Organ-specific autoimmunity is often characterized by autoantibodies targeting proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized... Show moreOrgan-specific autoimmunity is often characterized by autoantibodies targeting proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized by predominant autoantibodies of the IgG4 subclass (IgG4-autoimmune diseases; IgG4-AID). This group includes pemphigus vulgaris, thrombotic thrombocytopenic purpura, subtypes of autoimmune encephalitis, inflammatory neuropathies, myasthenia gravis and membranous nephropathy. Although the associated autoantibodies target specific antigens in different organs and thus cause diverse syndromes and diseases, they share surprising similarities in genetic predisposition, disease mechanisms, clinical course and response to therapies. IgG4-AID appear to be distinct from another group of rare immune diseases associated with IgG4, which are the IgG4-related diseases (IgG4-RLD), such as IgG4-related which have distinct clinical and serological properties and are not characterized by antigen-specific IgG4. Importantly, IgG4-AID differ significantly from diseases associated with IgG1 autoantibodies targeting the same organ. This may be due to the unique functional characteristics of IgG4 autoantibodies (e.g. anti-inflammatory and functionally monovalent) that affect how the antibodies cause disease, and the differential response to immunotherapies of the IgG4 producing B cells/plasmablasts. These clinical and pathophysiological clues give important insight in the immunopathogenesis of IgG4-AID. Understanding IgG4 immunobiology is a key step towards the development of novel, IgG4 specific treatments. In this review we therefore summarize current knowledge on IgG4 regulation, the relevance of class switching in the context of health and disease, describe the cellular mechanisms involved in IgG4 production and provide an overview of treatment responses in IgG4-AID. Show less
Background: Adjuvants are essential in the induction of immunity by vaccines and interact with receptors, including the Toll-like receptors (TLRs). Responsiveness of these receptors differs between... Show moreBackground: Adjuvants are essential in the induction of immunity by vaccines and interact with receptors, including the Toll-like receptors (TLRs). Responsiveness of these receptors differs between and within populations, which impacts vaccine effectiveness. Objective: Here we examine how the innate cytokine response towards TLR ligands differs between high and low socioeconomic status (SES) school-aged children from Makassar, Indonesia. Methods: We stimulated whole blood from children, of which 27 attended a high SES school and 27 children a low SES school, with ligands for TLR-2/1, -2/6, -3, -4, -5, -7, -9 and measured pro- (TNF) and anti-inflammatory (IL-10) cytokines released. Results: In the low SES there is an increased pro-inflammatory response after 24 h stimulation with TLR-2/1 ligand Pam3 and TLR-4 ligand LPS compared to the high SES. Comparison of the response to LPS after 24 h versus 72 h stimulation revealed that the pro-inflammatory response in the low SES after 24 h shifts to an antiinflammatory response, whereas in the high SES the initial anti-inflammatory response shifts to a strong proinflammatory response after 72 h stimulation. Conclusion: We observed differences in the TLR-mediated innate immune response between children attending low and high SES schools, which can have important implications for vaccine development Show less
In the last few decades, childhood allergy has alarmingly increased to epidemic levels in industrialized countries. Conversely, chronic helminth infections, which are highly prevalent in developing... Show moreIn the last few decades, childhood allergy has alarmingly increased to epidemic levels in industrialized countries. Conversely, chronic helminth infections, which are highly prevalent in developing countries, are negatively associated with allergic disorders. The work in this thesis revealed that, using B-cell IL-10-deficient mice, Schistosoma mansoni-mediated protection against experimental ovalbumin-induced allergic airway inflammation (AAI) was specifically dependent on splenic IL-10-producing CD1dhi regulatory B (Breg) cells. Furthermore, we demonstrated that another B cell subset, located in the lungs, provided protection against AAI, by showing a reduced capacity to initiate Th2 cytokine responses. Markedly, we found a similarly elevated population of IL-10-producing CD1dhi B cells in peripheral blood of Schistosoma haematobium-infected Gabonese children compared to uninfected children. We observed that schistosome-induced Breg cells reduced effector T-cell cytokines and induced more Treg cells. What is interesting in this aspect, is that we found that the Breg cell compartment of patients with allergic asthma is impairment in number and activity. Therefore, the identification of the mechanisms that underlying Breg cell induction by helminths, and the identification the helminth-derived molecules involved, may open novel avenues for the treatment of allergic disease disorders by driving potent Breg cells Show less
Vlugt, L.E.P.M. van der; Zinsou, J.F.; Ozir-Fazalalikhan, A.; Kremsner, P.G.; Yazdanbakhsh, M.; Adegnika, A.A.; Smits, H.H. 2014
Helminth parasites are able to induce immune regulation in their host. Suppression of the host immune system is beneficial for both the parasite, by inhibiting anti-parasite immunity, and for the... Show moreHelminth parasites are able to induce immune regulation in their host. Suppression of the host immune system is beneficial for both the parasite, by inhibiting anti-parasite immunity, and for the host, by preventing tissue damage due to excessive inflammation. There are indications that in countries where parasites have been eliminated the immune regulatory network is impaired, leading to inflammatory diseases such as allergies and asthma. An important player in immune regulation is the regulatory T cell (Treg). We have shown that the number and/or function of Tregs were indeed enhanced in several helminth and also malaria infections in humans. Tregs were not only involved in suppression of anti-parasite responses, but also of responses to other infections or vaccines. We further investigated the effect of helminth elimination in a randomized placebo-controlled trial. Treatment of helminths led to a strong increase in __mainly pro-inflammatory__ immune responses, which confirms the importance of immune regulation during infection. Furthermore, the prevalence of malaria was transiently increased and allergy was slightly on the rise in treated school children. These results further endorse the possible beneficial effects of helminthic therapy, which is currently being tested in a number of clinical trials. Show less
The host response to bacterial invasion requires first the recognition of the presence of pathogens. The presence of a pathogen is detected by binding of pathogen-preserved molecules called ... Show moreThe host response to bacterial invasion requires first the recognition of the presence of pathogens. The presence of a pathogen is detected by binding of pathogen-preserved molecules called 'pathogen-associated molecular patterns' or PAMPs on cell surface receptors known as 'pattern recognition receptors' or PRRs. Lipopolysaccharide (LPS; endotoxin), one of the major outer membrane components of the Gram-negative bacterial cell wall, is an important PAMP. In the last decade the mechanisms by which the host responds to the presence of microbial pathogens on its mucosal surfaces or in the tissues, have been elucidated, most up to their molecular level. With the sequencing of the genome and recognition of the genetic variation within the human population, it became clear this variation is responsible for the inter-individual differences in cytokine release after challenge with microbial products. Such genetically determined variations in cytokine release could be relevant to explain the variability in susceptibility too, and outcome from, sepsis. The thesis focuses on genes that encode for proteins involved in the pathogenesis of sepsis including those involved in the initial recognition of bacterial products such as Toll-like receptors, and cytokines known to mediate the host inflammatory response, such as tumor necrosis factor (TNF)-α, interleukin(IL)-6 and IL-10. Show less
