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Autoimmune Diseases: A Swing Dance of the Immune Cells

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 15170

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Prof. Dr. Balik Dzhambazov

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Faculty of Biology, Plovdiv University “Paisii Hilendarski”, 24 Tsar Assen Str., 4000 Plovdiv, Bulgaria
Interests: cell biology; immunology; immunomodulation; biomarkers; autoimmune diseases; allergy; cytotoxicity; anticancer activity; natural products; probiotics; prebiotics; nanoparticles
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Dear Colleagues,

The human body constantly interacts with other organisms and with the environment. Such interactions allow the body to recognize beneficial from harmful influences, as well as what is its own and what is foreign. This is achieved through the immune system, which is a complex network of specialized cells and organs. Therefore, the cells of the immune system are in a continuous "dance with different partners". Frequent "switching of partners" can lead to the inability of the immune system to distinguish between self and non-self, which can initiate the development of autoimmune diseases. There are more than 80 known autoimmune diseases, some of which are more common and well-studied (such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and lupus), although others are rare. Interestingly, the etiology of most autoimmune diseases remains a mystery.

In this Special Issue, the key word is "change", i.e., changes in key molecules during disease versus normal states. We discuss any changes in antigens, molecular interactions, antibody production, cell signaling, or tissue/organ structures which are associated with the initiation, development, or progression of autoimmune diseases. The development of therapeutic agents targeting signaling pathways that lead to changes in T cell or humoral immune responses are also welcome for consideration.

Prof. Dr. Balik Dzhambazov
Guest Editor

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Keywords

autoimmune diseases
antigens/autoantigens
post-translational modifications
antigen processing and presentation
shared epitopes
molecular mimicry
autoantibodies
immune signaling
animal models
therapeutic agents

Published Papers (10 papers)

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11 pages, 2392 KiB

Open AccessArticle

Elevated Fecal Calprotectin Accompanied by Intestinal Neutrophil Infiltration and Goblet Cell Hyperplasia in a Murine Model of Multiple Sclerosis

by Mehrnaz Nouri, Björn Weström and Shahram Lavasani

Int. J. Mol. Sci. 2023, 24(20), 15367; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242015367 - 19 Oct 2023

Viewed by 1046

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system caused by myelin-specific autoreactive T cells. We previously demonstrated intestinal barrier disruption and signs of inflammation in experimental autoimmune encephalomyelitis (EAE), a model of MS. Fecal calprotectin is a disease activity biomarker in inflammatory bowel diseases, released by neutrophils in response to inflammation. We aimed to further investigate EAE manifestations in the gastrointestinal tract and to determine whether calprotectin is a useful biomarker of intestinal inflammation in EAE. Calprotectin was analyzed in feces, cecal contents, and plasma of EAE mice. Infiltrating neutrophils and goblet cells were investigated in different parts of the gastrointestinal tract before the onset of neurological symptoms and during established disease. We found increased calprotectin levels in feces, cecal content, and plasma preceding EAE onset that further escalated during disease progression. Increased neutrophil infiltration in the intestinal tissue concomitant with IL-17 expression and myeloperoxidase activity was found to correlate well with clinical activity. Increased goblet cells in the intestine, similar to irritable bowel syndrome (IBS), were also observed. The results suggest calprotectin as a good biomarker of gastrointestinal inflammation in EAE and the potential of this model as a useful animal model for IBS. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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22 pages, 3178 KiB

Open AccessArticle

Histone and Histone Acetylation-Related Alterations of Gene Expression in Uninvolved Psoriatic Skin and Their Effects on Cell Proliferation, Differentiation, and Immune Responses

by Dóra Romhányi, Kornélia Szabó, Lajos Kemény and Gergely Groma

Int. J. Mol. Sci. 2023, 24(19), 14551; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241914551 - 26 Sep 2023

