Research

14 pages, 2542 KiB

Open AccessArticle

Lineage Reconstruction of In Vitro Identified Antigen-Specific Autoreactive B Cells from Adaptive Immune Receptor Repertoires

by Peter Blazso, Krisztian Csomos, Christopher M. Tipton, Boglarka Ujhazi and Jolan E. Walter

Int. J. Mol. Sci. 2023, 24(1), 225; https://doi.org/10.3390/ijms24010225 - 23 Dec 2022

Cited by 1 | Viewed by 1794

Abstract

The emergence, survival, growth and maintenance of autoreactive (AR) B-cell clones, the hallmark of humoral autoimmunity, leave their footprints in B-cell receptor repertoires. Collecting IgH sequences related to polyreactive (PR) ones from adaptive immune receptor repertoire (AIRR) datasets make the reconstruction and analysis [...] Read more.

The emergence, survival, growth and maintenance of autoreactive (AR) B-cell clones, the hallmark of humoral autoimmunity, leave their footprints in B-cell receptor repertoires. Collecting IgH sequences related to polyreactive (PR) ones from adaptive immune receptor repertoire (AIRR) datasets make the reconstruction and analysis of PR/AR B-cell lineages possible. We developed a computational approach, named ImmChainTracer, to extract members and to visualize clonal relationships of such B-cell lineages. Our approach was successfully applied on the IgH repertoires of patients suffering from monogenic hypomorphic RAG1 and 2 deficiency (pRD) or polygenic systemic lupus erythematosus (SLE) autoimmune diseases to identify relatives of AR IgH sequences and to track their fate in AIRRs. Signs of clonal expansion, affinity maturation and class-switching events in PR/AR and non-PR/AR B-cell lineages were revealed. An extension of our method towards B-cell expansion caused by any trigger (e.g., infection, vaccination or antibody development) may provide deeper insight into antigen specific B-lymphogenesis. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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18 pages, 2526 KiB

Open AccessArticle

The PI-3-Kinase P110α Catalytic Subunit of T Lymphocytes Modulates Collagen-Induced Arthritis

by María Montes-Casado, Gloria Ojeda, Gabriel Criado, José M. Rojo and Pilar Portolés

Int. J. Mol. Sci. 2021, 22(12), 6405; https://doi.org/10.3390/ijms22126405 - 15 Jun 2021

Cited by 1 | Viewed by 1862

Abstract

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that [...] Read more.

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α^−/−ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α^−/−ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4⁺ subpopulations; and an increased number of CXCR5⁺ T cells in the draining lymph nodes of the p110α^−/−ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α^−/−ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α^−/−ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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19 pages, 2836 KiB

Open AccessArticle

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

by Kyoko Kawahara, Tomoyuki Mukai, Masanori Iseki, Akiko Nagasu, Hajime Nagasu, Takahiko Akagi, Shoko Tsuji, Sumie Hiramatsu-Asano, Yasuyoshi Ueki, Katsuhiko Ishihara, Naoki Kashihara and Yoshitaka Morita

Int. J. Mol. Sci. 2021, 22(8), 4169; https://doi.org/10.3390/ijms22084169 - 17 Apr 2021

Cited by 7 | Viewed by 2608

Abstract

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the [...] Read more.

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Fas^lpr/lpr mice. Clinical and immunological phenotypes were compared between Fas^lpr/lpr and SH3BP2-deficient Fas^lpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220⁺CD4⁻CD8⁻ T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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13 pages, 1873 KiB

Open AccessArticle

Analysis of PI3K Pathway Associated Molecules Reveals Dysregulated Innate and Adaptive Functions of B Cells in Early Diffuse Cutaneous Systemic Sclerosis

by Diána Simon, Szabina Erdő-Bonyár, Judit Rapp, Péter Balogh, Tünde Minier, Gabriella Nagy, László Czirják and Tímea Berki

Int. J. Mol. Sci. 2021, 22(6), 2877; https://doi.org/10.3390/ijms22062877 - 12 Mar 2021

Cited by 4 | Viewed by 2017

Abstract

B cell activation is an early event in the development of systemic sclerosis (SSc). The classical activation of B cells downstream of the B-cell receptor (BCR) involves the phosphatidylinositol-3 kinase (PI3K) pathway that integrates the effects of multiple co-stimulatory receptors. Our analysis of [...] Read more.

B cell activation is an early event in the development of systemic sclerosis (SSc). The classical activation of B cells downstream of the B-cell receptor (BCR) involves the phosphatidylinositol-3 kinase (PI3K) pathway that integrates the effects of multiple co-stimulatory receptors. Our analysis of PI3K pathway associated molecules in peripheral blood B cells of early diffuse cutaneous SSc (dcSSc) patients showed altered mRNA expression of Toll-like receptor (TLR) homolog CD180, TLR4, complement component 3, IL-4 receptor and secreted phosphoprotein 1 (SPP1). Parallel to this, we found elevated basal SPP1 secretion in dcSSc B cells, but, with BCR + IL-4 receptor co-stimulation, we could not induce further secretion. CD180 stimulation alone resulted in NF-κB activation in more B cells than CD180 + BCR co-stimulation both in dcSSc and healthy control (HC), but the co-engagement increased the phosphorylation of NF-κB only in dcSSc B cells. Additionally, in contrast with HC B cells, the lower basal production of IL-10 by dcSSc B cells could not be elevated with CD180 stimulation. Furthermore, activation via CD180 increased the percentage of CD86+ switched memory (CD27+IgD−) B cells in dcSSc compared to HC. Our results suggest that alternative B cell activation and CD180 dysfunction cause imbalance of regulatory mechanisms in dcSSc B cells. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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Review

