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Shaun Jackson MD, PhD

Assistant Professor of Pediatrics

Seattle Children’s Hospital

Immunology

http://www.seattlechildrens.org/medical-staff/shaun-w-jackson/

B cell-Intrinsic Cytokine Reg of Spontaneous Germinal CTR Formation in SLE

B cells usually protect us from bacteria and viruses, but in lupus they release proteins, known as antibodies, that target patients’ own cells. Researchers don’t know which immune system molecules spur B cells to start making these destructive antibodies. In their study, they will use mice to test whether specific immune system molecules, called cytokines, activate B cells to promote production of these antibodies. By identifying the specific signals that trigger B cells to attack patients’ own cells, they hope to provide clues that will allow researchers to develop new, targeted lupus treatments.

 

What this study means to people with lupus

In lupus, B cells release proteins that damage patients’ own tissues. Dr. Jackson and his colleagues are taking a fresh look at B cells, zeroing in on two recently identified molecules that may act as signals to promote immune attacks. Identifying the specific signals responsible for activating B cells and producing dangerous autoantibodies will inform development of potential targeted lupus treatments.

 

Recent studies have demonstrated that spontaneous, autoimmune germinal centers (GCs) are an important source for autoantibody-producing B cells. In this context, we developed a chimeric model of murine lupus (“WAS chimera model”), which has allowed efficient testing of the B cell-intrinsic signals required for dysregulated GC formation. Using this strategy, we recently demonstrated that B cells directly initiate autoreactive T cell activation via MHC Class II-dependent antigen presentation, resulting in expansion of IFN-gamma-producing TH1 cells which promote B cell activation and GC formation via the IFN-gamma receptor (Jackson SW, et al. J Exp Med, 2016). In the current proposal, we will first examine whether B cell-derived IL-6, a pro-inflammatory cytokine implicated in GC formation, is required for systemic autoimmunity. Next, we will test whether the TH1-associated cytokine IL-12 exerts cell-intrinsic impacts on spontaneous GC formation and autoantibody production in SLE. Finally, a single-nucleotide polymorphism (SNP) in Tyrosine kinase 2 (TYK2P1104A), downstream of several cytokine receptors including IL-12, protects against the development of human SLE. To study how this SNP impacts lupus pathogenesis, we generated a murine knock-in of the protective human TYK2 allele, and will use this novel strain to test the cell-intrinsic impacts of variant TYK2 in autoimmune pathogenesis.

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