Clinical and immunological findings in four infants with Omenn's syndrome: A form of severe combined immunodeficiency with phenotypically normal T cells, elevated IgE, and eosinophilia

1987 ◽  
Vol 44 (2) ◽  
pp. 123-133 ◽  
Author(s):  
Luisa Businco ◽  
Armando Di Fazio ◽  
Maria Grazia Ziruolo ◽  
Attilio L. Boner ◽  
Enrico A. Valletta ◽  
...  
Keyword(s):  
T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency

scholarly journals Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Duilio Brugnoni ◽  
Luigi D. Notarangelo ◽  
Alessandra Sottini ◽  
Paolo Airò ◽  
Marta Pennacchio ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Cd4 T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
T Helper ◽  
T Helper 1 ◽  
In Vitro Susceptibility ◽  
And Function

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

scholarly journals EBV‐associated lymphoproliferative disorder in a patient with X‐linked severe combined immunodeficiency with multiple reversions of an IL2RG mutation in T cells

eJHaem ◽  
2020 ◽  
Vol 1 (2) ◽  
pp. 581-584
Author(s):  
Fumiya Wada ◽  
Tadakazu Kondo ◽  
Momoko Nakamura ◽  
Shunsuke Uno ◽  
Masakazu Fujimoto ◽  
...  
Keyword(s):  
T Cells ◽  
Lymphoproliferative Disorder ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency

Long-Term Chimerism and B-Cell Function After Bone Marrow Transplantation in Patients With Severe Combined Immunodeficiency With B Cells: A Single-Center Study of 22 Patients

Blood ◽  
1999 ◽  
Vol 94 (8) ◽  
pp. 2923-2930 ◽  
Author(s):  
Elie Haddad ◽  
Françoise Le Deist ◽  
Pierre Aucouturier ◽  
Marina Cavazzana-Calvo ◽  
Stephane Blanche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
B Cell Function ◽  
Host Origin

We retrospectively analyzed the B-cell function and leukocyte chimerism of 22 patients with severe combined immunodeficiency with B cells (B+ SCID) who survived more than 2 years after bone marrow transplantation (BMT) to determine the possible consequences of BMT procedures, leukocyte chimerism, and SCID molecular deficit on B-cell function outcome. Circulating T cells were of donor origin in all patients. In recipients of HLA-identical BMT (n = 5), monocytes were of host origin in 5 and B cells were of host origin in 4 and of mixed origin in 1. In recipients of HLA haploidentical T-cell–depleted BMT (n = 17), B cells and monocytes were of host origin in 14 and of donor origin in 3. Engraftment of B cells was found to be associated with normal B-cell function. In contrast, 10 of 18 patients with host B cells still require Ig substitution. Conditioning regimen (ie, 8 mg/kg busulfan and 200 mg/kg cyclophosphamide) was shown neither to promote B-cell and monocyte engraftment nor to affect B-cell function. Eight patients with B cells of host origin had normal B-cell function. Evidence for functional host B cells was further provided in 3 informative cases by Ig allotype determination and by the detection, in 5 studied cases, of host CD27+ memory B cells as in age-matched controls. These results strongly suggest that, in some transplanted patients, host B cells can cooperate with donor T cells to fully mature in Ig-producing cells.

Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2099-2101 ◽  
Author(s):  
Taizo Wada ◽  
Tomoko Toma ◽  
Hiroyuki Okamoto ◽  
Yoshihito Kasahara ◽  
Shoichi Koizumi ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Protein Function ◽  
Severe Combined Immunodeficiency ◽  
Somatic Mosaicism ◽  
Omenn Syndrome ◽  
Missense Mutations ◽  
Combined Immunodeficiency ◽  
Reading Frame ◽  
Recombination Activating Genes

Abstract Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID. (Blood. 2005; 106:2099-2101)

Expansion of clonotype-restricted HLA-identical maternal CD4+ T cells in a patient with severe combined immunodeficiency and a homozygous mutation in the Artemis gene

2003 ◽  
Vol 108 (2) ◽  
pp. 159-166 ◽  
Author(s):  
Norimoto Kobayashi ◽  
Kazunaga Agematsu ◽  
Haruo Nagumo ◽  
Kozo Yasui ◽  
Yoshihiko Katsuyama ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Severe Combined Immunodeficiency ◽  
Homozygous Mutation ◽  
Combined Immunodeficiency

scholarly journals Enhanced Engraftment of HTLV-I-Infected Human T Cells in Severe Combined Immunodeficiency Mice by Anti-asialo GM-1 Antibody Treatment

1996 ◽  
Vol 40 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Shiro Ishihara ◽  
Akihiko Okayama ◽  
Yasuhiro Nagatomo ◽  
Koichi Murai ◽  
Ryozo Yamashita ◽  
...  
Keyword(s):  
T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Antibody Treatment ◽  
Human T Cells

scholarly journals Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Duilio Brugnoni ◽  
Luigi D. Notarangelo ◽  
Alessandra Sottini ◽  
Paolo Airò ◽  
Marta Pennacchio ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Cd4 T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
T Helper ◽  
T Helper 1 ◽  
In Vitro Susceptibility ◽  
And Function

Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

scholarly journals Severe Combined Immunodeficiency Mice Engrafted With Human T Cells, B Cells, and Myeloid Cells After Transplantation With Human Fetal Bone Marrow or Liver Cells and Implanted With Human Fetal Thymus: A Model for Studying Human Gene Therapy

Blood ◽  
1997 ◽  
Vol 89 (5) ◽  
pp. 1800-1810 ◽  
Author(s):  
Sergey Yurasov ◽  
Tobias R. Kollmann ◽  
Ana Kim ◽  
Christina A. Raker ◽  
Moshe Hachamovitch ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
T Cells ◽  
Peripheral Blood ◽  
Severe Combined Immunodeficiency ◽  
Precursor Cells ◽  
Scid Mice ◽  
Combined Immunodeficiency ◽  
Human T Cells

To develop an in vivo model wherein human hematopoiesis occurs, we transplanted severe combined immunodeficiency (SCID) mice with either human fetal bone marrow (HFBM) or human fetal liver (HFL). After transplantation of SCID mice with cultured HFBM (BM-SCID-hu mice) or HFL cells (Liv-SCID-hu mice), significant engraftment of the mouse bone marrow (BM) and population of the peripheral blood with human leukocytes was detected. Human colony-forming unit–granulocyte macrophage and burst forming unit-erythroid were detected in the BM of the BM-SCID-hu and Liv-SCID-hu mice up to 8 months after transplantation. When the HFBM or HFL cells were transduced with a retroviral vector before transplantation, integrated retroviral sequences were detected in human precursor cells present in the SCID mouse BM and in leukocytes circulating in the peripheral blood (PB) up to 7 months after transplantation. The PB of the BM-SCID-hu mice also became populated with human T cells after implantation with human thymic tissue, which provided a human microenvironment wherein human pre-T cells from the BM could mature. When the HFBM was retrovirally transduced before transplantation, integrated retrovirus was detected in sorted CD4+CD8+ double positive and CD4+ single positive cells from the thymic implant and CD4+ cells from the PB. Taken together, these data indicated that the BM of our BM-SCID-hu and Liv-SCID-hu mice became engrafted with retrovirally transduced human hematopoietic precursors that undergo the normal human hematopoietic program and populate the mouse PB with human cells containing integrated retroviral sequences. In addition to being a model for studying in vivo human hematopoiesis, these mice should also prove to be a useful model for investigating in vivo gene therapy using human stem/precursor cells.

A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2803-2807 ◽  
Author(s):  
Chaim M. Roifman ◽  
Junyan Zhang ◽  
David Chitayat ◽  
Nigel Sharfe
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Clinical Presentation ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Cell Development ◽  
Combined Immunodeficiency ◽  
Cell Numbers ◽  
Partial Deficiency

Abstract Both in vitro and in vivo studies established that interleukin 7 (IL-7) is essential for differentiation of immature T cells and B cells but not natural killer (NK) cells in the mouse. In humans, although both T-cell and B-cell progenitors express the functional IL-7 receptor that consists of IL-7Rα and the γcommon (γc) chain, this lymphocyte receptor system is critical for T lineage but not for B lineage development. Indeed, complete γc deficiency like IL-7Rα deficiency results in the arrest of T-cell but not B-cell development (T−B+ SCID). However, partial deficiency of γc caused by missense mutations results in a T+B+ phenotype and a delay of clinical presentation. It was therefore plausible to assume that partial deficiency of IL-7Rα, like partial γc deficiency may lead to a milder clinical and immunologic phenotype. A P132S mutation in the IL-7Rα was identified in 3 patients with severe combined immunodeficiency (SCID) within an extensively consanguineous family. Substitution of proline with serine in the extracellular portion of IL-7Rα did not affect IL-7Rα messenger RNA (mRNA) and protein expression, but severely compromised affinity to IL-7, resulting in defective signal transduction. In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7Rα. Surprisingly, this partial deficiency of IL-7Rα resulted in a severe phenotype, including markedly reduced circulating T cells while sparing B-cell numbers similar to γc chain deficiency. However, unlike the previously reported cases, serum immunoglobulins were virtually absent. Further, unlike γc deficiency, NK cell numbers and function was preserved. Despite the partial deficiency, clinical presentation was indistinguishable from a complete γc deficiency, including severe and persistent viral and protozoal infections and failure to thrive. Unlike partial γc deficiency, a partial deficiency of IL-7Rα results in an arrest of T-cell development, leading to typical severe combined immunodeficiency. This underscores the critical role of IL-7Rα chain in the differentiation of T cells.

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