Many autoimmune diseases are characterized by B cells that mistakenly recognize autoantigens and produce antibodies toward self-proteins. Current therapies aim to suppress the immune system, which... Show moreMany autoimmune diseases are characterized by B cells that mistakenly recognize autoantigens and produce antibodies toward self-proteins. Current therapies aim to suppress the immune system, which is associated with adverse effects. An attractive and more specific approach is to target the autoreactive B cells selectively through their unique B-cell receptor (BCR) using an autoantigen coupled to an effector molecule able to modulate the B-cell activity. The cellular response upon antigen binding, such as receptor internalization, impacts the choice of effector molecule. In this study, we systematically investigated how a panel of well-defined mono-, di-, tetra-, and octavalent peptide antigens affects the binding, activation, and internalization of the BCR. To test our constructs, we used a B-cell line expressing a BCR against citrullinated antigens, the main autoimmune epitope in rheumatoid arthritis. We found that the dimeric antigen construct has superior targeting properties compared to those of its monomeric and multimeric counterparts, indicating that it can serve as a basis for future antigen-specific targeting studies for the treatment of RA. Show less
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin... Show moreImmune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (beta -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy. Show less
Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to... Show moreUnprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner. Show less
Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease that is hallmarked by fatigable muscle weakness of in particular the cranial and bulbar muscles. The... Show moreMuscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease that is hallmarked by fatigable muscle weakness of in particular the cranial and bulbar muscles. The disease is caused by auto-antibodies binding MuSK on the post-synaptic muscle membrane. MuSK orchestrates formation, differentiation and maintenance of neuromuscular synapses. The research outlined in this thesis aimed at identifying the pathomechanism of MuSK MG. In passive transfer studies with immune incompetent mice we showed that IgG4 subclass antibodies from these patients exclusively induced myasthenia. We furthermore showed that anti-MuSK IgG4 causes the disease by inhibiting MuSK-Lrp4 interaction which results in loss of acetylcholine receptor clustering and synaptic disassembly. Our retrospective longitudinal study in 53 patients from three different cohorts identified the N-terminal Ig-like domain of MuSK as the main immunogenic region of the protein and showed that titers against this domain correlate with disease severity. Epitope patterns did not correlate with sensitivity to acetylcholine esterase inhibitors. Lastly we observed that, next to MuSK MG, 12 other antibody-mediated autoimmune diseases are hallmarked by predominant involvement of IgG4 antibodies. As IgG4 antibody-mediated autoimmune diseases differ in several aspects from other autoimmune disease they might form a new niche in antibody-mediated autoimmune diseases Show less
Loeven, M.A.; Rops, A.L.; Lehtinen, M.J.; Kuppevelt, T.H. van; Daha, M.R.; Smith, R.J.; ... ; Vlag, J. van der 2016
