Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells.

Abstract The CD40 ligand (CD40L) is an activation-induced surface membrane protein expressed by CD4+ T helper cells in lymphoid follicles, and is involved in the contact-dependent signaling-mediated activation, proliferation, and differentiation of CD40+ B cells. Using immunohistochemistry, the present study analyzes the cell microenvironment of lymphoid tissues in two cases of X-linked hyper-IgM syndrome, a congenital immunodeficiency caused by mutations of the CD40L gene, and which represents a unique model to dissect the functional and morphologic consequences of disrupted CD40/CD40L interactions. Prominent primary B follicles are identified in the lymph nodes and in the extranodal lymphoid tissues from both cases, but tiny collections of Bcl-2-, MIB1/Ki67+ centroblasts are also found in one case. Despite the CD40L defect, intrafollicular CD4+CD57+ T helper cells, identified by anti-parvalbumin mAb, are normally present. However, a severe depletion of follicular dendritic cells, recognized by Abs against NGFR, CD21 and CD23, and lack of expression of the Ag recognized by KiM4p on these cells, are noticed. Finally, no major alterations of the architecture and cellular composition of the paracortical T cell area are found. A large number of plasma cells exclusively expressing IgM were detected in the colon lamina propria in one of the patients, who also had extremely elevated IgM serum levels. Taken together, these data support the idea that ineffective CD40/CD40L interactions determine both abortive germinal center cell reaction as well as severe depletion and phenotypical abnormalities of follicular dendritic cells, thus impairing the functional development of B follicles. Recurrent or persisting antigenic stimulation in mucosal tissues is likely to play a major role in determining and maintaining elevated IgM serum levels.