detailed presentation of all cytokines except chemokines

1. Dr.Amy Mary Sebastian

2. Topic overview
• Cytokines: definition & properties
• Nomenclature
• Primary & secondary CKs
• T cell subsets
• Signal transduction pathways- JAK-STAT, NF-kB
pathway
• Classification of CKs – 8 families based on receptors
• CK- Applied aspect
• Biologicals targeting CKs
• Adverse reactions to CKs

3. • Soluble polypeptide mediators – pivotal role –
communication b/n cells of hematopoietic system
& other cells in the body
• Non immunoglobulin proteins(8-30 kd)
• Released transiently in tissue micro environment
as emergency molecules

4. • Term cytokine coined by Cohen in 1975
• Functions:

5. General features of CKs
Pleiotropism
Multiple biologic activities
Redundancy
Overlapping biologic effects
• Endogenou
s pyrogen
• Lymphocyt
e activating
factor
• Leucocytic
endogenou
s mediator
IIL 1

6. •Cytokines were named according to:
•Cells of origin: Lymphocytes-Lymphokine
Monocytes- Monokine
•Function: GM-CSF- growth factor
Chemokines- chemotaxis
•Targets: Interleukins- leucocytes ,but also acts
on other cells
•All newly discovered CKs are called ILs- 1 to 38
according to order of discovery

7. Primary & Secondary CKs
Primary CKs –initiate all the
events for leucocyte
infiltration by themselves
Secondary CKs- Production
after stimulation by primary
CKs, Restricted spectrum of
activity
IL 1,TNF
IL-2 IL-15
IL-4
IL-13

8. Additional proposed subsets
Tfh(Follicular helper T cells)-
helps B cells in germinal
centres
Th9 cells-IL 9
-antiparasite immunity
Th22 cells- IL 22
-Skin inflammation

9. Signal transduction pathways: NF-kB
IL-17,18 Also by bac LPS, Viruses, UV, Oxidants
IkB Kinase complex (IKK), IKK⍺, IKK

10. JAK-STAT Pathway-
Janus kinase, Signal transducer & activation
of transcription
Signaling by Class I & II CKs
4 Tyrosine kinases: Jak 1
Jak 2
Jak 3
Tyk 2
SH2 domain- Src homology 2
domain
Docking proteins

11. CK families (according to receptors)
1.Class I- largest
Haematopoietin
Receptor
Family
2.Class II
IFN/IL 10
Receptor
family
3)TNF 4)IL-1 5)IL-17 6)TGF-β 8)PDGF
7)Chemokines

12. 1.Class I-Hematopoietin receptor family
• Membrane bound glycoproteins
• Jak-STAT pathway
• Multiple chain receptors-
CK specific ⍺ chain subunit
one or more shared subunits
• 5 shared receptor subunits:
𝜸c βc(IL-2,15) GP-130
IL-3Rβ
IL-3,5
GM-CSF
IL-12Rβ2
IL-12,23
IL-6,11,27
Leukemia inhibitory
factor

13. Receptors sharing common 𝛾 chain- 𝛾c
TSLP IL-21 IL-13
(CD-25)
Lymphoid cells Lymphoid cells
Keratinocytes
Fibroblasts
Dendritic cells,monocytes- LPS
UV induced

14. • Reigns autoreactive T
cells
• Inhibits proliferation of
memory CD8 T cells
• Prolonged stimulation-
FasL & activation
induced cell death
• + Effector function of
antigen specific T cells
• Promotes proliferation of
memory CD8 T cells, NK
cells
• IL 15 inhibits activation
induced cell death
i) IL-2 & IL 15

15. ii)IL-4 & IL-13-Th2
cells
(CD 124)
T cells ,NK cells
Specific
Keratinocytes,EC
Non specific
IL-4 –Growth &
differenciation of Th2 cells

16. iii)IL-7 & Thymic stromal lyphopoietin(TSLP)
Lymphocytes in skin
Regulated expression
DC- IFN 𝜸- KC- IL 7- DC
Immature lymphocytes in BM & Thymus
Lymphocytes
GF for B & T cells
Prime DC s
In some allergic Ds
Th2 cells (TGF 𝜷)
Mast cells (IL 10/SCF)
Allergic
Responce

