Search

Antibodies to DNA play an important role in the pathogenesis of autoimmune diseases. The elucidation of structural mechanisms of both the antigen recognition and the interaction of anti-DNA antibodies with DNA will help to understand the role of DNA-containing immune complexes in various pathologies and can provide a basis for new treatment modalities. Moreover, the DNA-antibody complex is an analog of specific intracellular DNA-protein interactions. In this work, we used in silico molecular dynamic simulations of bimolecular complexes of the dsDNA segment containing the Fab fragment of an anti-DNA antibody to obtain the detailed thermodynamic and structural characteristics of dynamic intermolecular interactions. Using computationally modified crystal structure of the Fab-DNA complex (PDB ID: 3VW3), we studied the equilibrium molecular dynamics of the 64M-5 antibody Fab fragment associated with the dsDNA fragment containing the thymine dimer, the product of DNA photodamage. Amino acid residues that constitute paratopes and the complementary nucleotide epitopes for the Fab-DNA construct were identified. Stacking and electrostatic interactions were found to play the main role in mediating the most specific antibody-dsDNA contacts, while hydrogen bonds were less significant. These findings may shed light on the formation and properties of pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus associated with skin photosensitivity and DNA photodamage.

The features of monovalent and bivalent binding of receptors (or antibodies) with a polyvalent ligand (or with an antigen) are considered. It is shown that the rigid connection of the binding sites of the receptor brings to high increase of binding affinity for the corresponding ligand, but only in case if its epitopes are fully complementary to both sites of the receptor binding. If not, then there is no advantage of the binding of bivalent receptor before univalent binding. If the binding sites of the receptor are connected by a flexible linker, then regardless of location of epitopes of the corresponding ligand there is the successful fastening of receptor and ligand. Exactly the connection by a flexible linker is used by Nature in most cases at constructing of polyvalent receptors.

It was shown using the model of L2-dependent proliferation of T-cells that IL2 forms complexes with gamma-globulin inhibiting IL2 activity. In this interaction IL2 acts as lectin binding with two-antenna terminals of 5 or 6 mannose residues in one and the same region of immunoglobulin. Similar effect is observed in vivo in case of induction of DTH to listerial antigens. This phenomenon accounts for suppression of the immune response after passive injection of autoantibodies and for the inverse relationship between humoral and cellular immunity. Reduction of IL2 activity after its interaction with IgG or immune complexes may be regarded as a universal feedback immunoregulatory mechanism. External and internal factors showing affinity to mannose, e.g. sodium polyprenyl phosphate or lactobacillus, can interfere with this process and exert immunomodulating effect.

There were examined 124 medical histories of patients with psoriatic disease in progressing stage. It's found that including of hardware-generated filtrational-membrane plasmapheresis, providing a middle-volume exfusion of plasma and following compensation of missing volume by water-electrolytic balanced solution at the beginning of intensive therapy of acute stage of disease is pathogenesisly proved and effective. Advancing using of plasmapheresis is shown on examples of patients with PASI more then 18 points, tending to decreasing of duration of acute form and severity of pathological process.

An association of neutrophilic intracellular metabolic changes with the occurrence of a fatal outcome was studied in 121 patients with coronary heart disease (CHD). On admission, all patients with CHD were found to have higher relative counts of neutrophils, C-reactive protein, and malonic dialdehyde in blood and that of lactate in neutrophils than those in the controls; their cellular activity was, on the contrary, lowered. The deceased patients were significantly older; they had more frequently a history of myocardial infarction and a lower left ventricular ejection fraction. These patients, as compared to the survivors, were observed to have a higher myeloperoxidase activity and suppressed neutrophilic glutathione reductase with increases in the blood levels of malonic dialdehyde and circulating immune complexes (CIC). It is believed that in patients with CHD and left ventricular systolic dysfunction with activated lipid free radical oxidation, the evident CIC-dependent activation of oxygen-dependent neutrophilic metabolism is able to deplete antioxidative defense of phagocytes, by favoring their mass intravascular death, followed by endothelial damage and hemostatic disorder.

In 45 patients with multiple gastroduodenal ulcers the humoral immunity indexes were studied up. Formation of secondary immune deficiency with simultaneous raising of the circulating immune complexes level on account of accumulation in the blood of their most pathogenic middle and small molecular fractions and reduction of large molecular fractions was established in patients with multiple gastroduodenal ulcers.

Clinical and immunological examinations are carried out in patients with preclinical, nonproliferative, preproliferative, and proliferative diabetic retinopathy (DR). On the whole, DR is characterized by a notable increase in antibody-dependent immune response, associated with appearance of antibodies to collagen of the II and IV types in the lacrimal fluid and serum, with the "local" reactions predominating. The level of reactions of cellular autoimmune response (tumor necrosis factor-alpha) and cell-to-cell reactions in the lacrimal fluid and serum is low. Increased level of circulating immune complexes in the serum and almost complete absence of free antibodies to collagen in the blood may be indicative of formation of pathogenic immune complexes precipitating on vascular walls and in other tissues. Various forms of immune response were revealed, conducive to a favorable or unfavorable course of DR.

