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Cytokines in allergic
inflammation
Reviewed by Sirapassorn Sornphiphatphong, MD.
Overview
• Classes of Cytokine receptors
• Allergic Immunity
• Antiinflammatory Cytokines
• T Helper Lymphocyte Families
•...
Cytokines
• Secreted proteins of immune system
• Growth, differentiation and activation functions that
regulate immune res...
Classes of Cytokine receptors
based on extracellular cytokine-binding domains
• Type I Cytokine Receptors (Hematopoietin R...
Classes of Cytokine receptors
Abbas AK, et al. Cellular and molecular immunology Ed 8th
Type I Cytokine Receptors
(Hematopoietin Receptor Family)
• Dimers or trimers
• Contain 1 or 2 domains with
a conserved cy...
Subunit composition of cytokine receptors
Abbas AK, et al. Cellular and molecular immunology Ed 8th
Subunit composition of cytokine receptors
• Divided into subgroups based on structural
homologies or use of shared signali...
Type II Cytokine Receptors
(IFN Receptor Family)
• 2 extracellular
domains with
conserved cysteines
• Do not contain
WSXWS...
TNF Receptor Family
• Preformed trimers
• Conserved cysteine-rich
extracellular domains
• Shared intracellular signaling
m...
TNF Receptor Family
Abbas AK, et al. Cellular and molecular immunology Ed 8th
TNF Receptor Family
• Binding ligands to trimeric receptors  conformational
change & recruits adaptor proteins to recepto...
IL-1/TLR Family
• Share a conserved cytosolic
sequence, called Toll-like/IL-1
receptor (TIR) domain  engage
similar signa...
Allergic Immunity
• Proinflammatory T cell activation → development
of allergic immunity
• Several features specifically a...
Cytokine in allergic immunity
• Regulation of IgE
– Induction of IgE: IL-4, IL-13, IL-9
– Inhibition of IgE Production: IF...
Regulation of IgE
• Inappropriate production of IgE in response to
allergen defines atopy
• Induction of IgE
• Primarily a...
IL-4 and IL-13
Middleton 8th edition
IL-4 and IL-13
• Shared use of IL-4Rα chain by IL-4 & IL-13
• Shares many biologic activities on mononuclear
phagocytic ce...
IL-4
• The limited distribution of IL-13Rα1 explains unique
ability of IL-4 to induce Th2 lymphocyte
differentiation and m...
IL-4
• Enhancing Ag-presenting capacity
- Stimulates MHC-II, B7 (CD80/CD86), CD40, surface
IgM, and low-affinity IgE R(CD2...
IL-13
• More in allergic inflammatory tissue
• Stimulate mucin production in asthma (more
than IL-4)
• Mucous hypersecreti...
IL-9
• Produced by Th9, Th2, mast cell, eosinophil
• Mast cell growth factor
• Synergizes with IL-4 to enhance production ...
Eosinophilia
• IL-5
• IL-3
• GM-CSF
Tetsuya Adachi , Rafeul Alam Cell Physiology 1998;275:C623-C633
IL-5Rα and β chain(CD1...
IL-5 IL-3 GM-CSF
Th2-like lymphocytes,
mast cells, NK T cells
T lymphocytes (major source)
Eosinophils, mast cells (in all...
Mast cell proliferation and activation
• Cytokine for mast cell growth, proliferation
– Stem cell factor (SCF) (formerly t...
IL-31
• IL-6–type cytokine family
• Expressed by Th2-like lymphocytes
• Targets keratinocytes, epithelial cells,
eosinophi...
Antiinflammatory Cytokines
• TGF-β
• IL-10 family: IL-10, IL-19, IL-20, IL-22,
IL-24, IL-26, IL-28, and IL-29
Transforming growth factor-β
• Regulate cell growth, both stimulatory and
inhibitory effects on different cell types
• Pro...
TGF-β
• Inhibits Ig secretion
and cytotoxicity of
mononuclear
phagocytes and NK
cells
• Chemoattractant for
macrophages
• ...
IL-10
• Source
– Treg: primary source
– Th1, Th2 lymphocytes,
cytotoxic T cells
– B lymphocytes
– mast cells
– Immature DC...
IL-10 family
• IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29
• Share structural homology with IL-10 and IL-10
recept...
IL-10 family
IL Source Pathway Function
IL-19 Monocytes, epithelial,
endothelial cells
STAT1,
STAT3
Promote Th2, asthma
IL...
T Helper Lymphocyte Families
• Th1
• Th2
• Th17-like lymphocytes
• Other T Helper Families: Th9, Th22, T Follicular
Helper...
