PMC:4419340 / 4346-11527 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4419340","sourcedb":"PMC","sourceid":"4419340","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4419340","text":"Clinical reports\nThe experiments described here were conducted in accordance with French regulations and were approved by the French Ministry of Research (IE-2010-547), the French Ethics committee (ID-RCB 2010-A00636-33), and ANSM (French National Agency for Medicines and Health Products Safety; B100712-40). Informed consent was obtained from all patients or their families, in the case of minors, in accordance with the World Medical Association, the Helsinki Declaration, and EU directives.\nThe index patient of kindred A (P1, kindred A.II.5, Fig. 1 A) is a 37-yr-old woman of Argentinean origin, living in Argentina, with no known parental consanguinity. The calculated homozygosity rate for P1 was 0.008 (not depicted; Purcell et al., 2007), providing further support for the notion that P1 was not from closely related parents. However, the mutation was located in a homozygous region of 7.1 Mb, which may be consistent with a cryptic consanguinity. Since the age of 4 yr, P1 has suffered from chronic intertrigo and pustules on her face, but with a normal scalp, nails, teeth, and sweating. She also developed recurrent oral (P1, kindred A.II.5, Fig. 1 C) and esophageal thrush. She had never suffered from any severe bacterial (staphylococcal, in particular), viral, or other fungal infection. P1 was treated with oral fluconazole. The response to treatment was good, with no drug resistance, but relapses occurred when treatment was stopped. Laboratory investigations showed normal immunophenotype (T, B, and NK). The T cell proliferations in response to phytohemagglutinin and antigens (tuberculin, candidin, and anatoxin) were normal. No endocrine, metabolic, or autoimmune abnormalities were reported. In particular, the patient did not display anti-DNA, antinuclear, or antithyroglobulin antibodies and had normal TSH levels. P1 had normal proportions of circulating IL-17A–, IL-17F–, IL-22–producing CD3+ and CD4+ T cells (Fig. 2, A–C) and displayed normal IL-17A production by freshly prepared leukocytes (Fig. 3 A). None of her sisters, parents, or sons had any particular relevant clinical history.\nFigure 1. Three kindreds with AR IL-17RC deficiency. (A) Pedigrees and familial segregation of the identified IL-17RC nonsense mutations. The proband is indicated in black and by an arrow. I, II, and III indicate the generations. E? indicates individuals whose genetic status could not be evaluated. (B) Schematic diagram of the IL-17RC protein, showing the signal sequence (SS), extracellular (EC), transmembrane (TM), intracellular (IC), and SEFIR (expression similar to fibroblast growth factor IL-17R) domains and the exons and amino acids affected by the mutations. (C) Recurrent thrush on tongue of P1 (kindred A.II.5) and P3 (kindred C.II.1).\nFigure 2. Normal ex vivo development and in vitro differentiation of IL-17– and IL-22–producing T cells from P1. (A–C) Each symbol represents a value from a healthy control individual (black circles), a heterozygous (WT/Q138*) relative of P1 (black triangles), and P1 (black squares). Horizontal bars represent means. (A and B) Percentages are shown of CD3+/IL-17A+, CD3+/IL-17F+, CD3+/IL-22+, and CD3+/IFN-γ+ (A) and CD4+/IL-17A+, CD4+/IL-17F+, and CD4+/IL-22+ (B) cells, as determined by flow cytometry, among nonadherent PBMCs activated by incubation for 12 h with PMA and ionomycin. (C) Percentages are shown of IL-17A+, IL-22+, and IFN-γ+ T cell blasts after in vitro expansion in the presence of anti-CD3 antibody, IL-2, IL-1β, and IL-23 for 5 d, followed by 12 h of stimulation with PMA and ionomycin. The experiments were repeated at least three times.\nFigure 3. Normal secretion of IL-17A and IL-22 by whole blood cells from patients. (A–E) IL-17A (A–C) and IL-22 (D and E) secretion was determined by ELISA, in the absence of stimulation (open symbols) and after stimulation with PMA and ionomycin for 24 h (closed symbols). Horizontal bars represent medians. Each symbol represents a value from healthy control individuals (circles), heterozygous patients’ relatives (triangles), or patients (squares). The experiments were repeated at least three times. The index patient of kindred B (P2, kindred B.II.1, Fig. 1 A) is a 12-yr-old boy born to Turkish parents, with no known parental consanguinity. The calculated homozygosity rate of P2 was 0.021 (not depicted), consistent with P2 originating from a family without close consanguinity. P2 has suffered from CMC since the age of 2 mo, with chronic intertrigo, aphthous stomatitis, oral thrush, and onychomycosis, but with no reported severe bacterial (staphylococcal in particular), viral, or other fungal infections. CMC was long lasting in this patient. It was treated with courses of oral and i.v. fluconazole and local nystatin, and a response to treatment was observed, but with relapse after treatment cessation. Routine laboratory investigations showed that lymphocyte counts were normal and serum IgG, IgA, IgM, and IgE levels were within the normal ranges. Thyroid function, as evaluated by determining TSH (2.4 IU/l) and T4 (1.19 ng/dl) levels, was normal. Normal levels of IL-17A and IL-22 were produced after ex vivo stimulation with PMA and ionomycin by freshly prepared leukocytes of P2 and other members of his family (Fig. 3, B and D). No endocrine, metabolic, or autoimmune abnormalities were reported. Neither the parents nor the siblings of this patient have ever suffered from severe infections.\nThe index patient of kindred C (P3, kindred C.II.1, Fig. 1 A) is an 8-yr-old boy from a third-degree consanguineous Turkish family. This information is consistent with the homozygosity rate of 0.039 obtained for this patient (not depicted). P3 displayed persistent oral candidiasis, with white plaques all over the buccal mucosa and dorsal surface of the tongue since early infancy (P3, kindred C.II.1, Fig. 1 C) and pustules on the skin and scalp. P3 had no history of any other significant infectious (bacterial, staphylococcal in particular, viral, or other fungal) disease or significant developmental defects, with normal hair, nails, teeth, and sweating. Leukocyte counts and absolute neutrophil and lymphocyte counts were normal. Serum IgG, IgA, and IgM levels were normal. No autoimmune antibodies, such as antinuclear, antiperoxisomal (anti-TPO and anti-TG), and antiparietal antibodies, were detected in the serum. Peripheral blood lymphocyte subsets were within the normal range. In vitro T cell proliferation tests showed that the percentages of CD3+CD25+ (66%; normal 43–97%) and CD3+CD69+ (68%; normal 45–100%) cells were within the normal ranges after stimulation with phytohemagglutinin. Normal levels of IL-17A and IL-22 secretion by freshly prepared leukocytes after ex vivo stimulation with PMA and ionomycin were observed for P3 and other members of his family (Fig. 3, C and E). No endocrine or metabolic abnormalities were found. Systemic antifungal therapy with oral fluconazole was initiated and moniliasis resolved. However, oral moniliasis recurred and persisted for some time after the cessation of treatment. Neither the parents nor the siblings of P3 had ever suffered from a severe infectious disease.","divisions":[{"label":"Title","span":{"begin":0,"end":16}},{"label":"Figure caption","span":{"begin":2117,"end":2769}},{"label":"Figure caption","span":{"begin":2768,"end":3631}},{"label":"Figure caption","span":{"begin":3630,"end":4137}}],"tracks":[{"project":"2_test","denotations":[{"id":"25918342-17701901-59633017","span":{"begin":741,"end":745},"obj":"17701901"}],"attributes":[{"subj":"25918342-17701901-59633017","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93eccc","default":true}]}]}}