Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 1; pp. 421 - 424.e11
• Main Authors: Hoshino, Akihiro, Yang, Xi, Tanita, Kay, Yoshida, Kenichi, Ono, Toshiaki, Nishida, Naonori, Okuno, Yusuke, Kanzaki, Takeyuki, Goi, Kumiko, Fujino, Hisanori, Ohshima, Koichi, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Miyano, Satoru, Ogawa, Seishi, Kojima, Seiji, Morio, Tomohiro, Kanegane, Hirokazu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019; Elsevier Limited
• Subjects: Antigens; Aplastic anemia; BZLF1 protein; Carboxyfluorescein diacetate; CD28 antigen; CD3 antigen; CD4 antigen; CD45 antigen; CD8 antigen; Cell activation; Cell proliferation; Cloning; Encephalitis; Exons; Flow cytometry; Graft-versus-host reaction; Immune reconstitution; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Interleukin 10; Interleukin 4; Lymphocytes; Lymphoma; Medical prognosis; Mutation; Patients; Peptides; R&D; Research & development; Sepsis; Vasculitis; Japan
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2018.07.044

[...]this family was diagnosed with XLP1. [...]intracellular IL-10 expression and inducible costimulator expression were preferentially observed in SAP+ CD4+ T cells from P25.3 and M25.1 (Fig 2, E and F), suggesting that this contributed to the patient's partially impaired humoral immunity.2 These findings are consistent with the observation of adequate cellular and humoral immune reconstitution in a patient with XLP1 after HSCT, despite 5% donor chimerism.4 The present study confirmed that the prognosis for patients with XLP1 treated with HSCT is good; the treatment of patients who cannot undergo HSCT because of an unavailability of donors or extremely severe XLP1 currently remain a challenge. Deep sequencing of the PCR products was also performed using a HiSeq 2000 platform (depth >20,000).Generation of EBV-specific T-cell lines PBMCs were pulsed for 60 minutes with overlapping oligopeptides, covering the sequence of the LMP2A, BZLF1, and EBNA1 protein (PepTivator, Miltenyi Biotec), and then cultured with IL-4 (1,000 U/mL, R&D Systems) and IL-7 (1000 U/mL, R&D Systems, Minneapolis, Minn) for 10 days.E6 To measure cell proliferation, PBMCs were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE, 3 μM, eBioscience, San Diego, Calif) for 5 minutes at room temperature before pulse with overlapping oligopeptides or stimulus with T-cell activation and expansion (TAE) beads (anti-CD3/CD28/CD2 mAb beads, Miltenyi Biotec). Patient SH2D1A mutation SAP expression Clinical presentation EBV status HSCT (age at HSCT) Outcome (age at death or presence) 1.1 ND ND Hypo-γ, LPD + – Died (12, posttransfusion GvHD) 1.2 D33Y ND Hypo-γ, LPD + + (7) Alive (28) 2.1 R55X ND FIM + – Died (3, FIM) 3.1 R55X ND FIM + – Died (2, FIM) 3.2 R55X ND FIM + – Died (2, FIM) 4.1 c.117C>T ND FIM + – Died (2, FIM) 4.2 c.117C>T Deficient Lymphoma, vasculitis, HLH – – Died (14, HLH) 5.1 del of whole gene ND FIM + – Died (1, FIM) 6.1 G27S ND FIM + – Died (1, FIM) 7.1 ND ND Hypo-γ, aplastic anemia + – Died (1, sepsis) 7.2 H8D Deficient Hypo-γ, vasculitis – + (24) Alive (36) 8.1 c.285delA, fs ND FIM + – Died (1, FIM) 9.1 R55X Deficient Hypo-γ + + (8) Alive (24) 9.2 R55X Deficient FIM + + (6) Died (6, sepsis) 10.1 G49V Deficient Lymphoma + + (4) Alive (21) 10.2 G49V Deficient Healthy – + (1) Alive (10) 11.1 del of exons 3, 4 ND FIM + – Died (1, FIM) 11.2. del of exons 3, 4 Deficient FIM + – Died (2, FIM) 11.3 del of exons 3, 4 Deficient Healthy – + (0.7) Alive (15) 12.1 S34G Deficient Hypo-γ, lymphoma + – Died (12, ML) 12.2 S34G Deficient Hypo-γ + – Alive (10) 13.1 Y7C Deficient FIM + – Died (23, FIM) 14.1 R55X Deficient Hypo-γ, ML + + (10) Alive (24) 15.1 H8D ND FIM + – Died (2, FIM) 16.1 c.246_247insA, fs Deficient Hypo-γ, HLH – + (11) Alive (23) 17.1 c.201+1G>A Deficient FIM + – Died (2, FIM) 17.2 c.201+1G>A Deficient ADEM – + (3) Alive (14) 18.1 c.13_14insG, fs Deficient Hypo-γ + + (7) Alive (17) 19.1 ND ND Hypo-γ + – Died (0.8, DIC) 19.2 ND ND FIM + – Died (1, sepsis) 19.3 del of exons 3, 4 Deficient Hypo-γ, HLH, lymphoma + + (15) Alive with leukoencephalopathy (25) 20.1 A3S Deficient FIM + – Died (42, FIM) 21.1 c.239_240insA, fs Deficient Encephalitis, LPD + – Died (3, encephalitis) 22.1 c.207_208insC, fs Deficient FIM + + (3) Alive (6) 22.2 c.207_208insC, fs Deficient Healthy – + (1) Alive (3) 23.1 c.208_209insC, fs Deficient Hypo-γ, HLH, lymphoma + + (19) Alive (21) 24.1 c.91_92insT, fs Deficient Hypo-γ, HLH, lymphoma + – Alive (11) 25.1 M1T Revertant (CD8+ T cells) Hypo-γ + – Alive (8) 25.2 M1T Revertant (CD8+ T cells) Hypo-γ + – Died (39, sepsis) 25.3 M1T Revertant (CD8+ and CD4+ T cells) IgG3 and IgG4 deficiency + – Alive (37) Table E1 Characteristics of patients with XLP1 Data P25.1 P25.2 P25.3 IgG (mg/dL) 390 (600-1500) 514∗ (639-1344) 924.3 (369-1344) IgG1 (mg/dL) ND ND 448 (422-1292) IgG2 (mg/dL) ND ND 564 (117-747) IgG3 (mg/dL) ND ND <5.0 (41-129) IgG4 (mg/dL) ND ND <3.0 (10-67) IgA (mg/dL) 45.3 (50-150) 5 (70-312) 82.5 (70-312) IgM (mg/dL) 24.6 (22-100) 28.2 (56-352) 178.3 (56-352) Table E2 Laboratory data from the patients Method P25.1 P25.2 P25.3 SAP+ cells/CD8+ CD45RO+ T cells by flow cytometry 15.4% (5.5/35.7) 6.4% (3.1/48.2) 9.4% (6.3/66.7) Wild sequences after TA cloning 8.9% (4/45) 4.4% (2/45) 10.6% (5/47) Wild sequences in deep sequencing 4.3% (949/22,238) 4.7% (1,036/22,274) 14.3% (4,866/34,103) Table E3 Frequencies of SAP+ cells and wild sequences in CD8+ CD45+ T cells