Middleton 8th edition
Middleton 8th edition
Cytokines Involved in Th1 Deviation
Middleton 8th edition
Cytokines Involved in Th2 Deviation
Middleton 8th edition
Epithelium-derived cytokines in
Th2 differentiation
IL 25: increase expression of CCL5 (RANTES), CCL11(eotaxin)
IL33: expr...
Th17 Differentiation
Middleton 8th edition
Th9 lymphocytes
Middleton 8th edition
• Subfamily of Th2 cells
• Prominent IL-9, moderate IL-10, less IL-4
• Result from t...
Th22 lymphocytes
• Prominent expression of IL-22, TNF-α
• Produced by keratinocytes or epithelial cells
• ↑IL-22 correlate...
T follicular helper cell (Tfh)
• Defined by their follicular location
• Interacts with B cells in the germinal center
– Su...
Treg
Middleton 8th edition
TREG, TR1, AND Th3 CELLS
• Thymus-derived natural
regulatory T cells (nTreg)
cells
– Response to thymus-
autologous Ag med...
Middleton 8th edition
Middleton 8th edition
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Cytokines in allergic inflammation

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Cytokines in allergic inflammation

Presented by Sirapassorn Sornphiphatphong, MD.

October16, 2015

Published in: Health & Medicine
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Cytokines in allergic inflammation

  1. 1. Cytokines in allergic inflammation Reviewed by Sirapassorn Sornphiphatphong, MD.
  2. 2. Overview • Classes of Cytokine receptors • Allergic Immunity • Antiinflammatory Cytokines • T Helper Lymphocyte Families • Cytokines Involved in Th1 Differentiation • Cytokines Involved in Th2 Differentiation
  3. 3. Cytokines • Secreted proteins of immune system • Growth, differentiation and activation functions that regulate immune responses • Produced by many different cell types • Others called interleukins • All cytokine receptors consist of one or more transmembrane proteins – Extracellular portions: for cytokine binding – Cytoplasmic portions: initiation of intracellular signaling pathways Middleton 8th edition
  4. 4. Classes of Cytokine receptors based on extracellular cytokine-binding domains • Type I Cytokine Receptors (Hematopoietin Receptor Family) • Type II Cytokine Receptors (IFN Receptor Family) • TNF Receptor Family • IL-1/TLR Family Abbas AK, et al. Cellular and molecular immunology Ed 8th
  5. 5. Classes of Cytokine receptors Abbas AK, et al. Cellular and molecular immunology Ed 8th
  6. 6. Type I Cytokine Receptors (Hematopoietin Receptor Family) • Dimers or trimers • Contain 1 or 2 domains with a conserved cysteines • Proximal peptide stretch containing a tryptophan- serine-X-tryptophan-serine (WSXWS) motif (X = amino acid) Abbas AK, et al. Cellular and molecular immunology Ed 8th
  7. 7. Subunit composition of cytokine receptors Abbas AK, et al. Cellular and molecular immunology Ed 8th
  8. 8. Subunit composition of cytokine receptors • Divided into subgroups based on structural homologies or use of shared signaling polypeptides • Common γ chain (CD132) – Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 • Common β chain (CD131) subunit – Receptors for IL-3, IL-5, GM-CSF • Common gp130 signaling component – For IL-6, IL-11, IL-27, LIF, CNTF
  9. 9. Type II Cytokine Receptors (IFN Receptor Family) • 2 extracellular domains with conserved cysteines • Do not contain WSXWS motif • Signaling through type I, type II cytokine receptor: JAK-STAT signaling Abbas AK, et al. Cellular and molecular immunology Ed 8th
  10. 10. TNF Receptor Family • Preformed trimers • Conserved cysteine-rich extracellular domains • Shared intracellular signaling mechanisms • TNFRI & TNFRII, CD40 protein, Fas, lymphotoxin receptor & BAFF receptor family Abbas AK, et al. Cellular and molecular immunology Ed 8th
  11. 11. TNF Receptor Family Abbas AK, et al. Cellular and molecular immunology Ed 8th
  12. 12. TNF Receptor Family • Binding ligands to trimeric receptors  conformational change & recruits adaptor proteins to receptor complex • Adaptors recruit enzymes which initiate downstream signaling • TNF receptor recruits adaptor protein TRADD (TNF receptor–associated death domain) • TRADD can recruit proteins called TRAFs (TNF receptor associated factors)  on NF-κB signaling • Type I TNF receptor (there are 2 R for TNF) & Fas (CD95) can also recruit adaptors  activation of caspase-8  apoptosis
