BASIS OF GENETIC REGULATION IN ALLERGIES

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BASIS OF GENETIC REGULATION IN ALLERGIES

• L.A. Réthy

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Main health-related challenges

• Cardiovascular
• Cancer
• Diabetes-obesity
• Undernutrition/malnutrition
• Infectious diseases
• Allergies (including asthma)- EU,USA approx.30
  of the population is affected !
• Ageing process

Complex biological problems! Polygenic
environmental effects!
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Main topics

• Relationship of GALT (Gut-associated lymphoid
  tissue) and allergies/asthma by
• host-microbe cross talk .
• Natural immunity
• toll-like receptors (TLR),
• Intracell.nukleotide oligomerisation domens (NOD
  1,2)
• Acquired immunity
• Reguláló T-sejteken keresztül
• The importance of the revised Hygiene-hypothesis
  in inflammatory diseases with special
  attention to allergies and asthma

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Our largest immune-organ is the GALT
(Gut-Associated Lymphoid Tissue)
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GALT Gut-associated lymphoid tissue
Peyerspatch
Villus epithelium
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Observations on germ-free mice
Macpherson, 2004

• GALT-
• Peyer patches Few IgA Plasm cells,
• Lamina propria few CD4T cells
• Perif. Lymphoid organs (spleen, lymph nodes)
• Underdeveloped, Serum IgG low level
• Smith, NAgler-Andrerson,
  J. Immunol. 2005

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The stepwise compositional development of the gut
microbiota (Rautava, J. Ped.
Gastroenterol Nutr, 2004)
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At the same time Development of immune
response Tolerance or atopy?
Rautava, 2004 J. Ped Gastroent
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Ingestion of probiotic bacteria by humans results
in

• Human leukocytes
• Trigger for IFN gamma production
• Blood T cells
• Increased IL-2 responses
• after stimulation by T cell mitogens
• Wheeler , Ann Allergy Asthma Immunol 1997
• Schiffrin J Dairy Sci 1995
• blood polymorphonuclear leukocytes
• Increased phagocytic capacity of
• Donnet-Hughes J Dairy Sci 1999
• Arunachalam Eur J Clin Nutr 2000
• Probiotic bacteria trigger respiratory burst
• (Wheeler, Am J. Med Sci 1997

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Innate immune responses to normal flora
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Host-microbe cross talk

• toll-like receptors (TLR),
• Intracell.nukleotide oligomerisation domenes (NOD
  1,2)
• Bacterial flora -DC interactions
• In mesenterial lymph nodes
• ? Dendritic Cell
• IgA B cells are induced
• Smith, NAgler-Andrerson, J.
  Immunol. 2005
• T-cell activation via regulatory T-cells

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New generation genes for allergy-susceptibility

• ADAM 33 - / Chr. 20
• A Disintegrin-And Metalloprotease
• PHF11 - atopy se IgE /Chr. 13
• PHF11(Plant Homeodomain Zinc Finger
• DPP 10 - bronchus hyperreactivity/ human? Chr. 2
  
• Dipeptidil Peptidáz
• GPR154/GPRA - atopia, asthma / - A izoform,
  ligand Neuropeptid S (NPSA1) theraeutic target
  ! Chr. 7. G-prot. Coupled receptor)
• IRAK M (TLR-IL1R NFkappaB pathway,
  negativ regulation) 12q13-24
• Natural immunity
• (IL-1 R-assoc. Kinase)
• Van Eerdewegh, Nature 2002, Zhang Y,
  Nat Genet 2003, Allen M , Nat Genet 2003
  Laitinen T, Science 2004 Vendelin, Am J Resp
  Cell Mol Biol. 2005, Balaci L et al Am J.Hum
  Gen 2007

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Pattern Recognition Receptors- I. The Toll-like
receptor (TLR) family
PAMP Pathogen- Associated Molecular
Patterns
TLR-s
Fiset PO, JACI 2005 Aug
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Probiotics and immune-cells Probiotics , APC and
T cells Vaarala, Clin Exp Allerg 2003
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PatternRecognition Receptors- II. NOD -
Nukleotide oligomerisation domains
Activity Reports 2002 - Institut Pasteur
http//www.pasteur.fr/recherche/RAR/RAR2002/Imis-e
n.html
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Probiotics

• living or inactivated organisms
• exerting beneficial effects on health when
  ingested,
• The most commonly used probiotics
• lactobacilli and bifidobacteria,
• enterococci and E. coli

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Examples of Probiotic bacteria
Adults Lactobacillus casei Lactobacillus
rhamnosus Streptococcus thermophilus Bifidobacteri
um breve Lactobacillus acidophilus Bifidobacterium
longum Lactobacillus bulgaricus

Children Lactobacillus casei Lactobacillus
rhamnosus Streptococcus thermophilus Bifidobacteri
um breve Lactobacillus acidophilus Bifidobacterium
infantis (child specific) Lactobacillus
bulgaricus
http//www.health-care-protexin.com
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Interactions of bacterial flora and immune
cells Kelly D Trends Immunol 2005
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Interactions of bacterial flora and immune cells
- Further examples

• Bifidobacterial DNA
• May induce IL-10 production in PBMCs , in vitro
• Lactobacillus paracasei
• Induction of IL-10 and TGF-beta production
• in Monocytes and regulatory T-cells
• von der Weid T et al Clin Diagn Lab Immunol
  20018695-701.
• Lammers KM, et al FEMS Immunol Med Microbiol
  200338165-72.