Viewed by 1157

Abstract

Psoriasis is a chronic immune-mediated skin disease in which the symptom-free, uninvolved skin carries alterations in gene expression, serving as a basis for lesion formation. Histones and histone acetylation-related processes are key regulators of gene expression, controlling cell proliferation and immune responses. Dysregulation of these processes is likely to play an important role in the pathogenesis of psoriasis. To gain a complete overview of these potential alterations, we performed a meta-analysis of a psoriatic uninvolved skin dataset containing differentially expressed transcripts from nearly 300 individuals and screened for histones and histone acetylation-related molecules. We identified altered expression of the replication-dependent histones HIST2H2AA3 and HIST2H4A and the replication-independent histones H2AFY, H2AFZ, and H3F3A/B. Eight histone chaperones were also identified. Among the histone acetyltransferases, ELP3 and KAT5 and members of the ATAC, NSL, and SAGA acetyltransferase complexes are affected in uninvolved skin. Histone deacetylation-related alterations were found to affect eight HDACs and members of the NCOR/SMRT, NURD, SIN3, and SHIP HDAC complexes. In this article, we discuss how histone and histone acetylation-related expression changes may affect proliferation and differentiation, as well as innate, macrophage-mediated, and T cell-mediated pro- and anti-inflammatory responses, which are known to play a central role in the development of psoriasis. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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19 pages, 3517 KiB

Open AccessArticle

NIH/3T3 Fibroblasts Selectively Activate T Cells Specific for Posttranslationally Modified Collagen Type II

by Balik Dzhambazov, Tsvetelina Batsalova, Patrick Merky, Franziska Lange and Rikard Holmdahl

Int. J. Mol. Sci. 2023, 24(13), 10811; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310811 - 28 Jun 2023

Viewed by 1297

Abstract

It has been shown that synovial fibroblasts (SF) play a key role in the initiation of inflammation and joint destruction, leading to arthritis progression. Fibroblasts may express major histocompatibility complex class II region (MHCII) molecules, and thus, they could be able to process and present antigens to immunocompetent cells. Here we examine whether different types of fibroblasts (synovial, dermal, and thymic murine fibroblasts, destructive LS48 fibroblasts, and noninvasive NIH/3T3 fibroblasts) may be involved in the initiation of rheumatoid arthritis (RA) pathogenesis and can process and present type II collagen (COL2)—an autoantigen associated with RA. Using a panel of MHCII/Aq-restricted T-cell hybridoma lines that specifically recognize an immunodominant COL2 epitope (COL2_259–273), we found that NIH/3T3 fibroblasts activate several T-cell clones that recognize the posttranslationally glycosylated or hydroxylated COL2_259–273 epitope. The HCQ.3 hybridoma, which is specific for the glycosylated immunodominant COL2 epitope 259–273 (Gal264), showed the strongest response. Interestingly, NIH/3T3 cells, but not destructive LS48 fibroblasts, synovial, dermal, or thymic fibroblasts, were able to stimulate the HCQ.3 hybridoma and other COL2-specific T-cell hybridomas. Our experiments revealed that NIH/3T3 fibroblasts are able to activate COL2-specific T-cell hybridomas even in the absence of COL2 or a posttranslationally modified COL2 peptide. The mechanism of this unusual activation is contact-dependent and involves the T-cell receptor (TCR) complex. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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14 pages, 2917 KiB

Open AccessArticle

Impaired Regulation by IL-35 in Systemic Sclerosis

by Rubén Osuna-Gómez, Ivan Castellví, Maria Mulet, Mª Àngels Ortiz, Douglas E. Brough, Helen Sabzevari, Roshanak T. Semnani and Silvia Vidal

Int. J. Mol. Sci. 2023, 24(13), 10567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310567 - 24 Jun 2023

Cited by 1 | Viewed by 1066

Abstract

This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, p < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β (p < 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, p < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, p < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, p < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, p < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, p < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, p < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β (p < 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, p < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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13 pages, 3073 KiB

Open AccessCommunication

Galectin-3 Mediates NETosis and Acts as an Autoantigen in Systemic Lupus Erythematosus-Associated Diffuse Alveolar Haemorrhage

by Shih-Yao Chen, Chung-Teng Wang, Ching-Yi Chen, Pin-Yu Kuo, Chrong-Reen Wang, Ai-Li Shiau, Cheng-Hsi Chang and Chao-Liang Wu

Int. J. Mol. Sci. 2023, 24(11), 9493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119493 - 30 May 2023

