Immune complex pathophysiology.

Antigen-antibody (Ab) interactions that lead to the formation of immune complexes (ICs) are subtle biochemical processes determining health or disease according to the outcome. Good laboratory practice (GLP)-acknowledged IC detection methods reveal that plasma levels of up to 15 microg/mL heat-aggregated immunoglobulin G (IgG) equivalents are normal, indicating the physiological role of ICs. Among the major variables that influence the equilibrium association constant Ka, are specificity and epitope density of the antigen, Ig class/subclass of the Ab, IC complement (C)-activating capacity, Fc receptor (FcR) interaction, and cytokine activation pattern. The Ka of antigen-Ab binding at approximately 20 degrees C ranges from low affinity (105) to high affinity (107-1011). Beneficial ICs serve to remove and/or neutralize infectious or toxic antigens, following an infectious attack in immune and vaccinated hosts. Circulating ICs are more prone for benefit than tissue-bound ICs, which reflect in situ formation and/or undesired deposition in tissues due to overflow from insufficient reticuloendothelial system (RES) removal. The classical textbook topic on ICs still holds true but is under revision because of the improved knowledge of effector systems, such as C, cytokine, and FcR apparatus. Therapeutic options to treat IC-associated diseases include intravenous immunoglobulins (IVIG) at their onset and monoclonal antibodies (mAb) directed at C activation products and/or cytokines.

Immunodeficiency and autoimmune phenomena in female hyper-IgM syndrome.

We report an unusual case that highlights the clinical problems associated with autoimmune phenomena. A female (born 1972) was referred to our hospital with systemic lupus erythematosus (SLE) diagnosis. During the follow-up (7 years), we observed the appearance and the disappearance of a lot of autoantibodies detected. The history of recurrent bacterial sinopulmonary infections since puberty and enlargement of lymphonodes, elevated IgM, very low IgA and normal IgG levels, and the variable autoantibody profile oriented toward a "defective Ig class switch recombination" disorder: the hyper-IgM syndrome. Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual and sometimes the differential diagnosis is difficult.

Association of endothelin with lung hemorrhage induced by immune complexes in rats.

The participation of endothelins (ETs) in a model of neutrophil-dependent lung injury induced by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigens (Arthus reaction) was investigated. Hemorrhagic lesions were evaluated by measuring the extravasations of hemoglobin in lung parenchyma. From 5 min to 24 h after the Arthus reaction (AR), endothelin (ir-ET) levels in bronchoalveolar lavage fluid (BALF) and in plasma were measured by radioimmunoassay. BALF levels of ir-ET were not different between control and AR animals for the first 90 min after the antigen challenge but increased from 2 to 24 h after induction of AR. ET levels in the plasma did not change from the respective controls over the same 24 h period. Increased ir-ET in BALF was not affected by pretreatment with L-NAME (30 mg/kg, i.v.). A PAF antagonist (BN52021; 5 and 10 mg/kg, i.v.) increased ET content in BALF and decreased the intensity of the AR. Thiorphan (2 mg/kg, i.v.) inhibited the AR-induced hemorrhagic lesions in lungs. An ET(A) receptor antagonist, BQ-123 (1 mg/kg, i.v.) potentiated, whereas the ET(B) antagonist, BQ-788 (1 mg/kg, i.v.) inhibited the lung hemorrhage. It is concluded that ETs are released during and play a role in the lung AR.

[Changes of luminol-dependent chemiluminescence of rabbit peripheral blood leukocytes during incubation with a specific allergen during the development of Arthus phenomenon]. / Izmenenie liuminolzavisimoi khemiliuminestsentsii leikotsitov perifericheskoi krovi krolikov pri inkubatsii so spetsificheskim allergenom v protsesse razvitiia fenomena Artiusa.

The authors studied luminol-dependent chemiluminescence of rabbit peripheral blood leukocytes during the development of Arthus' phenomenon. Samples with a specific allergen were previously incubated. It was established that in this type of allergic reactions the intensity of leukocyte chemiluminescence was determined by the concentration of the allergen with which they were incubated. Small doses of the allergen stimulate and large doses inhibit it. The inhibition is linked with the direct effect of the allergen on the cells and is not attended with diminution of their viability.

Ex vivo effects of nonsteroidal antiinflammatory drugs on arachidonic acid metabolism in neutrophils from a reverse passive Arthus reaction.

Rat neutrophils isolated from 4-h reverse passive Arthus reaction (RPAR) pleural exudates actively metabolize arachidonic acid via cyclooxygenase and lipoxygenase. Utilizing this system, the effect of oral doses of nonsteroidal antiinflammatory drugs on the ability of these cells to produce HHT, 5-HETE, and LTB from exogenously added arachidonic acid has been investigated. In vitro and ex vivo, indomethacin and timegadine inhibit cyclooxygenase activity in rat pleural neutrophils. In vitro, timegadine is a lipoxygenase as well as a cyclooxygenase inhibitor. This dual inhibition is confirmed by the observation that ex vivo timegadine inhibits the production of lipoxygenase as well as cyclooxygenase metabolites. While indomethacin, a cyclooxygenase inhibitor, primarily inhibits edema formation, the inhibition of both pathways of arachidonic acid metabolism by timegadine is reflected in the drug's ability to reduce cellular influx as well as edema formation in the RPAR pleural cavity inflammatory reaction.

Effect of piroxicam on the chemotaxis and random migration of polymorphonuclear leucocytes after induction of immune and non immune inflammations.

The effect of piroxicam on the chemotaxis and random migration of rat polymorphonuclear leucocytes was investigated with two techniques of assessment (filter and agarose assay) under various experimental conditions. The drug was administered in vivo or tested in vitro on polymorphonuclears collected in the pleural cavity after induction of an immune (reverse passive Arthus reaction) or an acute non-specific inflammation (pleurisy induced by a suspension) (1%) of calcium pyrophosphate crystals (CaPP). In all cases a dose-dependent inhibition of chemotaxis was observed, more striking in the case of CaPP elicited cells which were more reactive than cells collected after the induction of the Arthus reaction. No modification of random migration appeared using the filter assay while a slight inhibition was demonstrated at the higher dose using the agarose assay.

Prolongation of rat tail bleeding time caused by oral doses of a thromboxane synthetase inhibitor which have little effect on platelet aggregation.

N (7-carboxyheptyl) imidazole is an inhibitor of platelet thromboxane synthetase that has no effect on the cyclooxygenase activity. An oral dose of the substance to rats (10 mg/kg) prolonged tail bleeding time from 170 +/- 13 sec to 284 +/- 22 sec. This oral dose also inhibited platelet thromboxane B2 production induced by collagen ex vivo but had little effect on the aggregation dose response curve. There was no effect on thrombin-induced aggregation. Neither the thrombocytopenia induced by the Arthus reaction nor thrombus formation on an implanted cotton thread were inhibited by oral doses of carboxyheptylimidazole up to 30 mg/kg. Similarly neither the prothrombin nor activated partial thromboplastin time were affected. It is postulated that this thromboxane synthetase inhibitor prolongs bleeding time nor by inhibiting platelet aggregation or blood coagulation but rather by preventing the vasoconstriction which would normally be caused by thromboxane A2.

Arthus tonsillitis in the rabbit. Histological findings and fibrinolytic activity in the blood.

Arthus-type hypersensitivity was induced experimentally in the tonsils of rabbits. Histopathological studies were performed on the Arthus tonsillitis so produced, and estimations of the plasma fibrinolytic activity were made on the blood of these rabbits. The findings obtained by macroscopic inspection of the tonsil revealed significant bleeding and swelling. Furthermore, the histopathological studies demonstrated bleed and infiltration of leukocytes into various parts of the parenchyma and connective tissue surrounding the tonsil during the early stages of tonsillitis. From the results concerning certain parameters of the fibrinolytic system in the blood, it was demonstrated that, during the early stage of tonsillitis, the fibrinolytic activity increased and whole plasmin was consumed. Based on the above findings, it seems that the change in fibrinolytic activity found in rabbits affected by Arthus tonsillitis closely resembles that in patients suffering from acute tonsillitis.

Cyclic AMP and the mechanism of leucocyte lysosomal enzyme release during an immediate hypersensitivity reaction in vivo.

The pleural cavity of rats was used to study the effect of altering leucocyte cyclic AMP content on the release of B-glucuronidase activity during an immediate hypersensitivity reaction. The effect on intravenous colchicine was also studied. Despite an increase of 135 to 235% in leucocyte cyclic AMP content no decrease in B-glucuronidase release was observed. Similarly, colchicine had no effect on enzyme release. It was concluded that the cyclic nucleotides and leucocyte microtubules may have no significant role to play in the release of lysosomal enzymes during acute inflammation in vivo.

The effect of shock on the inflammatory response. A reevaluation of the role of platelets in the active arthus reaction.

The active Arthus reaction can be inhibited by hypovolemic shock or the infusion of catecholamines. A reevalution of previous work with platelet antiserum indicates that shock rather than thrombocytopenia was responsible for preventing the active Arthus reaction. Immunofluorescent studies of the inhibited Arthus sites reveal that immune precipitates are not present in the extravascular tissues. Since leukocyte aggregates can be seen within venules at the inhibited sites, and they phagocytize BSA-anti-BSA complexes, their failure to migrate out of the vessels is due to the absence of complexes in the extravascular spaces. (Am J Pathol 78:159-170, 1975)