CD4 T cell–restricted IL-2 signaling defect in a patient with a novel IFNGR1 deficiency

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 1; pp. 435 - 439.e7
• Main Authors: Khanolkar, Aaruni, Kirschmann, Dawn A., Caparelli, Edward A., Wilks, Jeffrey D., Cerullo, Jillian M., Bergerson, Jenna R.E., Jennings, Lawrence J., Fuleihan, Ramsay L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2018; Elsevier Limited
• Subjects: Age; Biomarkers; Candida; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Female; Genetic Association Studies; Genetic Predisposition to Disease; Herpes viruses; Humans; Immunophenotyping; Infant; Interferon gamma Receptor; Interleukin 2; Interleukin-2 - metabolism; Kinases; Lymphatic system; Lymphocyte Count; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Lymphocytes; Phenotype; Phosphorylation; Receptors, Interferon - deficiency; Sequence Analysis, DNA; Signal Transduction; Tetanus; Tuberculosis; Viral infections
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.08.018

The clinical findings coupled with a normal dihydrorhodamine test result (Table I), a negative family history of tuberculosis, or frequent and serious infections raised suspicion of a potential defect in the IFN-γ-IL-12 signaling axis.1-5 Hence treatment with Actimmune (IFN-γ-1b; Horizon Pharma, Lake Forest, Ill) was initiated at the time of initial referral (26 μg administered subcutaneously 3 times a week) and discontinued when the patient had the migratory arthralgias described above (a known side effect of Actimmune treatment)6 that were accompanied by increased WBC counts and serum IFN-γ levels (see Table E1). Flow cytometric analysis of lymphocyte subsets T cells, B cells, natural killer cells, T-cell subsets, and B-cell subsets were identified and quantified by using lineage-directed fluorochrome-conjugated mAbs, as described previously.E1-E3 Phosflow analyses of STAT proteins and intracellular cytokine staining were performed by using established protocols.E4-E6 Numeric values in histograms depict background-adjusted frequencies of gated cells expressing the indicated markers, and background-adjusted MFI values, wherever reported, are indicated in parentheses below the frequency values. DHR assay (neutrophil oxidative burst index values) Patient Healthy control subject Normal cutoff 708 620 >=30 Absolute counts/μL of blood Lymphocyte subset Patient (1.7 years old) Normal range (age, >0.92 and <1.9 y)∗ CD3+ 3433 2207-8192 (CD3+)CD8+ 714 750-3749 (CD3+)CD4+ 2658 1089-4552 (CD3−)CD16+CD56+ 109 182-1581 (CD3−)CD19+ 1231 704-2711 % (of lymphocytes) CD3(+)HLA-DR+ 27 4-8 T-cell subsets (% of CD4+ or CD8+ T cells) Patient (2.75 y) Normal range (1-3 y)∗ Naive CD4+ T cells 75 47-90 Recent thymic emigrants 72 35-75 CD4+ effector cells 0.1 0.1-0.8 Effector memory CD4+ T cells 2.7 0.7-10.7 Central memory CD4+ T cells 9.6 3.2-22.3 Naive CD8+ T cells 55.7 38.5-90.3 Effector memory CD8+ T cells 7.0 0.8-12.4 Central memory CD8+ T cells 1.4 0.1-1.2 TemRA CD8+ T cells 10.1 2.6-32.2 B-cell subsets (% of CD19+ B cells) Naive B cells 75 82-97 Isotype-unswitched memory B cells 12 1-8 Isotype-switched memory B cells 11 0.2-6.7 CD27− memory B cells 2.4 0.8-6.2 Plasmablasts 0.2 0.1-2.0 CD21+CD10+ transitional B cells† 0.7 0.0-3.4 CD21+CD10− transitional B cells† 13.1 4.3-26 CD21−CD10+ transitional B cells† 0.01 0.0-0.1 CD21−CD10− transitional B cells† 0.02 0.0-0.3 Tritiated thymidine incorporation assay (stimulation index) Antigen Patient (1.7 y) Healthy control subject Normal range Candida species (10 μg/mL) 5.0 60.0 >40.0 Candida species (5 μg/mL) 7.0 38.2 >33.0 Candida species (1.25 μg/mL) 2.4 25.0 >18.0 Tetanus (0.2 Lfu/mL) 1.4 161.8 >13.0 Tetanus (0.1 Lfu/mL) 0.5 198.7 >5.0 Tetanus (0.05 Lfu/mL) 1.1 191.5 >5.0 Table E1 Serology and mitogen-induced lymphocyte proliferation assay results ConA, Concanavalin A; PHA, phytohemagglutinin; PWM, pokeweed mitogen. Serum immunoglobulin levels Patient value Patient age Age-appropriate normal range IgM 257 mg/dL 3.6 y∗ 45-190 mg/dL IgM 158 mg/dL 4.6 y 41-186 mg/dL IgG 1590 mg/dL 3.6 y∗ 423-1090 mg/dL IgG 982 mg/dL 4.6 y 445-1187 mg/dL IgA 247 mg/dL 3.6 y∗ 22-157 mg/dL IgA 120 mg/dL 4.6 y 25-153 mg/dL IgE 126 KU/L 3.6 y∗ <72 KU/L IgE 69.8 KU/L 4.6 y <90 KU/L Egg white-specific IgE 10.60 kUa/L 1.7 y <0.35 kUa/L Egg white-specific IgE 3.29 kUa/L 2.8 y <0.35 kUa/L Egg white-specific IgE 0.58 kUa/L 4.6 y <0.35 kUa/L Cut-off for positivity Varicella-zoster virus-specific IgG 1.25 ISR 4.8 y >=1.10 ISR† Tetanus toxoid-specific IgG 0.34 IU/mL 4.8 y >0.15 IU/mL Serum IFN-γ levels Patient age Patient result (pg/mL) Normal range (pg/mL) 3.6 y∗ >400 <2.0 4.1 y 15.5 <2.0 4.6 y 14.3 <2.0 Tritiated thymidine incorporation assay (stimulation index) Mitogen Patient (1.7 years old) Healthy control subject Normal range PHA (10 μg/mL) 515 1440 >94.0 PHA (1.25 μg/mL) 111 730 >21.7 PWM (15.62 μg/mL) 535 112 >10.5 PWM (0.78 μg/mL) 138 135 >8.0 ConA (100 μg/mL) 232 646 >8.6 ConA (50 μg/mL) 226 1067 >75.7 ConA (12.5 μg/mL) 62 419 >25.6 1 S. 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