Cited by 3 | Viewed by 1662

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with enhanced NETosis and impaired degradation of neutrophil extracellular traps (NETs). Galectin-3 is a β-galactoside binding protein and is associated with neutrophil functions as well as involved in mediating autoimmune disorders. In this study, we plan to examine the associations of galectin-3 with the pathogenesis of SLE and NETosis. Galectin-3 expression levels were determined in peripheral blood mononuclear cells (PBMCs) of SLE patients for the association with lupus nephritis (LN) or correlation of SLE disease activity index 2000 (SLEDAI-2K). NETosis was observed in human normal and SLE and murine galectin-3 knockout (Gal-3 KO) neutrophils. Gal-3 KO and wild-type (WT) mice induced by pristane were used to evaluate disease signs, including diffuse alveolar haemorrhage (DAH), LN, proteinuria, anti-ribonucleoprotein (RNP) antibody, citrullinated histone 3 (CitH3) levels, and NETosis. Galectin-3 levels are higher in PBMCs of SLE patients compared with normal donors and positively correlated with LN or SLEDAI-2K. Gal-3 KO mice have higher percent survival and lower DAH, LN proteinuria, and anti-RNP antibody levels than WT mice induced by pristane. NETosis and citH3 levels are reduced in Gal-3 KO neutrophils. Furthermore, galectin-3 resides in NETs while human neutrophils undergo NETosis. Galectin-3-associated immune complex deposition can be observed in NETs from spontaneously NETotic cells of SLE patients. In this study, we provide clinical relevance of galectin-3 to the lupus phenotypes and the underlying mechanisms of galectin-3-mediated NETosis for developing novel therapeutic strategies targeting galectin-3 for SLE. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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21 pages, 3423 KiB

Open AccessArticle

αvβ3 Integrin as a Link between the Development of Fibrosis and Thyroid Hormones in Systemic Sclerosis

by Maia Yamila Kohon, Mor Zaaroor Levy, Tzipi Hornik-Lurie, Avshalom Shalom, Ariel Berl, Liat Drucker, Yair Levy and Shelly Tartakover Matalon

Int. J. Mol. Sci. 2023, 24(10), 8927; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108927 - 18 May 2023

Cited by 1 | Viewed by 1261

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Key players mediating fibrosis are myofibroblasts (MF) that, following transforming growth factor β (TGFβ) exposure, produce a collagen-rich extracellular matrix (ECM) that induces myofibroblast differentiation. Myofibroblasts express αvβ3 integrin (a membrane receptor for thyroid hormones) and miRNA-21 that promotes deiodinase-type-3 expression (D3), causing the degradation of triiodothyronine (T3) that attenuates fibrosis. We hypothesized that αvβ3 affects the fibrotic processes through its thyroid hormones (THs) binding site. To test this, dermal fibroblasts (DF) were cultured with/without TGFβ and removed with a base, leaving only normal/fibrotic ECMs in wells. Then, DF were cultured on the ECMs with/without tetrac (αvβ3 ligand, T4 antagonist), and evaluated for pro-fibrotic characteristics, αvβ3, miRNA-21, and D3 levels. Blood free-T3 (fT3), miRNA-21 levels, and the modified Rodnan skin score (MRSS) were evaluated in SSc patients. We found that the “fibrotic-ECM” significantly increased the pro-fibrotic characteristics of DF and the levels of miRNA-21, D3, and αvβ3, compared to the “normal-ECM.” Tetrac significantly inhibited the effects of the “fibrotic-ECM” on the cells. In accordance with tetrac’s effect on D3/miRNA-21, a negative correlation was found between the patients’ fT3 to miRNA-21 levels, and to the development of pulmonary arterial hypertension (PAH). We conclude that occupying the THs binding site of αvβ3 may delay the development of fibrosis. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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21 pages, 1819 KiB

Open AccessReview

Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis

by Kutty Selva Nandakumar, Qinghua Fang, Isabella Wingbro Ågren and Zoe Fuwen Bejmo

Int. J. Mol. Sci. 2023, 24(21), 15883; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115883 - 01 Nov 2023

Cited by 1 | Viewed by 1787

Abstract

Abnormal activation of multiple immune and non-immune cells and proinflammatory factors mediate the development of joint inflammation in genetically susceptible individuals. Although specific environmental factors like smoking and infections are associated with disease pathogenesis, until now, we did not know the autoantigens and arthritogenic factors that trigger the initiation of the clinical disease. Autoantibodies recognizing specific post-translationally modified and unmodified antigens are generated and in circulation before the onset of the joint disease, and could serve as diagnostic and prognostic markers. The characteristic features of autoantibodies change regarding sub-class, affinity, glycosylation pattern, and epitope spreading before the disease onset. Some of these antibodies were proven to be pathogenic using animal and cell-culture models. However, not all of them can induce disease in animals. This review discusses the aberrant activation of major immune and non-immune cells contributing to joint inflammation. Recent studies explored the protective effects of extracellular vesicles from mesenchymal stem cells and bacteria on joints by targeting specific cells and pathways. Current therapeutics in clinics target cells and inflammatory pathways to attenuate joint inflammation and protect the cartilage and bones from degradation, but none cure the disease. Hence, more basic research is needed to investigate the triggers and mechanisms involved in initiating the disease and relapses to prevent chronic inflammation from damaging joint architecture. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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14 pages, 1195 KiB

