Alex Pellerin's research while affiliated with University of Massachusetts Boston and other places

Publications (31)

Article
Full-text available
Gain-of-function polymorphisms in the transcription factor IRF5 are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduces disease in a murine lupus model....
Article
Autoantibodies are a hallmark of numerous neurological disorders, including multiple sclerosis, autoimmune encephalitides and neuromyelitis optica. Whilst well understood in peripheral myeloid cells, the pathophysiological significance of autoantibody-induced Fc receptor signalling in microglia remains unknown, in part due to the lack of a robust i...
Article
Full-text available
Objectives Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK. Methods BIIB091 was evaluated in v...
Data
Production of IFNα by pDCs can be detected in PBMC by flow cytometry and correlates with secreted IFNα levels measured by ELISA. (A) Representative dot plots from flow cytometry analyses of IFNα-producing pDCs from healthy donors PBMC using either BDCA2 (top panel) or BDCA4 and CD123 (bottom) as pDC-specific cell markers. Percents from red box repr...
Article
Full-text available
Objective: Plasmacytoid dendritic cells (pDCs) are a major source of Type-I Interferon (IFN-I), a key driver in cutaneous lupus erythematosus (CLE). Currently evaluated in Phase II clinical trial, 24F4A (BIIB059) is an antibody targeting BDCA2, an inhibitory receptor expressed on pDCs. Given that Hydroxychloroquine (HCQ), a widely-used CLE therapy,...
Data
24F4A further reduces pDC IFNα production after CpG-A, R848 or ssRNA stimulations of PBMC isolated from CLE patients under HCQ and Quinacrine treatment. Effect of 24F4A on the percentage of IFNα-producing pDCs induced by CpG-A, R848 and ssRNA stimulations and detected by flow cytometry in PBMC from CLE patients without detectable blood HCQ, with de...
Data
Effect of HCQ alone or in combination with 24F4 on IFNα release from human whole blood after CpG-A, R848 or ssRNA stimulation. (A) Whole blood from human healthy patients was stimulated or not with CpG-A (10 μM with n = 7 donors), R848 (1 μM with n = 6 donors) or ssRNA (4 μg/ml with n = 4 donors) complexed with pARG in presence HCQ with or without...
Data
Effect of 24F4A on pDC IFNs production after CpG-A or R848 stimulations of PBMC isolated from CLE patients regardless blood HCQ levels.
Data
Treatment with 24F4A, but not with isotype control mAb, inhibit pDC IFNα response to CpG-A, R848, and ssRNA stimulation. Representative dot plots of IFNα+ cells within a BDCA4+ and CD123+ gate from PBMC obtained from healthy donors (n = 2) after CpG-A (10 μM), R848 (1 μM) or ssRNA (4 μg/ml) or without pre-treatment with 24F4A or isotype control mAb...
Data
24F4A reduces pDC TNFα and IL-6 production after CpG-A and ssRNA, but not R848, stimulations of PBMC isolated from healthy donors similarly as or better than HCQ treatment. Whole blood samples from healthy donors were treated with HCQ (1000 ng/ml) or not for 1 h prior to PBMC isolation and then stimulated with CpG-A (10 μM), R848 (1 μM) or ssRNA (4...
Article
Background: Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-h...
Article
Full-text available
BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we uti...
Article
B-cell activating factor (BAFF) levels are increased in rheumatoid arthritis, lupus and primary Sjögren's syndrome (pSS). However, BAFF contribution to pathogenesis is not completely understood. In pSS, immune infiltration of the salivary and lacrimal glands leads to xerostomia and xerophtalmia. Glandular B cell hyperactivation, differentiation int...
Article
Full-text available
Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE, immune complexes bind to the CD32a (FcγRIIa) receptor on the surface of plasmacytoid dendritic cells (pDCs) and stimulate the secretion of IFN-I from pDCs. BDCA2 is a pDC-specific receptor that, when engaged, inhibits the production of IFN-I...
Data
Full-text available
Supplementary Materials and Methods, Supplementary Figure and Table Legends

