Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme

Complement. First of two parts.

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.

https://science.sciencemag.org/content/sci/288/5466/669.full.pdf

Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.

CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells

Generation of phenotypically different T cell populations by cell-free or cell-bound preparations of varicella zoster virus.

Recent advances in recombinant DNA technology have led to an increase in our understanding of the molecular basis of many genetic diseases. Approximately 3500 different human genetic diseases are known, and as the genes responsible for these diseases are identified and cloned, many advances in treatment and maintenance will be made. These advances have already translated into improved methods for the prenatal diagnosis of many diseases and the use of recombinant gene products in treatment regimes. It is envisaged, however, that with further developments it will soon be possible to correct the genetic defects themselves in affected individuals, through the use of somatic gene therapy techniques. The potential for this form of treatment has generated much interest and the possible applications of somatic gene therapy have been much discussed.\"' For the purposes of this annotation, however, we are confining the discussion to those genetic diseases which are currently treated by bone marrow transplantation. Somatic gene therapy is defined as the correction of a defective or absent gene with its cloned functional equivalent. It differs from germline gene therapy in that the gene is only introduced into the somatic cells of the patient and not into the germline (that is, sperm or ova). Therefore, the gene can only be expressed in those cells into which it was introduced and their progeny cells, but it cannot be passed on to subsequent generations of children. Most cases of genetic disease are the result of a point mutation rather than a gene deletion, and this means that the defective gene is still present, though not necessarily active, in the affected cells. Therefore, the introduction of a functional gene in addition to the defective gene would result in gene augmentation. However, because of the nonspecific nature of the integration event where the gene is inserted randomly into the human genome, a variety of problems may arise. These could include non-expression of the introduced gene or insertional mutagenesis, whereby a normally active gene is silenced or a silent deleterious gene may become activated. Despite these potential problems, this model has been the most widely studied so far and currently offers the best prospect for the treatment of genetic diseases. A much more difficult technique would be true gene replacement whereby the defective gene is removed from the affected cells and replaced with a functional gene in the correct orientation and chromosomal location. Such gene replacement would be technically difficult, although a model for gene targeting involving homologous recombination is being developed in the mouse5; this is currently only applicable to germline gene therapy.

https://adc.bmj.com/content/archdischild/65/1/72.full.pdf

Roland J. Levinsky

Papers

Generation of phenotypically different T cell populations by cell-free or cell-bound preparations of varicella zoster virus.

Somatic gene therapy for genetic disease.

Child health in the 1990s

Physical and genetic approaches to the isolation of the gene for X-linked agammaglobulinemia.

Measurement of human B cell responses to growth and differentiation factors: relevance for immunodeficiency disease.