Urticaria pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Wheal formation pathogenesis
There are some factors responsible in pathogenesis of wheals:[1]
- There are some endogenous anti-angiogenic mediators, which are degraded from extracellular matrix components such as endostatin (ES) and thrombospondin-1 (TSP-1). These mediators regulate the functional activity of vascular endothelial growth factor (VEGF).
- Endostatin (ES) and thrombospondin-1 (TSP-1) levels are elevated in patients with urticaria. Apart from their anti-angiogenic effects, they are responsible for destabilizing the endothelial cells contact, which leads to formation of wheals, the famous dermatologic presentation of urticaria.
- NO synthesis is one of the responses to endostatin (ES) which can also acts as a vasoactive mediator. The consequent vasodilation eventually leads to wheals formation through vascular leakage.
Acute urticaria
The pathophysiology of acute urticaria is production of specific IgE against food protein antigens.[2]
Chronic spontaneous urticaria
There are numerous mechanism hypothesized to be responsible in pathogenesis of chronic spontaneous urticaria:[3][4][5][6][7][8][9][10][11][12][13][14]
- Inflammation has been known as a responsible factor in the pathogenesis of urticaria, especially in chronic spontaneous urticaria.
- One of the findings that supports the role of inflammation in the urticaria pathogenesis is IL-31. This interleukin is primarily produced by activated Th2 lymphocytes and mast cells, as well as a skin-homing T cell (CD45R0 CLA+T cell) and plays a cardinal role in chronic skin inflammation.
- An imbalance in some anti-inflammatory adipokines (such as adiponectin) and proinflammatory adipokines (such as lipocalin-2 (LCN2)) has been found in chronic urticaria.
- Matrix metallopeptidases (MMPs) are elevated in patients with chronic spontaneous urticaria. MMPs are responsible in the inflammation process as shown below:
Macrophages, neutrophils, T cells, and mast cells → MMP-9 → Cleavage of pro-inflammatory chemokines/cytokines → Migration and activation of more immune cells
- Activation of mast cells and basophils has been increased in urticaria.[15] There are two known mechanisms that lead to mast cells and basophils activation in the process of urticaria:
#Defect in intracellular signaling: Improper activation of spleen tyrosine kinase (Syk) or improper inhibition of Src homology 2 (SH2)-containing inositol phosphatases (SHIP).
#Autoimmune mechanisms: Antibody-mediated mast cell and basophils activation via IgG- or IgE- mediated pathways.
- At least 200 IgE autoantigens (soluble or membrane-bound), were recently found in patients with chronic spontaneous urticaria. IgE anti-IL-24 is one of these IgE autoantigens that have been found in all patients with chronic spontaneous urticaria.
- Approximately, 35%–40% of patients have IgG anti-FcεRIα (an α subunit of the high affinity IgE receptor).
- A basophilic abnormality has been seen in a number of patients with chronic spontaneous urticaria. Elevated levels of phosphatases, such as Src homology tyrosine phosphatase-1 (SHP-1), has been detected in the defective basophils.[16]
- Complement system is also responsible in pathogenesis of chronic spontaneous urticaria.
- Increased expression of tissue factor by activated eosinophils first activates extrinsic coagulation pathway and then the intrinsic coagulation pathway and consequent generation of thrombin has been reported.
- In-vitro experiments have been demonstrated the role of C5a in enhancement of IgG-dependent histamine release from basophils and mast cells in chronic urticaria.[4]
- In a study done on 70 patients with chronic spontaneous urticaria significant elevated levels of C3 and C4 have been detected, compared to the normal population.
- Increased production of C3 and C4 by liver is probably due to elevation in pro-inflammatory cytokines, such as IL-1β, IL-6 or tumor necrosis factor (TNF). C3a itself further stimulates the secretion of other pro-inflammatory cytokines and chemokines and expresses on cells responsible in urticaria formation, such as mast cells, basophils, eosinophils, neutrophils and monocytes. Anaphylatoxin C3a is also able to stimulate histamine release which is capable of causing vasodilatation and consequent increased permeability of small blood vessels.
- Tumor necrosis factor alpha (TNF-alpha) produced by dermal mast cells has been detected at the site of urticaria lesions.
- The following table is a summary of some elevated mediators in chronic urticaria.[15]
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Non-Allergic Urticaria
Mechanisms other than allergen-antibody interactions are known to cause histamine release from mast cells. Many drugs, for example morphine, can induce direct histamine release not involving any immunoglobulin molecule. Also, a diverse group of signaling substances called neuropeptides have been found to be involved in emotionally induced urticaria. Dominantly inherited cutaneous and neurocutaneous porphyrias (porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been associated with solar urticaria. The occurrence of drug-induced solar urticaria may be associated with porphyrias. This may be caused by IgG binding not IgE.