Open AccessReview

Localized Cutaneous Nodular Amyloidosis: A Specific Cutaneous Manifestation of Sjögren’s Syndrome

by José María Llamas-Molina, Juan Pablo Velasco-Amador, Francisco Javier De la Torre-Gomar, Alejandro Carrero-Castaño and Ricardo Ruiz-Villaverde

Int. J. Mol. Sci. 2023, 24(8), 7378; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087378 - 17 Apr 2023

Viewed by 1731

Abstract

Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare condition attributed to plasma cell proliferation and the deposition of immunoglobulin light chains in the skin without association with systemic amyloidosis or hematological dyscrasias. It is not uncommon for patients diagnosed with PLCNA to also suffer from other auto-immune connective tissue diseases, with Sjögren’s syndrome (SjS) showing the strongest association. This article provides a literature review and descriptive analysis to better understand the unique relationship between these two entities. To date, 34 patients with PLCNA and SjS have been reported in a total of 26 articles. The co-existence of PLCNA and SjS has been reported, especially in female patients in their seventh decade of life with nodular lesions on the trunk and/or lower extremities. Acral and facial localization, which is a typical localization of PLCNA in the absence of SjS, seems to be much more unusual in patients with associated SjS. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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12 pages, 300 KiB

Open AccessReview

The Search for the Pathogenic T Cells in the Joint of Rheumatoid Arthritis: Which T-Cell Subset Drives Autoimmune Inflammation?

by Hisakata Yamada

Int. J. Mol. Sci. 2023, 24(8), 6930; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24086930 - 08 Apr 2023

Cited by 2 | Viewed by 1887

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting systemic synovial tissues, leading to the destruction of multiple joints. Its etiology is still unknown, but T-cell-mediated autoimmunity has been thought to play critical roles, which is supported by experimental as well as clinical observations. Therefore, efforts have been made to elucidate the functions and antigen specificity of pathogenic autoreactive T cells, which could be a therapeutic target for disease treatment. Historically, T-helper (Th)1 and Th17 cells are hypothesized to be pathogenic T cells in RA joints; however, lines of evidence do not fully support this hypothesis, showing polyfunctionality of the T cells. Recent progress in single-cell analysis technology has led to the discovery of a novel helper T-cell subset, peripheral helper T cells, and attracted attention to the previously unappreciated T-cell subsets, such as cytotoxic CD4 and CD8 T cells, in RA joints. It also enables a comprehensive view of T-cell clonality and function. Furthermore, the antigen specificity of the expanded T-cell clones can be determined. Despite such progress, which T-cell subset drives inflammation is yet known. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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8 pages, 2879 KiB

Open AccessCase Report

Localized Cutaneous Nodular Amyloidosis in a Patient with Sjögren’s Syndrome

by José María Llamas-Molina, Juan Pablo Velasco-Amador, Francisco Javier De La Torre-Gomar, Alejandro Carrero-Castaño and Ricardo Ruiz-Villaverde

Int. J. Mol. Sci. 2023, 24(11), 9409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119409 - 28 May 2023

Viewed by 1409

Abstract

Primary localized cutaneous nodular amyloidosis (PLCNA) is included in the primary forms of cutaneous amyloidosis along with macular and lichenoid amyloidosis. It is a rare disease attributed to plasma cell proliferation and deposition of immunoglobulin light chains in the skin. We present the case of a 75-year-old woman with a personal history of Sjogren’s syndrome (SjS), who consulted for asymptomatic yellowish, waxy nodules on the left leg. Dermoscopy of the lesions showed a smooth, structureless, yellowish surface with hemorrhagic areas and few telangiectatic vessels. Histopathology revealed an atrophic epidermis and deposits of amorphous eosinophilic material in the dermis with a positive Congo red stain. The diagnosis of nodular amyloidosis was made. Periodic reevaluation was indicated after the exclusion of systemic amyloidosis. PLCNA is often associated with autoimmune connective tissue diseases, and up to 25% of all PLCNA cases occur in patients with SjS. Therefore, in addition to ruling out systemic amyloidosis, screening for possible underlying SjS should be performed when the diagnosis of PLCNA is confirmed. Full article

(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of the Immune Cells)

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