The Impact of the Bone Marrow Niche's Immune Privilege on Psoriatic Arthritis - Abstact: Psoriatic arthritis (PsA) is a chronic, inflammatory, and heterogeneous disease that affect various distinct anatomical sites; inclusive of the joints, skin, and bone marrow (BM). The etiology of PsA remains to be elucidated. The clinical and experimental evidence from our group and others, have firmly demonstrated that BM plays the crucial roles in the PsA pathogenesis. This R01 proposal investigates the roles of the hematopoietic stem cell (HSC) microenvironment within the BM, in this PsA pathogenesis. HSCs localize at the specialized, confined microenvironments within the BM, termed niches. The HSC niches have been extensively studied as sites that regulate stem cell fate or functions. Yet, immunological attributes of the niche have remained largely uninvestigated. It is further unknown whether any potential immunological properties of the HSC niches can impact systemic immunity or inflammatory diseases; inclusive of PsA. The overall hypothesis is that the HSC niche acts as an immunological sanctuary for stem cells, termed “immune-privileged sites”. This immune privilege of the HSC niche limits the generation of BM inflammatory myeloid cells and osteoclasts required for PsA development; whereas the breakdown of the immune privilege elicits the disease development. It was originally demonstrated in 1950s that the testis and placenta serve as immune privileged sites. While it had remained largely unclear whether somatic stem cell niches are broadly immunosuppressive, our recent studies have indicated BM HSCs are immune privileged. HSCs localize at potent FoxP3+ regulatory T cells (niche Tregs), rendering HSCs immune privileged. Our most recent manuscript (Nature) has further identified highly immune-privileged niches, amongst BM sites, composed of the distinctive endosteum capillaries near the epiphyseal line. These specialized capillaries are characterized by primary cilia; and molecular/phenotypic features of “sprouting” blood vessels. Such ciliated capillaries shield highly primitive HSCs, amongst other HSCs; as identified by high levels of nitric oxide (NO). The ciliated capillaries further accommodate unique niche Treg populations; that express high levels of HSC definitive genes. The capillaries maintain the abundance of these “stem cell-like Tregs”, enabling the robust immunoprotection of the NOHi HSCs. These studies have firmly identified: (A) novel stem cell-like Tregs; (B) ciliated, sprouting capillaries; and (C) highly primitive NOHi HSCs, as the three linked key players inducing high levels of immune privilege. Yet, little is known about whether the immune privilege and the above three specific cell populations (A-C), control the systemic immunity and whether dysfunction predisposes to PsA. This proposal addresses these questions using our previously-established approaches: (I) PsA induction using gene transfer; and (II) the targeted deletions in Tregs, HSCs, or vessels to disrupt the immune privilege. We will further develop new therapeutic approaches to transfer or modulate: stem cell-like Tregs; ciliated capillary cells and NOHi HSCs. Successful studies will create a new paradigm that the novel immune privilege of the stem cell niche controls systemic inflammation and PsA.
