ABSTRACT
Omenn syndrome (OS) is an inherited disorder characterized by an absence of circulating B cells and an infiltration of the skin and the intestine by activated oligoclonal T lymphocytes, indicating that a profound defect in the lymphoid developmental program could be accountable for this condition. Inherited mutations in either the recombination activating genes RAG1 or RAG2, resulting in partial V(D)J recombinase activity, were shown to be responsible for OS. This study reports on the characterization of new RAG1/2 gene mutations in a series of 9 patients with OS. Given the occurrence of the same mutations in patients with T-B-severe combined immune deficiency or OS on 3 separate occasions, the proposal is made that an additional factor may be required in certain circumstances for the development of the Omenn phenotype. The nature of this factor is discussed.
Subject(s)
DNA-Binding Proteins , Genes, RAG-1 , Mutation , Severe Combined Immunodeficiency/genetics , DNA Nucleotidyltransferases/genetics , DNA Nucleotidyltransferases/metabolism , Female , Gene Expression Regulation, Enzymologic/immunology , Humans , Infant , Male , Nuclear Proteins , Severe Combined Immunodeficiency/enzymology , Severe Combined Immunodeficiency/etiology , Syndrome , VDJ RecombinasesABSTRACT
Severe combined immunodeficiency-X1 (SCID-X1) is an X-linked inherited disorder characterized by an early block in T and natural killer (NK) lymphocyte differentiation. This block is caused by mutations of the gene encoding the gammac cytokine receptor subunit of interleukin-2, -4, -7, -9, and -15 receptors, which participates in the delivery of growth, survival, and differentiation signals to early lymphoid progenitors. After preclinical studies, a gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells. After a 10-month follow-up period, gammac transgene-expressing T and NK cells were detected in two patients. T, B, and NK cell counts and function, including antigen-specific responses, were comparable to those of age-matched controls. Thus, gene therapy was able to provide full correction of disease phenotype and, hence, clinical benefit.
Subject(s)
Genetic Therapy , Hematopoietic Stem Cells , Receptors, Interleukin/genetics , Severe Combined Immunodeficiency/therapy , Antigens, CD34/analysis , B-Lymphocytes/immunology , Gene Transfer Techniques , Genetic Vectors , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Humans , Immunoglobulins/blood , Infant , Killer Cells, Natural/immunology , Lymphocyte Activation , Lymphocyte Count , Moloney murine leukemia virus/genetics , Mutation , Receptors, Antigen, T-Cell/analysis , Receptors, Interleukin/biosynthesis , Severe Combined Immunodeficiency/genetics , T-Lymphocyte Subsets/immunology , T-Lymphocytes/immunology , TransgenesABSTRACT
Severe hypoglycaemia developed seven months after a bone marrow transplantation in a child with severe combined immunodeficiency. His serum exerted potent insulin-like activity: (a) it stimulated insulin receptor autophosphorylation and kinase activity in cell-free systems, this effect being additive to insulin; (b) it increased glucose transport in isolated soleus muscle. These insulin-like effects were due to immunoglobulins against the insulin receptor. Indeed, the patient serum immunoprecipitated human or murine insulin receptors from different tissues and inhibited insulin binding to receptor on human IM-9 lymphocytes. After corticoids and immunosuppressive therapy by azathioprine, the patient hypoglycaemic episodes disappeared, and concomitantly, the antibodies to insulin receptor were no longer detected, as judged by both immunoprecipitation of insulin receptor and stimulation of glucose transport.