Bardet-Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self-tolerance.

Oksana Tsyklauri,Jan Prochazka,Martina Huranova,Petr Kasparek,Ondrej Stepanek,Ales Drobek,Kathryn Sparks,Elizabeth Forsythe,Radislav Sedlacek,Avishek Prasai,Philip Beales,Zdenek Trachtulec,Veronika Niederlova

doi:10.15252/embr.202050785

Abstract

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.

Highlights

Bardet-Biedl Syndrome (BBS) is a recessive genetic disorder caused by complete or partial loss-of-function mutations in any of more than 20 BBS genes known to date
We studied the potential role of the BBSome in the immune system
These findings suggested that the BBSome has an intrinsic or extrinsic role in the immune system, in the immune tolerance

Summary

Introduction

Bardet-Biedl Syndrome (BBS) is a recessive genetic disorder caused by complete or partial loss-of-function mutations in any of more than 20 BBS genes known to date. BBS belongs to a group of ciliopathies, i.e., disorders caused by defective formation and/or function of primary cilia. Other commonly mutated BBS genes (ARL6/BBS3, MKKS/BBS6, BBS10, and BBS12) assist the BBSome assembly or function [1, 5]. The immune system of patients with ciliopathies including BBS has not been studied in detail. The possible connection between ciliopathies and the immune system has not been addressed most likely because immune cells do not form primary cilia [10, 11]. There are several lines of evidence suggesting that the BBS might affect the function of the immune system

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Conclusion