Production and glyco-engineering of immunomodulatory helminth glycoproteins in plants

Host-parasite interactio

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI’s major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change

Immune modulation by schistosomes: mechanisms of regulatory B cell induction and inhibition of allergic asthma

Parasitic helminths modulate host immune responses. While the induction of type 2 immune responses is a widely recognized feature of helminth infections, a network of regulatory immune responses is often dominant during the chronic phase of infection. Suppression of the host immune system during helminth infections inhibits anti-parasite immunity, prevents tissue damage due to excessive inflammation and conveys spill-over suppression to inflammatory conditions such as allergy and asthma. The first part of this thesis focuses on the role of regulatory B cells, a prominent member of the immune regulatory network, in protection from allergic asthma by chronic Schistosoma (S.) mansoni infections. It furthermore identifies signals required for schistosome-induced regulatory B cell development. The second part of this thesis describes the protective effect of S. mansoni eggs, and a specific egg-derived glycoprotein, against allergic asthma in the absence of chronic infection. A better understanding how helminthes including S. mansoni modulate host immune responses, and the implications this has for inflammatory diseases such as allergic asthma, may provide valuable leads for the development of novel pharmaceutical agents for the treatment of allergic disorders.</p

Microorganism-induced suppression of allergic airway disease: novel therapies on the horizon?

Pathogenesis and treatment of chronic pulmonary disease

Exome sequencing identifies compound heterozygous mutations in <em>C12orf57</em> in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures.

In patients with genetically heterogeneous disorders such as intellectual disability or epilepsy, exome sequencing is a powerful tool to elucidate the underlying genetic cause. Homozygous and compound heterozygous mutations in C12orf57 have recently been described to cause an autosomal recessive syndromic form of intellectual disability, including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures. Here, we report on two siblings from nonconsanguineous parents harboring two compound heterozygous loss-of-function mutations in C12orf57 identified by exome sequencing, including a novel nonsense mutation, and review the patients described in the literature

Schistosome-induced pulmonary B cells inhibit allergic airway inflammation and display a reduced Th2-driving function.

Chronic schistosome infections protect against allergic airway inflammation (AAI) via the induction of IL-10-producing splenic regulatory B (Breg) cells. Previous experiments have demonstrated that schistosome-induced pulmonary B cells can also reduce AAI, but act independently of IL-10. We have now further characterized the phenotype and inhibitory activity of these protective pulmonary B cells. We excluded a role for regulatory T (Treg) cell induction as putative AAI-protective mechanisms. Schistosome-induced B cells showed increased CD86 expression and reduced cytokine expression in response to Toll-like receptor (TLR) ligands compared with control B cells. To investigate the consequences for T cell activation we cultured ovalbumin (OVA)-pulsed, schistosome-induced B cells with OVA-specific transgenic T cells and observed less Th2 cytokine expression and T cell proliferation compared with control conditions. This suppressive effect was preserved even under optimal T cell stimulation by anti-CD3/28. Blocking of the inhibitory cytokines IL-10 or TGF-β only marginally restored Th2 cytokine induction. These data suggest that schistosome-induced pulmonary B cells are impaired in their capacity to produce cytokines to TLR ligands and to induce Th2 cytokine responses independent of their antigen-presenting function. These findings underline the presence of distinct B cell subsets with different stimulatory or inhibitory properties even if induced by the same type of helminth