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Cell studies: CD40 receptor expression in hyper IgM syndrome

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Hyper-IgM (HIGM) syndrome represents a heterogeneous group of immune disorders that arise 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.
The most common subtype is CD40 ligand (CD40L) deficiency. This is an X-linked recessive condition (XHIGM) that arises from a mutation in the CD40LG gene, which encodes CD40L (primarily expressed on activated T cells). The rarer autosomal-recessive HIGM (ARHIGM), on the other hand, results from a mutation in the TNFRSF5 gene. This gene encodes transmembrane cell-surface receptor CD40, which is present on both hematopoietic and non-hematopoietic cells. The binding of this receptor by its T-cell ligand (CD40L) is essential for B cells’ terminal maturation and proliferation.
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 fluorescent co-labels for different intracellular structures: the endoplasmic reticulum (co-label: calnexin), Golgi apparatus (giantin), trans-Golgi network (TGN46), 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 (Figure 1). Partial results for two patients with ARHIGM are shown in Figure 2.
Figure 1 Colocalization of wild-type CD40 with fluorescent labels for intracellular structures; colocalization is visible as signal in the merged micrographs
Figure 2 Colocalization of CD40 in ARHIGM patient 1 and patient 5
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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