling
g
basophils in vivo suggest that
PI3K
P
I3K
pathw
way
way
y
pathway
p
p38
responses can develop in the a
NF-B
NFNF
B
ERK
ER
RK
K
of basophils in some circums
(57, 58). However, in these mi
sophils were constitutively d
Cell
from birth, but not all basophil
deleted, so it is not clear whethe
pensatory mechanisms such
hanced TH2-inducing capaci
Mast cell Eosinophil Basophil NK-T
other cells such as mast cells an
may contribute to developing
responses in these settings. The
Th2
to which DCs or basophils con
to developing type 2 responses a
Cell-cell
to be context-dependent. Differe
cooperation
Th1
the relative roles of these two ce
Th0
observed in different studies may
differences in experimental con
Th17
Macrophage
and models or, alternatively, ma
minate heterogeneity in the pa
that promote type 2 inflammati
Treg
NK
can be influenced by stimulus- or
Innate
Treg
lymphoid cell
dependent factors. This is clea
area requiring further investiga
What signals do DCs and
phils impart to promote TH2 cell
entiation? In the case of TH1
Tissue microenvironment
IL-12 produced by DCs is ess
and it has been proposed that
brasiliensis
and
S.
mansoni
deal of functional plasticity. Thus, pathogen Nippostrongylus
that
fail
to
induce
IL-12 in DCs program t
SCIENCE VOL 337 27 JULY 2012
products such as LPS from P. gingivalis (12), (51, 52). Finally, a subset of FceR1+ CD11c+ in- induce TH2 responses (3, 4, 6). Evidence f
omega-1 [a T2 ribonuclease glycoprotein derived flammatory DCs were shown to be necessary default mechanism of TH2 cell response
from Schistosoma mansoni egg antigen (SEA)] for the induction of TH2 responses to inhaled served with stimuli such as certain TLR2 l
(43, 44), helminth-derived stimuli (45), cholera HDM antigens (40).
or allergens or helminth products that d
Bacteria
eria

Fungi

Virus
us

Helminths

Fig. 3. Hierarchies of organization in the innate immune system. The complexity

of the innate immune system
in sensing stimuli and orchestrating type 2 immune responses can be conceptualized
as occurring in different hierarchies of organization. The
cell (that is, the dendritic
cell) can be considered as
the ground level; the innate
receptors expressed by the
cell and the signaling networks within the cell represent
higher-resolution levels of the
hierarchy. Conversely, cell-cell
cooperation and the impact
of the tissue microenvironment represent more global
views of the hierarchy. This
model offers a conceptual
framework for therapeutic
interventions to allergic inflammation. Thus, one might
envision targeting the signaling level (for instance, by
inhibiting ROS in DCs), the
cellular level (for example,
by inhibiting migration of
cells such as DCs or basophils),
or the cell-cell cooperation
level (by inhibiting molecules
such as TSLP, IL-25, and IL-33
that mediate cell interactions).
RLR, RIG-Ilike receptors; PI3K,
phosphatidylinositol 3-kinase;
NK-T, natural killer T cells.

Classical
monolithic
view

Population subsets
Cytokines
Tfh

IL-21

Bcl-6
Transcription
factors

Naive
CD4+
T cell

STAT3

Th2

Gata3

STAT6

STAT4

Th1

T-bet

STAT3

Dendritic
cell

IL-4
IL-13

STAT5

Th17

iTreg

Ror t

Foxp3

IFN-

IL-17a
IL-17f

IL-10
IL-35
TGF

SCIENCE VOL 327 26 FEBRUARY 2010

within the
T cell fat
even four T
the many
ine the nee
how the sy
threat and
what the
increasing
lineage.

To What E
Productio
More chal
TH cell su
that cytok
tially thoug
ples of fle
Once thou
recognized
TH1, TH2
Similarly,
capacity in
can also b
quisition o
cells, parti
IL-17 and

