CSU is an
immune-mediated
inflammatory
skin disease1

The pathophysiology of CSU is not completely clear, but mast cells are
central; other immune cells are also involved, eg, Th1 and Th2 cells,
basophils, eosinophils, neutrophils, and monocytes1-4

Basophils
Th2 cells
Eosinophils
Mast cells

CSU pathophysiology involves a
complex interplay among
multiple immune cells,
immune mediators, and cytokines,
eg, IgE, histamine, IL-4, IL-13,
IL-5, and IL-311,4-7

IgE
Histamine and other
immune mediators
IL-4
IL-13
IL-5
IL-31

Mast cells are central to CSU pathophysiology, and work with key
elements of type 2 signaling including IL-4 and IL-131,3

Mast cell
Basophil
IgE
IgG
IgM
Histamine
and other
immune mediators
Eosinophil
Th2 cell
Self-antigen
FcεRI
Primary/secondary
effectsc
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A positive feedback loop is created as more IL-4 is produced,
promoting Th2 cell production and type 2 signaling3,9,13

IL-4 promotes the differentiation of Th0 cells into Th2 cells. These Th2 cells then proliferate in
response to IL-4 and produce more IL-4 and other type 2 cytokines, in a positive feedback loop4,9,11

Type 2 cytokines promote B-cell Ig isotype class switching and prime the mast
cells and basophils for activation9,13

Many immune cell types, including basophils, produce
IL-4 and IL-13, which drive B-cell Ig isotype class
switching, leading to IgE/IgG production and IgE-
dependent and independent activation of mast cells1,3,13



IL-4 and IL-13 increase IgE
receptor FcεRI expression,
priming mast cells and basophils
for activation3,9,13



IL-4 helps drive mast cell activation, leading to the production of type 2 cytokines13,18

IL-4 and IL-13 help drive the activation of mast cells. Upon activation, skin mast cells secrete IL-4 and
IL-13, among other immune mediators, further contributing to type 2 inflammation13,18

Mast cell activation leads to the release of histamine and other immune mediators4

Mast cell activation can be IgE-dependent or independent8

Mast cell
FcεRI
IgG
Self-antigen
Histamine
and other
immune
mediators
IgE
IgM
Mast cell
FcεRI
IgG
IgM
Histamine
and other
immune
mediators
IgE
Self-antigen

Mast cell and basophil degranulation lead to the release of histamine and other
immune mediators that drive many CSU disease features1,8,9

Basophil
Mast cell
Histamine and other
immune mediators
  • Histamine and other immune mediators cause vasodilation,
    inducing vascular permeability, and promoting plasma extravasation and skin homing of immune cells contributing to itch and edema1,5
  • In addition, IL-4 and IL-13 along with other cytokines such as IL-5 and IL-31 may also contribute to these disease features1,5,7,13
    • For example, IL-4 and IL-13 sensitize nerve cells to pruritogens, such as IL-31 and histamine7,17
    • IL-4, IL-5 and IL-13 collectively help with eosinophil trafficking5
Although CSU is considered a
mast cell-centric disease, type 2
inflammation may play a key
role at multiple levels sustaining
the disease chronicity1

CSU, chronic spontaneous urticaria.

a IL-4 and/or IL-13 are also produced by basophils, Th2 cells, and other immune cells.
b IL-4 and/or IL-13 signaling leads to B-cell class switching, IgE production, and increased FcεRI expression.8
c Mediated via both primary and secondary effects, including B-cell class switching, immune cell trafficking, cellular infiltration
and/or release of immune mediators via, eg, IgE/IgG binding (such as basophils and mast cells).

References: 1. Kocatürk E, Maurer M, Metz M, Grattan C. Looking forward to new targeted treatments for chronic spontaneous urticaria. Clin Transl Allergy. 2017;7:1. Published correction appears in: Clin Transl Allergy. 2017;7:11. 2. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-1414. 3. Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev. 2018;282(1):121-150. 4. Asero R, Cugno M, Tedeschi A. Eosinophils in chronic urticaria: supporting or leading actors? World Allergy Organ J. 2009;2(9):213-217. 5. Altrichter S, Frischbutter S, Fok JS, et al. The role of eosinophils in chronic spontaneous urticaria. J Allergy Clin Immunol. 2020;145(6):1510-1516. 6. Edukulla R, Singh B, Jegga AG, Sontake V, Dillon SR, Madala SK. Th2 cytokines augment IL-31/IL-31RA interactions via STAT6-dependent IL-31RA expression. J Biol Chem. 2015;290(21):13510-13520. 7. Gibbs BF, Patsinakidis N, Raap U. Role of the pruritic cytokine IL-31 in autoimmune skin diseases. Front Immunol. 2019;10:1383. 8. Bracken SJ, Abraham S, MacLeod AS. Autoimmune theories of chronic spontaneous urticaria. Front Immunol. 2019;10:627. 9. Gandhi NA, Bennett BL, Graham NMH, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35-50. 10. Kolkhir P, Altrichter S, Munoz M, Hawro T, Maurer M. New treatments for chronic urticaria. Ann Allergy Asthma Immunol. 2020;124(1):2-12. 11. Keegan AD, Leonard WJ, Zhu J. Recent advances in understanding the role of IL-4 signaling. Fac Rev. 2021;10:71. 12. Severinson E. Identification of the IgG1 induction factor (interleukin 4). Front Immunol. 2014;5:628. 13. McLeod JJA, Baker B, Ryan JJ. Mast cell production and response to IL-4 and IL-13. Cytokine. 2015;75(1):57-61. 14. Altrichter S, Zampeli V, Ellrich A, Zhang K, Church MK, Maurer M. IgM and IgA in addition to IgG autoantibodies against FcɛRIα are frequent and associated with disease markers of chronic spontaneous urticaria. Allergy. 2020;75(12):3208-3215. 15. Sánchez-Borges M, Ansotegui IJ, Baiardini I, et al. The challenges of chronic urticaria part 1: epidemiology, immunopathogenesis, comorbidities, quality of life, and management. World Allergy Organ J. 2021;14(6):100533. 16. Saini SS. Chronic spontaneous urticaria: etiology and pathogenesis. Immunol Allergy Clin North Am. 2014;34(1):33-52. 17. Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017;171(1):217-228.e13. 18. Babina M, Guhl S, Artuc M, Zuberbier T. IL-4 and human skin mast cells revisited: reinforcement of a pro-allergic phenotype upon prolonged exposure. Arch Dermatol Res. 2016;308(9):665-670.