Chronic Urticaria Linked to a Th2/Th17 Shift in Skin Lesions

Urticaria and Th2 Th17 Shift
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.
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Abstract of the original article

Background: Chronic urticaria is a condition with many inciting factors and often presents a therapeutic challenge to clinicians. In addition to a central role for mast cells, an immune dysregulated state related to cytokine/chemokine alterations is increasingly being recognized.

Methods: Biopsies of chronic urticaria (n = 11) and normal skin (n = 5) were evaluated with immunostains for CD117, CD3 and dual stains for CD4/T-bet, GATA-3, STAT-3 or BNC-2 (transcription factors specific and mutually exclusive for Th1, Th2, Th17 and Th22 cells, respectively). Clinical data, including autoantibodies and thyroid function tests, and the number of CD117+ mast cells and percent of Th1, Th2, Th17 and Th22 of CD3+ T-cells were compared.

Results: Th2 cells and Th17 cells were significantly more frequent in chronic urticaria than controls. In contrast, there was no significant difference in mast cells, Th1 cells or Th22 cells. Three of nine chronic urticaria patients had evidence of autoimmune disease; biopsies from these patients trended toward a greater number of mast cells and decreased percent of Th-cell subtypes as compared with those without autoimmunity markers, with significantly less Th22 cells.

Conclusions: These findings provide novel insight into the role of Th2 and Th17 in chronic urticaria pathophysiology and may impact therapy.