Disturbed Homeostasis and Multiple Signaling Defects in the Peripheral Blood B-Cell Compartment of Patients with Severe Chronic Sarcoidosis

The presence of hypergammaglobulinemia, autoantibodies, and circulating immune complexes suggests that humoral immunity may contribute to the pathogenesis of sarcoidosis. However, little is known about the role played by B cells in the development of this disease. Here we investigated the subpopulation distribution, response to stimulation, and levels of the nuclear transcription factor NF-kappa B/p65 in peripheral blood B cells from patients with severe chronic sarcoidosis. Patients with severe chronic sarcoidosis had absolute B-cell lymphopenia and exhibited significantly decreased frequencies and total numbers of memory (CD19(+) CD27(+)) B cells. The reduced numbers of memory B cells in these patients reflected a decrease in the total numbers of class-switched (CD19(+) CD27(+) IgD(-)) and unswitched (CD19(+) CD27(+) IgD(+)) memory B cells and coincided with an increased frequency of circulating (CD19(+/-) CD20(-) CD27(++)) plasmablasts. Polyclonal stimulation of sarcoid B cells resulted in reduced expression of activation markers (i.e., CD25, CD69, and CD86), decreased proliferation, and impaired plasma cell differentiation. Baseline expression of p65 in B cells was reduced in 65% of the patients. These results suggest disturbed homeostasis, intrinsic signaling defects, and anergy within the peripheral B-cell compartments of patients with severe chronic sarcoidosis.