  13. 13. IL-1/TLR Family • Share a conserved cytosolic sequence, called Toll-like/IL-1 receptor (TIR) domain  engage similar signal transduction pathways  induce new gene transcription • Adaptors link TLRs to different IRAK (IL-1R–associated kinase) Abbas AK, et al. Cellular and molecular immunology Ed 8th
  14. 14. Allergic Immunity • Proinflammatory T cell activation → development of allergic immunity • Several features specifically associated with the asthmatic state are regulated by cytokines, including IgE production, eosinophil activation, and mast cell proliferation
  15. 15. Cytokine in allergic immunity • Regulation of IgE – Induction of IgE: IL-4, IL-13, IL-9 – Inhibition of IgE Production: IFN-γ, IL-21 • Eosinophilia – IL-5, IL-3, GM-CSF • Mast cell proliferation and activation • Other Th2 derived cytokines involved in the development of allergic inflammation – IL-31
  16. 16. Regulation of IgE • Inappropriate production of IgE in response to allergen defines atopy • Induction of IgE • Primarily a function of IL-4, IL-13 • Synergistic by IL-9 • Inhibitors of IgE isotype switch: IFN-ɣ, IL-21
  17. 17. IL-4 and IL-13 Middleton 8th edition
  18. 18. IL-4 and IL-13 • Shared use of IL-4Rα chain by IL-4 & IL-13 • Shares many biologic activities on mononuclear phagocytic cells, endothelial cells, epithelial cell, B cells • Activation signaling protein STAT6 • Induces IgE isotype switch, VCAM-1 expression Middleton 8th edition
  19. 19. IL-4 • The limited distribution of IL-13Rα1 explains unique ability of IL-4 to induce Th2 lymphocyte differentiation and mast cell activation Middleton 8th edition
  20. 20. IL-4 • Enhancing Ag-presenting capacity - Stimulates MHC-II, B7 (CD80/CD86), CD40, surface IgM, and low-affinity IgE R(CD23) on macrophages • Downregulate antibody-dependent cellular cytotoxicity • Inhibit expression of Fcγ receptors • IL-4 receptors present on mast cells - Stimulate IgE receptor expression - Expression of LTC4 synthase  produce cyst LT
  21. 21. IL-13 • More in allergic inflammatory tissue • Stimulate mucin production in asthma (more than IL-4) • Mucous hypersecretion, nonspecific airway hyperreactivity (AHR) • Airway metaplasia of asthma
  22. 22. IL-9 • Produced by Th9, Th2, mast cell, eosinophil • Mast cell growth factor • Synergizes with IL-4 to enhance production of IgE, memory B cell differentiation • Enhanced IL-5 • Induce T cell & eosinophil chemotactic factors • Important role in inducing goblet cell hyperplasia & expression of mucin genes
  23. 23. Eosinophilia • IL-5 • IL-3 • GM-CSF Tetsuya Adachi , Rafeul Alam Cell Physiology 1998;275:C623-C633 IL-5Rα and β chain(CD131) shared with GM-CSF, IL-3 receptors
  24. 24. IL-5 IL-3 GM-CSF Th2-like lymphocytes, mast cells, NK T cells T lymphocytes (major source) Eosinophils, mast cells (in allergic inflammation) Eosinophil •Stimulating production •Chemotactic and activates mature eosinophils •Inducing secretion and enhancing cytotoxicity •Promotes accumulation of eosinophils •upregulate responses to chemokines, β2 integrins on eosinophils •promote adherence to VCAM-1 expressing endothelial cells •Prolongs eosinophil survival by blocking apoptosis Induce basophil differentiation supports growth: DCs, erythrocytes, granulocytes (especially basophils), macrophages, mast cells, and lymphoid cells supports the maturation of DCs, neutrophils, and macrophages
  25. 25. Mast cell proliferation and activation • Cytokine for mast cell growth, proliferation – Stem cell factor (SCF) (formerly termed c-kit ligand) – IL-3, IL-5, IL-6, IL-9, IL-10, IL-11, nerve growth factor Stem cell factor (SCF) • Derived from bone marrow stromal cells, endothelial cells, fibroblasts • Induces histamine release • Stimulate myeloid, lymphoid, and erythroid progenitor cell growth and mast cell differentiation
  26. 26. IL-31 • IL-6–type cytokine family • Expressed by Th2-like lymphocytes • Targets keratinocytes, epithelial cells, eosinophils, basophils and monocytes • Recruitment of neutrophils, monocytes, and T cells • Overexpression: AD
  27. 27. Antiinflammatory Cytokines • TGF-β • IL-10 family: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29
