Physiological up-regulation of inhibitory receptors Fc RII and CR1 on memory B cells is lacking in SLE patients

Abstract

Under physiological conditions immune complexes (IC) are efficiently cleared from the circulation and meanwhile provide important feedback signals for the immune system via Fc gamma Rs and complement receptors. Dysregulation of these mechanisms have been implicated in conditions where IC concentrations reach pathological levels and inflict diseases, like systemic lupus erythematosus (SLE). Our aim was to compare distinct sub-populations of CD19(+) B cells of healthy individuals and SLE patients with regard to their expression of Fc gamma R type II (Fc gamma RII, CD32), complement receptor type 1 (CR1, CD35) and complement receptor type 2 (CR2, CD21) and sIgG/IgM. The following four groups of peripheral CD19(+) B cells were investigated: IgM(+)/CD27(-) naive, IgM(+)/CD27(+) and IgM(-)/CD27(+) memory cells and CD27(high) plasmablasts. We demonstrate that the expression of the inhibitory receptors Fc gamma RII and CR1 is up-regulated on peripheral memory B cells of healthy controls, whereas this up-regulation is considerably impaired on the memory B cells of SLE patients. This reduction affects both the IgM(+) and switched memory B cells. We found a striking difference between the expression of complement receptors CD21 and CD35; namely, no up-regulation of CD21 occurred on the memory B cells of healthy donors, and its decreased expression in SLE patients was characteristic for both the CD27(-) naive and the CD27(+) memory B-cell populations. Our results clearly demonstrate that the previously reported reduced expression of IC-binding receptors is mainly due to the disturbed memory compartment; however, the higher frequency of CD19(+)/CD27(high)/sIg(low) plasmablasts expressing minimal levels of these receptors also contributes to this diminution.

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

“…Consistent with this observation, a subset of SLE patients have reduced levels of Lyn and a significant increase in levels of the protein tyrosine phosphatase CD45 in lipid raft microdomains (24). Impaired expression and activity of the immunoglobulin-binding receptor CD32 is another factor that might account for intrinsic changes in B-cell signaling in SLE (30). CD32 contains an immunoreceptor tyrosinebased inhibitory motif (ITIM) that, upon phosphorylation, recruits protein tyrosine phosphatases that destabilize and downregulate the BCR signaling complex (59).…”

“…If memory B cells are preferentially attracted by these chemokines (44), then selective recruitment of memory (30,52). Since B cells from patients with severe chronic sarcoidosis exhibited significantly reduced levels of CD32 (Fc␥RII) and CD35 (CR1) expression, it is possible that down-modulation of these two receptors could have disrupted those inhibitory signals, thus contributing to the B-cell hyperactivation observed in sarcoidosis.…”

The expression of Fcγ receptors in Hashimoto’s thyroiditis

“…Altered FccRIIB expression on leukocytes has also been linked to systemic lupus erythematosus (SLE), and an FccRIIB allele variant is associated with the degree of joint damage in rheumatoid arthritis (RA) [16][17][18]. These studies provide support for the suggestion that FccRs of immune cells could provide useful information on the humoral response in the pathogenesis of HT.…”

CD40 Mediates Downregulation of CD32B on Specific Memory B Cell Populations in Rheumatoid Arthritis

“…Specifically, CD32B gene deficiency increases both the susceptibility to autoimmunity and disease severity in mice (9)(10)(11). In humans, decreased CD32B expression on B cells has been observed in patients with Ab-dependent autoimmune diseases, such as systemic lupus erythematosus (SLE), RA and chronic inflammatory demyelinating polyneuropathy (CIDP) (12)(13)(14)(15)(16). The precise population of B cells that are affected by CD32B downregulation is disease specific.…”