Recurrent inflammatory disease caused by a heterozygous mutation in CD48

• Published in: Journal of allergy and clinical immunology 2019-11, Vol.144 (5), p.1441-1445.e17
• Main Authors: Volkmer, Benjamin, Planas, Raquel, Gossweiler, Emanuel, Lünemann, Anna, Opitz, Lennart, Mauracher, Andrea, Nüesch, Ursina, Gayden, Tenzin, Kaiser, Daniela, Drexel, Barbara, Dumrese, Claudia, Jabado, Nada, Vavassori, Stefano, Pachlopnik Schmid, Jana
• Format: Article
• Language: English
• Subjects: Arthritis; Assaying; Autografts; Bone marrow; CD48 antigen; Cell lines; Criteria; Cytokines; Cytotoxicity; Degranulation; Disease; Edema; Families & family life; Family medical history; Fever; Gene expression; Hypertriglyceridemia; Inflammatory diseases; Lymphatic system; Lymphocytes; Mutation; Myalgia; Natural killer cells; Pain; Plasmids; Proteins; Splenomegaly; Stimulation; Target masking; Tumor necrosis factor; Tumor necrosis factor receptors
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.07.038

Importantly, we could not identify an infectious trigger; in particular, results of PCR assays for EBV in blood samples were repeatedly negative. Because the patient met the criteria for HLH (ie, fever, splenomegaly, bicytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow hemophagocytosis),7 we considered (and ruled out) known forms of hereditary HLH by running functional assays and genetic tests (see Fig E2 and Table E3 in this article's Online Repository at www.jacionline.org). Degranulation of NK cells of a healthy donor was lower on stimulation with autologous B-LCL cells preincubated with inhibitory anti-CD48 antibody than on stimulation with autologous B-LCL cells preincubated with isotype control antibody or without any prior addition of antibodies (Fig 2, H). [...]NK cell degranulation was decreased by masking CD48 on autologous target cells, showing that the amount of CD48 on target cells regulates susceptibility to cytotoxicity. To further evaluate the effect of CD48S220Yhet mutation, we performed a killing assay with CD48S220Yhet HEK 293 cell lines transfected with plasmids encoding CD48-WT or CD48S220Yhet as targets and the NK92 cell line as killers and observed that the CD48-WT plasmid-expressing cells were killed more efficiently (Fig 2, I). [...]CD48S220Yhet increases target cell resistance to cell-mediated cytotoxicity. None of the clinical criteria for TNF receptor–associated periodic fever syndromes (periorbital edema, episode duration >6 days, migratory rash with centrifugal migration, myalgia, and/or affected relatives) were met. [...]the TNF receptor–associated periodic fever syndrome criteria were not included in Table E3.