| 1. |
- Bersellini Farinotti, Alex, et al.
(författare)
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Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons
- 2019
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:8, s. 1904-1924
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
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| 2. |
- Cao, D., et al.
(författare)
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Pathogenic autoreactive B cells are not negatively selected toward matrix protein collagen II
- 2011
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 187:9, s. 4451-4458
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Tidskriftsartikel (refereegranskat)abstract
- We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.
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| 3. |
- Khmaladze, Ia, et al.
(författare)
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B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production
- 2015
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Ingår i: European Journal of Immunology. - Weinheim : Wiley-VCH Verlagsgesellschaft. - 0014-2980 .- 1521-4141. ; 45:8, s. 2243-2251
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knock-in mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collagen-induced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.
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| 4. |
- Khmaladze, Ia, et al.
(författare)
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Lactobacillus reuteri DSM 17938 : A comparative study on the effect of probiotics and lysates on human skin.
- 2019
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Ingår i: Experimental dermatology. - : John Wiley & Sons. - 0906-6705 .- 1600-0625. ; 28:7, s. 822-828
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Tidskriftsartikel (refereegranskat)abstract
- Human skin microbiota might play an important role in maintaining skin health and potentially prevent premature skin ageing. The use of probiotics in therapeutic skin applications is an attractive idea, as it could offer an alternative option for certain inflammatory skin disorders and dry or sensitive skin. Here, we investigated for the first time, a comparative study of live and the lysate products of probiotic strain Lactobacillus reuteri DSM 17938 in skin topical applications using ex vivo skin models focusing on anti-inflammatory and skin barrier function and in vitro assays for antimicrobial activity. Our results in ultraviolet B radiation (UVB-R)-induced inflammation model demonstrated that both live bacteria and the lysate of L. reuteri DSM 17938 reduced proinflammatory IL-6 and IL-8, illustrated in both reconstructed human epidermis (RHE) and native skin models. Live L reuteri DSM 17938 significantly increased aquaporin 3 (AQP3) gene expression, while the lysate enhanced laminin A/B levels in a healthy (unstimulated) state of RHE, suggesting a positive impact on skin barrier. In addition, live L. reuteri DSM 17938 had antimicrobial action against pathogenic skin bacteria (Staphylococcus aureus, Streptococcus pyogenes M1, Cutibacterium acnes AS12, Pseudomonas aeruginosa), whereas the lysate did not have such an effect. Therefore, it is hypothesized that L. reuteri DSM 17938 could be beneficial for general skin health, to avoid the UVB-R-mediated inflammatory cascade and/or prevent photoageing, improve barrier function or in the management of unhealthy skin prone to inflammatory conditions due to its antimicrobial, anti-inflammatory and skin barrier enhancing functions.
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| 5. |
- Khmaladze, Ia, et al.
(författare)
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Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3669-E3678
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gammadelta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcgamma receptor III, mast cells, and histamine) and adaptive immune players (alphabeta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gammadelta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
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| 6. |
- Khmaladze, Ia, et al.
(författare)
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Psoriasis : Genetic Predisposition, Pathogenesis, Treatment and the Role of Microbiome
- 2019. - 1
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Ingår i: Autoimmune Disorders. - USA : Nova Science Publishers, Inc.. - 1536160466 - 9781536160468 ; , s. 103-131
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Bokkapitel (refereegranskat)abstract
- Psoriasis (Ps) is a common immune-mediated disease characterized by red, scaly patches with painful phenotypes. The distribution of Ps is approximately 0.2–2% worldwide and is driven by the interactions between inherited susceptibility alleles and environmental triggers. So far, the strongest Ps susceptibility locus identified is PSORS1 (Ps susceptibility locus 1), located within the major histocompatibility complex (MHC). Other genes, such as IL12B, IL23R, IL23A, TNFAIP3, IL13 etc., are also strong contributors for this complex disease. Ps is associated with the DCs and T cells, in which inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate Th17, Th1 and Th22 cells to produce abundant Ps-associated cytokines such as IL-17, IFN-γ, TNF-α, and IL-22. These cytokines affect keratinocyte responses to amplify Ps inflammation. Ps can be provoked or exacerbated by specific microbial pathogens such as bacteria (S. aureus and, Streptococcus pyogenes), viruses (human papillomavirus and endogenous retroviruses), and fungi (Malassezia and Candida albicans). A recent research suggests that the skin microbiome in patients with Ps is distinct from that of healthy controls. Moreover, the gut microbiome and enterotype also showed for the first time a specific “psoriatic core intestinal microbiome” that clearly differs from the one present in healthy population. The treatment options for Ps symptoms fall into three major categories: Topical (vitamin D analogues, corticosteroids, retinoids, dithranol and coal-tar products), phototherapy [UVB, UVB + psoralen, UVA, UVA + psoralen (PUVA)] and systemic treatments (biologics alone or in combination with methotrexate or cyclosporin). Thus, understanding disease causative factors and mechanisms are important for developing future therapeutics and for optimal disease management. © 2004 - 2023 Nova Science Publishers
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| 7. |
- Khmaladze, Ia, et al.
