Evaluation of salivary soluble TREm-!, IL-8, and IL-3 as diagnostic markers in chronic urticaria at University Hospital Southampton

  • Witness Dzobo

Student thesis: Doctoral Thesis

Abstract

Background
Chronic urticaria (CU) is a common skin disorder of the upper dermal tissue characterized by itchy, large, erythematous rashes that persist for more than 6 weeks. It can exist on its own or coexist with angioedema. A third of CU patients usually present with both hives and angioedema, whereas 30-40% present with isolated hives and 10-20% with isolated angioedema. The diagnosis of CU is difficult and complicated. Current methods are clinically based. They involve history, physical examinations, provocation/challenge, and diagnostic tests.
The association of the soluble Triggering Receptor Expressed on Myeloid Cells-1
(sTREM-1) with CU was investigated in this study. sTREM-1 is a small soluble protein synthesised by the alternative splicing of the Trem-1 gene or the proteolytic cleavage of the TREM-1 receptor protein by metalloproteinases (MMPs). In recent years, the essential role of sTREM-1 has been noted in bacterial, viral, parasitic, and fungal infections, and has been strongly suggested that it can be used as a marker of infection.
The association of IL-8 with chronic urticaria was also investigated in this study. IL-8 is a multifunctional proinflammatory cytokine that is produced under conditions of infectious inflammatory stimulation. It is primarily released from monocytes, macrophages,
fibroblasts, keratinocytes, epithelial and endothelial cells.
The association of IL-3 with chronic urticaria was also investigated in this study. IL-3 is an early activation cytokine that is expressed in hematopoietic stem cells, T cells, basophils, and many other cell types in the immune system. It is suspected to be instrumental in the exacerbation of chronic urticaria symptoms. It is associated with the upregulation of CD203c as well as CD69 expression that results in basophil activation and histamine release. IL-3 is also released as a mediator by activated mast cells undergoing degranulation.
It was hypothesized that there is significantly higher salivary sTREM-1, IL-8, and IL-3 levels in chronic urticaria patients compared to normal control subjects and that sTREM-1 levels are correlated with salivary IL-8 and are predictive of CU.

Aim
To determine and compare the levels of sTREM-1, IL-8, and IL-3 in the saliva of healthy subject controls and patients with chronic urticaria.

Method and Materials
A total of 77 subjects participated in the pilot case-control study. 43 subjects had CU (13 males and 30 females with chronic urticaria, with or without angioedema) and 34 subjects were normal controls. The levels of the salivary sTREM-1, IL-8, and IL-3 were analysed using an enzyme-linked immunosorbent assay (ELISA).

Results
The total levels of salivary sTREM-1 (p<0.05) and IL-8 (p<0.0001), but not IL-3, were significantly higher in CU patients than those of the control group. The median (25th -75th percentile) value for salivary sTREM-1 in healthy controls was 16.41 pg/ml (16.41-37.28 pg/ml) and for patients with chronic urticaria was 32.0 pg/ml (16.41-185.7 pg/ml). The median (25th-75th percentile) value for salivary IL-8 in healthy controls was 127 pg/ml (58-164 pg/ml) and for patients with chronic urticaria was 232.0 pg/ml (148.8-557 pg/ml). The median (25th-75th percentile) value for salivary IL-3 in healthy controls was 5.230 pg/ml (5.230-39.63 pg/ml) and for patients with urticaria was 5.230 pg/ml (5.230-65.10 pg/ml). The ROC curve for salivary sTREM- in untreated patients was highly significant (p =0.0034), area under the ROC curve 0.7645, std. error 0.07825, 95% confidence interval 0.6113 to 0.9181. The ROC curve for salivary IL-8 was also significant, (p=0.0001), area under the ROC curve 0.796, std. error 0.052, 95% confidence interval 0.69 to 0.898. The ROC curve for salivary IL-3 was not significant, (p= 0.9598), area under the ROC curve 0.5035, std. error 0.06868, 95% confidence interval 0.3689 to 0.6381. The levels of the routine blood tests (ESR, CRP, FBC, C3C4, and Vitamin D) were normal for CU patients with Vitamin D on the lower side. There were no blood tests for the healthy controls. There were no significant correlations between salivary IL-8 and sTREM-1 or between salivary IL-8, sTREM-1, and blood biomarkers (ESR, CRP, C3, C4, Vitamin D) in the patient group.

Conclusion
The data from this study showed raised salivary sTREM-1 and IL-8 in chronic urticarial patients compared to normal controls. These elevated levels of salivary sTREM-1 and IL-8 suggest the persistent presence of oral bacterial infection in CU patients, although no infection analysis was done in the patients in this study. sTREM-1 and IL-8 may play a key role in the host response to infection in the oral cavities of CU patients. The data also showed that there was no significant difference in salivary IL-3 of healthy subjects and chronic urticaria patients. The results cast a new light on biomarkers that may be added to a list of other biomarkers that are already used to aid the diagnosis of CU. Using salivary sTREM-1 and IL-8 together with the other biomarkers may therefore help to accelerate the diagnosis and treatment of chronic urticarial patients.
Date of AwardJun 2021
Original languageEnglish
Awarding Institution
  • University of Portsmouth
SupervisorJan Shute (Supervisor)

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