Immunoglobulin G4: an odd antibody Aalberse, R. C.; Stapel, S. O.; Schuurman, J. ...
Clinical and experimental allergy,
April 2009, Letnik:
39, Številka:
4
Journal Article
Recenzirano
Summary
Despite its well‐known association with IgE‐mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved ...in a continuous process of half‐molecules (i.e. a heavy and attached light‐chain) exchange. This process, also referred to as ‘Fab‐arm exchange’, results usually in asymmetric antibodies with two different antigen‐combining sites. While these antibodies are hetero‐ bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T‐helper type 2 (Th2) cells, the IgG4 response is largely restricted to non‐microbial antigens. This Th2‐dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE‐mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen‐blocking effect at the mast cell level and/or at the level of the antigen‐presenting cell (preventing IgE‐facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL‐10 and other anti‐inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non‐activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti‐inflammatory cytokines triggering an overwhelming expansion of IgG4‐producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen‐specific IgG4 indicates that anti‐inflammatory, tolerance‐inducing mechanisms have been activated. The existence of the IgG4 subclass, its up‐regulation by anti‐inflammatory factors and its own anti‐inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.
Background In a subset of patients, anti tumour necrosis factor (TNF) therapeutic antibodies are immunogenic, resulting in the formation of antidrug antibodies (ADAs). Neutralising ADAs compete with ...TNF for its binding site and reduces the effective serum concentration, causing clinical non-response. It is however unknown to which extent ADAs are neutralising. Objectives To study which proportion of antibodies to human(ised) anti-TNF (adalimumab, golimumab, certolizumab) as well as chimeric anti-TNF (infliximab) is neutralising. Methods Neutralising capacity of ADAs was assessed using a TNF competition assay in ADA-positive sera of patients treated with adalimumab (n=21), golimumab (n=4), certolizumab (n=9) or infliximab (n=34) sent in to our diagnostic department. Results In 34 sera with ADAs to adalimumab, golimumab or certolizumab, >97% of the antibodies were neutralising. In 34 sera with ADAs to infliximab >90% of the antibodies were neutralising. Further characterisation of the broader antibody response to infliximab revealed that non-neutralising antibodies to infliximab do not target murine domains, but may bind infliximab-unique domains not involved in TNF binding (located outside the paratope). Conclusions Our study shows that ADAs to human(ised) as well as chimeric anti-TNF therapeutic antibodies are largely neutralising. This highly restricted ADA response suggests an immunodominant role for the paratope of anti-TNF therapeutics.
Summary
Background
Formation of antibodies to infliximab (ATI) inversely correlates with functional drug levels and clinical outcome. Comparison of drug levels and anti‐drug antibody monitoring is ...hampered by lack of standardisation.
Aim
To determine the correlation between three different assays for measuring infliximab and ATI.
Methods
Serum samples and spiked controls (total 62) were evaluated in a blinded way in infliximab and ATI assays developed by Sanquin Amsterdam, Netherlands (A), Laboratory for Pharmaceutical Biology, KU Leuven, Belgium (B) and a commercially available kit from Biomedical Diagnostics (BMD), Paris, France (C) performed by the University Medical Center Groningen (UMCG), Netherlands.
Results
All infliximab assays showed a linear quantitative correlation (Pearson r = 0.91 for A vs. B, 0.83 for A vs. C and 0.73 for B vs. C). Assay C detected infliximab in 11 samples (18%) not detected by A and B, including samples containing only ATI. All ATI assays showed a good linear correlation (Pearson r = 0.95 for A vs. B, 0.99 for A vs. C and 0.97 for B vs. C). Assay A detected ATI in five samples with low ATI that were not detected by assays B and C. Assay B did not detect ATI in three patient samples with low ATI according to assays A and C.
Conclusions
There is a good correlation of infliximab and antibodies to infliximab measurements between these assays. Nevertheless, the Biomedical Diagnostics kit detected false positive infliximab levels in 18% of the samples.
A series of highly soluble fullerene derivatives with varying acceptor strengths (i.e., first reduction potentials) was synthesized and used as electron acceptors in plastic solar cells. These ...fullerene derivatives, methanofullerene 6,6‐phenyl C61‐butyric acid methyl ester (PCBM), a new azafulleroid, and a ketolactam quasifullerene, show a variation of almost 200 mV in their first reduction potential. The open circuit voltage of the corresponding devices was found to correlate directly with the acceptor strength of the fullerenes, whereas it was rather insensitive to variations of the work function of the negative electrode. These observations are discussed within the concept of Fermi level pinning between fullerenes and metals via surface charges.
A variation of almost 200 mV has been found for the first reduction potential of a series of highly soluble fullerene derivatives with varying acceptor strengths that were used as electron acceptors in plastic solar cells. This observation, which also relates the open circuit voltage to the acceptor strengths, is discussed within the concept of Fermi level pinning between fullerenes and metals. The Figure shows an azafulleroid that was used in this investigation.
With biologic drugs dominating the therapeutic space for severe immune‐mediated inflammatory disease, it is critical for clinicians to be familiar with the concept of drug immunogenicity, with the ...potential for our patients to develop antidrug antibodies (ADA) of clinical relevance. Whilst there are clear differences between different therapeutic biologics in terms of reported ADA rates, there is no accepted dermatology guideline or grouping of drugs by risk of clinically relevant ADA, nor a consensus on approach to ADA management. This is partly because making valid comparisons of immunogenicity across drugs is fundamentally flawed: the differing types of ADA assay, trial design and included patient population – as well as the molecular structure of the biologic molecules themselves – are all highly influential on reported ADA prevalence and impact on clinical response. Therefore, the first part of this article aims to give an overview of ADA that also clarifies common misconceptions on the subject, whilst the second part of this article outlines Phase III immunogenicity data on commonly used biologics for psoriasis, the most common dermatological indication. Based on this, and acknowledging current limitations in available evidence, we propose a working categorization of biologics together with a broad approach to management: Group 1 – biologics with higher risk of clinically relevant ADA; Group 2 – biologics with lower risk of clinically relevant ADA; and Group 3 – biologics with no established risk of clinically relevant ADA. However, these groupings represent a working concept only; more research is required, using comparable ADA assays and consistent reporting of related outcomes. Finally, there is an urgent need for better characterization of individuals at particular risk of developing ADA to inform future clinical decision‐making.
Two crystal structures of PCBM, obtained from different crystallisation solvents, are presented; a proposed link with solvent dependence of the efficiency of MDMO-PPV:PCBM solar cells is described.
Crystalline organization of a methanofullerene, 6,6‐phenyl C61 butyric acid methyl ester (PCBM), as achieved in various thin‐film deposition techniques, is reported. Mechanically stable, and thus ...self‐supporting, thin films obtained via fast solvent evaporation techniques are found to be composed of densely and homogeneously distributed PCBM nanocrystals with various crystallographic orientations, as shown schematically in the Figure.
COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, ...KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT.
In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection.
The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events.
This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT.
The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.
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