IgA Complexes Induce Neutrophil Extracellular Trap Formation More Potently Than IgG Complexes

Neutrophil extracellular trap (NET) formation is a powerful instrument to fight pathogens, but may induce collateral damage in the affected tissues. Besides pathogen-derived factors, immune complexes are potent inducers of NET formation. Neutrophils express IgA and IgG specific Fc receptors (FcRs) and therefore respond to complexed IgA and IgG. Especially in the context of autoimmune diseases, IgA and IgG immune complexes have been shown to trigger NET formation, a process that putatively contributes to disease severity. However, it is of question if both antibody classes stimulate neutrophils to the same extent. In this study, we compared the capability of IgA and IgG complexes formed by heat aggregation to induce NET formation. While stimulation of neutrophils with IgA complexes robustly induced NET formation, complexed IgG only marginally increased the amount of NETs compared to the unstimulated control. Mixing IgA with IgG before heat aggregation did not increase the effect of complexed IgA on neutrophils. By contrast, the presence of IgG complexes seemed to disturb neutrophil stimulation by IgA complexes. The capacity of complexed IgG to induce NET formation could not be increased by the addition of autologous serum or the removal of terminal sialic acid in the Fc glycan. Together, our data show that IgA is a much more potent inducer of NET formation than IgG. IgA may thus be the main driving force in (auto)immune complex-mediated NET formation.

Sialylation of IgG inhibits the formation of galactose-deficient IgA1-containing immune complexes and protects mesangial cells from injury in IgA nephropathy

Background The addition of sialic acid alters IgG from a pro-inflammatory state to an anti-inflammatory state. However, there is a lack of research on the changes of IgG sialylation in IgA nephropathy (IgAN). Methods This study included a total of 184 IgAN patients. The sialylated IgG (SA-IgG), IgG-galactose-deficient IgA1 complex (IgG-Gd-IgA1-IC), IL-6, TNF-α, and TGF-β were detected using commercial ELISA kits. SA-IgG, non-sialylated IgG (NSA-IgG), sialylated IgG-IgA1 complex (SA-IgG-IgA1), and non-sialylated IgG-IgA1 complex (NSA-IgG-IgA1) were purified from IgAN patients and healthy controls (HCs). Results The mean SA-IgG levels in plasma and B lymphocytes in IgAN patients were significantly higher than those of healthy controls. A positive correlation was found between SA-IgG levels in plasma and B lymphocytes. In vitro, the results showed that the release of IgG-Gd-IgA1-IC was significantly decreased in peripheral blood mononuclear cells (PBMCs) cultured with SA-IgG from both IgAN patients and healthy controls. The proliferation ability and the release of IL-6, TNF-α, and TGF-β in human mesangial cells (HMCs) were measured after stimulating with SA-IgG-IgA1-IC and NSA-IgG-IgA1-IC. The mesangial cell proliferation levels induced by NSA-IgG-IgA1-IC derived from IgAN patients were significantly higher than those caused by SA-IgG-IgA1-IC derived from IgAN patients and healthy controls. Compared with NSA-IgG-IgA1 from healthy controls, IgAN-NSA-IgG-IgA1 could significantly upregulate the expression of IL-6 and TNF-α in mesangial cells. The data showed that there weren’t any significant differences in the levels of IL-6, TNF-α, and TGF-β when treated with IgAN-SA-IgG-IgA1 and HC-NSA-IgG-IgA1. Conclusions The present study demonstrated that the sialylation of IgG increased in patients with IgA nephropathy. It exerted an inhibitory effect on the formation of Gd-IgA1-containing immune complexes in PBMCs and the proliferation and inflammation activation in mesangial cells.

Hydrolytic enzymes in therapy of gestosis

The clinical effectiveness o f complex enzymotherapy with preparation Vobenzim in treatment o f gestosis was studied in comparison with traditional therapy. The author analyzes the course оf gestation and delivery, and the state оf neonates in women with nephropathy o f I degree, who got common treatment (28 patients) and complex treatment including Vobenzim (17patients). Positive clinical effect o f complex enzymotherapy in case o f nephropathy is displayed in decreasing of edematic syndrome, eliminating or decreasing o f proteinuria, lowering o f blood pressure and impairment o f fetalhypoxia in labors. It goes along with the reduction o f immune complexes fixed in placenta.

