Regulatory B10 Cells Increase after Rituximab Therapy but Not after Conventional Immunosuppression in Patients with Pemphigus

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare diseases mediated by IgG autoantibody-induced damage of the skin (Kasperkiewicz et al., 2017Kasperkiewicz M. Ellebrecht C.T. Takahashi H. Yamagami J. Zillikens D. Payne A.S. al.Pemphigus. Nat Rev Dis Primers. 2017; 3: 17026Crossref PubMed Scopus (193) Google Scholar). These commonly treated with high-dose systemic corticosteroids. However, patients can have difficulty stopping corticosteroid treatments often require additional adjunctive immunosuppression, including azathioprine, mycophenolate mofetil, or methotrexate. Rituximab, a mAb directed against CD20 on B cells, is an effective first-line therapy for when compared prednisone treatment alone, clinical responses persisting even after B-cell recovery (Joly 2017Joly P. Maho-Vaillant Prost-Squarcioni C. Hebert V. Houivet E. Calbo S. al.First-line rituximab combined short-term versus alone (Ritux 3): prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 389: 2031-2040Abstract Full Text PDF (260) Conventional therapy, however, in some subjects, no prospective-controlled study has demonstrated superiority over conventional other steroid-sparing immunosuppression regimens (azathioprine, etc.) (Agarwal 2018Agarwal A. Hall 3rd, R.P. Bañez L.L. Cardones A.R. Comparison adjuvant vulgaris: retrospective analysis.PLoS One. 2018; 13e0198074Crossref (9) Whereas exact mechanism(s) to likely complex, depletes circulating cells significantly variably tissue cells. Circulating reconstitution includes significant increases human naive transitional phenotypes (Colliou 2013Colliou N. Picard Caillot F. Le Corre Lim al.Long-term remissions severe associated prolonged failure desmoglein cell response.Sci Transl Med. 2013; 5: 175ra30Crossref (151) Spleen negative regulatory properties were first shown suppress delayed-type hypersensitivity guinea pigs (Katz 1974Katz S.I. Parker Turk J.L. suppression delayed reactions.Nature. 1974; 251: 550-551Crossref (231) More recently, that competent secrete cytokine, IL-10, been inhibit inflammation autoimmune reactivity mouse models (Bouaziz 2008Bouaziz J.D. Yanaba K. Tedder T.F. Regulatory as inhibitors immune inflammation.Immunol Rev. 2008; 224: 201-214Crossref (349) express IL-10 named B10 distinguish them from immunoregulatory subsets. progenitor (B10pro) develop response low-level chronic antigen autoantigen stimulation mature into functionally CD40 ligation, subsequent production regulation innate adaptive immunity (Yoshizaki 2012Yoshizaki Miyagaki T. DiLillo D.J. Matsushita Horikawa Kountikov E.I. al.Regulatory control T-cell autoimmunity through IL-21-dependent cognate interactions.Nature. 2012; 491: 264-268Crossref (459) Mouse B10pro quantified vitro ligation plus lipopolysaccharide (LPS) CpG stimulation, cultured induced cytoplasmic following acute activation phorbol esters ionomycin, which enables their accurate quantification flow cytometry (Iwata 2011Iwata Y. Venturi G.M. al.Characterization IL-10-competent subset man parallels cells.Blood. 2011; 117: 530-541Crossref (787) Both increased numbers frequencies IL-10‒producing described depending patient cohorts methods Increased B10-cell reported intravenous Ig Scholar; Kabuto 2017Kabuto Fujimoto Tanaka Decreased level interleukin-10-producing but not pemphigoid.Br J Dermatol. 176: 1204-1212Crossref (12) Scholar, 2016Kabuto Increase long-term remission i.v. immunoglobulin pemphigus.J 2016; 43: 815-818Crossref (10) Zhu 2015Zhu H.Q. Xu R.C. Chen Y.Y. Yuan H.J. Cao Zhao X.Q. al.Impaired function CD19(+) CD24(hi) CD38(hi) pemphigus.Br 2015; 172: 101-110Crossref (44) also seen rituximab-treated neuromyelitis optica, although this was methylprednisolone (Quan 2015Quan ZhangBao Lu Cai Wang B. al.The balance between memory NMO changes therapy.J Neuroimmunol. 