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High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)'[sub.2]-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB[sub.2]) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)'[sub.2]-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)'[sub.2]. This binding could interfere with the role of C3a and C5a in inflammation., Author(s): Milan Basta (corresponding author) [1]; Fredric Van Goor [2]; Stefano Luccioli [3]; Eric M. Billings [4]; Alexander O. Vortmeyer [5]; Lajos Baranyi [6]; Janos Szebeni [6]; Carl R. Alving [...]

Liposome-induced pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallergic reaction. Am J Physiol Heart Circ Physiol 279: H1319-H1328, 2000.--Intravenous injection of liposomes can cause significant pulmonary hypertension in pigs, a vasoconstrictive response that provides a sensitive model for the cardiopulmonary distress in humans caused by some liposomal drugs. The reaction was recently shown to be a manifestation of 'complement activation-related pseudoallergy' (CARPA; Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, Stahl GL, Bunger R, and Alving CR. Circulation 99: 2302-2309, 1999). In the present study we demonstrate that the composition, size, and administration method of liposomes have significant influence on pulmonary vasoactivity, which varied between instantaneously lethal (following bolus injection of 5 mg lipid) to nondetectable (despite infusion of a 2,000-fold higher dose). Experimental conditions augmenting the pulmonary hypertensive response included the presence of dimyristoyl phosphatidylglycerol, 71 mol% cholesterol, distearoyl phosphatidylcholine, and hemoglobin in liposomes, increased vesicle size and polydispersity, and bolus injection vs. slow infusion. The vasoactivity of large multilamellar liposomes was reproduced with human C3a, C5a, and xenore-active immunoglobulins, and it correlated with the complement activating and natural antibody binding potential of vesicles. Unilamellar, monodisperse liposomes with 0.19 [+ or -] 0.10 [micro]m mean diameter had no significant vasoactivity. These data indicate that liposome-induced pulmonary hypertension in pigs is multifactorial, it is due to natural antibody-triggered classic pathway complement activation and it can be prevented by appropriate tailoring of the structure and administration method of vesicles. hypersensitivity reactions; anaphylatoxin; hemoglobin; IgM-enriched intravenous immunoglobulin; hemodynamics

Background: Ischemic stroke causes a high rate of deaths and permanent neurological damage in survivors. Ischemic stroke triggers the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1), which activate toll-like receptors (TLRs) and receptor for advanced glycation endproducts (RAGE) in the affected area, leading to an exaggerated inflammatory response and cell death. Both TLRs and RAGE are transmembrane pattern recognition receptors (PRRs) that have been shown to contribute to ischemic stroke-induced brain injury. Intravenous immunoglobulin (IVIg) preparations obtained by fractionating human blood plasma are increasingly being used as an effective therapeutic agent in the treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke has been proposed, but little is known about the direct neuroprotective mechanisms of IVIg. We therefore investigate whether IVIg exerts its beneficial effects on the outcome of neuronal injury by modulating HMGB1-induced TLR and RAGE expressions and activations. Methods: Primary cortical neurons were subjected to glucose deprivation or oxygen and glucose deprivation conditions and treated with IVIg and recombinant HMGB1. C57/BL6J mice were subjected to middle cerebral artery occlusion, followed by reperfusion, and IVIg was administered intravenously 3 h after the start of reperfusion. Expression of TLRs, RAGE and downstream signalling proteins in neurons and brain tissues were evaluated by immunoblot. Results: Treatment of cultured neurons with IVIg reduced simulated ischemia-induced TLR2, TLR4, TLR8 and RAGE expressions, pro-apoptotic caspase-3 cleavage and phosphorylation of the cell death-associated kinases such as c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) as well as the p65 subunit of nuclear factor kappa B (NF-κB). These results were recapitulated in an in vivo model of stroke. IVIg treatment also upregulated the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) in cortical neurons under ischemic conditions. Finally, IVIg protected neurons against HMGB1-induced neuronal cell death by modulating TLR and RAGE expressions and signalling pathways. Conclusions: Taken together, these results provide a rationale for the potential use of IVIg to target inappropriately activated components of the innate immune system following ischemic stroke. [ABSTRACT FROM AUTHOR]

A single intravenous injection of 4 to 8 mg/kg of large, multilamellar, cholesterol-enriched lipid vesicles (containing 71% cholesterol; HC-MLV) induced marked bradycardia, arrhythmia, and transient decrease in systemic blood pressure in rats. A single higher dose (15-20 mg/kg), or repeated injections of 4 to 8 mg/kg HC-MLV, resulted in severe pulmonary hemorrhage and edema (ARDS-like histologic changes), systemic microthrombus formation, hemorrhage in the kidneys and liver, as well as early signs of diffuse myocardial damage. Complement depletion with cobra venom factor, or the use of thromboxane A2 receptor inhibitor (SQ30741), prevented these adverse reactions, pointing to the involvement of C activation and TXA[sub2] release in the pathomechanism. The likely role of C activation was supported by the demonstration of strong C activation by HC-MLV in rat serum in vitro, along with the binding of natural IgG and IgM antibodies to these vesicles. The C activation by HC-MLV seems to proceed by way of the classic pathway mediated by natural antilipid antibodies. These studies present a novel, powerful method for inducing anaphylactoid shock and other C activation-related pathologic changes providing a model for multiple organ failure, semicrystalline cholesterol embolism, and C activation-related pseudoallergy. [ABSTRACT FROM AUTHOR]

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)'[SUB2]-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB[SUB2]) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)'[SUB2]-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)'[SUB2]. This binding could interfere with the role of C3a and C5a in inflammation. [ABSTRACT FROM AUTHOR]

Background: The frequency of Huntington's disease (HD) may vary considerably, with higher estimates in non-Asian populations. We have recently examined the prevalence of HD in the southern part of Sardinia, a large Italian Mediterranean island that is considered a genetic isolate. We observed regional microgeographic differences in the prevalence of HD across the study area similar to those recently reported in other studies conducted in European countries. To explore the basis for this variability, we undertook a study of the incidence of HD in Sardinia over a 10-year period, 2009 to 2018., Methods: Our research was conducted in the 5 administrative areas of Sardinia island. Case patients were ascertained through multiple sources in Sardinia and Italy., Results: During the incidence period 53 individuals were diagnosed with clinically manifested HD. The average annual incidence rate 2009-2018 was 2.92 per 10 6 persons-year (95% CI, 2.2 to 3.9). The highest incidence rate was observed in South Sardinia (6.3; 95% CI, 4.2-9.5). This rate was significantly higher (p<0.01) than the rates from Cagliari, Oristano, and Sassari provinces but did not significantly differ (p = 0.38) from the Nuoro rate., Conclusions: The overall incidence of HD in Sardinia is close to the correspondent estimates in Mediterranean countries. Our findings highlight also the possibility of local microgeographic variations in the epidemiology of HD that might reflect several factors, including a possible founder effect in the rural areas of South Sardinia and Nuoro., (© 2021. Fondazione Società Italiana di Neurologia.)