Modulation of B effector cells and regulatory B cells by iNKT cells in systemic sclerosis patients

• Applicant: Professor Dr. Dominik Schneidawind
• Subject Area: Rheumatology ; Clinical Immunology and Allergology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 453517594

Systemic sclerosis (SSc) is an autoimmune disease characterized by inflammation and consecutive fibrosis of the skin and internal organs. Therapeutic options, prognosis and quality of life are limited. Dysregulated B-cell responses and production of auto-antibodies are a pathogenetic hallmark of this disease. Invariant natural killer T (iNKT) cells are potent immunoregulatory T lymphocytes that promote immune tolerance after allogeneic hematopoietic cell transplantation (HCT). Our group has published recently that iNKT cells are reduced and show a functional deficit in SSc patients. Moreover, we could show that iNKT cells inhibit IL-6 release from effector B cells while promoting Breg function in SSc patients.With this research proposal we aim to further study the crosstalk of iNKT cells and B cells from SSc patients. First, we intend to increase our SSc biobank focusing on patients that are treated with cyclophosphamide, B cell-depleting rituximab and autologous HCT. We will then study the impact of these different therapeutic concepts on iNKT cell numbers, subsets and function as well as T helper cells and B cells. We assume that successful treatment leads to an increase of iNKT cells and a shift of B effector cells towards regulatory B cells resulting in decreased fibrosis and disease manifestations. We will correlate our experimental data with clinical outcomes.Next, we will study the cellular and humoral interactions between iNKT cells and SSc-B cells. We hypothesize that iNKT cells are activated by SSc-B cells in a contact-dependent manner through CD1d signaling. Consequently, IL-21 release by iNKT cells might modulate B-cell function and phenotype. We will use RNA sequencing, transwell assays and monoclonal blocking antibodies to dissect this complex cellular crosstalk.Gaining further mechanistic insight into the role of iNKT cells for the pathogenesis of SSc is a pivotal prerequisite to use iNKT cells as a novel cytotherapeutic to treat SSc patients.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Co-Investigator: Professor Dr. Jörg Henes