CD40 ligand (CD40LG) is expressed by activated CD4+ cells. Interaction of CD40LG-expressing CD4+ cells with B lymphocytes that constitutively express CD40 delivers a signal for B-cell proliferation and class-switch recombination in the presence of appropriate cytokines (see Fig. 1). Furthermore, interaction between CD40LG-expressing CD4+ lymphocytes and CD40+ dendritic cells and macrophages promotes secretion of IL-12, and thus enables the development of Th1 responses against intracellular pathogens.
Fig1. GENETIC DEFECTS ASSOCIATED WITH HYPOGAMMAGLOBULINEMIA. Schematic of B-cell development in bone marrow and secondary lymphoid organs, including migration of B cells into the follicular zone where they undergo activation, class-switch recombination (CSR), and somatic hypermutation (SHM). “X” denotes maturation steps at which the genes indicated are required, resulting in a block in differentiation at that stage when the gene is deficient. ActB, Activated B cell; AID, activation-induced cytidine deaminase; BTK, Bruton’s tyrosine kinase; Foll-B, follicular B cell; HSC, hematopoietic stem cell; IGLL, immunoglobulin light-like chain; IL-21, interleukin-21; immB, immature B cell (also termed transitional B cell); memB, memory B cell; MZ-B, marginal zone B cell; PC, plasma cell; Pre-B, precursor B cell; Pre-BCR, pre–B-cell receptor; Pro-B, progenitor B cell; RAG1, recombination activating gene 1; RAG2, recombination-activating gene 2; sIgA, surface IgA; sIgD, surface IgD; sIgG, surface IgG; sIgM, surface immunoglobulin M; UNG, uracil-DNA glycosylase.
The CD40LG gene is located on the X chromosome (at Xq26). Males with CD40LG mutations suffer from a combined immunodeficiency characterized by recurrent infections, often caused by opportunistic pathogens. P. jiroveci pneumonia classically occurs in the first year of life, but may occur at any age. Cryptosporidium parvum infection may cause chronic watery diarrhea and lead to sclerosing cholangitis. Chronic or intermittent neutropenia has been frequently observed. Patients with CD40LG deficiency are also uniquely prone to tumors of the liver and biliary tract.
Levels of serum IgG and IgA are markedly reduced or undetectable; IgM may be normal or increased, and for this reason the dis ease is also known as X-linked hyper-IgM syndrome. The number of memory B cells is also markedly reduced.
In vitro activation of T cells with phorbol myristate acetate and ionomycin fails to induce expression of CD40LG on the surface of CD4+ cells, whereas other activation markers (e.g., CD69) are normally expressed.
The prognosis is severe. Death may occur early in life secondary to infections, or during late childhood and young adulthood due to severe liver disease and tumors. Clinical management consists of continuous prophylaxis of Pneumocystis infection with TMP-SMZ, regular use of intravenous immunoglobulins, and hygiene measures to limit the risk of exposure to Cryptosporidium. SCT is the only definitive cure, with overall and disease-free survival of ~70% to 78% reported in Europe. Preexisting pulmonary disease and Cryptosporidium infection are risk factors for less favorable outcomes.
CD40 deficiency is a very rare autosomal recessive disorder, whose clinical and immunological phenotype is indistinguishable from CD40LG deficiency (see Fig.1). The diagnosis is based on the lack of expression of CD40 on the surface of circulating B lymphocytes. Management is similar to that for CD40LG deficiency
