Abstract
Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.
Highlights
HLA-GHuman leukocyte antigen-G (HLA-G)Human leukocyte antigen-G (HLA-G) is an HLA class Ib antigen characterized by a restricted tissue expression, low polymorphism and 7 isoforms (HLA-G1 to HLA-G7) generated by alternative splicing of the primary HLA-G transcript [1, 2]
HLA-G may induce immune tolerance leading to the development of tolerogenic dendritic cells (DC) with induction of anergic and immunosuppressive T cells promoting the expansion of CD4+ CD25+ Forkhead Box P3 (FoxP3)+ T regulatory lymphocytes (Tregs) and triggering the differentiation of CD4+ T-cells in suppressor cells [9]
HLA-G seems to be involved in the tuning of immune responses, as incubation of peripheral blood mononuclear cells (PBMC) with HLA-G-expressing cells favors a shift towards a Th-2 cytokine profile, whereas incubation with soluble HLA-G molecules may have a counterbalancing effect by creating an anti-inflammatory environment due to the release of interleukin (IL)-10 [10, 11]
Summary
Human leukocyte antigen-G (HLA-G) is an HLA class Ib antigen characterized by a restricted tissue expression, low polymorphism and 7 isoforms (HLA-G1 to HLA-G7) generated by alternative splicing of the primary HLA-G transcript [1, 2]. Increased percentages of circulating and tissue-infiltrating HLA-G+ immune cells (e.g., T and NK cells, monocytes, DCs, mast cells) can be observed in different pathological situations such as infections, cancers, transplants and autoimmune disorders suggesting a potential role for these cells in the pathogenesis of diseases in which immune system is strictly implicated [1, 2, 24, 36,37,38] Based on these findings, it has been proposed that HLA-G should be qualified as an ‘immune checkpoint’ molecule [39]. Serum sHLA-G levels are higher in patients with seasonal allergy than in those with perennial allergy [42,43,44,45,46, 51] sHLA-G levels significantly decrease 3 months after the end of allergen-specific immunotherapy and correlate with the increased production of IFN-g by peripheral blood mononuclear cells suggesting a successful shift from Th2 to Th1 immune response [52, 53]
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