Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy

Abstract

The inhibitory Fc-γ receptor FcγRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcγRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcγRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcγRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare −386C/−120A FcγRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcγRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcγRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcγRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.

Intravenous immunoglobulin up‐regulates the expression of the inhibitory FcγIIB receptor on B cells

“…The increase in this receptor on immune/inflammatory cells could be used therapeutically to switch off unwanted immune responses. Our observation is confirmed by Tackenberg et al 18 who have just described an IVIg-induced upregulation of FcgRIIB on circulating B cells and monocytes in patients with a chronic inflammatory demyelinating polyneuropathy. The effect of IVIg in our experiments, was mediated by interactions of its F(ab') 2 fragments with an unknown target(s) on immune cells.…”

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

“…In humans, either a promoter polymorphism in the fcgr2b gene or an FcγRIIB allelic variant carrying an isoleucine to threonine exchange in the transmembrane domain (FcγRIIB-232T variant), resulting in impaired inhibitory signaling function because of reduced association with lipid rafts, were associated with the development or severity of autoimmune disease in different patient groups (2,(13)(14)(15). Moreover, impaired up-regulation of FcγRIIB on memory B cells was observed in human patients with SLE and CIDP (chronic inflammatory demyelinating polyneuropathy) (16,17). Obtaining more direct evidence for a potential function of human FcγRIIB as a checkpoint of humoral tolerance on a diverse genetic background is not possible with genetic association studies.…”

“…Low-resolution genotyping for HLA-A, -B, DRB1, and DQB1 was carried out using the respective commercial LABType SSO typing kit (One Lambda) according to the manufacturer's instructions. FcγRIIB genotyping was carried out with a two-step PCR protocol as previously described (17). Briefly, a 15-kb product was amplified using the Qiagen LongRange PCR Kit (Qiagen) followed by purification via gel electrophoresis and by using the Qiagen Gel purification Kit.…”

Immune Mediated Diseases and Immune Modulation in the Neurocritical Care Unit

“…IVIG may also affect the cellular immune response by altering the interaction of T-cells with antigen presenting cells and by hastening apoptosis of autoreactive T-cells [352]. Additionally, IVIG may interfere with the differentiation, activation, and proliferation of B cells, enhance their apoptosis, and block the activity of cells that release autoantibodies [359][360][361][362]. Additional mechanisms of action for IVIG have also been postulated, but by and large, the mechanism of action of IVIG remains unclear [363][364][365].…”