B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid

Abstract

Bullous Pemphigoid is the most common auto-immune bullous skin disease. It is characterized by the production of auto-antibodies directed against 2 proteins of the hemi-desmosome (BP180 and BP230). We assessed the efficacy and mechanisms of action of rituximab, an anti-CD20 monoclonal antibody, in 17 patients with severe and relapsing type of bullous pemphigoid. The phenotype, cytokine gene expression, and rearrangement of BP180-specific B-cell receptor genes were performed over 2 years following treatment. At the end of the study, 5 patients had died, 3 had withdrawn from the study, and 9 patients were in complete remission. The one- and two-year relapse rates were 44.1% (95% Confidence Interval (CI): 21.0–76.0%) and 66.5%, (95% CI: 38.4–91.4%), respectively. Phenotypic analyses confirmed dramatic B-cell depletion, which lasted for 9 to 12 months. The ELISA values of serum anti-BP180 antibodies and the frequency of BP180-specific circulating B cells decreased dramatically following treatment, which paralleled the improvement of skin lesions. During B-cell reconstitution, a polyclonal IgM repertoire appeared and a shift in the rearrangement of the B-cell receptor genes of BP180-specific circulating B cells was observed. Concurrently, we observed a decrease of IL-15, IL-6 and TNFα expressing BP180-specific B cells, and the emergence of IL-10 and IL-1RA-expressing BP180-specific IgM+ B cells in patients in complete remission off therapy, suggesting the functional plasticity of BP180-specific auto-immune B cells after rituximab treatment.

Rapid Disease Control in First-Line Therapy-Resistant Mucous Membrane Pemphigoid and Bullous Pemphigoid with Omalizumab as Add-On Therapy: A Case Series Of 13 Patients

“…Notably, the eosinophil blood count showed a dramatic decrease within the first month, mirroring the rapid decrease in urticaria and pruritus. The decrease in anti-BP180 IgG level was slower and progressive over the one-year follow-up for BP patients but also for MMP patients positive at baseline; most of them still demonstrated positive levels of anti-BP-180 IgG at one-year follow-up which was already described in BP patients with other therapies such as B-cell depletion therapy with rituximab ( 52 ). A similar slow decrease was observed for anti-BP180 IgE in patients with high anti-BP180 IgE levels at baseline, whereas other patients in CR had stable levels despite OMZ.…”

CD11c+ B Cells Are Mainly Memory Cells, Precursors of Antibody Secreting Cells in Healthy Donors

“…Three nanograms of each RNA sample were retro-transcribed and preamplified in a 96-well plate containing 0.2 µl Platinum Taq polymerase and SuperScript III reverse transcriptase (Invitrogen), a mixture of Taqman primer probes specific for the transcripts of interest (18), and 5 µl CellsDirect quantitative realtime PCR buffer (Invitrogen). After centrifugation, samples were incubated at 50 • C for 15 min for reverse transcription, followed by 20 cycles of 95 • C, 15 s and 60 • C, 4 min for amplification.…”

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

“…A lately published study indicates that the reappearing pool of B cells after depletion with RTX mainly consists of naïve and transitional B cells, while memory B cells are diminished [103]. The same holds true for patients treated with RTX for various autoimmune diseases and for CD20 depletion in EAE induced with MOG peptide [102,[104][105][106]. Interestingly, in EAE, B cells repopulate after anti-CD20 depletion with a higher amount of memory B cells when using the MOG protein immunization model, which points towards a pathologic reactivation in the presence of autoantigen [104].…”