Fetal kidneys from mothers with late gestosis, diabetes mellitus-1 and chronic glomerulonephritis were studied. There were features of the maturation slowing down and some disturbances in differentiation of rental tissue were revealed. Local degenerative, membranous, proliferative and fibroplastic changes with formation of immune complexes including IgM and C3-complement in late gestosis, IgA, G, C3-complement fractions IgG, M, C3-complement fraction and traces of membranous and proliferative alteration were observed in chronic glomerulonephritis, they were less frequent in diabetes mellitus in mothers, and not so often in late gestosis. Activation of collagen production of types I, III, IV and V was most commonly observed in diabetes mellitus, in chronic glomerulonephritis and late gestosis, it being more rare.

In 165 patients with the different forms of cholelithiasis, a level of the circulating immune complexes (CIC) was measured in the blood serum and bile from the common bile duct at the postoperative period. In associated purulent-resorptive and cholemic intoxication, the CIC level in the blood serum and bile increases. This, in turns, enhances the likelihood of the development of purulent-septic complications at the postoperative period, and requires performance of target immunocorrection.

Serum levels of circulating immune complexes (CIC) and those in the liquor were studied in patients with spinal trauma using enzyme immunoassay. CIC and clinical--laboratory findings characterizing the activity of the inflammation were consistent. Assessment of CIC factor in spinal trauma seems clinically valuable as it is involved in inflammation and tissue damage suggesting a prognosis of CIC-related pathology.

The lipoproteids of low and very low density (LDL and VLDL), being the main carriers of plasma cholesterol, in their interaction with the arterial wall constitute the material basis for development of atherosclerosis, determining the key aspects of its patho- and morphogenesis. The development of hypercholesterolemia is associated with qualitative changes of interactions of lipoproteids with cell membranes. The electrostatic charge of lipoproteid particle acquires in this process specific importance. Early stages of atherosclerotic lesions are accompanied by an activation of LDL-nonspecific endocytosis. Actually, the main problem in the atherosclerosis pathogenesis resides in LP and arterial wall homeostasis.

Profound changes in epithelial and lymphoid tissues were detected by the immunofluorescent technique in the thymus of myopathy patients. The characteristic immunomorphological manifestation indicating injuries to the thymic epithelial tissue is the sedimentation of IgG, IgA and complement in basal membranes and in the cytoplasm of adjacent poorly differentiated epithelial cells. Another remarkable sign of the changes in the thymic epithelial tissue during the disease is a sharply marked cystic degeneration of Hassall bodies, eventuating in the sedimentation of keratinized material in the internal environment of the organ. The changes in the thymic lymphoid tissue during myopathy are confirmed by the sedimentation of immune complex granules, containing IgM, IgA, IgG, and complement, in the intercellular space bordering individual groups of corticomedullar zone lymphocytes. The data obtained suggest that the thymic changes play an important part in the development and course of progressing muscle dystrophy.

The complement-fixing capacity of aggregated immunoglobulins with varying molecular weights has been explored. It has been demonstrated that as the molecular weight of a complex rises, the complement-fixing capacity increases. The amount of unfixed complement depends nonlinearly on the concentration of complement added and aggregated complexes in solution. The size of the complexes rather than their concentration plays the key role in the measurement of the complement-fixing capacity of aggregated immunoglobulins.

Physico-chemical properties of model immune complexes from normal and myeloma immunoglobulins were compared, and complement-binding activity of these aggregates was studied. No considerable differences were observed between aggregates from normal and myeloma Ig. Myeloma complexes have a higher complement-binding activity, as compared to normal ones, and are structurally more stable. Complement-binding activity of both types of complexes depends on the complex molecular mass and is maximal in complexes of medium molecular mass.

The authors studied and compared the complement-fixing activity of model immune complexes with different molecular mass. The complement-fixing activity of the complexes was found to be linearly independent of the molecular mass, being mainly determined by the size of the complex, and to be slightly dependent on the concentration of aggregated immunoglobulins. As far as the aggregates with a molecular mass over 20 IgG are concerned, addition of complement leads to the dissociation of the complexes.

Immunization of BALB/c mice by sheep red blood cells and Salmonella typhi vaccine has been shown to augment the immune complexes in plasma and erythrocytes in blood fixing the immune complexes on their surface. The inactivation of immune complexes in immunized mice by intravenous injection of the antiserum against aggregated immunoglobulins decreases the hemoglobin in blood serum. The data obtained show that the fixation of immune complexes on erythrocytes is one of the reasons of erythrocytes destruction activation in immunization.

Biopsies of the thigh skin from 145 patients with immuno-independent diabetes mellitus were studied morphologically. Diabetical microangiopathy was found in 123 patients. IgG, IgM, complement, albumin, beta-lipoproteins, fibrinogen were determined immunohistochemically in the walls of altered vessels. The frequency of IgG fixation of the vascular wall and its level in the serum were significantly higher than in patients without alteration of small vessels. The conclusion on the leading role of plasmatic inhibition in the development of diabetic microangiopathy and on the participation of not only metabolic but also immune (immunocomplex most likely) mechanisms in its development is drawn.