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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) GPI protein TLR-6 TLR-2 LPS(G-) RSV F TLR-1 CD14 MD-2 TLR-4 dsRNA TLR-3 Flagellin TLR-5 Bacterial CpG DNA 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 T cell receptor MHC Antigen presenting cell (APC) T cell 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 NaglerAntigen Anderson: presentation without activation of the innate immune system leads to non-responsiveness (anergy) Pathogens TLRs Antigen presentation T APC TH1 Costimulatory molecules IL-12, IL-18 Soluble Proteins TLRs Antigen presentation T APC Costimulatory molecules IL-12, IL-18 Anergy IFN-g + CD4 T helper cells Th1 Th2 IL-2 IFN-g TNF IL-4 IL-5 IL-13 cell mediated responses help antibody 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 Th11 Bacteria Gram - (tuberculosis) negative Viruses (measles) bacteria Th 2 Th2 Helminthic Helminthic Parasites (worms) parasites 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 Right subclavian vein Superior vena cava Liver Stomach Mesenteric nodes Peyer’s patches Appendix Oesophagus Trachea Left subclavian vein Mediastinal lymph nodes Lungs Heart Spleen Thoracic duct Large intestine Small intestine Gut-associated lymphoid tissue Peyer’s patch Villus epithelium The induction of nonresponsiveness 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 wall Adult Lumen Adult Small Intestine L3 2 - 6 Days L2 H. polygyrus establishes a chronic, noninvasive niche in the intestinal lumen From Telford et al, Parasite Immunol. 1998: 20, 601 QuickTime™ and a GIF decompressor are needed to see this picture. Oral Ag primes for a Th2 response in helminth infected mice pg/ml (+SE) 2000 6000 IFN-g (Th1) 5000 1500 IL-5 (Th2) 4000 1000 3000 2000 500 1000 0 0 PBS OVA fed fed Non-infected PBS OVA fed fed Infected PBS OVA fed fed PBS OVA fed fed 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 clonal expansion Antigen specific reduction in proliferative capacity Subsequent challenges Profound reduction in proliferative capacity; functional non-responsiveness due to failure to clonally expand antigen specific clones and/or cell death Clonal expansion enhanced by each antigen challenge leads to productive immune response The relationship between infection and allergic disease In developed countries: In developing countries: High incidence of allergic disease Low incidence of allergic disease Low incidence of infectious diseases (Th1) High incidence of infectious diseases (Th1) Low infection with worms (helminths) Allergic disease (Th2) Helminth Infection (Th2) High infection with worms (helminths) Microbial Infection (Th1) TLR signaling regulates the development of Th1 and Th2 cells Pathogens IFN-g Antigen presentation TLRs T APC TH1 IFN-g Costimulatory molecules IL-12, IL-18 Helminths, Allergens ? ? TLRs APC ? IL-4 Antigen presentation T Costimulatory molecules IL-4, IL-10 ? TH2 IL-4, IL,5 IL-13 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 10000 400 7500 300 5000 200 2500 100 ∆ - Histamine ng/ml Peanut IgE ng/ml 500 0 0 PBS PBS/CT PN PN/CT HP/PBS PN/HP Bashir et al J. Immunol. 2002, 169:3284 1000 4000 750 3000 500 2000 250 1000 ∆ - Histamine ng/ml Peanut IgE ng/ml Helminth infection protects against peanut allergy 0 0 PN/CT PN HP/PN/CT HP/PBS PBS/CT Bashir et al J. Immunol. 2002, 169:3284 Counter-regulation hypothesis Organ specific autoimmune disease TH1 INFLAMMATION TH2 Commensal gut Microflora Protozoa Viruses Bacteria IL-10 (TGF-b) Helminths Viruses Bacteria Protozoa CD4+ regulatory T cells CD8+ T cells B cells Dendritic cells Monocytes/ macrophages Epithelial cells Allergic disease Inhibitory Commensal gut Microflora Adapted from Wills-Karp, et al 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 3000 7500 2000 5000 1000 2500 0 0 D - Histamine PN-IgE ng/ml 10000 Removal of gut bacteria by antibiotic treatment induces an allergic response to peanut in TLR-4 positive mice 3000 2000 2000 1000 0 1000 0 D - Histamine PN-IgE ng/ml 3000 Allergy is induced in the absence of TLR-4 signaling by luminal bacteria T T T B B T T B B B B IL-10 Tr1 Tr1 IL-10 Tr1 TLR-4 IgE IFN-g Immature (or mature?) DC in GALT (PP, MLN?) Th3 Th3 Th3 TGF-b TGF-b