The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody... Show moreThe presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies. Show less
Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We studied the effects of coinfections on the... Show moreCoinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We studied the effects of coinfections on the antibody profile in a cohort of 715 Mozambican children and adults using the Luminex technology with a panel of 16 antigens from P. falciparum and 11 antigens from helminths (Ascaris lumbricoides, hookworm, Trichuris trichiura, Strongyloides stercoralis, and Schistosoma spp.) and measured antigen-specific IgG and total IgE responses. We compared the antibody profile between groups defined by P. falciparum and helminth previous exposure (based on serology) and/or current infection (determined by microscopy and/or qPCR). In multivariable regression models adjusted by demographic, socioeconomic, water, and sanitation variables, individuals exposed/infected with P. falciparum and helminths had significantly higher total IgE and antigen-specific IgG levels, magnitude (sum of all levels) and breadth of response to both types of parasites compared to individuals exposed/ infected with only one type of parasite (P <= 0.05). There was a positive association between exposure/infection with P. falciparum and exposure/infection with helminths or the number of helminth species, and vice versa (P <= 0.001). In addition, children coexposed/coinfected tended (P = 0.062) to have higher P. falciparum parasitemia than those single exposed/infected. Our results suggest that an increase in the antibody responses in coexposed/coinfected individuals may reflect higher exposure and be due to a more permissive immune environment to infection in the host.IMPORTANCE Coinfection with Plasmodium falciparum and helminths may impact the immune response to these parasites because they induce different immune profiles. We compared the antibody profile between groups of Mozambican individuals defined by P. falciparum and helminth previous exposure and/or current infection. Our results show a significant increase in antibody responses in individuals coexposed/coinfected with P. falciparum and helminths in comparison with individuals exposed/infected with only one of these parasites, and suggest that this increase is due to a more permissive immune environment to infection in the host. Importantly, this study takes previous exposure into account, which is particularly relevant in endemic areas where continuous infections imprint and shape the immune system. Deciphering the implications of coinfections deserves attention because accounting for the real interactions that occur in nature could improve the design of integrated disease control strategies. Show less
Glycosylation of immunoglobulins is suspected to play a key role in the regulation of the immune system. In this thesis, mass spectrometry-based glycoproteomics methods were used to characterize... Show moreGlycosylation of immunoglobulins is suspected to play a key role in the regulation of the immune system. In this thesis, mass spectrometry-based glycoproteomics methods were used to characterize the glycosylation of various immunoglobulins. In Chapter 2 we describe the development of a glycoproteomics method to analyze IgE glycosylation. In Chapter 3 we reported partial O-glycosylation of IgG3. In addition to structural glycosylation research, we also analyzed antibody glycosylation in population cohorts. In Chapter 4 and Chapter 5, IgG Fc glycopeptide analysis was performed on blood samples using LC-MS(/MS). In a cohort of 76 ANCA vasculitis patients, low galactosylation and sialylation of IgG was associated with a higher chance of future relapse. Furthermore, in the approximately 1800 participants of the Leiden Longevity study (LLS), low galactosylation and sialylation of IgG, together with high fucosylation, showed association with markers of inflammation. We hope that the novel data presented in this thesis may contribute to the elucidation of the role of antibody glycosylation in the immune system, of which the understanding is currently still very limited. Show less
There has been a global increase in prevalence of allergic diseases. This is particularly so in developed and in urban centres of developing countries. At the same time, in rural areas of... Show moreThere has been a global increase in prevalence of allergic diseases. This is particularly so in developed and in urban centres of developing countries. At the same time, in rural areas of developing countries helminth infections are still highly prevalent. The immune response against helminths and allergens is generally characterized by high levels of IgE and increased numbers of Th2 cells, eosinophils, and mast cells, yet the clinical outcome with respect to immediate hypersensitivity and inflammation is clearly not the same. High levels of IgE are seen to allergens during helminth infections; however, these IgE responses do not translate into allergy symptoms. The role of socio-economic status (SES) which can be intertwined with presence or absence of helminth infections, has been examined in relation to development of allergic disorders in several studies. This thesis summarizes the evidence of the association between helminth infections and allergic disorders. It discusses how helminth infection can lead to IgE cross-reactivity with allergens and how this IgE has poor biological activity. The studies presented in this thesis shed light on the relationship between helminth infection, SES and atopic disorders in a developing country (Indonesia) where large differences in life-style, environmental exposure and SES are seen. Show less
Hamid, F.; Wahyuni, S.; Leeuwen, A. van; Ree, R. van; Yazdanbakhsh, M.; Sartono, E. 2015
The studies present in this thesis fall into two broad areas: the first focusing on filarial infection, Ig (immunoglobulin)E levels and risk factors for infection, while the second deals with the... Show moreThe studies present in this thesis fall into two broad areas: the first focusing on filarial infection, Ig (immunoglobulin)E levels and risk factors for infection, while the second deals with the possible associations between nematode infection and allergy. Compared to ELISA, RAST is superior in detecting filarial specific IgE in endemic area of Brugia malayi. Levels of filaria-specific IgE and IgG4 in children up to 10 years correlated with maternal antibody levels. Genetic factors had a more pronounced effect in children than in adults. The use of objective measurements, such as skin prick test (SPT) and IgE levels are required when conducting epidemiological studies of allergic diseases in Indonesia. Study on risk factors of allergy in Indonesia showed that nutritional status of children in the high socioeconomic school negatively associate with SPT and IgE positivity but we did not show a statistically significant role for helminths in inhibiting SPT responses. In endemic area of lymphatic filariasis, genetic factors contribute significantly to both total and allergen-specific IgE, whereas environmental factors influence the clustering of SPT positivity. By using several TLR ligands it was demonstrated that the dynamics of cytokine production following the innate immune stimulation can differ according to helminth infection status. Show less
