De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4- related disease Hamid Mattoo, PhD, Vinay S. Mahajan, MBBS, PhD,

Slides:

Advertisements

Similar presentations

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy Erik Wambre, PhD, Jonathan.

Advertisements

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Hamid Mattoo, PhD, Vinay S

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion

Hamid Mattoo, PhD, Vinay S

Identification and isolation of a Fel d 1–like molecule as a major rabbit allergen Christiane Hilger, PhD, Stéphanie Kler, MSc, Karthik Arumugam, PhD,

Correlation of allergen-specific T follicular helper cell counts with specific IgE levels and efficacy of allergen immunotherapy Yin Yao, MD, Cai-Ling.

Zeynep Yesim Kucuk, MD, Louis-Marie Charbonnier, PhD, Richard L

Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy Mattias Levin, PhD, Jasmine J. King, BS, Jacob.

B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome Maria Carmina Castiello, PhD, Samantha.

A novel mutation in CD132 causes X-CID with defective T-cell activation and impaired humoral reactivity Taco W. Kuijpers, MD, PhD, Paul A. Baars, PhD,

Peanut oral immunotherapy transiently expands circulating Ara h 2–specific B cells with a homologous repertoire in unrelated subjects Sarita U. Patil,

Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation Menno C. van Zelm, PhD, Sophinus J.W. Bartol,

Immunologic defects in 22q11.2 deletion syndrome

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Magdalena A. Berkowska, PhD, Jorn J

Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3) Aleena.

Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL- 5 and IL-5 receptor levels Miguel L. Stein, MD, Joyce M. Villanueva,

Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy Julie Wang, MD,

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion

Noninvasive Molecular Monitoring in Multiple Myeloma Patients Using Cell-Free Tumor DNA Giulia Biancon, Silvia Gimondi, Antonio Vendramin, Cristiana.

Persistence of the IgE repertoire in birch pollen allergy

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells Erin Janssen, MD, PhD,

CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation Clarisa M. Buckner, PhD, Susan Moir, PhD, Lela Kardava,

T-cell receptor sequencing reveals decreased diversity 18 years after early thymectomy Judith Gudmundsdottir, MD, Christina Lundqvist, MSc, Hanna Ijspeert,

Type 3 innate lymphoid cells induce proliferation of CD94+ natural killer cells Shuo Li, PhD, Hideaki Morita, MD, PhD, Beate Rückert, Sci Tec, Tadech.

The IgE repertoire in PBMCs of atopic patients is characterized by individual rearrangements without variable region of the heavy immunoglobulin chain.

Autoreactivity in Human IgG+ Memory B Cells

Glucocorticoids promote intrinsic human TH17 differentiation

Ramona A. Hoh, PhD, Shilpa A

Flow cytometric measurement of STAT1 and STAT3 phosphorylation in CD4+ and CD8+ T cells—clinical applications in primary immunodeficiency diagnostics

Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing.

Natural regulatory T cells in isolated early responders compared with dual responders with allergic asthma Takashi Kinoshita, MD, Adrian Baatjes, MSc,

A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils Sathisha Upparahalli Venkateshaiah, PhD, Akanksha.

Peanut oral immunotherapy transiently expands circulating Ara h 2–specific B cells with a homologous repertoire in unrelated subjects Sarita U. Patil,

Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1–high T cells Jong Hoon.

Kathleen R. Bartemes, BA, Gail M. Kephart, BS, Stephanie J

T-cell receptor diversity is selectively skewed in T-cell populations of patients with Wiskott-Aldrich syndrome Junfeng Wu, MD, Dawei Liu, MS, Wenwei.

CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis Esther Morel, PhD, Salvador Escamochero,

Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells Cathryn A. Weston, PhD, Batika M.J. Rana,

Katherine G. MacDonald, BSc, Nicholas A. J

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells Erin Janssen, MD, PhD,

Defective B-cell memory in patients with Down syndrome

Dissection of the IgE and T-cell recognition of the major group 5 grass pollen allergen Phl p 5 Margarete Focke-Tejkl, PhD, Raffaela Campana, PhD, Renate.

