Urticaria Linked to a Th2/Th17 Shift
A new study by Andrea Moy, Mandakolathur Murali and Rosalynn Nazarian, published in the Journal of Cutaneous Pathology, indicates that in the chronic urticaria (CU) skin lesions the immune response is characterized by a Th2/Th17 shift.
Urticaria (from the Latin word urtica, (to burn) or hives), are a kind of skin rash notable for dark red, raised, itchy bumps. It affects 15-20% of the population once or more during a lifetime.
Chronic urticaria (hives) is a condition where an itchy rash persists on and off for six weeks or more. A multitude of etiologies have been implicated in the causation of CU, including physical, infective, vasculitic, psychological and idiopathic. An autoimmune basis of most of the ‘idiopathic’ forms is now hypothesized. Histamine released from mast cells is the major effector in pathogenesis and it is clinically characterized by wheals that have a tendency to recur.
The majority cases of CU have unknown (idiopathic) causes, but more than 50% of the chronic idiopathic urticaria cases are thought to be driven by autoimmune mechanism(s). Furthermore, it appears that CU is associated with other autoimmune diseases, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus and Sjögren’s syndrome.
This is particularly relevant to autoimmune thyroid diseases. It is estimated that nearly one-fourth of chronic urticaria patients have serological evidence of thyroid autoimmunity.
Previous research indicates that CU is associated with a significant increase in interleukin (IL)-4 and IL-5, known to drive T-helper (Th)2-mediated immunity, which, in turn, induces mast cell activation and degranulation. A more recent study also demonstrates an increased expression of Th2-initiating cytokines, such as IL-33, IL-25 and thymic stromal lymphopoietin in lesional skin of chronic urticaria.
In the Journal of Cutaneous Pathology study, Moy et al., from the Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA report that Th17 and Th2 cells are significantly more frequent in chronic urticaria lesions, and their lymphocytic infiltrate, as compared with normal skin. In apparent contrast, there was no significant difference in mast cells, Th1 or Th22 cells.
Of note, in samples from patients with and without markers of autoimmunity, and/or thyroid disease, there was no significant difference in the number of mast cells or percentage of Th1, Th2 and or Th2.
Interestingly, samples from patients with both CU and autoimmune diseases were characterized by a significant reduction in Th22 cells numbers, and an increased density of mast cells.
In conclusion, the study indicates that in chronic urticaria the local skin immunity is skewed towards a Th2/Th17 shift, without the presence of mast cell prevalence in the lymphocytic infiltrate, and perhaps, no evidence that an additional autoimmune disease contribute to this immune phenotype.
Source: J Cutan Pathol, 2016, 43:372-8. doi: 10.1111/cup.12673. Epub 2016 Feb 16.
Read more: onlinelibrary.wiley.com
AI–Assisted Updates (see footnote below)
A study from 2018 found that patients with chronic spontaneous urticaria (CSU) have higher levels of Th2 and Th17-related cytokines compared to healthy people. It also noted that acute urticaria shows an even stronger Th2 response, and in CSU, the presence of certain autoantibodies or allergies changes which cytokines are elevated. In conclusion, these findings highlight that the Th2/Th17 shift is not uniform, with acute urticaria leaning more toward Th2 and CSU showing mixed Th1/Th2/Th17 involvement, potentially guiding targeted therapies.
A 2020 study measured cytokines like IL-17 (linked to Th17) and found they were much higher in urticaria patients, correlating with how severe the condition was, suggesting these immune responses worsen symptoms. Serum levels of IL-17, IL-18, IL-23, and TNF-α were significantly higher in CSU patients, with positive correlations to UAS. This underscores the role of Th17-related cytokines in disease severity, supporting a Th17 shift in chronic urticaria. This underscores the role of Th17-related cytokines in disease severity, supporting a Th17 shift in chronic urticaria.
A 2022 study using genetic data showed Th2 and Th17 pathways are active in CSU, with Th2 activity linking to disease severity, indicating these immune changes are central to the condition’s impact. This study provides genetic evidence for the Th2/Th17 shift, with Th2 severity correlations offering a biomarker potential for clinical management.
Discussion
The research collectively supports a Th2/Th17 shift in chronic urticaria, particularly CSU, with varying emphasis on Th2 in acute forms and Th17 in chronic severity. The findings suggest these immune responses are central to lesion formation and disease activity, with potential implications for personalized medicine, such as targeting IL-17 or Th2 pathways. However, the complexity, with differences based on autoreactivity and allergen sensitivity, indicates further studies are needed to refine these insights, especially for therapeutic applications.
Unexpected Detail
An unexpected detail is the variation in Th2/Th17 involvement between acute and chronic urticaria, with acute forms showing a stronger Th2 response, which might suggest different treatment approaches based on disease duration, a nuance not always highlighted in general discussions.
Conclusion
This analysis confirms the Th2/Th17 shift as a significant aspect of urticaria pathogenesis, with robust evidence from 2018, 2020, and 2022 studies. The findings provide a foundation for future research into targeted therapies and personalized management strategies for urticaria patients.
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Professional AI assistance:
Updates assisted and generated by an Artificial Intelligence (AI) using the professional services of Zlatin Balevsky (contact@balevsky.ai).