cell

Once thought to be a TH2 cyto

recognized as produced by mu
IL-10
iTreg Foxp3
TH1, TH2, Tregs, and TH1
IL-35
Similarly, TH2 cells can acqui
TGF
capacity in the presence of TG
can also be produced by TH1
quisition of IFN-gproducing
cells, particularly the simultane
IL-17 and IFN-g, is a com
B
especially in vivo (19, 20). TH
Flexibility
Bcl-6
extinguish production of their c
Th9
and plasticity Tfh
becoming selective IFN-g p
Although TH1 cells do no
Gata3
producers, under the right c
Th2
can make IL-13 (24). TH17 ce
Th22
but cells that make IL-22 an
recently been identified (25,
production of IL-22 and IFNindeed, IL-22 was originally
Naive
CD4+
cytokine. More concerning fo
T cell
notion of cytokine production
T-bet
Th1
finding that in vitro differentiate
TH2 cells specific for lym
meningitis virus (LCMV) pro
transferred into mice subseque
LCMV (27). Whether cells pri
robust TH2-inducing conditio
Th17
Ror t
propensity to acquire IFN-gp
has not been established.
Collectively, these finding
flexibility in cytokine produc
frequency with which TH cells a
T-bet
T
bet
producing potential in vivo is st
Foxp3
iTreg
precisely, to what extent do ce
Foxp3
Not just by expressing a c
formerly did not, but rather by
properties that define TH cells.
such plasticity is a major fe
Fig. 1. Helper T cell differentiation. (A) The classical monolithic view: lineages and master regulators. Initial responses, the stakes are raise
SCIENCE VOL 327 26 FEBRUARY 2010
studies arising from in vitro cultured TH1 and TH2 cells led to the idea that these subsets behaved like lineages, understand how the system read
meaning that their phenotype (i.e., selective cytokine production) was inflexible. Accordingly, these subsets and orders up the right respon
expressed lineage-defining transcription factors that were sufficient to impart this selective cytokine production.

Mark Larch, Cezmi A. Akdis and Rudolf Valenta. Immunological mechanisms of allergen-specific immunotherapy

Nature Reviews Immunology 6, 761-771 October 2006

Mark Larch, Cezmi A. Akdis and Rudolf Valenta. Immunological mechanisms of allergen-specific immunotherapy

Nature Reviews Immunology 6, 761-771 October 2006

Negative Control

CD4/CD8 Ratio = 3.26

N= 1,5 0,3

Th2

R1

IL-2
IL-4
IL-6
IL-10
TNF-alpha
IFN-gamma

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS

Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico y Tolerancia Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

Mark Larch, Cezmi A. Akdis and Rudolf Valenta. Immunological mechanisms of allergen-specific immunotherapy

Nature Reviews Immunology 6, 761-771 October 2006

Innate immune Subsystems Surface epithelium

Turner J.R. Intestinal mucosal barrier function in health and disease.

Nature reviews Immunology. Volume 9: 799-809. November 2009

Innate immune Subsystems Surface epithelium

Occludin

Claudin-2

TNF-

IL-13

Turner J.R. Intestinal mucosal barrier function in health and disease. Nature reviews Immunology. Volume 9: 799-809.
November 2009

Innate Immune Surface Epithelium

Turner J.R. Intestinal mucosal barrier function in health and disease. . Nature reviews Immunology. Volume 9: 799-809. November 2009

inductive sites, which are classically equated

anatomically with lymph nodes and spleen.
However, at mucous sites induction of the
immune response occurs not only in draining
lymph nodes but also in local collections of lym-

however, no such follicles are recognized. Therefore, the obvious question that arises is: Is a more
effective immune response in the anogenital
mucosa engendered by immunization at a distant
mucosal site such as the nose (Fig. 2.3)?

Circulacion Linfocitaria

GI tract

GALT

NALT

Nose

Does nasal
immunization
illicit useful immunity
i n the genital tract?

MALT
?

Mammary gland

Genital tract

Uterus
Cervix

Figure 2.3. Major sites of mucosa-associated lymphoid tissue (MALT).

There is a potential for immunologic interactions between mucosal
tissues. This diagram emphasizes the possibility that immunization in the
common mucosal immune system may be an effective means of pro-

tecting distant mucosal sites. For instance, it has been demonstrated in

principle that nasal immunization protects efficiently against genital
herpes (20) and papilloma virus infections (18). NALT, nose-associated
lymphoid tissue.

Simmons A. Chap 2. Anogenital Mucosal Immunology and Virology. Book:Mucosal immunology and Virology . Springer,
Germany. 2006. Reimpresion 2011.

