Hyper-IgM syndrome associated with CD40 deficiency (HIGM3): symptoms, treatment

Autosomal recessive variant associated with CD40 deficiency (HIGM3) is a rare form of hyper-IgM syndrome (HIGM3) with an autosomal recessive type of inheritance, so far described in only 4 patients from 3 unrelated families. The CD40 molecule is a member of the tumor necrosis factor receptor superfamily, constitutively expressed on the surface of B lymphocytes, mononuclear phagocytes, dendritic fibers and activated epithelial cells.

Activated T cells express CD40L, which binds to CD40 on B cells, signaling B cells to synthesize proteins/enzymes required for immunoglobulin class switching and somatic hypermutation. CD40 binding triggers a signal that increases B7 expression by B cells. Interaction of B7 with the T cell surface molecules CD28 and CTLA-4 results in the inclusion of an additional costimulatory signal for T cell activation. Although CD40 ligand-mediated signal transduction in T cells remains controversial, there is experimental evidence that T cell costimulation following CD40-ligand interaction is required for direct T cell activation via tyrosine-dependent phosphorylation of cellular proteins including PLC-γ.

However, the intracellular receptor pair for CD40 ligand in CD4+ lymphocytes is unknown.

Symptoms

Like patients with CD40 ligand deficiency, patients with CD40 mutations develop the disease in early childhood, with severe clinical manifestations, including opportunistic infections, growth failure, and physical development, reminiscent of combined immunodeficiency. Insufficient activation of monocytes and dendritic cells in the absence of CD40 may explain the development of opportunistic infections in patients with both CD40 and CD40L deficiency.

CD40-deficient patients identified to date have a complete absence of CD40 expression on the B lymphocyte and monocyte surface. In vitro stimulation of B lymphocytes with anti-CD40 antibodies and IL-10 does not induce IgA and IgG synthesis, in contrast to the X-linked form of hyper-IgM syndrome. Like patients with XHIGM, patients with CD40 deficiency have a reduced number of IgD CD27+ memory B lymphocytes.

Treatment

Treatment includes replacement therapy with intravenous immunoglobulin every 3-4 weeks, prophylaxis against Pneumocystis carinii infection, and maintenance of normal nutritional status. Bone marrow stem cell transplantation is likely to be less effective because it will restore CD40 expression only on hematopoietic stem cell-derived cell lines, which will not occur for other cells whose normal function also depends on CD40 expression on them.

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