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Intravenous immunoglobulin (IVIG) is used to treat several autoimmune and inflammatory diseases, but some patients are refractory to IVIG and require alternative treatments. Identifying a biomarker that could segregate IVIG responders from non-responders has been a subject of intense research. Unfortunately, previous transcriptomic studies aimed at addressing IVIG resistance have failed to predict a biomarker that could identify IVIG-non-responders. Therefore, we used a novel data mining technique on the publicly available transcriptomic data of Kawasaki disease (KD) patients treated with IVIG to identify potential biomarkers of IVIG response. By studying the boolean patterns hidden in the expression profiles of KD patients undergoing IVIG therapy, we have identified new metabolic pathways implicated in IVIG resistance in KD. These pathways could be used as biomarkers to segregate IVIG non-responders from responders prior to IVIG infusion. Also, boolean analysis of the transcriptomic data could be further extended to identify a universal biomarker that might predict IVIG response in other autoimmune diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Intravenous immunoglobulin (IVIg) can exert beneficial effects in autoimmune and inflammatory diseases via several mutually non-exclusive mechanisms. While, IVIg can directly modulate the functions of both innate and adaptive immune cells such as dendritic cells (DC), macrophages, B and T cells, several reports have also highlighted that the regulation of immune responses by IVIg can be indirect. In view of these results, we aimed at exploring whether indirect regulation of immune cells by 'IVIg-educated' innate cells is a universal phenomenon. We addressed this question by deciphering the modulation of B cell functions by 'IVIg-educated' DC. Our results indicate that human B cells are resistant to immunomodulation by 'IVIg-educated' DC. However, IVIg at therapeutic concentrations can directly inhibit B cell activation and proliferation. These results thus suggest that, indirect modulation of immune cells by IVIg is not a universal phenomenon., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Kawasaki disease (KD) is an acute febrile childhood vasculitis, associated with the development of coronary artery abnormalities in 25-30% of untreated patients. The aetiopathogenesis is not well known but it is accepted that an undefined infectious trigger in genetically predisposed individuals results in the disease. KD is characterized by an endothelial cell injury, which could be due to abnormal cytokine production and to generation of cytotoxic antibodies against the endothelial cells. Intravenous immunoglobulin IVIG is an effective treatment in preventing the occurrence of coronary artery abnormalities in KD. Several mechanisms may explain the anti-inflammatory effects of IVIG in this disease. They include modification of the cytokine balance, and alteration on both the differentiation and the function of monocytes/macrophages, neutrophils and lymphocytes., (Copyright 2009 Elsevier B.V. All rights reserved.)

Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. Although a considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory functions in these diseases, they remain not fully elucidated. The mode of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of: idiotype network, expression of Fc receptors, and activation, differentiation and effector functions of T and B cells and of antigen-presenting cells such as dendritic cells. The therapeutic effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.

Dendritic cells (DCs) are professional antigen-presenting cells, which have a central role in the initiation of primary immune responses and in maintaining immune tolerance. The functions of DCs can be regulated both by environmental signals as well as signals delivered by endogenous molecules. Recently we have examined regulation of human DCs by B cells via natural IgG antibodies. Natural antibodies (NAbs) are defined as antibodies that circulate in normal individuals in the absence of deliberate immunization or microbial aggression. We demonstrate that the differentiation of DCs is severely impaired in primary immunodeficient patients such as X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID) at least in part due to the deficiency of circulating NAbs. Further, we show that NAbs are able to restore normal phenotypes of DCs from patients with XLA and CVID. Our results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.

Dendritic cells (DC) are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. Because of their capacity to stimulate naive T cells, DC have a central role in the initiation of primary immune responses and are considered promising tools and targets for immunotherapy. Emerging data suggest a role for DC in initiating autoimmune attacks. Direct analysis of DC phenotypes and DC-T-cell interactions in rodent and human autoimmune diseases should shed light on how pathogenesis occurs, and suggest novel avenues of treatment aimed at alleviating deviant DC function.

Hemophilia A is an X-linked, recessive, bleeding disorder caused by defective or deficient factor VIII (FVIII) molecules. Infusion of purified FVIII to patients with severe hemophilia A results in approximately 25% of the cases, in the emergence of anti-FVIII antibodies (inhibitors) that are known to neutralize the pro-coagulant activity of FVIII by steric hindrance. We recently reported on the proteolysis of FVIII by allo-antibodies in the plasma of high responder patients with severe hemophilia A, demonstrating a new mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. Hemophilia is the first model where a direct link between the hydrolysis of the target molecule and the occurrence of the clinical manifestations may be established. It also represents the first example in humans, of the induction of catalytic antibodies following the exogenous administration of an antigen. The characterization of FVIII inhibitors as site-specific proteases may provide new approaches to the treatment of inhibitors.

Anti-Factor VIII (FVIII) antibodies represent a unique model to study the relationship between natural autoreactivity (natural antibodies to FVIII of healthy individuals) and disease-associated autoimmunity ('spontaneous' FVIII inhibitors of patients with anti-FVIII autoimmune disease) to a single human protein antigen. Although natural and disease-associated anti-FVIII antibodies are not readily distinguished based on the comparison of their isotypic distribution and epitope mapping, available studies of cross-reacting idiotypes suggest that FVIII inhibitors in patient's plasma encompass two populations of anti-FVIII antibodies - some antibodies result from the clonal expansion of B lymphocytes that exist previous to the treatment with FVIII and secrete anti-FVIII antibodies with properties similar to those of natural anti-FVIII antibodies present in healthy individuals, other inhibitors are produced by B cell clones that have undergone affinity-maturation and hypermutation of the V-regions of the antibodies they produce. The implications for the treatment of autoimmune patients with anti-FVIII inhibitors are discussed.