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TReg The Natural Balance
Taylor et al., Microbes Infect 2005
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Intestinal flora, Regulatory T cells,
immune-response (Rautava, J. Ped.
Gastroenterol Nutr, 2004)
Bifidobacteria, etc.
Toll-like receptorok LPS kötés
Reg. T sejtek
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Subsets of CD4 regulatory cells
(Akbari, Curr. Opin. Immunol, 2003)
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Subsets of CD4 regulatory cells

• Main subsets
• Th3, TR and CD4CD25 cells
• can inhibit effector T cells
• NKT cells (T and NK surface markers)
• may enhance their differentiation and development.

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Regulatory T cells

• Regulatory T cells control or suppress the
  function of other cells.
• Control the development of autoimmune disorders,
  asthma, allergy, transplantation rejections.
• Specific mechanisms are still being investigated

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The effects of respiratory allergens in
non-allergic versus asthmatic individuals.

• Exposure to respiratory allergens ?
• in non-allergic individuals
• development of TR cells?TOLERANCE
• in atopic/asthmatic individuals
• development of Th2 cell-dominace
• as an aberration of TR-cell development, because
  of inadequate production of IL-10,
• or as a consequence of enhanced production of
  IL-4 and IL-13 by NKT cells in particular,
• which leads to the development of allergy and
  asthma.

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The effects of respiratory allergens in
non-allergic versus asthmatic individuals
(Akbari, Curr. Opin. Immunol, 2003)
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Allergic asthma- part of the atopic march

• Adapted from Saarinen, Lancet 1995

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Atopic dermatitis Face, skalp, trunk,
extremities
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Barrel-chest configuration in asthma
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Evidences of a relationship between allergies
and composition of intestinal microflora

• Swedish-Estonian study among infants
• Atopic infants prevalence of coliforms
• Healthy controls prevalence of bifidobacteria
• (Bjorksten, JACI 2001)
• Finland
• Atopic infants
• more clostridia, fewer bifidobacteria in the
  first 3 weeks of life
• Lower prevalence rates of bifidobacteria through
  the first year of life
• (Kalliomaki, JACI, 2001)

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Hygiene hypothesis, original Hayfever,
hygiene, houshold size (Stratchan, BMJ, 1989)

• Immunological background
• Th1/Th2 paradigm of adaptive immune responses
  (Mosmann, J Immunol, 1986)
• Bacterial load Th1 Immune response
• no allergy/atopy
• No bacterial load Th2 Immune response
• allergies/atopies (?)

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Th1
Treg
IL-12
Th2
IgG1
IL-10
IgG4, IgA
IL-4
IgE
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Children in Lambaréné, Gabon, get infected with
schistosomes. The village has negligible rates
of asthma, even as tested by responses to
dust-mite allergens (inset).Schubert C, Nature
Medicine  10, 1271 - 1272 (2004)

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Treg
Th2
Th1
IL-4
IL-10
IL-12
IgG4, IgA
IgE
IgG1
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Children of farmers Reduced risk of
asthma/atopies

• Von Ehrenstein, O. S., (2000) Reduced risk of hay
  fever and asthma among children of farmers. Clin.
  Exp. Allergy 30, 187193.
• Riedler, J., (2001)Exposure to farming in early
  life and development of asthma and allergy a
  cross-sectional survey. Lancet 358, 11291133.
• Braun-Fahrlander, (2002) Environmental exposure
  to endotoxin and its relation to asthma in
  school-age children. N. Engl. J. Med. 347,
  869877.

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Expanded hygiene hypothesis Microbial
exposition in early life !
Feleszko, Eur J. Pharmacol 2006
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Probiotics , adults

• Target group adults , with birch-pollen
  allergy
• Treatment Orally given, intestinal probiotic
  bacterial strain
• (Lactobacillus rhamnosus (ATCC 53103),
• placebo-controlled , double-blind study
• No significant difference (Helin, Allergy 2002)

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Farming lifestyleKabesch M, Lauener RP J
Leukocyte Biol, 2004, 75 383

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Extended hygiene hypothesis Rautava, JACI, 2005
?
?
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Clinical studies in infants-I.

• Infants with atopic eczema/cows milk allergy
• Ext. hydrolysed formula alone or with
  Lactobacillus rhamnosus GG (LGG)
• Clinical sypmtoms decreased significantly in the
  LGG group
• (Majamaa, JACI 1997)
• Ext. hydrolysed formula alone or with
  Bifidobacterium lactis (Bb12) or with
  Lactobacillus rhamnosus GG (LGG)
• Clinical sypmtoms decreased significantly in the
  Bb12 and in the LGG group
• Isolauri, Clin. Exp. Allergy 2000)

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Clinical studies in infants-II

• 132 newborn children, with family history of
  allergy
• LGG or placebo were administered
• 2-4 weeks preceding delivery to mothers,
• After birth to mothers if breast feeding, or
  orally
• Result within 12 months
• Atopic eczema decreased to 25 in LGG treated
  group
• vs. 46 in placebo-recieving group
• Kalliomaki, Lancet 2001

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(No Transcript)
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Protective (1 ug/ml) and detectable (0,3 ug/ml)
HIBIgG antibody conc. After primery Hib
conjugate vaccine dose in infants receiving
probiotics
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Conclusions

• Recent observations suggest a basic role of
  probiotic bacteria in the prevention of
  allergies/ asthma,
• furthermore in the prevention of autoimmune
  disorders
• They are able to modulate the maturation of the
  immune system in infants host-microbe cross
  talk .
• Natural immune response
• Toll-Like Receptors (TLR),
• Intracell.nukleotide oligomerisation domens (NOD
  1,2)
• Acquired /adaptive immune response
• By reg. T-cells
• Further studies are necessary to know more on
  their effects.

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Perspectives

• Evidence supporting the use of probiotics in the
  prevention or treatment of allergic diseases
• is still preliminary,
• preclinical studies are of interest, but clinical
  studies are not conclusive yet.
• More studies are essential.
• Any clinical trials using probiotics in newborns
  should be carefully monitored.