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Massive, multiple fire ant, Solenopsis invicta, stings are often treated aggressively, particularly in the elderly, despite limited evidence of systemic toxicity due to the venom. Over 95% of the S. invicta venom is composed of piperidine alkaloid components, whose toxicity, if any, is unknown. To assess a possible pharmacological basis for systemic toxicity, an alkaloid-rich, protein-free methanol extract of the venom from whole ants was assayed for inhibitory activity on the following nitric oxide synthase (NOS) isoforms, rat cerebellar neuronal (nNOS), bovine recombinant endothelial (eNOS), and murine recombinant immunologic (iNOS). Cytosolic NOS activity was determined by measuring the conversion of [(3)H]arginine to [(3)H]citrulline in vitro. Rat nNOS activity was inhibited significantly and in a concentration-dependent manner by the alkaloid-rich venom extract. For nNOS, enzyme activity was inhibited by approximately 50% with 0.33 +/- 0.06 microg of this venom extract, and over 95% inhibition of the three isoforms, nNOS, eNOS, and iNOS, was found with doses of 60 microg in 60 microl reaction mixture. These results indicate that the alkaloid components of S. invicta venom can produce potent inhibition of all three major NOS isoforms. Isosolenopsin A (cis-2-methyl-6-undecylpiperidine), a naturally occurring fire ant piperidine alkaloid, was synthesized and tested for inhibitory activity against the three NOS isoforms. Enzyme activities for nNOS and eNOS were over 95% inhibited with 1000 microM of isosolenopsin A, whereas the activity of iNOS was inhibited by only about 20% at the same concentration. The IC(50) for each of three NOS isoforms was approximately 18 +/- 3.9 microM for nNOS, 156 +/- 10 microM for eNOS, and >1000 microM for iNOS, respectively. Kinetic studies showed isosolenopsin A inhibition to be noncompetitive with L-arginine (K(i) = 19 +/- 2 microM). The potency of isosolenopsin A as an inhibitor of nNOS compares favorably with the inhibitory potency of widely used nNOS inhibitors. Inhibition of NOS isoforms by isosolenopsin A and structurally similar compounds may have toxicological significance with respect to adverse reactions to fire ant stings.

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Bed bugs may cause mild to severe cutaneous reactions. We studied the ability of bed bug salivary extract (SGE) to induce inflammatory reactions responsible for cutaneous manifestations and found that SGE stimulated the production of several potent chemokines and cytokines from macrophages. Chemokines induced by SGE included those known to recruit eosinophils (eotaxin), attract neutrophils [interleukin (IL)-8] or induce their survival and proliferation (granulocyte colony-stimulating factor). Cytokines involved in cell-mediated immunity, including IL-7, IL-10 and IL-12, were also induced. Saliva of bed bugs contains protein and non-protein molecules that have pleotropic effects on macrophages, orchestrating the immune response in the skin after bed bug bites.

Immune complexes derive from complex interactions between antibody, antigens, complement and various receptors as a part of adaptive immunity. Antigens bound to antibodies in immune complexes are normally cleared by various cellular mechanisms physiologically capable of eliminating even small quantities of ‘foreign’ antigens from circulation. Immune complexes can form when humans are exposed to foreign substances like proteins (infections, vaccines, drugs, etc.) or nonprotein materials (haptens) which need a protein carrier to activate the cascade. Autoimmune disorders develop when immune complexes deposit pathologically in different organs, initiating inflammatory cascades which lead to organ damage/disease. Immune complex disease can manifest in a myriad of ways when dysregulation in one or more of these components occur. Even some recombinant protein therapeutic agents used to treat autoimmunity may paradoxically form immune complexes, neutralizing therapeutic efficacy and/or manifesting as immune complex disease. Key Concepts Immunological defence mechanisms evolved from primitive, unspecialized ‘innate’ mechanisms of lower animals to more sophisticated, highly specialized ‘adaptive’ mechanisms as seen in higher animals and man. Adaptive immunity uniquely involves specialized cells called lymphocytes capable of producing antibodies against a wide range of microbial and nonmicrobial antigens. Antibodies are capable of complexing with soluble and/or immobilized antigens, forming a tightly bound structure called an immune complex. Soluble antigens bound to antibodies in immune complexes are normally cleared by various cellular mechanisms physiologically capable of eliminating even small quantities of ‘foreign’ antigens from circulation. If sufficiently large quantities of soluble antigens and their antibodies develop, large latticed immune complexes may form for a variety of different reasons. Latticed immune complexes are pathologically capable of depositing systemically in any of a variety of tissue sites, creating downstream cellular damage with many different clinical presentations, all of which fall into the category of ‘immune complex disease’ (the prototype originally being referred to as ‘serum sickness’). Several experimental animal models of immune complex disease have emerged yielding useful information on the cellular and soluble elements involved in its pathogenesis. Immune complex disease in humans is seen primarily in the setting of infection and/or in response to various therapeutic agents of protein or nonprotein nature. Adaptive immunity has also evolved to readily discriminate between self‐ and foreign antigens. Loss of ability to recognize self‐antigens results in ‘Autoimmunity’ in which both cellular and soluble immune responses against self‐antigens pathologically occur. Many different autoimmune disorders in humans feature immune complex disease manifestations and generally derive from unknown self‐antigens complexed to self‐antibodies. Even some recombinant protein therapeutic agents used to treat autoimmunity may induce formation of immune complexes, neutralizing therapeutic efficacy and/or manifesting as immune complex disease.

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