  28. 28. Transforming growth factor-β • Regulate cell growth, both stimulatory and inhibitory effects on different cell types • Produced by osteocytes, epithelial cells, fibroblasts, platelets, monocytes, eosinophils, and T cells • Stimulant of fibrosis, formation of ECM and the promotion of wound healing and scar formation
  29. 29. TGF-β • Inhibits Ig secretion and cytotoxicity of mononuclear phagocytes and NK cells • Chemoattractant for macrophages • Supports the α isotype switch to IgA TGF-β in gut lymphoid tissue by Th3 cells • secretory IgA production • immune nonresponsiveness to benign gut pathogens and food allergens TGF-β production by regulatory cells • lessens allergic inflammation through a capacity to inhibit IgE synthesis and mast cell proliferation
  30. 30. IL-10 • Source – Treg: primary source – Th1, Th2 lymphocytes, cytotoxic T cells – B lymphocytes – mast cells – Immature DCs, mononuclear phagocytic cells (M2 cells) • Signaling through activation of JAK1-STAT3 Function • Inhibit cytokine: – Th1 cytokine (IFN-γ) – Th2 cytokine(IL4, IL5) – mononuclear phagocytes cytokine (IL-1β, IL-6, IL-8, IL-12, and TNF-α) – NK cells cytokine (IFN-γ and TNF-α) • Inhibits MHC class II, CD23, ICAM-1 and CD80/CD86 • Enhances isotype switching to IgG4 • Growth cofactor for cytotoxic T cells
  31. 31. IL-10 family • IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29 • Share structural homology with IL-10 and IL-10 receptors • Antiviral activity • None of these cytokines inhibit cytokine synthesis, an activity that remains unique to IL-10
  32. 32. IL-10 family IL Source Pathway Function IL-19 Monocytes, epithelial, endothelial cells STAT1, STAT3 Promote Th2, asthma IL-20 Monocytes, DCs, epithelial cells, endothelial cells, skin keratinocytes STAT1, STAT3 keratinocyte proliferation, psoriatic lesions IL-22 Th17 and Th1 cells), NK cells STAT3 Innate pathogen defense, induces MHC class I antigen expression Il-24 Monocytes, Th2 STAT3 Promotes secretion of TNF-α , IL- 6 from human monocytes, antineoplastic activity IL-26 T memory cells, Th17 cells, and NK cells STAT1, STAT3 Induce CXCL8 (IL-8), ICAM-1 IL-28A, IL-28B JAK/STAT Antiviral, Shift immature DCs to produce Treg
  33. 33. T Helper Lymphocyte Families • Th1 • Th2 • Th17-like lymphocytes • Other T Helper Families: Th9, Th22, T Follicular Helper Cells • Regulatory T lymphocytes families: Treg, TR1, AND Th3 CELLS
  34. 34. Middleton 8th edition
  35. 35. Middleton 8th edition
  36. 36. Cytokines Involved in Th1 Deviation Middleton 8th edition
  37. 37. Cytokines Involved in Th2 Deviation Middleton 8th edition
  38. 38. Epithelium-derived cytokines in Th2 differentiation IL 25: increase expression of CCL5 (RANTES), CCL11(eotaxin) IL33: express in bronchial epithelial cell induces fibrosis Middleton 8th edition
  39. 39. Th17 Differentiation Middleton 8th edition
  40. 40. Th9 lymphocytes Middleton 8th edition • Subfamily of Th2 cells • Prominent IL-9, moderate IL-10, less IL-4 • Result from the differentiation of Th2 cells in the presence of TGF-β
  41. 41. Th22 lymphocytes • Prominent expression of IL-22, TNF-α • Produced by keratinocytes or epithelial cells • ↑IL-22 correlated with severity disease of Psoriasis, Crohn disease, interstitial lung diseases and rheumatoid arthritis Middleton 8th edition TGF -B
  42. 42. T follicular helper cell (Tfh) • Defined by their follicular location • Interacts with B cells in the germinal center – Support affinity maturation – Isotype switching – Produce memory B and long-lived plasma cells • BCL6: master regulator – Increases expression of CXCR5, PD-1 -> express IL-21 Middleton 8th edition
  43. 43. Treg Middleton 8th edition
  44. 44. TREG, TR1, AND Th3 CELLS • Thymus-derived natural regulatory T cells (nTreg) cells – Response to thymus- autologous Ag mediate tolerance to self Ag – Secrete membrane- bound TGF-β • Inducible Treg (iTreg) cells – Secrete IL-10 – Response to peripherally expressed self Ag • Unique expression profiles and functions • TGF-β–producing Th3 cells of the gut mucosa – Mediate IgA production • IL-10–producing lymphocytes; Tr1 – Mechanism of IT
  45. 45. Middleton 8th edition
  46. 46. Middleton 8th edition

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