A thymic stromal lymphopoietin–responsive dendritic cell subset mediates allergic responses in the upper airway mucosa Guro R. Melum, MD, Lorant Farkas,

The presentation and natural history of immunodeficiency caused by nuclear factor κB essential modulator mutation Jordan S Orange, MD, PhD, Ashish Jain,

Chronic cat allergen exposure induces a TH2 cell–dependent IgG4 response related to low sensitization Amedee Renand, PhD, Luis D. Archila, MSc, John.

Role of hyaluronan and hyaluronan-binding proteins in human asthma

Brent E. Palmer, PhD, Douglas G. Mack, PhD, Allison K

Autoreactivity in Human IgG+ Memory B Cells

Marc C. Levesque, MD, PhD, E. William St. Clair, MD

Kevin G. Haworth, Christina Ironside, Zachary K. Norgaard, Willimark M

Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma Chaoyu.

Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation Abel Suárez-Fueyo, PhD, Tania.

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy Erik Wambre, PhD, Jonathan.

Allergen specificity of IgG4-expressing B cells in patients with grass pollen allergy undergoing immunotherapy Louisa K. James, PhD, Holly Bowen, PhD,

Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3–positive regulatory T cells Amir H. Massoud, MSc,

Xin-Zi Tang, PhD, James B. Jung, BS, Christopher D.C. Allen, PhD

Dysregulated extracellular signal-regulated kinase signaling associated with impaired B- cell receptor endocytosis in patients with common variable immunodeficiency

Allergen-specific CD8+ T cells in peanut-allergic individuals

Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome Florence Roufosse, MD, PhD, Aurore de Lavareille, PhD,

CD45RA depletion in HLA-mismatched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study Fabien.

Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: Possible contribution to skin inflammation Takeshi Echigo, MD, Minoru Hasegawa,

Wasp venom immunotherapy expands a subpopulation of CD4+CD25+ forkhead box protein 3–positive regulatory T cells expressing the T-cell receptor Vβ2 and.

Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity Gertjan.

IgG4 production is confined to human IL-10–producing regulatory B cells that suppress antigen-specific immune responses Willem van de Veen, MSc, Barbara.

Allergen specificity of IgG4-expressing B cells in patients with grass pollen allergy undergoing immunotherapy Louisa K. James, PhD, Holly Bowen, PhD,

Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency Paul J. Maglione, MD,

Invariant natural killer T cells from children with versus without food allergy exhibit differential responsiveness to milk-derived sphingomyelin Soma.

Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity Gertjan.

Presentation transcript:

