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CD40 receptor expression in hyper IgM syndrome

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The Hyper-IgM (HIGM) syndrome represents a rare and heterogeneous group of immune disorders arising from a failure of B cells’ somatic hypermutation and/or class-switch recombination. Patients typically present with recurrent infections, and have low serum levels of immunoglobulins G and A with normal-to-elevated levels of immunoglobulin M. To date, five different genetic defects leading to HIGM have been characterized; each has its own distinct pattern of inheritance. The most common subtype is CD40L deficiency, which is an X-linked recessive condition (XHIGM). It arises from mutation of the CD40LG gene.
The rare autosomal-recessive HIGM (ARHIGM) results from a mutation in the TNFRSF5 gene. This gene encodes a transmembrane cell-surface receptor (CD40), which is present on both hematopoietic and non-hematopoietic cells. Binding of this receptor by its T-cell ligand (CD40L, the protein product of CD40LG) is essential for B cells’ terminal maturation and proliferation. CD40 also causes stimulation of important co-stimulatory molecules.
Researchers performed an experiment to figure out why the CD40 receptor might not be expressed on the cell surface in ARHIGM. B cells were taken from patients with a genetic diagnosis of ARHIGM. The researchers fluorescently labeled CD40 and also added a fluorescent co-label for different intracellular structures: the endoplasmic reticulum (co-label: calnexin), trans-Golgi network (TGN), Golgi apparatus (giantin), and the endosomal compartment (transferrin). Under confocal microscopy the researchers tracked the signal for each co-label/receptor pair, and found that wild-type CD40 exhibited colocalization with calnexin, giantin, and transferrin, and was also detected on the cell surface. However, in patients with ARHIGM, the expected CD40/co-label colocalization was only observed with calnexin, as seen in Patient 2 (Figure 1).
Figure 1. Colocalization study of wild-type and mutant CD40 with fluorescent labels for intracellular structures.
Image adapted from Lanzi, Gaetana, et al. Different molecular behavior of CD40 mutants causing hyper-IgM syndrome. Blood 116.26 (2010): 5867-5874. C, control patient; P2, Patient 2; P5, Patient 5.
CD40 colocalization with different co-labels indicates that, in ARHIGM, CD40 was:
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