Egawa G. And Kabashima K. Skin as a Peripheral Lymphoid Organ: Revisiting the Concept of Skin-Associated Lymphoid
Tissues. Journal of Investigative Dermatology (2011), Volume 131 . 2178-2185

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS

Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico y Tolerancia Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

MALT
MUCOSAL
GALT
GUT

Peyers
patches

Cryptopatch
es and
Isolated
Lymphoid
Follicles

NALT
NOSE

UGALT
Urogenital

LALT
LUNG
SALT
SKIN

Nodulos LinfaOcos y Traco Linfoide

Abbas, A. Inmunologa Celular y Molecular. McGraw Hill. Phyladelphia.2008.

Nodulos LinfaOcos y Traco Linfoide

Nodulos LinfaOcos y Traco Linfoide

Nodulos LinfaOcos y Traco Linfoide,

MulOples Senales Inamatorias

Nodulos LinfaOcos y Traco Linfoide

Tolerance educaOon in
distant LN and Lymph
Ossues

Tolerance in Regional's LN

High and Ecient

Draining LN

Alvarez D; Swirski FK; Yang TC; et al. Inhalation tolerance is induced selectively in thoracic lymph nodes but executed pervasively at distant
mucosal and nonmucosal tissues.JOURNAL OF IMMUNOLOGY Volume: 176 Issue: 4 Pages: 2568-2580. FEB 15 2006

Tolerancia

Perdida de Tolerancia Inmune

Perdida de Tolerancia
Se relaciona con incremento en la acOvidad inamatoria del

sistema inmune
HiperreacOvidad celular y humoral
Perdida de la regulacion de anO-inamacion celular y humoral
Disminucion del numero y acOvidad de T-Reguladoras, T
Supresoras
Perdida del balance Th2-Th3

Schmidt-Weber, C. B.; Blaser, K. T-cell tolerance in allergic response. Allergy: European Journal of Allergy and Clinical Immunology. 2002;57(9):
762768

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The Journal of Clinical Investigation,
Volume 114 Number
10 November 2004

Claudia Mauri & Paul A. Blair. Regulatory B cells in autoimmunity: developments and controversies. Nature Reviews
Rheumatology 6, 636-643 (November 2010)

Claudia Mauri & Paul A. Blair. Regulatory B cells in autoimmunity: developments and controversies. Nature Reviews
Rheumatology 6, 636-643 (November 2010)

Claudia Mauri & Paul A. Blair. Regulatory B cells in autoimmunity: developments and controversies. Nature Reviews
Rheumatology 6, 636-643 (November 2010)

Claudia Mauri & Paul A. Blair. Regulatory B cells in autoimmunity: developments and controversies. Nature Reviews
Rheumatology 6, 636-643 (November 2010)

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS

Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

Evolucin de la Flora IntesOnal con la Edad

Log de recuento de bacterias fecales

12

10

2
E. Coli,
Streptococus

Bifidobacterium

Bacteroides
Eubacterium
Peptococae

Lactobacillus

Clostridium
perfringens

Human Microbiome

Can Human Microbiota Promote Treg Prole ?

Lee S.K. and Mazmanian S.K. Has the Microbiota Played a Critical Role in the Evolution of the Adaptive Immune System?.
Science 330, 1768 (2010)

Can Human Microbiota Promote Treg Prole ?

Can Human Microbiota Promote Treg Prole ?

Lee S.K. and Mazmanian S.K. Has the Microbiota Played a Critical Role in the Evolution of the Adaptive Immune System?.
Science 330, 1768 (2010)

distinctive anatomical adaptations in the mucosal

immune system allow immune responses directed
against commensals to be distributed widely while
still being confined to mucosal tissues.
Other immune cell populations also promote
the containment of commensal bacteria to intestinal sites. Innate lymphoid cells reside in the
lamina propria and have effector cytokine pro-

The compartmentalization of mucosal and

systemic immune priming can be severely perturbed in immune-deficient mice. For example,
mice engineered to lack IgA show priming of
serum IgG responses against commensals, indicating that these bacteria have been exposed to
the systemic immune system (22). A similar outcome is observed when innate immune sensing is