Nonspecific protective factors in patients with early latent syphilis (report 1)

The objective of this work is to study nonspecific protective factors in patients with latent early syphilis. The results of the study are based on the data of a comprehensive examination before treatment of 142 patients with early latent syphilis and 20 patients of the comparison group. Methods of investigation: serological methods for the diagnosis of syphilis complex of serological reactions, enzyme-linked immunosorbent assay (IgM, IgG), Indirect immunofluorescence reaction (RIF) RIF-200, RIF-abs; determination of cytokines IL-2, IL-6, IL-10, TNFα and INFγ in blood serum by enzyme-linked immunosorbent assay; determination of the phenotype of lymphocytes (CD-receptors), the concentration of circulating immune complexes, phagocytic number, phagocytic index, Nitroblue tetrazolium test. In the blood serum of patients the concentration of IL-2, IL-6, IL-10 and TNFα, INFγ was significantly increased. The concentration of IL-10 and IL-6 was also significantly increased in patients with more than 1 year of infection. The most significant disorders of the parameters of the metabolic activity of neutrophils were found in patients with an infection of more than 1 year; an imbalance in the circulating immune complexes concentration was also established. Under the increasing duration of the infection, the concentration of CD16+ in the blood serum progressively decreases. The content of pro-inflammatory and anti-inflammatory cytokines in the blood serum of patients with early latent syphilis was significantly increased and depended on the timing of infection. This relationship was most pronounced for IL-6 and IL-10. In patients with early latent syphilis there is also an imbalance between CD25+ and late activation factor HLA-DR against the background of a progressive decrease in the number of CD16+ lymphocytes. A direct relationship was established between the time of infection and the number of NK-cells. The revealed disorders may be the consequence of significant disorders on the part of neutrophils and may be one of the factors of the latent course of syphilitic infection.

Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.

Peculiarities of immunophysiological shifts in adaptation to climatic and geographical conditions of mountains

The functioning of the immune system of people exposed to prolonged exposure to natural factors has been monitored and the main immunity indicators have been studied in practically healthy population of different mountain heights in Chui and Naryn regions. Indicators of specific immunity in the residents of the zone of compensated discomfort is reduced compared with the standards of the zone of relative comfort and refers to the mixed type with suppression of cellular and humoral immunity, apparently, this is associated with the climatic and geographical and environmental characteristics of the region. Key words: adaptation, immune system, T- lymphocytes, B- lymphocytes, immunoglobulins, circulating immune complexes, mountainous conditions.

Type II Activation of Monocytes in Multiple Sclerosis

<p><b>Multiple sclerosis (MS) is an incurable autoimmune disease of the CNS. Although its cause is not known, immune cells are involved in the disease progression. Among these cells, type I monocytes are first to arrive to the brain and initiate inflammation; however, if monocytes are type II activated, they can inhibit inflammation. Previous research has shown that immune responses can be modulated by treatments, such as glatiramer acetate (GA) and immune complexes (IC). Therefore, we aimed to determine whether GA and IC can induce type II activation of monocytes in MS.</b></p> <p>Human blood monocytes from healthy volunteers and MS patients were stimulated in vitro with bacterial lipopolysaccharide (classical activation) in the presence or absence of GA and immune complexes (IC) composed of IVIG and human red blood cells (type II activation). Flow cytometry, ELISA and cytometric bead array were used to assess levels of marker expression and cytokine production in order to define the activation of monocytes.</p> <p>Interestingly, while both GA and IC induced type II activation of monocytes, the characteristics of these type II monocytes were distinct. We have found that monocytes from both healthy people and MS patients have significantly lower levels of inflammatory marker CD40 and higher levels of the anti-inflammatory cytokine IL-10 after treatment with IC. In contrast, GA treatment reduced the levels of CD40, CD86 and the inflammatory cytokine IL- 12. Moreover, the combined addition of GA and IC appeared to be more effective in type II activating monocytes than either agent alone. We also found that both CD14++CD16- and CD14+CD16+ monocyte subsets can be type II activated by the treatments; however, an interaction between the subsets impaired their response to the treatments.</p> <p>Our study suggests that treatments with GA and IC, especially in combination, are effective in type II activation of human monocytes and can be beneficial therapeutic approaches for multiple sclerosis.</p>

