Cytokines in allergic inflammation Presented by Sirapassorn Sornphiphatphong, MD. October16, 2015

1. Cytokines in allergic
inflammation
Reviewed by Sirapassorn Sornphiphatphong, MD.

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. 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. 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. Classes of Cytokine receptors
Abbas AK, et al. Cellular and molecular immunology Ed 8th

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. Subunit composition of cytokine receptors
Abbas AK, et al. Cellular and molecular immunology Ed 8th

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. 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. 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. TNF Receptor Family
Abbas AK, et al. Cellular and molecular immunology Ed 8th

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. 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. 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. 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. 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. IL-4 and IL-13
Middleton 8th edition

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Middleton 8th edition

35. Middleton 8th edition

36. Cytokines Involved in Th1 Deviation
Middleton 8th edition

37. Cytokines Involved in Th2 Deviation
Middleton 8th edition

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. Th17 Differentiation
Middleton 8th edition

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. 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. 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. Treg
Middleton 8th edition

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. Middleton 8th edition

46. Middleton 8th edition