Defective Expression of CD40 Ligand on T Cells Causes “X‐Linked Immunodeficiency with Hyper‐IgM (HIGM1)”

Abstract

X-linked immunodeficiency with hyper-IgM (HIGM1) is a rare disorder, characterized by recurrent infections associated with very low or absent IgG and IgA, and normal to increased IgM serum levels. The disease has been earlier mapped to the q26-27 region of the X-chromosome. We have identified a novel molecule expressed on the surface of activated T cells, which was designated TRAP (Tumor necrosis factor Related Activation Protein), and could demonstrate that TRAP is a ligand for the CD40 receptor expressed on B cells. Our mapping of the TRAP gene to the Xq26.3-27.1 region suggested a causal relationship to HIGM1. Further work revealed that various mutations of the TRAP/CD40 ligand (CD40L) gene may lead to a defective expression of the TRAP/CD40L molecule on the T-cell surface in HIGM1 patients. A combination of structural and functional analyses finally demonstrated that the failure of TRAP/CD40L on T cells to interact with CD40 on B cells is responsible for the inefficient T-cell help for B cells observed in HIGM1. The observations made in HIGM1 allowed us to conclude that TRAP/CD40L is not required for IgM synthesis. In contrast, functional expression of TRAP is a prerequisite for effective immunoglobulin isotype switching and subsequent production of IgG, IgA and IgE by B cells in vivo. The interaction of TRAP/CD40L with CD40 thus provides a very critical link between the cellular and the humoral part of the immune system. The knowledge of TRAP/CD40L cDNA sequence, the availability of various reagents for the testing of expression and function of TRAP/CD40L, and our recent elucidation of the exon-intron structure of the TRAP/CD40L gene now provide all necessary tools for early diagnosis of affected patients and the detection of female carriers of HIGM1. The available information will also provide a basis for future attempts at gene therapy in this disease.

Human Platelets Stimulate Mesangial Cells to Produce Monocyte Chemoattractant Protein-1 via the CD40/CD40 Ligand Pathway and May Amplify Glomerular Injury

“…CD40L, a transmembrane protein structurally related to tumor necrosis factor-␣ (TNF-␣), was originally identified on activated T cells. 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 (14). CD40 is also found on monocytes, macrophages, and endothelial cells, suggesting that CD40L has a broader immunologic function in vivo (15).…”

Immunoglobulin class switch recombination deficiencies

“…Intermittent or chronic neutropenia is also a common feature of X-linked CD40L deficiency and may result from defective 'stress'-induced CD40-dependent granulo poiesis since myeloid progenitors express CD40 mole cules [36]. Complications such as auto-immune manifes tations or cancer have been reported but are not frequent.…”

Introduction of a CD40L genomic fragment via a human artificial chromosome vector permits cell-type-specific gene expression and induces immunoglobulin secretion

“…For example, hyperimmunoglobulin (Ig)M syndrome (HIGM) is a genetic disorder caused by deficiency in a gene encoding the CD40 ligand, which requires intrinsic regulation. HIGM is a rare, X-linked, recessive immunodeficiency disease characterized by the failure of IgM to undergo immunoglobulin-isotype switching to IgG, IgA, and IgE (Kroczek et al 1994). The CD40 ligand is a cell-surface ligand expressed by CD4 + T cells, the expression of which is regulated by cell activation (DiSanto et al 1993;Korthauer et al 1993;Roy et al 1993).…”