Citations

... ). Monoallelic deletion of IRF5 in B cells was also recently found to decrease ABCs in a TLR7-driven lupus model.150 Thus, the expansion and differentiation of autoimmune ABCs exhibit a striking requirement for B-cell IRF5 in different lupus models. ...
... It also plays active roles in brain regions important for the emotional and memory-related aspects of chronic pain (25). The activation of microglia and recruitment of immunoinflammatory cells leads to the production and release of cytokines, chemokines and growth factors, all of which might exert pain induction and amplification effect (16,(26)(27)(28)(29). For example, MOG-IgG can trigger the tightly-controlled FcR and BTKdriven microglia proliferative response (30). Astrocyte damage and microglial activation, induced by AQP4-IgG in NMO, may influence the microglia-astrocyte signaling pathway in neuropathic pain (25). ...
... Together, our in vitro findings indicated that inhibition of BTK results in reduced B-cell mitochondrial respiration and decreases the capacity of B cells to stimulate and activate T cells. To test whether these effects of BTKi can occur in vivo in humans, we were able to take advantage of PBMC samples obtained as part of the phase I healthy control clinical trial of the highly selective oral BTK inhibitor (BIIB091) [4]. Using samples obtained both prior to, and after 7 days of daily treatment (Fig. 6a), we first confirmed that BTK inhibition reduced B-cell mitochondrial respiration in vivo including both basal respiration and maximal respiration ( Fig. 6b-d). ...
... 16,17 Accordingly, several proteins involved in the lysosomal pathway have been involved in IFN-I production by pDC, 17,18 and chloroquine inhibition of endosomal acidification interferes with IFNa responses to TLR7 and TLR ligands in pDC. 19,20 While much of the characterization of this traffic is characterized using TLR9, it is likely that TLR7 signaling and trafficking uses the same pathways. 21 SIDT1 is a multispan transmembrane protein belonging to the SID1 transmembrane family, with certain sequence homology to C. elegans ChUP-1, a cholesterolbinding protein located in intracellular vesicles, 22,23 and involved in the immune responses of the nematode. ...
... The pDC/IFN-I pathway has been specifically implicated in the pathogenesis of skin manifestations in chronic inflammatory/autoimmune diseases in which an enrichment of pDCs in the inflammatory infiltrate in association with an IFN-I signature has been demonstrated (9,18). Of note, a recent therapeutic approach in the treatment of cutaneous lupus targeting pDCs has shown promising results (80), which may prove useful in treating ENL as well. Moreover, the data herein generated open new avenues in the process of identifying new biomarkers for early ENL diagnosis that could pave the way toward the better management of reactional patients. ...
... This would be due to interspecies difference of FcRn binding between rodents and humans. Although several case studies, such as BIIB059 (anti-BDCA2 antibody) [41], M701 (anti-CD3/EpCAM bispecific antibody) [42], and JNJ-61178104 (anti-TNFα/IL-17A bispecific antibody) [43], have used the allometric scaling approach with cynomolgus monkeys to predict two-compartment model parameters in humans, each of these case studies used a different scaling exponent without solid evidence for an optimal exponent. Thus, we established an optimal exponent for the allometric scaling of all two-compartment model parameters of mAbs in humans based on cynomolgus monkey data. ...
... More than two decades ago, studies by Robinson et al. [57] using the NOD-Igµ −/− gene knockout (KO) mouse model revealed an absolute requirement for B cells and immunoglobulin in the development and onset of SS-like disease that normally develops spontaneously in parental NOD/ShiLtJ autoimmune mice. Studies in both BAFF [32][33][34] and B6.Il14α transgenic (TG) mice [28,29] not only support this earlier finding, but have further shown that elimination of the MZB cell population or blocking the lymphotoxin activity required for MZB cell ontogeny [35] prevents development of SS-like diseases, including lymphomagenesis. MZB cells are an unique subpopulation of bone marrow-derived B lymphocytes characterized by limited expression of immunoglobulin variable region genes that produce predominantly IgM antibodies, many of which are self-reactive [46]. ...
... The TLR2 receptor, which recognizes bacterial lipopeptides (LP), collaborates to form functional heterodimers with either TLR1 or TLR6 to mediate intracellular signaling [157,171,172]. TLR2 is regulated in chronic obstructive pulmonary disease (COPD) and predominantly detects invasive Gram-positive bacteria, mycobacteria, and fungi [173][174][175][176]. TLR2 heterodimers with either TLR1 or TLR6 enhanced proinflammatory responses during viral infection by identifying viral glycoproteins [177,178]. ...