Pathophysiology

CSU is driven by the activation of mast cells, which release histamines and other immune modulators, although the precise mechanism is not fully known. In this section we present the current understanding of the molecular and immune processes involved in urticaria.

Mast Cell Activation

Urticaria is a mast-cell-driven disease (Zuberbier et al., 2018).

Interactions of mast cells on urticaria symptoms.

Figure 1. Interactions of mast cells on urticaria symptoms.

The pathophysiology of urticaria is complex and yet to be fully characterised. It is thought that activated mast cells release histamine and other inflammatory mediators, such as platelet-activating factor (PAF) and cytokines. The mediators cause sensory nerve activation, vasodilatation, and plasma extravasation as well as cell recruitment to urticarial lesions, and form the basis for antihistamines being first-line management (Beck et al., 2017; Chang et al., 2015; Guillén-Aguinaga et al., 2016).

CSU skin lesions show recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes (Elias et al., 1986; Natbony et al., 1983; Sabroe et al. 1999; Ying et al., 2002; Zuberbier et al., 2018; Ito et al., 2011).

The recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes in chronic spontaneous urticaria (CSU) skin lesions.

Figure 2. The recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes in CSU skin lesions (Elias et al., 1986; Natbony et al., 1983; Sabroe et al. 1999; Ying et al., 2002; Zuberbier et al., 2018; Ito et al., 2011).

The mast cell activating signals in urticaria are ill-defined and likely to be heterogeneous and diverse (Zuberbier et al., 2018).

Basophils

Basophils along with mast cells play an important role in the pathophysiology of CSU. Peripheral blood basophils from CSU patients have unique features that reverse upon remission and in response to therapy (Ferrer M, 2015; Sterba PM et al., 2015):

  • Basopaenia is typically found in CSU patients
  • Basophils from CSU patients also tend be less responsive to stimuli that act through the IgE receptor
  • Basophils from CSU patients are hyperesponsive when stimulated with other sera regardless of source

The role of PAF in urticaria

It is widely acknowledged that histamine plays a significant role in the allergic response and the pathophysiology of urticaria. However, other inflammatory mediators also play a role and offer an additional therapeutic target for the management of urticaria.

Platelet-activating factor (PAF) is a phospholipid-derived mediator of the allergic response and has been shown to promote mast cell degranulation, platelet aggregation, activation of macrophages and neutrophils as well as the chemotaxis and activation of eosinophils (Mullol et al., 2015). The role of PAF in urticaria has been recognised and is highlighted as an additional mast cell mediator in the EAACI/GA2LEN/EDF/WAO CSU guidelines (Zuberbier et al., 2018).

PAF and the pathophysiology of urticaria

What is the role of PAF in urticaria and can it be addressed? Dr Masatoshi Abe discusses this in this video taken from the Uriach-sponsored symposium at EAACI 2018.

The presence of PAF is consistently observed in patients with urticaria. However, while PAF is capable of inducing mast cell degranulation in the lung and peripheral blood, it does not appear to do so within the skin. Furthermore, data suggests that PAF is capable of inducing a wheal response independently of histamine and mast cell degranulation (Mullol et al., 2015).

Immunoglobulin E

Immunoglobulin E (IgE) is key to the release of histamine and other pro-inflammatory mediators from mast cells and basophils and may play a role in the pathogenesis of CSU (Zuberbier et al., 2018).

IgE binds to high-affinity (FcεRI) receptors on mast cells, basophils, eosinophils, alveolar macrophages and antigen-presenting cells (Metzger et al., 1986; Ishizaka et al., 1983; Dehlink & Fiebiger, 2009). Cross-linking of IgE bound to FcεRI receptors triggers degranulation and release of inflammatory mediators (Ishizaka et al., 1983; Dehlink & Fiebiger, 2009; Rabe et al., 2011). There is a strong association between IgE and allergic conditions (Rabe et al., 2011).

The FcεRI receptor on mast cells plays a key role in activation of these cells and in the pathophysiology of CSU (Vonakis & Saini, 2008; Stone et al. 2010).

IgE interactions with mast cells in chronic spontaneous urticaria (CSU).

Figure 3. IgE interactions with mast cells in CSU.

Mast cell activation may either be via autoimmune, allergic or idiopathic mechanisms (Greaves, 2000; Kaplan & Greaves, 2009; Metz & Maurer, 2012; Altricher et al., 2011). It is generally believed that allergy is not an underlying cause of CSU, although total IgE levels are typically higher in CSU patients than in healthy individuals (Metz & Maurer, 2012; Staubach et al., 2009).

Pathogenesis

A summary of the current understanding of the pathogenesis of CSU is illustrated in Figure 4.

Pathogenesis of chronic spontaneous urticaria (CSU).

Figure 4. Pathogenesis of CSU summary
CSU, chronic spontaneous urticaria; IgE, immunoglobulin E; IgG, immunoglobulin G; TPO, thyroperoxidase.

Potential Role of Histamine Intolerance in CSU

It has been suggested that chronic infections, autoreactivity and intolerance to food may play a role in CSU. The type of food intolerance described differs from regular IgE-mediated food allergy as it involves a pseudoallergenic response to artificial additives, natural compounds and dietary histamines. A study was conducted by Siebenhaar et al. (2016) with the aim of determining the rate that this histamine intolerance was evident in CSU.

It was noted that from history alone it was impossible to determine whether a pseudoallergen-free diet would help the symptoms of CSU sufferers, however, avoidance diets did improve the symptoms of some urticaria sufferers. It was noted that this was a rare co-morbidity however (Siebenhaar et al., 2016).