Bardet-Biedl Syndrome (BBS) is a pleiotropic genetic disease caused by the dysfunction of primary cilia. The immune system of patients with ciliopathies has not been investigated. However, there are multiple indications that the impairment of the processes typically associated with cilia may have influence on the hematopoietic compartment and immunity. In this study, we analyze clinical data of BBS patients and corresponding mouse models carrying mutations in Bbs4 or Bbs18. We find that BBS patients have a higher prevalence of certain autoimmune diseases. Both BBS patients and animal models have altered red blood cell and platelet compartments, as well as elevated white blood cell levels. Some of the hematopoietic system alterations are associated with BBS-induced obesity. Moreover, we observe that the development and homeostasis of B cells in mice is regulated by the transport complex BBSome, whose dysfunction is a common cause of BBS. The BBSome limits canonical WNT signaling and increases CXCL12 levels in bone marrow stromal cells. Taken together, our study reveals a connection between a ciliopathy and dysregulated immune and hematopoietic systems.

Czech Centre for Phenogenomics Division BIOCEV Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Faculty of Science Charles University Prague Czech Republic

Genetics and Genomic Medicine Programme University College London Great Ormond Street Institute of Child Health London UK

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Germ Cell Development Division BIOCEV Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Transgenic Models of Diseases Division BIOCEV Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

National Bardet Biedl Syndrome Service Department of Clinical Genetics Great Ormond Street Hospital London UK

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