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B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of <i>Staphylococcus aureus</i>, protein L of <i>Peptostreptococcus magnus</i>, and gp120 of HIV are typical immunoglobulin superantigens. Mast cells are immune cells expressing the high-affinity receptor for IgE (Fc&#949;RI) and are strategically located in the human heart, where they play a role in several cardiometabolic diseases. Here, we investigated whether immunoglobulin superantigens induced the activation of human heart mast cells (HHMCs). Protein A induced the de novo synthesis of cysteinyl leukotriene C₄ (LTC₄) from HHMCs through the interaction with IgE V_H3⁺ bound to Fc&#949;RI. Protein L stimulated the production of prostaglandin D₂ (PGD₂) from HHMCs through the interaction with &#954; light chains of IgE. HIV glycoprotein gp120 induced the release of preformed (histamine) and de novo synthesized mediators, such as cysteinyl leukotriene C₄ (LTC₄), angiogenic (VEGF-A), and lymphangiogenic (VEGF-C) factors by interacting with the V_H3 region of IgE. Collectively, our data indicate that bacterial and viral immunoglobulin superantigens can interact with different regions of IgE bound to Fc&#949;RI to induce the release of proinflammatory, angiogenic, and lymphangiogenic factors from human cardiac mast cells.