(författare)
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Reactive oxygen species in psoriasis and psoriasis arthritis : relevance to human disease
- 2015
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 166:2, s. 135-149
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Forskningsöversikt (refereegranskat)abstract
- Psoriasis (Ps) is a chronic, immune-mediated, skin inflammatory disease affecting up to 3% of the population worldwide. Different environmental triggers initiate this complex multifactorial syndrome. Many individuals affected by Ps (6-26%) develop inflammatory disease in other organs, often in the joints as in psoriasis arthritis (PsA). Animal models that reflect the typical Ps syndrome, including both skin and joint pathology as in Ps and PsA, are valuable tools for dissecting disease pathways leading to clinical manifestations. In this context, we developed a new acute Ps and PsA-like disease model that appears after exposure to Saccharomyces cerevisiae mannan in certain mouse strains. The disease was found to be triggered by mannan-activated macrophages, leading to the activation of a pathogenic interleukin-17 pathway involving innate lymphocytes. Interestingly, the production of reactive oxygen species protected the mice from the triggering of this pathway and ameliorated Ps and PsA development.
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| 8. |
- Khmaladze, Ia
(författare)
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Understanding inflammatory mechanisms in rheumatic diseases
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA), Psoriasis (Ps) and Psoriasis arthritis (PsA) are chronic inflammatory autoimmune disorders, where primary targets are peripheral joints, skin and skin/joints respectively. Both innate and adaptive immunity play a role in disease initiation and progression. B cell selection processes were studied by using a VDJ replacement mouse strain ACB (anti-C1 B cell mouse strain), which spontaneously produces anti-C1 antibodies. C1 is one of the major, well-defined immunodominant epitopes on CII molecule. This model allowed for the first time to understand B cell tolerance mechanisms to CII, a matrix protein. We demonstrated that C1-specific B cells are neither negatively selected nor functionally anergized. Thus, this study contributed to better understanding of autoimmunity and pathogenesis of human RA. Tolerance mechanisms toward CII were explored using the classical collagen induced arthritis mouse (CIA) model. Interestingly, ACB mice were protected from arthritis development despite having elevated auto-antibodies in the sera. Introducing a mutation in the Ncf1 gene leading to ROS deficiency initiated arthritis that was associated with enhanced germinal centre (GC) formation, increased T cell responses and epitope-spreading of the CII-specific antibody repertoire. Hence, ROS mediated auto-B cell tolerance mechanisms might have important implications for understanding the epitope spreading events leading to onset of RA. A new mouse model of Ps and PsA in mice triggered by previously regarded nonpathogenic mannan from Saccharomices cerevisiae was characterised. A new pathogenic pathway driven by macrophages and γδ T cells secreting IL-17A was demonstrated. Moreover, cutaneous and articular inflammation in mice was significantly increased under reduced oxidative environment. This novel Ps and PsA model could be extremely useful for testing new therapeutics for Ps and PsA patients. Different scoring techniques for Ps and PsA were evaluated in mice, in order to better assess disease severity for skin and joint inflammation in mannan induced model. This method will be most valuable to quantify disease activity for testing novel therapeutics.
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| 9. |
- Li, Xi, et al.
(författare)
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Targeting microRNA for improved skin health
- 2021
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Ingår i: Health Science Reports. - Hoboken, NJ : John Wiley & Sons. - 2398-8835. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In human skin, miRNAs have important regulatory roles and are involved in the development, morphogenesis, and maintenance by influencing cell proliferation, differentiation, immune regulation, and wound healing. MiRNAs have been investigated for many years in various skin disorders such as atopic dermatitis, psoriasis, as well as malignant tumors. Only during recent times, cosmeceutical use of molecules/natural active ingredients to regulate miRNA expression for significant advances in skin health/care product development was recognized.AIM: To review miRNAs with the potential to maintain and boost skin health and avoid premature aging by improving barrier function, preventing photoaging, hyperpigmentation, and chronological aging/senescence.METHODS: Most of the cited articles were found through literature search on PubMed. The main search criteria was a keyword "skin" in combination with the following words: miRNA, photoaging, UV, barrier, aging, exposome, acne, wound healing, pigmentation, pollution, and senescence. Most of the articles reviewed for relevancy were published during the past 10 years.RESULTS: All results are summarized in Figure 1, and they are based on cited references.CONCLUSIONS: Thus, regulating miRNAs expression is a promising approach for novel therapy not only for targeting skin diseases but also for cosmeceutical interventions aiming to boost skin health.
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