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A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS - Nat. Genet. (2015)

Bottom Line: The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface.We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia.These findings demonstrate the importance of TfR1 in adaptive immunity.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.

ABSTRACT
Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

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Correction of lymphocyte defects in Patients A1–3 with iron citrateEffect of addition of iron citrate on: (a) T cell proliferation to three stimuli, (b) B cell proliferation and IgE synthesis to anti-CD40+IL-4, and (c) molecular events in IgE isotype switching. Bars represent means ± SEM from three independent experiments; *P<0.05, ***P<0.001.
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Figure 3: Correction of lymphocyte defects in Patients A1–3 with iron citrateEffect of addition of iron citrate on: (a) T cell proliferation to three stimuli, (b) B cell proliferation and IgE synthesis to anti-CD40+IL-4, and (c) molecular events in IgE isotype switching. Bars represent means ± SEM from three independent experiments; *P<0.05, ***P<0.001.

Mentions: Ligation of CD40 on B cells by CD40 ligand expressed on activated T cells in the presence of IL-4 causes proliferation-dependent immunoglobulin class-switch recombination from IgM to IgG and IgE, reflective of high-affinity, protective antibody production2. Proliferation and secretion of IgG and IgE in response to anti-CD40+IL-4 were significantly decreased in patients’ PBMCs (Fig. 1b). IgE switching requires expression of Iε-Cε germline transcripts, which are early products of class-switch recombination, and activation-induced cytidine deaminase (AICDA), which initiates deletional switch recombination followed by expression of mature Iμ-Cε transcripts3. The patients had normal expression of immature Iε-Cε germline transcripts and AICDA mRNA in their B cells, but undetectable mature Iμ-Cε transcripts (Fig. 1c and Fig. 3c). Collectively, these data demonstrate impaired T cell proliferation as well as defective B cell proliferation and class switching, which in combination constitute the mechanism underlying the susceptibility to severe infections characteristic of CID1.


A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS - Nat. Genet. (2015)

Correction of lymphocyte defects in Patients A1–3 with iron citrateEffect of addition of iron citrate on: (a) T cell proliferation to three stimuli, (b) B cell proliferation and IgE synthesis to anti-CD40+IL-4, and (c) molecular events in IgE isotype switching. Bars represent means ± SEM from three independent experiments; *P<0.05, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4696875&req=5

Figure 3: Correction of lymphocyte defects in Patients A1–3 with iron citrateEffect of addition of iron citrate on: (a) T cell proliferation to three stimuli, (b) B cell proliferation and IgE synthesis to anti-CD40+IL-4, and (c) molecular events in IgE isotype switching. Bars represent means ± SEM from three independent experiments; *P<0.05, ***P<0.001.
Mentions: Ligation of CD40 on B cells by CD40 ligand expressed on activated T cells in the presence of IL-4 causes proliferation-dependent immunoglobulin class-switch recombination from IgM to IgG and IgE, reflective of high-affinity, protective antibody production2. Proliferation and secretion of IgG and IgE in response to anti-CD40+IL-4 were significantly decreased in patients’ PBMCs (Fig. 1b). IgE switching requires expression of Iε-Cε germline transcripts, which are early products of class-switch recombination, and activation-induced cytidine deaminase (AICDA), which initiates deletional switch recombination followed by expression of mature Iμ-Cε transcripts3. The patients had normal expression of immature Iε-Cε germline transcripts and AICDA mRNA in their B cells, but undetectable mature Iμ-Cε transcripts (Fig. 1c and Fig. 3c). Collectively, these data demonstrate impaired T cell proliferation as well as defective B cell proliferation and class switching, which in combination constitute the mechanism underlying the susceptibility to severe infections characteristic of CID1.

Bottom Line: The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface.We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia.These findings demonstrate the importance of TfR1 in adaptive immunity.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.

ABSTRACT
Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

Show MeSH
Related in: MedlinePlus