17. iv)IL-3, IL-5 & GM-CSF
(CD-131)
Produced by: CD4 cells T cells,KC,EC Th2,Mast cells
Mutilineage CSF GF for myeloid Pool of eosinophil
(Myeloid cells) DC to mature DC precursors in BM
Eotaxin

18. • IL-6- Highly pleiotropic,from KC,EC,fibroblasts
• B cell stimulatory factor- Ig secretion
• Plasmacytoma GF- mitogenic for plasmacytoma
• Hepatocyte stimulatory factor
- synthesize acute phase proteins
• IL 11-inhibits production of inflam CKs-Psoriasis
v) gp 130- IL-6, IL-11, IL-27,
Leukemia inhibitory factor, Oncostatin M

19. Pivotal CKs regulating Th1 & Th17 response
Contact
allergens
UV
exposure
Anti tumor immunity Memory T cells Early T cell Treg cells +
Intracellular bacteria Th17 subset response suppress Th17 cells

20. • 3 types of IFNs-Type 1- IFN⍺ (leucocyte IFN)
- IFNβ (Fibroblast IFN)
• (2 chain IFN⍺β receptor)
• Inhibits viral replication
• Some bacterial & protozoal immunity
• Type 2-IFN 𝛾-specific 2 chain receptor-
Stimulation of T cells, antiviral,antiproliferative
• Type 3-IFN𝜆1 / IL 28A
- IFN𝜆2/ IL 28B
• Antiviral, Receptor IL28R & IL 10R
2.Class II family- IFNs

21. 2.Class II family- IFNs & IL-10
Jak1 & Tyk2
STAT 1 & 3

22. 2.Class II family- IFNs & IL-10
• IL-10- antinflammatory CK
-produced by Th2 cells
-IL10R ⍺ & β
-decreases production of IL- 1, 6 & 12, Th1 CKs
-activates Th2 cells
-Keratinocytes are the major source-UV radiation
-Novel IL-10 related CKs-IL-19,20,22,24,26

23. 3.TNF receptor family
• TNF-⍺ -soluble form-resp for most actions-TACE
-Trans membrane protein form
• TNF-β (Lymphotoxin ⍺)
-homotrimer

24. 3.TNF receptor family
DD- Death domain
TRADD- TNF
Receptor asso DD
FADD-Fas
associated DD
DED-Death effector
domain
TRAF2 –TNF
receptor asso
factor 2

25. 4.IL-1 receptor family-IL-1⍺, 1β, 18 & 33
• IL-1- 31kDa
• IL-1⍺ biologically active, stored in keratinocytes
• IL-1β –must be cleaved by Caspase 1 in
inflammasome
- Egress of LCs from skin to draining LNs

26. 4.IL-1 receptor family-IL-1⍺, 1β, 18 & 33
IL-1R asso
kinases
TNF Receptor
asso Factor 6
IL-1ra

27. 4.IL-1 receptor family-IL-1⍺, 1β, 18 & 33
• IL-1R2 -68kDa receptor,regulatory function
-binds IL-1 but not IL-1ra
-after binding-cleaves into a 45kDa
molecule- sequesters IL-1
- also binds to IL1AcP-sequestering it
• IL-1R2 – upregulated by corticosteroids,IL-4
-Inflam CKs-IFN𝛾, IL-1
• IL-18 –proposed name IL-1𝛾
+ Th1 & NK cells

28. 5.IL-17 receptor family (IL-17 & 32)
• Th17 cells-produce IL-17A & IL-17F
• IL-17 mobilizes neutrophils
• TNF⍺,IL-1β,IL-8,IL-6 & G-CSF
• ICAM 1 by monocytes & fibroblasts
• Modulates CK production by keratinocytes-
Ps,AD,CD
• IL-32 : TNF⍺,IL-1β,IL-6
• Several autoimmune ds

29. • Misnomer- anti-proliferative
• Includes – prototypic TGFs- β 1 to β3
- BMP
- growth or differenciation factors
- activins
• Inactive precursor- prodomain cleaved- dimers of
mature domain
• TGF+ Type II receptor-Type I & II Cx- SMADs
6.TGF-𝛽 receptor family

30. • TGF β1 functions-
Treg cell & DC lineage formation
Pro fibrogenic- + Metalloproteinase formation
- TIMP
6.TGF-𝛽 receptor family