De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4- related disease Hamid Mattoo, PhD, Vinay S. Mahajan, MBBS, PhD, Emanuel Della-Torre, MD, Yurie Sekigami, BS, Mollie Carruthers, MD, Zachary S. Wallace, MD, Vikram Deshpande, MD, John H. Stone, MD, MPH, Shiv Pillai, MBBS, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 3, Pages 679-687 (September 2014) DOI: 10.1016/j.jaci.2014.03.034 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Expansion of CD19+CD20−IgG4+ plasmablasts in patients with IgG4-RD. A, Hematoxylin and eosin (H&E) and immunohistochemical staining for CD19, CD20, and IgG4 performed on serial sections of a submandibular gland biopsy are shown. An area peripheral to a CD19+CD20+ B-cell follicle that is enriched for IgG4+CD19+CD20− cells is marked. B, Flow cytometric gating scheme used to identify circulating CD19+CD27+CD38hi plasmablasts (red box). FSC, Forward scatter. C, Surface staining of CD19+CD27+CD38hi plasmablasts for IgG4, IgG, CD20, and SLAMF7 cells. Data from representative subjects are shown as histograms overlaid on CD19+CD27−CD38− B cells as a negative control. D, Numbers of plasmablasts in peripheral blood of patients with IgG4-RD (n = 84) and healthy control subjects (n = 16) are shown (means ± SEMs, P < .001). Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Restricted repertoire of expanded plasmablast populations. A, The immunoglobulin heavy chain (IGH) repertoire of CD19+CD27+CD38hi plasmablasts sorted from a representative patient (P26) is shown as a 3-dimensional histogram. The x- and y-axes represent the IGHV and IGHJ regions, respectively, and the z-axis indicates the number of productive IGH rearrangements detected by using next-generation sequencing. B, Comparison of read counts of expanded clones from patient P26 detected by using next-generation sequencing (green bars) and single-cell PCR sequencing (orange bars). The corresponding CDR3 sequences ordered by frequency, as seen on next-generation sequencing, are shown in the table inlay. C, Correlation between the absolute read counts of the most frequent IGH CDR3 sequences determined by using next-generation sequencing and the number of cells with the corresponding CDR3 sequence determined by using single-cell PCR (n = 80 cells) of flow-sorted IgG4+ plasmablasts from patient P26. Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Rituximab-mediated depletion of plasmablasts improves clinical outcome. A, Measurement of the therapeutic response to rituximab using the IgG4-RD Responder Index. B, Decrease in plasma IgG4 concentrations after rituximab infusion. Colored lines represent individual patients followed up to 15 months after rituximab infusion. The dashed horizontal line indicates the upper limit of normal (135 mg/dL). C and D, Rituximab-induced decrease in the proportion of circulating B cells (n = 23, P < .001; Fig 3, C) and plasmablasts (n = 23, P < .001; Fig 3, D) by day 30. Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Repopulation of plasmablasts as a marker of disease relapse. A, Longitudinal follow-up of the CD19+ B-cell compartment in 14 patients with IgG4-RD after rituximab therapy plotted as a percentage of the baseline B-cell count. B and C, Longitudinal follow-up of CD19+CD27+CD38+ plasmablast counts after rituximab treatment in 6 patients with IgG4-RD who experienced sustained remission (Fig 4, B) and 6 patients who relapsed (Fig 4, C). Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Clonal divergence in a relapsing pool of plasmablasts. Heat maps show the degree of expansion of plasmablast clones bearing specific IGHV and IGHJ combinations in 2 patients who relapsed, P11 (A) and P15 (B), by using a blue-red color gradient, with the most expanded clones shown in red. Unused V-J combinations are colored black. The tables show a comparison of the CDR3 amino acid sequences of the dominant clones sharing the same IGHV-J combinations before and after rituximab therapy. Highly expanded clones are colored red in the tables, and numbers in parentheses indicate CDR3 nucleotide sequence identity. Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Expanded populations of plasmablasts exhibit enhanced somatic hypermutation and autoreactivity. A and B, Comparison of replacement (R) and silent (S) mutations and R/S ratio in FR3 and CDR3 regions of IGHV-sequences of plasmablasts from 5 untreated patients with IgG4-RD (Fig 6, A) and 3 patients with relapsing IgG4-RD (Fig 6, B) after rituximab therapy with CDR3 sequences from naive B cells from 3 control samples, as analyzed from NGS reads (mean ± SEM). *P < .05 and **P < .005. C, Immunofluorescence staining of Hep-2–coated slides with single plasmablast–derived antibody clones. Clones with bright cytosolic staining are labeled in red. Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 A speculative model for the role of activated B cells and plasmablasts in a presumed CD4+ T cell–mediated pathogenic process causing IgG4-RD. Activated somatically hypermutated B cells or plasmablasts might serve as effective antigen-presenting cells for pathogenic effector CD4+ T cells in disease sites. In patients who relapse after rituximab-mediated B-cell depletion therapy, plasmablasts can be generated de novo from naive B cells (solid arrow) or from CD20+ memory B cells that survive rituximab therapy (dashed arrow) facilitated by T-B cooperation in secondary lymphoid organs (not shown). Journal of Allergy and Clinical Immunology 2014 134, 679-687DOI: (10.1016/j.jaci.2014.03.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions