IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.

BACKGROUND: Allergen-specific IgGs are known to inhibit IgE-mediated mast cell degranulation by two mechanisms, allergen-neutralization and engagement of the inhibitory FcγRIIB recruiting the phosphatase SHIP-1. Here we unravel an additional mechanism of IgG-mediated mast cell desensitization in mice: down-regulation of allergen-specific IgE. METHODS: Mast cells were loaded in vitro and in vivo with monoclonal IgE antibodies specific for Fel d1 and exposed to immune complexes consisting of Fel d1-specific IgG antibodies recognizing different epitopes. Down regulation of IgE was followed by flow cytometry. RESULTS: Mast cells loaded with 2 different IgE antibodies efficiently internalized the IgE antibodies if exposed to recombinant Feld d1. In contrast, no down-regulation occurred if mast cells were loaded with IgE antibodies exhibiting a single specificity before stimulation with recombinant Fel d1 [corrected]. Interestingly, however, IgEs of a single specificity were rapidly down-regulated in vitro and in vivo in the presence of Fel d1-specific monoclonal IgGs recognizing another epitope on Fel d1. Despite FceRI-internalization, little calcium flux or mast cell degranulation occurred. FcγRIIB played a dual role in the process since it enhanced IgE internalization and prevented cellular activation as documented by the inhibited calcium flux and mast cell degranulation. Similar observations were made in the presence of low concentrations of IgEs recognizing several epitopes on Fel d1. CONCLUSION: We demonstrate here that Fel d1-specific IgG antibodies interact with FcγRIIB which (i) promotes IgE internalization; and (ii) inhibits mast cell activation. These results broaden our understanding of allergen-specific desensitization and may provide a mechanism for long-term desensitization of mast cells by selective removal of long-lived IgE antibodies on mast cells.

Immunity to glycolipid antigens in microbial infections.

T cells recognize ligands of different chemical structures. Recently, it has become clear that also self glycosphingolipids and bacterial lipoglycans may act as T cell stimulatory ligands. This type of antigen recognition is restricted by the non-polymorphic CD1 molecules, which have a structure resembling that of classical MHC molecules. Glycolipids insert their hydrophobic lipid tails in two pockets below the antigen-binding groove and position their hydrophilic heads on the external part of CD1 molecules. TCR interacts with these carbohydrates and discriminates their structural variations. Glycolipid-specific T cells may provide protection during bacterial and parasite infection probably with different mechanisms: by secreting pro-inflammatory lymphokines, by the direct killing of infected target cells, and by helping specific B cells in Ig production. Lipoglycans represent excellent candidates for new anti-microbial vaccines due to their wide distribution in the microbial world and their structural composition which does not change and thus cannot give rise to escape mutants. Moreover, these vaccines might induce anti-microbial protective T cell responses in the whole population due to the non-polymorphic nature of CD1 presenting molecules.

Advanced glycosylated end products activate the functions of cell adhesion molecules on lymphoid cells.

It has been proposed that advanced glycosylated end products (AGEs) are involved in the pathogenesis of vascular damages in both type 1 and type 2 diabetes. Furthermore, it has been assumed that AGEs cause an alteration of both expression and activity of cell adhesion molecules which are responsible for migration of circulating cells through the endothelial layer of the vessels. The effect of AGEs on the activity of cell adhesion molecules was studied in our experiments using the homotypic adhesion assay, specific monoclonal antibodies and lymphoid cell lines. It was shown that proteins glycosylated in vitro seemed to increase the percentage of homotypic aggregation of lymphoid cells. This effect was mediated via the interaction between LFA-1 and ICAM-1 which was demonstrated by the fact that specific monoclonal antibodies against these cell adhesion molecules could block the effect of the AGEs. The results obtained reveal that the advanced glycosylated end products activate the function of cell adhesion molecules on lymphoid cells. It can be speculated that the activation of cell adhesion molecules might enhance the direct cellular contacts between the lymphoid cells in the immune response. Moreover, the effect of AGEs might be responsible for an enhanced adhesion of monocytes to endothelial cells and their migration through the vessel wall.

Tn-polyagglutinability of red blood cells and acquired A-like specificity.

A woman whose red blood cells are polyagglutinable due to Tn-activation is reported. The true blood group of the patient is B but her cells have an acquired A-like specificity. The importance of the lectins, especially of Salvia sclarae extract, for the identification of Tn-polyagglutinability is demonstrated. The possibilities of A-like specificity of Tn-activated group B red blood cells is discussed.

[Immune hemolytic anemia caused by catergen]. / Imunna khemolitichna anemiia, predizvikana ot katergen.

A case is presented of a man with chronic active hepatitis who developed immune hemolytic anemia in the course of a prolonged treatment with Catergen/(+)-Cianidanol-3/Zyma (four therapeutic courses in two years). The possible mechanism of hemolysis during Catergen treatment are discussed. The most probable mechanism is the absorption of the drug on the erythrocytes. The Catergen fixation on the erythrocytes does not require any special structure connected with the blood group antigens. Probably the link is non-covalent since the drug is easily removed from the erythrocytes--for 10 min at 56 degrees C.

[Immunohematological problems in blood transfusion with patients with autoimmune hemolytic anemia]. / Imunokhematologichni problemi pri kruvoprelivane na bolni s avtoimunna khemolitichna anemiia.

The immunologic problems of blood transfusion of patients with antoimmune hemolytic anemia are discussed on the base of the authors' observations. They emerge and are mainly conditioned by the character and serological characteristic of autoantibodies (AAB) as well as by the presence of free iso-antibodies (erythro-, leuko- and thrombocyte-). The cold AAB conditioned the difficulties in blood groups determination, direct compatibility test and rarely of RH, where as the warm ones -- impede the determination of Rh and the selection of compatible blood for transfusion. The emerging of iso-antibodied complicates further the immunologic status of the patients. Owing to the characteristic specificity of AAB (against the widely found antigens -- nl, w, I, Pr, etc), the finding of compatible blood for transfusion proved practically to be extremely difficult. The forces hemotransfusion to be turned to only in case of vital indications.

Cross-reacting idiotypes on anti-insulin autoantibodies in autoimmune diseases, identified by monoclonal antibodies.

Investigations on the specific idiotypes of autoantibodies are supposed to help with the understanding of the control mechanisms participating in the pathogenesis of autoimmune diseases. This study describes three monoclonal antibodies (Mabs) that recognize distinct idiotypic determinants on anti-insulin autoantibodies. The preabsorption by IAA-positive sera of insulin inhibits their subsequent binding to the anti-Id, thus suggesting that the Mabs recognize epitopes located at or near the binding site of insulin autoantibodies (IAA). These idiotypes are detected in sera from patients with insulin-dependent diabetes mellitus (IDDM), which are IAA-negative, also. It is possible that the expression of the idiotypes recognized might generally be associated with induction of autoantibodies, since they were found in sera from patients with rheumatoid arthritis (RA), autoimmune thyroid disease (AITD), and cataract (K). It can be assumed that the corresponding idiotypes of these Mabs, or similar structures (sequential or conformational), are expressed on autoantibodies with various antigen-binding specificities. These data suggest that some autoimmune diseases are preceded by the secretion of autoantibodies which express a common or similar pathological idiotype.

A new aspect in glycolipid biology: glycosphingolipids as antigens recognized by T lymphocytes.

T cells may recognize a large variety of ligands with different chemical structures. Recently, glycosphingolipids have also been shown to stimulate human T lymphocytes. Recognition of glycosphingolipids is restricted by the nonpolymorphic CD1 molecules, expressed by professional antigen-presenting cells and by macrophages infiltrating inflammatory sites. CD1 molecules have a structure resembling that of classical MHC class I molecules, with the terminal extracellular domains characterized by two antiparallel alpha helices placed on two hydrophobic pockets. The glycosphingolipids bound to CD1 insert the lipid tails in the two pockets and position the hydrophilic head on the external part of CD1. The TCR interacts with aminoacids present in the two alpha helices and with residues provided by the carbohydrate moiety of glycosphingolipids and discriminates their structural variations. T cells recognizing self-glycosphingolipids release proinflammatory cytokines and may have a pathogenetic role in autoimmune diseases such as multiple sclerosis.