B Cell–Specific Expression of Inducible Costimulator Ligand Is Necessary for the Induction of Arthritis in Mice

Hamel, Keith M.; Cao, Yong; Olalekan, Susan; Finnegan, Alison

doi:10.1002/art.38207

Cited by 25 publications

(23 citation statements)

References 41 publications

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“…A number of candidate DEGs whose presence has been well validated in studies of autoimmunity, including the cyclin kinase p21 ( CDKN1A ) (), ubiquitin ligase PelI1 (), and costimulatory molecule ICOSLG () genes, were identified. The EGF ligand gene AREG was identified as the transcript with the largest change in expression (Figure B).…”

Section: Resultsmentioning

confidence: 99%

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA‐Sequencing

Mahendra

Abnouf

Adolacion

et al. 2019

Arthritis & Rheumatology

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Objective. To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA).Methods. Citrulline-and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays.Results. Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor α (IL-15Rα) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Rα protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts.Conclusion. To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA‐Sequencing

Mahendra

Abnouf

Adolacion

et al. 2019

Arthritis & Rheumatology

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“…Only very few individuals appear to be autoantibody-positive later during the disease course [61]. Consequently, B cell depletion therapy with anti-CD20 antibody (rituximab) has become an important biologic therapy with positive clinical results [62]. Indeed, B cell depletion reduces rheumatoid factor and anti-citrullinated protein antibodies (ACPA), which are prevalent biomarkers of RA [62].…”

Section: Adaptive Immunity In Ra and The Effect Of Mscsmentioning

confidence: 99%

“…Consequently, B cell depletion therapy with anti-CD20 antibody (rituximab) has become an important biologic therapy with positive clinical results [62]. Indeed, B cell depletion reduces rheumatoid factor and anti-citrullinated protein antibodies (ACPA), which are prevalent biomarkers of RA [62]. Therefore, autoreactive B cells participating in antigen presentation, costimulation, and cytokine production likely play an important role but are not the main mediators of RA, since a decrease in autoantibodies does not necessarily correlate with clinical outcome [63].…”

Section: Adaptive Immunity In Ra and The Effect Of Mscsmentioning

confidence: 99%

“…In this context, it has been shown that the T cell population is altered after B cell depletion, resulting in reduced T cell activation and cytokine production. In proteoglycan-induced arthritis (PGIA), an experimental murine model of arthritis, Treg cell percentage was elevated in B cell-depleted mice, compared to control treated mice that exhibited a higher proportion of CD4 + T cells expressing Foxp3 and CD25 [62]. Of note, CD4 + CD25 + cells from B cell-depleted mice expressed higher amounts of Foxp3 and were significantly more suppressive than those from the control group.…”

Section: Adaptive Immunity In Ra and The Effect Of Mscsmentioning

confidence: 99%

“…Of note, CD4 + CD25 + cells from B cell-depleted mice expressed higher amounts of Foxp3 and were significantly more suppressive than those from the control group. Interestingly, when Treg cells were removed with an anti-CD25 monoclonal antibody simultaneously with B cell depletion therapy, the severity of PGIA was decreased to the level of untreated mice [62]. Thus, B cells have the capacity to regulate the inflammatory responses in arthritis, in part, by educating T cells within a regulatory phenotype.…”

Section: Adaptive Immunity In Ra and The Effect Of Mscsmentioning

confidence: 99%

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Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

Contreras-López

Figueroa

Djouad

et al. 2016

Stem Cells International

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Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studied in vitro and in vivo in experimental animal model of autoimmune and inflammatory disorders. Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression.

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Editorial: B Cells: Not Just Making Immunoglobulin Anymore

Mamula

2013

Arthritis & Rheumatology

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B Cell–Specific Expression of Inducible Costimulator Ligand Is Necessary for the Induction of Arthritis in Mice

Abstract: Objective. Inducible costimulator (ICOS)-

Cited by 25 publications

References 41 publications

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA‐Sequencing

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA‐Sequencing

Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

Editorial: B Cells: Not Just Making Immunoglobulin Anymore

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