HDC

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Introduction

Allergic reactions are rapid in onset and can be life-threatening in severe cases. The clinical manifestations include symptoms involving the skin, gastrointestinal tract, respiratory system, and cardiovascular system.  Allergies can be caused by allergies to a variety of substances, including food, insect venom, drugs, and more. In developed countries, the incidence of food-induced anaphylaxis has risen sharply. In the United States alone, the cost of treating food allergies is estimated to be approximately $25 billion annually.

Histamine plays an essential role in IgE-medicated anaphylaxis. Histamine was first purified from ergot fungus in 1910 and purified from human tissue in 1927. Histamine has pleiotropic effects on the skin and cardiovascular, respiratory, digestive, central nervous and immune systems. It is a vasodilator that significantly increases blood vessel permeability, allowing leukocytes to enter tissues to promote inflammatory responses. Relatively large amounts of histamine cause a rapid decrease in body temperature due to massive leakage of plasma into the extravascular space. The rapid release of large amounts of histamine causes anaphylaxis.  Histamine belongs to the family of biogenic amines, which include neurotransmitters such as serotonin and dopamine, and hormones such as epinephrine. Histamine is a monoamine synthesized from the amino acid histidine by histidine decarboxylase (HDC), the enzyme responsible for the removal of the carboxyl group from histidine.

Figure 1. Histamine synthesis (Huang, H.; et al. 2018)

HDC and Histamine Synthesis in Mammals

After several groups purified mammalian HDC protein from fetal rat liver and mouse mastocytoma P-815 cells, a cDNA encoding the protein was subsequently cloned. The Hdc gene encodes the HDC protein, which has a molecular mass of 74 kDa and is a proenzyme with little enzymatic activity. When the site near the C-terminus of the proenzyme is cleaved, presumably by Caspase-9, it produces a 53 kDa N-terminal and a 20 kDa C-terminal subunit thought to have inhibitory activity. The 53 kDa N-terminal subunit forms a homodimer and is an active decarboxylase. HDC is the primary enzyme that catalyzes histamine synthesis, and mice deficient in the Hdc gene cannot synthesize histamine and have reduced or absent IgE-mediated anaphylactic responses. Several potent HDC inhibitors have been identified, such as the histidine derivative α-fluoromethyl histidine, histidine methyl ester, and pirodoxal histidine methyl ester. However, these HDC inhibitors have not been further used in clinical applications. 

HDC Gene Expression and Histamine Synthesis in Basophils and Mast Cells

Hdc gene expression and histamine synthesis are positively and negatively regulated by many factors. Mast cell activation-induced increases in Hdc mRNA expression and histamine synthesis are mediated by phorbol 12-myristate 13-acetate. As mast cells mature, Hdc mRNA expression and histamine synthesis also increase. Bone marrow-derived mast cells (BMMCs) appear immature because they contain relatively little histamine and express relatively low levels of FcεRI. If these immature mast cells are transferred into the peritoneal cavity, they develop into mature mast cells with higher amounts of histamine in vivo.

Studies have demonstrated that Hdc gene expression in BMMCs is strongly up-regulated after treatment with chlorotoxin, but the mechanism by which chlorotoxin enhances Hdc gene transcription remains to be determined. It is conceivable that chlorotoxin activates mast cells by binding to an acidic glycosphingolipid, ganglioside G, which has been shown to be expressed on the mast cell surface. Chlorotoxin-triggered signals activate transcription factors that directly promote Hdc gene transcription.

Consistent with the notion that factors that promote mast cell maturation also enhance histamine synthesis, cytokines that promote basophil and mast cell maturation (e.g., IL-3, IL-18, IL-33, GM-CSF, and SCF) also increase HDC activity. It is unclear by which mechanism these cytokines regulate Hdc gene transcription. Other substances, including chemokines, neuropeptide substance P, and IL-1α, have also been reported to induce Hdc mRNA and histamine synthesis.

Figure 2. Genomic structures of the human and mouse histidine decarboxylase (HDC) gene. Red bars indicate the enhancers we described (Huang, H.; et al. 2018)