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Microbes and Allergic Disease Cathryn Nagler-Anderson

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Microbes and Allergic Disease Cathryn Nagler-Anderson Powered By Docstoc
					Microbes and Allergic Disease



Cathryn Nagler-Anderson
Massachusetts General Hospital
Harvard Medical School
1. Examine what we know about how
the body discriminates between harmful
pathogens and innocuous foreign
substances (antigens).
2. Introduce the mucosal immune
system, the portal through which most
foreign substances and microbes enter
the body.
 3. Present some work from our
laboratory on the influence of intestinal
microbes on allergic disease.
There are two arms to the immune
response to any foreign substance
   (antigen) entering the body:

   the innate immune response

 the adaptive immune response
Innate Immune Response

• rapidly deployed - first line defense
• encoded in genome - conserved from
flies to humans
• broad recognition of microbial“patterns”
• no memory of past encounter with
antigen
Adaptive Immune Response

• exquisitely specific recognition
of millions of different potential antigens
• requires gene rearrangement to generate
antigen specific receptors
• long-term memory of past antigen
 encounter
Pattern recognition receptors (PRR) of the
innate immune system see pathogen
associated molecular patterns (PAMPS)


PAMPS are typically highly conserved,
essential components of microbial structure
or metabolism
            The Toll-like receptor (TLR) family of
              Pattern Recognition Receptors

     Peptidoglycan (G+)
         Lipoprotein
    Lipoarabinomannans
      Zymosan (Yeast)          LPS(G-)                                Bacterial
        GPI protein             RSV F        dsRNA      Flagellin     CpG DNA




TLR-6     TLR-2      TLR-1 CD14 MD-2 TLR-4      TLR-3         TLR-5        TLR-9




                                Based on Nat. Rev. Immunol. 2001; 1: 135
Antigen specific receptors on
T cells and B cells characterize the
adaptive immune response.

T cells - cell mediated immunity

B cells - antibody mediated (humoral)
immunity
T cells see peptide fragments of antigen
 presented by MHC proteins on antigen
             presenting cells

                     MHC              T cell receptor




        Antigen presenting   T cell
            cell (APC)
Two signals are required for T cell activation

                     MHC

                                   TCR




         Costimulatory molecules
         on APC provide the
         second signal
Adjuvant - a substance that activates the
innate immune system to produce signals
required for an adaptive immune response


Adjuvants potentiate T cell immunity by:
1. Enhancing expansion of antigen
      specific T cells
2. Altering antigen presentation (upregulation
of costimulation).
3. Influencing differentiation of T cell subsets.
Adjuvants
Cathryn
Nagler-
           presentation without activation of the innate
      Antigen
Anderson:
    immune system leads to non-responsiveness (anergy)
       Pathogens

                       Antigen
          TLRs         presentation

                                T            TH1    IFN-g
          APC
                      Costimulatory
                      molecules

                            IL-12, IL-18

   Soluble Proteins


                       Antigen
           TLRs        presentation

                                T          Anergy
          APC
                      Costimulatory
                      molecules

                            IL-12, IL-18
            +
   CD4 T helper cells
   Th1             Th2
     IL-2            IL-4
    IFN-g            IL-5
     TNF            IL-13


cell mediated   help antibody
 responses       responses
 Most immune responses have both a Th1 and Th2
component. The T cell response to some infectious
   agents becomes polarized to one Th subset.

                   Degree of polarization
                Degree of polarization




         Th 1
         Th1                            Th 2
                                        Th2
   Bacteria- (tuberculosis)         Helminthic
     Gram negative                     Helminthic
   Viruses (measles)                Parasites (worms)
                                        parasites
         bacteria
Work in our laboratory has
examined the influence of two types
of microbes on the development of
food allergy

•Intestinal worms (helminths)

•Intestinal (commensal) bacteria
Antigens enter through mucosal surfaces

                                   Oesophagus
                                   Trachea
Right subclavian vein        Left subclavian vein
Superior vena cava       Mediastinal lymph nodes
                                  Lungs
                                  Heart
Liver                             Spleen
Stomach
Mesenteric nodes                   Thoracic duct
Peyer’s patches                   Large intestine
Appendix                          Small intestine
Gut-associated lymphoid tissue
Peyer’s patch




Villus epithelium
The induction of non-
responsiveness to orally
administered antigens
(including food) is called oral
tolerance.
     Microbes living in the gut
influence the immune response to a
     food antigen through their
  interactions with the innate and
     adaptive immune system.
Life cycle of an intestinal worm,
Heligmosomoides polygyrus

                                    24 - 36 h
                                                              L1
                            Eggs



                                    L4 9 - 11 Days
                                                     Adult
                             wall

                                                      Lumen

                                                 Adult
                Small Intestine



                                    2 - 6 Days
           L3                                                 L2
H. polygyrus
establishes
a chronic, non-
invasive
niche in the
intestinal
lumen                                 QuickTime™ and a
                                      GIF decompressor
                               are needed to see this picture.