282: 45-53Abstract (45) We therefore hypothesized PV PF could result proportions (B10 + cells) Colliou immunosuppressive increasing who achieved similar responses. Patients had successfully either whom before successful studied obtaining written informed consent. A total 10 subjects (7 3 PF) given therapies (systemic corticosteroids azathioprine mofetil), whereas seven (5 2 (Table 1). There differences median frequency therapies: (CpG–rituximab = 3.44% 4.12% LPS–rituximab 1.78% 1.82%) 1 Figure By contrast, disease (P 0.018 CpG, P 0.033 LPS; Wilcoxon‒Mann‒Whitney) (after therapy: LPS 8.49% 11.6 %; 3.94%). therapeutic groups anti-desmoglein antibody levels dosages at start observation therapies. The 7 group achieving partial complete 9 (Murrell 2008Murrell D.F. Dick Ahmed Amagai Barnadas M.A. Borradori L. al.Consensus statement definitions disease, end points, pemhigus.J Am Acad 58: 1043-1046Abstract (390) After 6 minimal 4 group. found rituximab, present therapy.Table 1Clinical Laboratory ResultsDiagnosisTreatmentBefore Treatment: anti-DSG1, AU/mlAfter AU/mlBefore anti- DSG3, anti-DSG3, CD40L (% Total Cells)After Cells)Before Treatment:Prednisone, mg/dAfter mg/dDays ObservationBefore TreatmentPVRitux193313034.2526.93.4411.6200367PFRitux1,90664700.2213.88.635.7800504PVRitux004061136.198.4915.212.300450PVRitux102514.860.93.4415.9305434PFRitux922400.497.091.784.5600371PVRitux222191571.7815.96.7621.8405343PVRitux32108540.43.70.474.99300642PVConv10418101433.171.024.542.56407455PVConv10611,7081831.31.811.514.97500602PVConv1149223.681.7611.11.4300427PVConv2435,1714052.5212.75.64.800922PVConv109483350.674.762.9410.41212721PVConv00891181.412.740.953.076015468PFConv561382001.91.573.217.79010967PFConv2111410.660.224.41.66400455PVConv484870561.740.353.831.9200273PFConv11835123.724.435.366.13001,134Abbreviations: AU, absorbance unit; Conv, mofetil; DSG, desmoglein; LPS, lipopolysaccharide; PF, foliaceus; PV, vulgaris; Ritux, Open table new tab Abbreviations: studies suggest positive outcome pemphigus. Comparable observed equally outcomes suggests activates different pathways control. Similar findings optica those Evaluation rheumatoid arthritis decreased correlation activity factor (Miyagaki 2015Miyagaki Sato inflammatory diseases: research.Int Immunol. 27: 495-504Crossref (74) In animal collagen-induced arthritis, passive transfer IL-10+ marginal zone precursor limited initiation ameliorated existing (Evans 2007Evans J.G. Chavez-Rueda K.A. Eddaoudi Meyer-Bahlburg Rawlings Ehrenstein M.R. al.Novel suppresive experimental arthritis.J 2007; 178: 7868-7878Crossref (432) Our confirm Scholar may be related induction. we despite remission. This possibility effectiveness duration improved identifying increase All performed approved Duke University Institutional Review Board— Board number: Pro00017693. No datasets generated analyzed during study. Alan Chen: http://orcid.org/0000-0003-4625-5060 Ayumi Yoshizaki: http://orcid.org/0000-0002-8194-9140 Tomomitsu Miyagaki: http://orcid.org/0000-0003-1879-3128 Robert Streilein: http://orcid.org/0000-0002-7714-2360 Thomas Tedder: http://orcid.org/0000-0003-0653-7354 Russell III: http://orcid.org/0000-0001-7621-4935 authors state conflict interest. work supported Pinnell Center Investigative Dermatology , School Medicine, Durham, NC. Conceptualization: RPH III, TFT; Data Curation: Formal Analysis: TFT, AC; Funding Acquisition: Investigation: AC, AY, TM, RDS, III; Methodology: Project Administration: Resources: Supervision: Validation: Visualization: Writing - Original Draft Preparation: Editing: III