Downloaded from www.sciencemag.org on October 27, 2012

the potential for pathologic outcomes. This occurs at two distinct levels: first, by minimizing
direct contact between intestinal bacteria and the
epithelial cell surface (stratification) and, second,
by confining penetrant bacteria to intestinal sites
and limiting their exposure to the systemic immune compartment (compartmentalization).
Several immune effectors function together to
stratify luminal microbes and to minimize bacterialepithelial contact. Intestinal goblet cells secrete
mucin glycoproteins that assemble into a ~150-mmthick viscous coating at the intestinal epithelial
cell surface. In the colon, there are two structurally
distinct mucus layers. Although the outer mucus
layer contains large numbers of bacteria, the inner
mucus layer is resistant to bacterial penetration
(16). In contrast, the small intestine lacks clearly
distinct inner and outer mucus layers (17). Here,
compartmentalization depends in part on antibacterial proteins that are secreted by the intestinal
epithelium. RegIIIg is an antibacterial lectin that
is expressed in epithelial cells under the control of
Toll-like receptors (TLRs) (1820). RegIIIg limits
bacterial penetration of the small intestinal mucus
layer, thus restricting the number of bacteria that
contact the epithelial surface (5).
Stratification of intestinal bacteria on the
luminal side of the epithelial barrier also depends
on secreted immunoglobulin A (IgA). IgA specific for intestinal bacteria is produced with the
help of intestinal dendritic cells that sample the
small numbers of bacteria that penetrate the overlying epithelium. These bacteria-laden dendritic
cells interact with B and T cells in the Peyers
patches, inducing B cells to produce IgA directed
against intestinal bacteria (21). IgA+ B cells home
to the intestinal lamina propria and secrete IgA
that is transcytosed across the epithelium and
deposited on the apical surface. The transcytosed
IgAs bind to luminal bacteria, preventing microbial translocation across the epithelial barrier (22).
Mucosal compartmentalization functions to
minimize exposure of resident bacteria to the systemic immune system (Fig. 1B). Although bacteria
are largely confined to the luminal side of the
epithelial barrier, the sheer number of intestinal
bacteria makes an occasional breach inevitable. Typically, commensal microorganisms that
penetrate the intestinal epithelial cell barrier are
phagocytosed and eliminated by lamina propria
macrophages (23). However, the intestinal immune system samples some of the penetrant bacteria,
engendering specific
responses
Nicholson
J. Etl immune
al. Host-Gut
that are distributed along the length of the intestine (21). Bacteria that penetrate the intestinal
barrier are engulfed by dendritic cells (DCs) re-

Fig. 1. Looking inside-out: immune system control of the microbiota. Several immune effectors function
together to stratify luminal microbes and to minimize bacterial-epithelial contact. This includes the mucus
layer, epithelial antibacterial proteins, and IgA secreted by lamina propria plasma cells. CompartmenMicrobiota
Metabolic
8 JUNE
2012
VOL
336

talization is accomplished
by uniqueInteractions.
anatomic adaptationsScience
that limit commensal
bacterial
exposure
to the
immune system. Some microbes are sampled by intestinal DCs. The loaded DCs traffic to the mesenteric
lymph nodes through the intestinal lymphatics but do not penetrate further into the body. This
compartmentalizes live bacteria and induction of immune responses to the mucosal immune system.

distinctive anatomical adaptations in the mucosal

immune system allow immune responses directed
against commensals to be distributed widely while
still being confined to mucosal tissues.
Other immune cell populations also promote
the containment of commensal bacteria to intestinal sites. Innate lymphoid cells reside in the
lamina propria and have effector cytokine pro-

The compartmentalization of mucosal and

systemic immune priming can be severely perturbed in immune-deficient mice. For example,
mice engineered to lack IgA show priming of
serum IgG responses against commensals, indicating that these bacteria have been exposed to
the systemic immune system (22). A similar outcome is observed when innate immune sensing is

Downloaded from www.sciencemag.org on October 27, 2012

the potential for pathologic outcomes. This occurs at two distinct levels: first, by minimizing
direct contact between intestinal bacteria and the
epithelial cell surface (stratification) and, second,
by confining penetrant bacteria to intestinal sites
and limiting their exposure to the systemic immune compartment (compartmentalization).
Several immune effectors function together to
stratify luminal microbes and to minimize bacterialepithelial contact. Intestinal goblet cells secrete
mucin glycoproteins that assemble into a ~150-mmthick viscous coating at the intestinal epithelial
cell surface. In the colon, there are two structurally
distinct mucus layers. Although the outer mucus
layer contains large numbers of bacteria, the inner
mucus layer is resistant to bacterial penetration
(16). In contrast, the small intestine lacks clearly
distinct inner and outer mucus layers (17). Here,
compartmentalization depends in part on antibacterial proteins that are secreted by the intestinal
epithelium. RegIIIg is an antibacterial lectin that
is expressed in epithelial cells under the control of
Toll-like receptors (TLRs) (1820). RegIIIg limits
bacterial penetration of the small intestinal mucus
layer, thus restricting the number of bacteria that
contact the epithelial surface (5).
Stratification of intestinal bacteria on the
luminal side of the epithelial barrier also depends
on secreted immunoglobulin A (IgA). IgA specific for intestinal bacteria is produced with the
help of intestinal dendritic cells that sample the
small numbers of bacteria that penetrate the overlying epithelium. These bacteria-laden dendritic
cells interact with B and T cells in the Peyers
patches, inducing B cells to produce IgA directed
against intestinal bacteria (21). IgA+ B cells home
to the intestinal lamina propria and secrete IgA
that is transcytosed across the epithelium and
deposited on the apical surface. The transcytosed
IgAs bind to luminal bacteria, preventing microbial translocation across the epithelial barrier (22).
Mucosal compartmentalization functions to
minimize exposure of resident bacteria to the systemic immune system (Fig. 1B). Although bacteria
are largely confined to the luminal side of the
epithelial barrier, the sheer number of intestinal
bacteria makes an occasional breach inevitable. Typically, commensal microorganisms that
penetrate the intestinal epithelial cell barrier are
phagocytosed and eliminated by lamina propria
macrophages (23). However, the intestinal immune system samples some of the penetrant bacteria,
engendering J.
specific
immune
responses
Nicholson
Etl al.
Host-Gut
that are distributed along the length of the intestine (21). Bacteria that penetrate the intestinal
barrier are engulfed by dendritic cells (DCs) residing in the lamina propria and are carried alive

Fig. 1. Looking inside-out: immune system control of the microbiota. Several immune effectors function
together to stratify luminal microbes and to minimize bacterial-epithelial contact. This includes the mucus
layer, epithelial antibacterial proteins, and IgA secreted by lamina propria plasma cells. CompartmenMicrobiota
Metabolic
8 JUNE
2012
VOL
336

talization is accomplished
by uniqueInteractions.
anatomic adaptationsScience
that limit commensal
bacterial
exposure
to the
immune system. Some microbes are sampled by intestinal DCs. The loaded DCs traffic to the mesenteric
lymph nodes through the intestinal lymphatics but do not penetrate further into the body. This
compartmentalizes live bacteria and induction of immune responses to the mucosal immune system.

acid metabolism and in energy-related metabolites. For example, bacterial products of choline
metabolism may be inversely associated with
age in children under 12 years old (16). Changes
in the urinary excretion of 4-hydroxyphenylacetic
acid, indoleacetic acid, and tricarboxylic acid

composition include an increase in the total

number of facultative anaerobes, shifts in the ratio
of Bacteroidetes to Firmicutes species, and a
marked decrease in bifidobacteria in people >60
years old, around the time that the immune
system starts to decline (Fig. 1) (15). Metabolic

Ba
c

Symbiosis

Disease

ter
oid
ete
s

ng
mi

Fir
mi
cu

og
ol

am
gr
ro

tes

i
ys

The Microbial Ages of Man

The microbiota of the infant is seeded
at birth and is initially undifferentiated
across the various body habitats. A variety of factorsincluding method of
delivery (vaginal versus Cesarian secPathogens
No
tion), breast feeding, and weaning
Microbiota
rm
al
status
influence the infant microbiota (Fig. 1).
Ph
ph
ys
For example, the microbiota of baiol
og
Bifidobacteria
ica
bies delivered vaginally are domil
En p
nated by Lactobacillus, Prevotella, and
er
gy
Atopobium, whereas babies delivered
by Cesarian section have a microbiota
A
that more closely resembles that of
Bile, lipid, drug
the maternal skin community, with
and glucose
metabolism
staphylococci being a dominant early
member (4). Evidence is beginning to
emerge that the in utero environment
Viscerosensing
vagus nerve
H. pylori
may not be sterile as originally thought,
with bacteria such as Enterococcus
B
fecalis, Staphylococcus epidermidis,
Host
Antibiotic
and Escherichia coli having been isogenome
enhanced
susceptibility
C
lated from the meconium (earliest feces)
Microbiota to adult
Microbiota
Mother to baby
immune signaling,
of healthy neonates (11). The domito infant
microbiota
signaling host metabolic pathway
nance of aerobic bacteria at birth is
interactions
coregulation
altered during peri- and postnatal deAbnormal
D
Delivery
velopment. The microbiota diversimicrobiota
Breast/bottle feeding
development
fies over the first few weeks of life to
Epigenetics
Clostridium spp.
form a complex anaerobe-dominated
Desulfovibrio spp.
Antibiotics
microbial community (12). This early
Composition and activity
Diet
Targets:
Hormone
colonization period coincides with ac Drugs
(GLP-1)
Immune system
tivation of the hypothalamic-pituitary Disease
signaling
Endocannabinoids
Age-related
Injury
adrenal (HPA) axis, which has an
Hormones
decline
Surgery
Bile acids
impact on the enteric nervous system
Stress
SCFAs
that innervates the gastrointestinal (GI)
Dy
Biogenic amines
sb
tract. Enteroendocrine cells of the gut
ios
Xenometabolites
i
s
secrete a variety of metabolically reot a
lated peptides all known to be conrobi
c
i
m
t
nected to food intake, lipid storage,
Altered gu
and energy homeostasis and can be
activated by microbial metabolites, Fig. 1. The gut microbiota in development and disease. The influence of the gut microbiota on human health is
such as SCFAs, that act through het- continuous from birth to old age. The maternal microbiota may influence both the intrauterine environment and the
postnatal
health of the
fetus. At birth,Interactions.
about 100 microbial
species populate
the colon.
environmental
Nicholson
J. nucleotidebinding
Etl al. Host-Gut
Microbiota
Metabolic
Science
8 JUNE
2012Early
VOL
336
factors
erotrimeric
guanine
(e.g., method of delivery), nutritional factors (e.g., breast or bottle-feeding), and epigenetic factors have been
protein (G protein)coupled receptors,
implicated in the development of a healthy gut and its microbial symbionts. Changes in gut microbial composition in
such as the GPR41 receptor expressed
early life can influence risk for developing disease later in life. During suckling, the microbial community develops
by enteroendocrine cells (13). The gut rapidly; shifts in microbial diversity occur throughout childhood and adult life; and in old age, there is a decrease in

Downloaded from www.sciencemag.org on October 27, 2012

supraorganism contribute to disease risk and health

sustainability will point the way to new therapeutic interventions and disease prevention strategies
[see Review by Holmes et al. (10)].

INMUNOMODULACION Y TOLERANCIA EN
ALERGIAS

Epidemiologia En Aumento
Factores De Riesgo
Inmunopatologia
Alteraciones Inflamatorias De Mucosas
Trafico Linfoide
Microbiota
Inmunomodulacion Con Medicamentos Bioreguladores

Tratamiento Ajustado al Paciente

Las polarizaciones inflamatorias del sistema inmune

pueden ser temporales y requerir una terapia

biologicamente logica mas que una terapia
inmunosupresora.
Cada paciente puede estar en un momento diferente de
la enfermedad y requerir una terapeutica diferente
Anque la fisiopatologia se presuma igual, cada
pacientes es geneticamente e inmunologicamente
diferente.

Tratamiento Ajustado al Paciente

No se pueden masificar los tratamientos en alergias,
dada la subjetividad de la enfermedad.
El uso de guias o protocolos son una ayuda no un
orden.
El tratamiento debe estar dirigido hacia la situacion
inmune real del paciente.
Pensar en los pilares basicos en cada uno de los
pacientes:
Inmunomodulacion
Detoxificacion
Soporte Organico

Inmuno-Modulacion

Inmunomodulacion
Estrategias de inmunomodulacion en Alergias

Disminucion de la Inflamacion local y a distancia.

Disminucion de los estimulos inflamatorios
Eliminacion de Toxinas y estimulantes de sensibilizacion
Induccion de citoquinas Th3
Polarizacion inmune Th1
Aumentar la movilizacion y detoxificacion linfatica.

Disminucion
Inamacion
Mucosas
Disminucion
Degra nulacion

Aumento del
Drenaje,
Traco y
Detoxicacion
LinfaUca

Restauracion
MicrobiotaPre
bioUcos,
ProbioUcos

Aumento
Tolerancia
Inmune Treg

Inmuno
Modulacion :
induccion de
Th1/Th3 (IFN-
, TGF-)

Inmuno
Regulacion
Inamacion

Balance
nutricional
(Hipograsa,
Hiperproteica)

Soporte
Organico
Regeneracion
Usular (Suis)

Tratamiento
Integral
Alergias

Control
Ambiental