From Telford et al, Parasite
Immunol. 1998: 20, 601
               Oral Ag primes for a Th2 response
                  in helminth infected mice
              2000                             6000
                      IFN-g (Th1)                       IL-5 (Th2)
                                               5000
              1500
pg/ml (+SE)




                                               4000

              1000                             3000

                                               2000
              500
                                               1000

               0                                0
                     PBS OVA        PBS OVA           PBS OVA        PBS OVA
                     fed fed        fed fed           fed fed        fed fed

                   Non-infected     Infected          Non-infected Infected


                                                      Shi et al, J. Immunol. 1998, 160: 2449
Response to different forms of antigen presented to the GALT
    leads to systemic nonresponsiveness or immunity
          Soluble Ag                                Ag + adjuvant, microbes


  T cell proliferation and activation              T cell proliferation and activation
                                    1st Ag challenge

  Antigen specific reduction in                   Antigen specific clonal expansion
  proliferative capacity
                              Subsequent challenges


  Profound reduction in
  proliferative capacity;                            Clonal expansion enhanced
  functional non-responsiveness                      by each antigen challenge
  due to failure to clonally expand                  leads to productive immune
  antigen specific clones and/or cell death          response
 The relationship between infection and allergic disease

In developed countries:                         In developing countries:

High incidence of                               Low incidence of
allergic disease                                allergic disease

Low incidence of                                High incidence of
infectious diseases (Th1)                       infectious diseases (Th1)

Low infection with          Allergic disease    High infection with
worms (helminths)                 (Th2)         worms (helminths)




  Helminth Infection                           Microbial Infection
        (Th2)                                        (Th1)
TLR signaling regulates the development of Th1 and Th2 cells
    Pathogens
                                                   IFN-g
                             Antigen
                             presentation
      TLRs
                                     T             TH1     IFN-g
        APC                 Costimulatory
                            molecules

                                   IL-12, IL-18

     Helminths, Allergens

                                                    IL-4
                ? ?           Antigen
                              presentation
       TLRs
                ?                     T             TH2     IL-4, IL,5
                                                            IL-13
         APC                 Costimulatory
                             molecules

                                   IL-4, IL-10 ?
     The Hygiene Hypothesis
Allergy and asthma have increased during the last
20-50 years due to reduced exposure to childhood
bacterial and viral infections brought about by
improvements in vaccination and sanitation.


In the absence of these Th1 polarizing stimuli
mucosal immune responses fail to overcome their
inherent Th2 bias and become slanted in the
direction of allergy.
Does helminth infection induce an allergic response?




                          QuickTime™ and a
                     Photo - JPEG decompressor
                   are needed to see this picture.
                   Interleukin-13




                                                     (N. Engl. J. Med. 2001, 344: 30)
A model for food allergy
An allergic response to a food antigen
(peanut) can be induced in C3H/HeJ
mice by repeated oral administration
of peanut plus a mucosal adjuvant
(cholera toxin)

An allergic response is measured by:
• 1. Symptoms of anaphylaxis
(itching,wheezing, labored
respiration, convulsions)
•2. Elevated levels of plasma
histamine
•3. Induction of peanut specific IgE
Helminth infection (HP) does not induce
 an allergic response to a food antigen

                   500                                            10000

                   400




                                                                          ∆ - Histamine ng/ml
Peanut IgE ng/ml




                                                                  7500
                   300
                                                                  5000
                   200

                                                                  2500
                   100


                     0                                            0
                         PBS   PBS/CT   PN   PN/CT HP/PBS PN/HP




                                              Bashir et al J. Immunol. 2002, 169:3284
Helminth infection protects against peanut allergy

                           1000
                                                                        4000




                                                                                ∆ - Histamine ng/ml
        Peanut IgE ng/ml


                            750
                                                                        3000


                            500                                          2000


                            250                                          1000



                              0                                          0
                                  PN/CT   PN   HP/PN/CT HP/PBS PBS/CT




                                                    Bashir et al J. Immunol. 2002, 169:3284
              Counter-regulation hypothesis
                        Commensal gut
Organ specific auto-    Microflora
immune disease

                        Protozoa
                                             CD4+ regulatory T cells
    TH1                 Viruses
                        Bacteria
                                                   CD8+ T cells
                                                      B cells
      INFLAMMATION        IL-10                   Dendritic cells
                          (TGF-b)                  Monocytes/
                                                  macrophages
                        Helminths                 Epithelial cells
    TH2                 Viruses
                        Bacteria
                        Protozoa
 Allergic disease
                        Commensal gut
                        Microflora      Adapted from Wills-Karp, et al
       Inhibitory
                                        Nat.Rev.Immuno.1, 2001:69
Mice lacking TLR-4, the receptor for bacterial
  LPS, are highly susceptible to an allergic
         response to peanut plus CT

                 10000            3000




                                         D - Histamine
                 7500
  PN-IgE ng/ml




                                  2000

                 5000

                                  1000
                 2500



                     0            0
Removal of gut bacteria by antibiotic treatment induces an
   allergic response to peanut in TLR-4 positive mice

                       3000
                                     3000




                                            D - Histamine
        PN-IgE ng/ml



                       2000
                                     2000


                       1000
                                     1000



                          0          0
Allergy is induced in the absence of TLR-4
signaling by luminal bacteria




                 T
                              T
                T
                              B
                B T   T   B
                B B       B                      Tr1
                                                               IL-10
                                                        Tr1
                                                  Tr1          IL-10

                      TLR-4       Immature (or    Th3
                                                                TGF-b
                                  mature?) DC           Th3
                                  in GALT        Th3
                                                              TGF-b
                                  (PP, MLN?)
       IgE
                     IFN-g

				
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