Occurrence of nodular lymphocyte-predominant hodgkin lymphoma in hermansky-pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects

Luisa Lorenzi; Giovanna Tabellini; William Vermi; Daniele Moratto; Fulvio Porta; Lucia D Notarangelo; Ornella Patrizi; Silvano Sozzani; Genevieve de Saint Basile; Sylvain Latour; David Pace; Silvia Lonardi; Fabio Facchetti; Raffaele Badolato; Silvia Parolini

doi:10.1371/journal.pone.0080131

Occurrence of nodular lymphocyte-predominant hodgkin lymphoma in hermansky-pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects

PLoS One. 2013 Nov 26;8(11):e80131. doi: 10.1371/journal.pone.0080131. eCollection 2013.

Authors

Luisa Lorenzi¹, Giovanna Tabellini, William Vermi, Daniele Moratto, Fulvio Porta, Lucia D Notarangelo, Ornella Patrizi, Silvano Sozzani, Genevieve de Saint Basile, Sylvain Latour, David Pace, Silvia Lonardi, Fabio Facchetti, Raffaele Badolato, Silvia Parolini

Affiliation

¹ Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Brescia, Italy.

Abstract

Hermansky Pudlak type 2 syndrome (HPS2) is a rare autosomal recessive primary immune deficiency caused by mutations on β3A gene (AP3B1 gene). The defect results in the impairment of the adaptor protein 3 (AP-3) complex, responsible for protein sorting to secretory lysosomes leading to oculo-cutaneous albinism, bleeding disorders and immunodeficiency. We have studied peripheral blood and lymph node biopsies from two siblings affected by HPS2. Lymph node histology showed a nodular lymphocyte predominance type Hodgkin lymphoma (NLPHL) in both HPS2 siblings. By immunohistochemistry, CD8 T-cells from HPS2 NLPHL contained an increased amount of perforin (Prf) + suggesting a defect in the release of this granules-associated protein. By analyzing peripheral blood immune cells we found a significant reduction of circulating NKT cells and of CD56(bright)CD16(-) Natural Killer (NK) cells subset. Functionally, NK cells were defective in their cytotoxic activity against tumor cell lines including Hodgkin Lymphoma as well as in IFN-γ production. This defect was associated with increased baseline level of CD107a and CD63 at the surface level of unstimulated and IL-2-activated NK cells. In summary, these results suggest that a combined and profound defect of innate and adaptive effector cells might explain the susceptibility to infections and lymphoma in these HPS2 patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Biopsy
CD56 Antigen / metabolism
Child
Child, Preschool
Cytotoxicity, Immunologic
Female
Hermanski-Pudlak Syndrome / complications*
Hermanski-Pudlak Syndrome / diagnosis
Hermanski-Pudlak Syndrome / immunology*
Hodgkin Disease / complications*
Hodgkin Disease / diagnosis
Hodgkin Disease / immunology*
Humans
Immunohistochemistry
Immunophenotyping
Interferon-gamma / biosynthesis
Killer Cells, Natural / immunology*
Killer Cells, Natural / metabolism
Lymph Nodes / pathology
Lymphocyte Count
Lymphocyte Subsets / immunology
Lymphocyte Subsets / metabolism
Lysosomal-Associated Membrane Protein 1 / metabolism
Male
Middle Aged
Natural Killer T-Cells / immunology*
Natural Killer T-Cells / metabolism
Phenotype
Siblings
Tetraspanin 30 / metabolism
Young Adult

Substances

CD56 Antigen
Lysosomal-Associated Membrane Protein 1
Tetraspanin 30
Interferon-gamma

Supplementary concepts

Hermansky Pudlak syndrome 2

Grants and funding

This work was funded by EU Grant FP7 (HLH-cure) and Ministero dell'Istruzione dell'Università e della Ricerca (PRIN 2009) to RB. WV is supported by Ministero dell'Istruzione dell'Università e della Ricerca (PRIN 2009 CKARAL_002). FF is supported by Ministero dell'Istruzione dell'Università e della Ricerca (PRIN 2008 B5CN7S_005). SP and GT are supported by Ministero dell'Istruzione dell'Università e della Ricerca (PRIN 2008 PTB3HC_002) and by Centro di Studio e Ricerca “Quality and Technology Assessment, Governance and Communication Strategies in Health Systems.” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.