31. • CSF-1 isoform a
• EGF
• Hepatocyte GF isoform 1 preprotein
• PDGF C
• VEGF B
• VEGF C preprotein
6.PDGF family

32. • Psoriasis-
Th1 & Th17 inflam ds
• Shift from Th1 to Th2
improves psoriasis
• Over expression of type 1 CKs-IL-2 , IL-6, IL-8,
IL-12, IFN-𝛾, TNF ⍺
• IL-15-triggers production of IFN-𝛾, TNF ⍺,IL-17
• Over expression of IL8 -Neutrophil accumulation
• Th22 cells
Applied aspects

33. Applied aspects
Atopic dermatitis- Th2 phenotype
• TSLP(keratinocytes) through its interaction
with mast cells & DC- Th2 response
• TSLP, Th2 & Th22 lymphoid cells are
increased in atopic skin
• Th2 & Th22 – IL 31-itching & reduced filaggrin
expression

34. •
Applied aspects
• Bullous pemphigoid- Th2 CKs are important
• TNF⍺, IL-6,IL-8,IL-15,IL-21 levels correlate with
disease activity
• IL4 & 13 producing lymphocytes are increased in
peripheral blood
• Recently Th17 cells
• SLE-Ag-Ab Cx- stimulate TLRs 9 & 7-IFN⍺,TNF-⍺
• Increased IFN𝛾 ,IL-6 & IL-10

35. Applied aspects
“The mystery behind Koebner”
• Keratinocytes are rich in IL-1
• IL1ra also coexist
• Mechanical stress- releases large amounts of IL1
• Induces- E selectins,ICAM-1 & VCAM-1-
Chemokines
• Stimulates memory T cells & release of CKs
IL 1
IL1ra

36. Biologicals targeting CKs
• Anti-TNF⍺: Etanercept , Infliximab , Adalimumab
Certolizumab, Golimumab
• Anti-IL1:Anakinra, Rilonacept, Canakinumab
(r-IL-1Ra) (IL-1R+IL-1RacP) (anti IL-1β Ab)
• Anti-IL6:Tocilizumab, Siltuximab
•
• Th 17 CKs: Ustekinumab, Secukinumab,
Ixekizumab

37. •G-CSF-Induction of sweets syndrome, bullous PG
-Rarely thrombotic & necrotising panniculitis
-Exacerbation of leukocytoclastic vasculitis
•IFN⍺,IFN-𝛾,G-CSF- exacerbation of psoriasis
•IL-2-Pruritus,diffuse erythema,mucositis
Inj of iodinated contrast media within 2 wks,HS in
30% cases
Adverse reactions to cytokines

38. Adverse reactions to Anti-TNF⍺
• Psoriasis & psoriasiform
dermatitis(Adalimumab)
• Vasculitis (Etanercept)
• Lichenoid drug eruption (all three)
• Sarcoidosis & drug induced lupus rarely
• ACD can occur
• Slightly increased risk of non melanoma skin
cancer (esp if taken Mtx)

39. In a nut
shell
Small soluble polypeptide
mediators – pivotal role –
communication b/n cells
• Pleiotropism & Redundancy
• Primary & Secondary CKs
• T cell subsets- Th1, Th2, Th12, Treg
• Signal transduction pathways: NF-kB & Jak-STAT
• 8 CK receptor families:
 Haematopoietin receptor- common chain:
 𝛾c - IL-2 & 15 , IL-4 & 13 , IL-9 & 21, IL- 7 & TSLP

40. Class 2- IFN & IL-10
TNF- TNF β, LT-⍺
IL-1 – IL-1⍺, 1β, 18 & 33
TGF β family
IL-17
Chemokines
 βc – IL-2 & 15
 IL-3Rβ - IL-3,5, GM-CSF
 IL-12Rβ2 - IL-12,23
 Gp 130- IL-6,11,27,
Oncostatin M
In a nut
shell

41. • Psoriasis- Th1 & Th 17
• AD - Th2
• BP - Th2
• Biologicals- Anti TNF⍺, AntiIL-1, anti- IL-6, Th-17
• Adverse reactions to CKs
In a nut
shell

42. Thank
you!
“For not falling
asleep”