Genetics
- In one study upregulation of 506 genes and downregulation of 51 genes have been reported in the affected skins with chronic spontaneous urticaria. Most of the upregulated genes were involve in adhesion (such as SELE (1q24)), cell activation (such as CD69), and chemotaxis (such as CCL2).[17]
- CIAS1 gene mutation has been linked to cryopyrin-associated periodic syndrome (CAPS) a neonatal-onset multisystem inflammatory disorder (NOMID) which presents with urticaria.[2]
- The following table is a summary of genes that have been significantly associated with some phenotypes of urticaria: [18]
Abbreviations: AICU: aspirin-intolerant chronic urticaria; AIU: aspirin-intolerant urticaria; CU: chronic urticaria;
| Genes | Associated phenotype | Country |
|---|---|---|
| FcεRIα | AICU | Korea |
| FcεRIβ | AICU | Korea |
| FcεRIγ | AICU | Korea |
| HNMT | AICU | Korea |
| TNF-α | AIU | Korea |
| TGF-β1 | CU, AICU | Iran |
| ADORA3 | AIU | Korea |
| IL-10 | AIU | Korea |
| ALOX5 | AIU | Korea |
| CYSLTR1 | AICU | Korea |
| LTC4S | AIU | Poland, Venezuela |
| PTGER4 | AICU | Korea |
| CYP2C9 | AIU | Korea |
| ACE | CU with angioedema | Turkey |
| PTPN22 | CU | Poland |
Associated Conditions
- Autoimmune disease: Presence of autoimmune conditions, such as autoimmune thyroid disease has been found in a fraction of patients with urticaria. Moreover, some studies detected IgE and IgG anti-TPO antibodies in some patients with chronic spontaneous urticaria. These antibodies might be responsible for mast cells and basophils degranulation.[19][20][21][22][23]
- Elevated antithyroid antibodies, such as IgG antithyroglobulin, immunoglobulin E (IgE) antithyroperioxidase and immunoglobulin G (IgG) antithyroperioxidase, has been detected in patients with chronic spontaneous urticaria.
- Hashimoto's thyroiditis has been detected in a sub-population of patients with chronic spontaneous urticaria.
- Systemic lupus erythematosus[11]
- Concurrent angioedema has been seen in 40% of patients who suffer from chronic urticaria.[18]
Gross Pathology
Microscopic Pathology
The following changes have been found in microscopic evaluation of urticaria pathology:[3][24][17]
- Angiogenesis
- vascular formation has been detected in urticaria biopsies, especially in chronic urticaria.
- Elevation in some pro-angiogenic mediators, such as VEGF, has been directly linked with formation of new blood vessels in the skin of chronic spontaneous urticaria patients.
- High concentration of inflammatory cells (predominantly mononuclear cells) per high-powered field.
References
- ↑ Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD (2006). "CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1". J Biol Chem. 281 (36): 26069–80. doi:10.1074/jbc.M605040200. PMID 16835222.
- ↑ 2.0 2.1 Deacock SJ (2008). "An approach to the patient with urticaria". Clin Exp Immunol. 153 (2): 151–61. doi:10.1111/j.1365-2249.2008.03693.x. PMC 2492902. PMID 18713139.
- ↑ 3.0 3.1 Puxeddu I, Petrelli F, Angelotti F, Croia C, Migliorini P (2019). "Biomarkers In Chronic Spontaneous Urticaria: Current Targets And Clinical Implications". J Asthma Allergy. 12: 285–295. doi:10.2147/JAA.S184986. PMC 6759208 Check
|pmc=value (help). PMID 31571935. - ↑ 4.0 4.1 Kikuchi Y, Kaplan AP (2002). "A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria". J Allergy Clin Immunol. 109 (1): 114–8. doi:10.1067/mai.2002.120954. PMID 11799375.
- ↑ Schmetzer O, Lakin E, Topal FA, Preusse P, Freier D, Church MK; et al. (2018). "IL-24 is a common and specific autoantigen of IgE in patients with chronic spontaneous urticaria". J Allergy Clin Immunol. 142 (3): 876–882. doi:10.1016/j.jaci.2017.10.035. PMID 29208545.
- ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID doi.org/10.1186/1476-9255-10-22 Check
|pmid=value (help). - ↑ Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O (2004). "Reference distributions for complement proteins C3 and C4: a comparison of a large cohort to the world's literature". J Clin Lab Anal. 18 (1): 9–13. doi:10.1002/jcla.10095. PMC 6808116 Check
|pmc=value (help). PMID 14730551. - ↑ Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF (1991). "Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1". Proc Natl Acad Sci U S A. 88 (10): 4220–4. doi:10.1073/pnas.88.10.4220. PMC 51630. PMID 1709737.