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14 pages, 1752 KiB

Open AccessReview

Treatment of Sjögren’s Syndrome with Mesenchymal Stem Cells: A Systematic Review

by Najwa Chihaby, Marie Orliaguet, Laëtitia Le Pottier, Jacques-Olivier Pers and Sylvie Boisramé

Int. J. Mol. Sci. 2021, 22(19), 10474; https://doi.org/10.3390/ijms221910474 - 28 Sep 2021

Cited by 19 | Viewed by 2859

Abstract

Mesenchymal stem cells (MSCs) are ubiquitous in the human body. Mesenchymal stem cells were initially isolated from bone marrow and later from other organs such as fatty tissues, umbilical cords, and gingiva. Their secretory capacities give them interesting immunomodulatory properties in cell therapy. [...] Read more.

Mesenchymal stem cells (MSCs) are ubiquitous in the human body. Mesenchymal stem cells were initially isolated from bone marrow and later from other organs such as fatty tissues, umbilical cords, and gingiva. Their secretory capacities give them interesting immunomodulatory properties in cell therapy. Some studies have explored the use of MSCs to treat Sjögren’s syndrome (SS), a chronic inflammatory autoimmune disease that mainly affects exocrine glands, including salivary and lacrimal glands, although current treatments are only palliative. This systematic review summarizes the current data about the application of MSCs in SS. Reports show improvements in salivary secretions and a decrease in lymphocytic infiltration in salivary glands in patients and mice with SS after intravenous or infra-peritoneal injections of MSCs. MSC injections led to a decrease in inflammatory cytokines and an increase in anti-inflammatory cytokines. However, the intrinsic mechanism of action of these MSCs currently remains unknown. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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20 pages, 724 KiB

Open AccessReview

From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment

by Silvia Vidal, Lluís Puig, José-Manuel Carrascosa-Carrillo, Álvaro González-Cantero, José-Carlos Ruiz-Carrascosa and Antonio-Manuel Velasco-Pastor

Int. J. Mol. Sci. 2021, 22(13), 6740; https://doi.org/10.3390/ijms22136740 - 23 Jun 2021

Cited by 14 | Viewed by 3672 | Correction

Abstract

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal [...] Read more.

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural—containing a SEFIR/TILL domain—and functional—requiring ACT-1 for signaling—properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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14 pages, 1245 KiB

Open AccessReview

Hyposialylation Must Be Considered to Develop Future Therapies in Autoimmune Diseases

by Anne Bordron, Marie Morel, Cristina Bagacean, Maryvonne Dueymes, Pierre Pochard, Anne Harduin-Lepers, Christophe Jamin and Jacques-Olivier Pers

Int. J. Mol. Sci. 2021, 22(7), 3402; https://doi.org/10.3390/ijms22073402 - 26 Mar 2021

Cited by 11 | Viewed by 2568

Abstract

Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens [...] Read more.

Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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21 pages, 1819 KiB

Open AccessReview

The Involvement of Innate and Adaptive Immunity in the Initiation and Perpetuation of Sjögren’s Syndrome

by Clara Chivasso, Julie Sarrand, Jason Perret, Christine Delporte and Muhammad Shahnawaz Soyfoo

Int. J. Mol. Sci. 2021, 22(2), 658; https://doi.org/10.3390/ijms22020658 - 11 Jan 2021

Cited by 31 | Viewed by 4416

Abstract

Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by the infiltration of exocrine glands including salivary and lachrymal glands responsible for the classical dry eyes and mouth symptoms (sicca syndrome). The spectrum of disease manifestations stretches beyond the classical sicca syndrome with [...] Read more.

Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by the infiltration of exocrine glands including salivary and lachrymal glands responsible for the classical dry eyes and mouth symptoms (sicca syndrome). The spectrum of disease manifestations stretches beyond the classical sicca syndrome with systemic manifestations including arthritis, interstitial lung involvement, and neurological involvement. The pathophysiology underlying SS is not well deciphered, but several converging lines of evidence have supported the conjuncture of different factors interplaying together to foster the initiation and perpetuation of the disease. The innate and adaptive immune system play a cardinal role in this process. In this review, we discuss the inherent parts played by both the innate and adaptive immune system in the pathogenesis of SS. Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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Other

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1 pages, 599 KiB

Open AccessCorrection

Correction: Vidal et al. From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment. Int. J. Mol. Sci. 2021, 22, 6740

by Silvia Vidal, Lluís Puig, José-Manuel Carrascosa-Carrillo, Álvaro González-Cantero, José-Carlos Ruiz-Carrascosa and Antonio-Manuel Velasco-Pastor

Int. J. Mol. Sci. 2022, 23(5), 2649; https://doi.org/10.3390/ijms23052649 - 28 Feb 2022

Viewed by 1062

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Lymphocyte Signalling and Function in Systemic Autoimmune Diseases)

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