The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

Abstract

Key Points Hermansky-Pudlak syndrome type 2 confers a moderate risk for hemophagocytic lymphohistiocytosis.

Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells

“…[2][3][4][5][6][7][8][9][10] In this context, prf 2/2 mice develop a striking increase of CD8 1 and CD4 1 T-cell activation, associated with increased antigen presentation by as yet undefined cells. 5 While the possibility of negative feedback from cytotoxic lymphocytes (both T and natural killer [NK]) to antigen-presenting cells (APCs) has been recognized for many years, 11,12 the details of this putative immune regulatory loop remain undefined or in dispute.…”

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

“…The cytotoxicity defect is linked to a risk of developing hemophagocytic lymphohistiocytosis (HLH) mainly in CHS, GS2, and HPS2. [2][3][4] Chronic neutropenia is characteristic in HPS2 5 and late endosomal/ lysosomal adaptor, MAPK and MTOR activator 2 deficiency, 6 whereas it is usually transient in CHS and GS2. Apart from immunodeficiency, albinism syndromes can also present with other systemic manifestations, including bleeding as a result of a storage pool disorder (HPS2, CHS) 7 and progressive lung fibrosis (HPS2) 8 as well as neurologic disorders (CHS, GS2).…”

“…Overall, the impaired degranulation response of lymphocytes in our patient was similar to that of patients with HPS2. 2,29 It was most evident in fresh NK cells, in which the response was very low and was indistinguishable from that of patients with familial HLH, GS2, or CHS. 25,44 However, in contrast to these conditions and similar to our observations in HPS2, the response of PHA/IL-2-stimulated cytotoxic T lymphocytes was less markedly impaired.…”

“…The resulting infection susceptibility is at least in part favored by a defect in neutrophil development and, as in HPS2, probably also by functional defects in other immune cell populations. 47 This includes an impaired degranulation and cytotoxicity of lymphocytes 2,25,48 and could also imply impaired dendritic cell function, as demonstrated in a mouse model of HPS2. 49 We previously showed that HPS2 patients carry a small but relevant risk of developing HLH.…”

Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency

“…All HPS2 patients described to date are homozygous or compound heterozygous for mutations in the AP3B1 gene, resulting in the complete absence of beta3A expression. [1][2][3][4] HPS2 patients display recurrent viral and bacterial infections due to defects of cytotoxic T cells, natural killer cells, 5,6 and CD1-dependent antigen presentation. 7,8 Neutrophils are also involved, but neutropenia that is observed in all HPS2 patients is usually responsive to granulocyte colony-stimulating factor (CSF) treatment, suggesting that the neutrophil abnormalities do not account for the susceptibility to infections.…”