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

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

Activated T cells, expressing CD40L binding to CD40 on B lymphocytes, generate a signal to B cells to synthesize proteins / enzymes necessary for switching the synthesis of immunoglobulin classes and somatic hypermutation. Binding of CD40 triggers a signal, which increases the expression of B7 B cells. The interaction of B7 with the T-cell surface molecules of CD28 and CTLA-4 leads to the inclusion of an additional co-stimulatory signal for T-cell activation. Although signaling in T lymphocytes mediated by the CD40 ligand remains controversial, there is experimental evidence that co-stimulation of the T lymphocyte following the interaction of CD40 and its ligand is necessary for the direct activation of T lymphocytes through the tyrosine-dependent phosphorylation of cellular proteins , including PLC.

However, the intracellular receptor pair for the CD40 ligand in CD4 + lymphocytes is not known.

Symptoms

Just like patients with CD40 ligand deficiency, patients with a mutation in CD40 become ill in early childhood, severe clinical manifestations, including opportunistic infections, growth and physical development disorders, resemble combined immunodeficiency. Inadequate activation of monocytes and dendritic cells in the absence of CD40 may explain the development of opportunistic infections with deficiency both CD40 and CD40L

In patients with CD40 deficiency identified to date, complete absence of CD40 expression on the B-lymphocyte surface and monocytes was found. In vitro stimulation of B lymphocytes with ant-CD40 antibodies and IL-10 does not lead to induction of the synthesis of IgA and IgG, in contrast to the X-linked form of the hyper-IgM syndrome. Just like patients with XHIGM, patients with CD40 deficiency have a reduced amount of IgD CD27 + B-lymphocytes in memory.

Treatment

Treatment includes replacement therapy with intravenous immunoglobulin every 3-4 weeks, preventing pneumocystis infection, maintaining a normal nutritional status. Bone marrow stem cell transplantation is likely to be less effective because it will restore CD40 expression only on cell lines originating from the stem hematopoietic cell, which will not happen for other cells whose normal function is also associated with the expression of CD40 on them.

[1], [2], [3], [4]