IMMUNOHISTOLOGIC ANALYSIS OF INEFFECTIVE CD40-CD40 LIGAND INTERACTIONIN LYMPHOID-TISSUES FROM PATIENTS WITH X-LINKED IMMUNODEFICIENCY WITHHYPER-IGM - ABORTIVE GERMINAL CENTER CELL REACTION AND SEVERE DEPLETION OF FOLLICULAR DENDRITIC CELLS

The CD40 ligand (CD40L) is an activation-induced surface membrane prot ein expressed by CD4(+) T helper cells in lymphoid follicles, and is i nvolved in the contact-dependent signaling-mediated activation, prolif eration, and differentiation of CD40(+) B cells. Using immunohistochem istry, the present study analyzes the cell microenvironment of lymphoi d tissues in two cases of X-linked hyper-IgM syndrome, a congenital im munodeficiency caused by mutations of the CD40L gene, and which repres ents a unique model to dissect the functional and morphologic conseque nces of disrupted CD40/CD40L interactions. Prominent primary B follicl es are identified in the lymph nodes and in the extranodal lymphoid ti ssues from both cases, but tiny collections of Bcl-2(-), MIB1/Ki67(+) centroblasts are also found in one case. Despite the CD40L defect, int rafollicular CD4(+)CD57(+) T helper cells, identified by anti-parvalbu min mAb, are normally present. However, a severe depletion of follicul ar 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 cellula r composition of the paracortical T cell area are found. A large numbe r of plasma cells exclusively expressing IgM were detected in the colo n lamina propria in one of the patients, who also had extremely elevat ed IgM serum levels. Taken together, these data support the idea that ineffective CD40/CD40L interactions determine both abortive germinal c enter cell reaction as well as severe depletion and phenotypical abnor malities of follicular dendritic cells, thus impairing the functional development of B follicles. Recurrent or persisting antigenic stimulat ion in mucosal tissues is likely to play a major role in determining a nd maintaining elevated IgM serum levels.