- ↑ Raap U, Wieczorek D, Gehring M, Pauls I, Ständer S, Kapp A; et al. (2010). "Increased levels of serum IL-31 in chronic spontaneous urticaria". Exp Dermatol. 19 (5): 464–6. doi:10.1111/j.1600-0625.2010.01067.x. PMID 20163453.
- ↑ Trinh HK, Pham DL, Ban GY, Lee HY, Park HS, Ye YM (2016). "Altered Systemic Adipokines in Patients with Chronic Urticaria". Int Arch Allergy Immunol. 171 (2): 102–110. doi:10.1159/000452626. PMID 27902979.
- ↑ 11.0 11.1 Kolkhir P, Pogorelov D, Olisova O, Maurer M (2016). "Comorbidity and pathogenic links of chronic spontaneous urticaria and systemic lupus erythematosus--a systematic review". Clin Exp Allergy. 46 (2): 275–87. doi:10.1111/cea.12673. PMID 26545308.
- ↑ Kessel A, Bishara R, Amital A, Bamberger E, Sabo E, Grushko G; et al. (2005). "Increased plasma levels of matrix metalloproteinase-9 are associated with the severity of chronic urticaria". Clin Exp Allergy. 35 (2): 221–5. doi:10.1111/j.1365-2222.2005.02168.x. PMID 15725195.
- ↑ Asero R, Tedeschi A, Marzano AV, Cugno M (2017). "Chronic urticaria: a focus on pathogenesis". F1000Res. 6: 1095. doi:10.12688/f1000research.11546.1. PMC 5506533. PMID 28751972.
- ↑ Cugno M, Marzano AV, Tedeschi A, Fanoni D, Venegoni L, Asero R (2009). "Expression of tissue factor by eosinophils in patients with chronic urticaria". Int Arch Allergy Immunol. 148 (2): 170–4. doi:10.1159/000155748. PMID 18802362.
- ↑ 15.0 15.1 Jain S (2014). "Pathogenesis of chronic urticaria: an overview". Dermatol Res Pract. 2014: 674709. doi:10.1155/2014/674709. PMC 4120476. PMID 25120565.
- ↑ Vonakis BM, Vasagar K, Gibbons SP, Gober L, Sterba PM, Chang H; et al. (2007). "Basophil FcepsilonRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria". J Allergy Clin Immunol. 119 (2): 441–8. doi:10.1016/j.jaci.2006.09.035. PMID 17125820.
- ↑ 17.0 17.1 Patel OP, Giorno RC, Dibbern DA, Andrews KY, Durairaj S, Dreskin SC (2015). "Gene expression profiles in chronic idiopathic (spontaneous) urticaria". Allergy Rhinol (Providence). 6 (2): 101–10. doi:10.2500/ar.2015.6.0124. PMC 4541630. PMID 26302730.
- ↑ 18.0 18.1 Losol P, Yoo HS, Park HS (2014). "Molecular genetic mechanisms of chronic urticaria". Allergy Asthma Immunol Res. 6 (1): 13–21. doi:10.4168/aair.2014.6.1.13. PMC 3881394. PMID 24404388.
- ↑ Bracken SJ, Abraham S, MacLeod AS (2019). "Autoimmune Theories of Chronic Spontaneous Urticaria". Front Immunol. 10: 627. doi:10.3389/fimmu.2019.00627. PMC 6450064. PMID 30984191.
- ↑ Kaplan AP (2017). "Chronic Spontaneous Urticaria: Pathogenesis and Treatment Considerations". Allergy Asthma Immunol Res. 9 (6): 477–482. doi:10.4168/aair.2017.9.6.477. PMC 5603475. PMID 28913986.
- ↑ Leznoff A, Sussman GL (1989). "Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients". J Allergy Clin Immunol. 84 (1): 66–71. doi:10.1016/0091-6749(89)90180-2. PMID 2754146.
- ↑ Sugiyama A, Nishie H, Takeuchi S, Yoshinari M, Furue M (2015). "Hashimoto's disease is a frequent comorbidity and an exacerbating factor of chronic spontaneous urticaria". Allergol Immunopathol (Madr). 43 (3): 249–53. doi:10.1016/j.aller.2014.02.007. PMID 25088672.
- ↑ Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A (2012). "Chronic urticaria and autoimmunity: associations found in a large population study". J Allergy Clin Immunol. 129 (5): 1307–13. doi:10.1016/j.jaci.2012.01.043. PMID 22336078.
- ↑ Kay AB, Ying S, Ardelean E, Mlynek A, Kita H, Clark P; et al. (2014). "Elevations in vascular markers and eosinophils in chronic spontaneous urticarial weals with low-level persistence in uninvolved skin". Br J Dermatol. 171 (3): 505–11. doi:10.1111/bjd.12991. PMC 4282040. PMID 24665899.