Type II Activation of Monocytes in Multiple Sclerosis

<p><b>Multiple sclerosis (MS) is an incurable autoimmune disease of the CNS. Although its cause is not known, immune cells are involved in the disease progression. Among these cells, type I monocytes are first to arrive to the brain and initiate inflammation; however, if monocytes are type II activated, they can inhibit inflammation. Previous research has shown that immune responses can be modulated by treatments, such as glatiramer acetate (GA) and immune complexes (IC). Therefore, we aimed to determine whether GA and IC can induce type II activation of monocytes in MS.</b></p> <p>Human blood monocytes from healthy volunteers and MS patients were stimulated in vitro with bacterial lipopolysaccharide (classical activation) in the presence or absence of GA and immune complexes (IC) composed of IVIG and human red blood cells (type II activation). Flow cytometry, ELISA and cytometric bead array were used to assess levels of marker expression and cytokine production in order to define the activation of monocytes.</p> <p>Interestingly, while both GA and IC induced type II activation of monocytes, the characteristics of these type II monocytes were distinct. We have found that monocytes from both healthy people and MS patients have significantly lower levels of inflammatory marker CD40 and higher levels of the anti-inflammatory cytokine IL-10 after treatment with IC. In contrast, GA treatment reduced the levels of CD40, CD86 and the inflammatory cytokine IL- 12. Moreover, the combined addition of GA and IC appeared to be more effective in type II activating monocytes than either agent alone. We also found that both CD14++CD16- and CD14+CD16+ monocyte subsets can be type II activated by the treatments; however, an interaction between the subsets impaired their response to the treatments.</p> <p>Our study suggests that treatments with GA and IC, especially in combination, are effective in type II activation of human monocytes and can be beneficial therapeutic approaches for multiple sclerosis.</p>

Leptin-reactive antibodies are distinctly correlated with body composition parameters and metabolic risk indexes in children and adolescents

Studies have demonstrated the presence of low-affinity immunoglobulins (Igs) directed to leptin, a key hormone of the neuroendocrine axis that regulates appetite and metabolism, in adult healthy subjects, patients with obesity and type 2 diabetes mellitus. In the present exploratory study, IgG leptin-reactive antibodies were analyzed for the first time in children and adolescents according to body mass index (BMI) and were correlated with biochemical profile (lipid profile, insulin, glucose and leptin) and metabolic risk indexes (HOMA-IR, HOMA-β, AIP). One hundred and thirty-six participants were included (children n=63, adolescents n=73). An in-house ELISA test was performed to measure IgG anti-leptin antibodies (free, total and immune complexes). In adolescents, free and total IgG anti-leptin antibodies levels were higher in groups with overweight or obesity than in normal-weight group (p&lt;0.01), while in children, the total fractions were lower in groups with overweight and obesity than in normal-weight (p&lt;0.02). Immune complexes percentage showed opposite correlations with BMI in children (r=0.4004, p=0.0473) and adolescents (r=-0.3983, p=0.0133). IgG anti-leptin antibodies were also correlated with HOMA-IR in children (r=-0.4569, p=0.0217) and adolescents (r=-0.3589, p=0.0316), and with AIP (r=-0.3608, p=0.0261) in adolescents. Our data suggest that the production and affinity of IgG anti-leptin antibodies can be affected by age, body composition and metabolic conditions; additionally, in normal conditions, IgG anti-leptin antibodies may have a protective role in insulin resistance and cardiovascular events.