Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.

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Proteomics of Pancreatic Neuroendocrine Tumors: A Systematic Review

Protein and Peptide Letters ◽

10.2174/0929866527666200504122116 ◽

2020 ◽

Vol 27 (12) ◽

pp. 1276-1287

Author(s):

Brigida Anna Maiorano ◽

Giovanni Schinzari ◽

Sabrina Chiloiro ◽

Felicia Visconti ◽

Domenico Milardi ◽

...

Keyword(s):

Systematic Review ◽

Neuroendocrine Tumors ◽

Prognostic Markers ◽

State Of The Art ◽

Therapeutic Targets ◽

The State ◽

Pancreatic Neuroendocrine Tumors ◽

Rare Tumors ◽

Personalized Approach ◽

Future Management

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors having usually an indolent behavior, but sometimes with unpredictable aggressiveness. PanNETs are more often non-functioning (NF), unable to produce functioning hormones, while 10-30% present as functioning (F) - PanNETs, such as insulinomas , gastrinomas , and other rare tumors. Diagnostic and prognostic markers, but also new therapeutic targets, are still lacking. Proteomics techniques represent therefore promising approaches for the future management of PanNETs. We conducted a systematic review to summarize the state of the art of proteomics in PanNETs. A total of 9 studies were included, focusing both on NF- and F-PanNETs. Indeed, proteomics is useful for the diagnosis, the prognosis and the detection of therapeutic targets. However, further studies are required. It is also warranted to standardize the analysis methods and the collection techniques, in order to validate proteins with a relevance in the personalized approach to PanNETs management.

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Viral Infections and Autoimmune Disease: Roles of LCMV in Delineating Mechanisms of Immune Tolerance

Viruses ◽

10.3390/v11100885 ◽

2019 ◽

Vol 11 (10) ◽

pp. 885

Author(s):

Georgia Fousteri ◽

Amy Dave Jhatakia

Keyword(s):

Immune System ◽

Autoimmune Disease ◽

Viral Infections ◽

Molecular Mimicry ◽

Short Review ◽

Organ Damage ◽

Lymphocytic Choriomeningitis ◽

Immune Deviation ◽

Viral Pathogen ◽

Lcmv Infection

Viral infections are a natural part of our existence. They can affect us in many ways that are the result of the interaction between the viral pathogen and our immune system. Most times, the resulting immune response is beneficial for the host. The pathogen is cleared, thus protecting our vital organs with no other consequences. Conversely, the reaction of our immune system against the pathogen can cause organ damage (immunopathology) or lead to autoimmune disease. To date, there are several mechanisms for virus-induced autoimmune disease, including molecular mimicry and bystander activation, in support of the “fertile field” hypothesis (terms defined in our review). In contrast, viral infections have been associated with protection from autoimmunity through mechanisms that include Treg invigoration and immune deviation, in support of the “hygiene hypothesis”, also defined here. Infection with lymphocytic choriomeningitis virus (LCMV) is one of the prototypes showing that the interaction of our immune system with viruses can either accelerate or prevent autoimmunity. Studies using mouse models of LCMV have helped conceive and establish several concepts that we now know and use to explain how viruses can lead to autoimmune activation or induce tolerance. Some of the most important mechanisms established during the course of LCMV infection are described in this short review.

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CD47 prevents the elimination of diseased fibroblasts in scleroderma

10.1101/2020.06.06.138222 ◽

2020 ◽

Author(s):

Tristan Lerbs ◽

Lu Cui ◽

Megan E. King ◽

Tim Chai ◽

Claire Muscat ◽

...

Keyword(s):

Clinical Trials ◽

Immune System ◽

Autoimmune Disease ◽

Skin Fibrosis ◽

Transfer Model ◽

Self Renewal ◽

Syngeneic Mouse ◽

Fibrotic Tissue

AbstractScleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression, but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated JUN and increased promotor accessibilities of both JUN and the CD47. Next, we established our scleroderma model demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1-fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study is the first to demonstrate the efficiency of combining different immunotherapies in treating scleroderma and provide a rationale for combining CD47 and IL6 inhibition in clinical trials.

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Apoptosis Modulation as a Promising Target for Treatment of Systemic Sclerosis

International Journal of Rheumatology ◽

10.1155/2011/495792 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Stéphane Chabaud ◽

Véronique J. Moulin

Keyword(s):

Systemic Sclerosis ◽

Autoimmune Disease ◽

Therapeutic Targets ◽

Immune Dysfunction ◽

Vascular Damage ◽

Loss Of Function ◽

Internal Organs ◽

Promising Target ◽

New Findings ◽

Diffuse Systemic Sclerosis

Diffuse systemic sclerosis (SSc) is a fatal autoimmune disease characterized by an excessive ECM deposition inducing a loss of function of skin and internal organs. Apoptosis is a key mechanism involved in all the stages of the disease: vascular damage, immune dysfunction, and fibrosis. The purpose of this paper is to gather new findings in apoptosis related to SSc, to highlight relations between apoptosis and fibrosis, and to identify new therapeutic targets.

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Next-Generation Gene Therapy for Parkinson’s Disease Using Engineered Viral Vectors

Journal of Parkinson s Disease ◽

10.3233/jpd-212674 ◽

2021 ◽

pp. 1-9

Author(s):

Tomas Björklund ◽

Marcus Davidsson

Keyword(s):

Parkinson’S Disease ◽

Gene Therapy ◽

Parkinson's Disease ◽

Clinical Trials ◽

Genome Editing ◽

Viral Vectors ◽

State Of The Art ◽

The State ◽

Next Generation ◽

Suitable Vector

Recent technological and conceptual advances have resulted in a plethora of exciting novel engineered adeno associated viral (AAV) vector variants. They all have unique characteristics and abilities. This review summarizes the development and their potential in treating Parkinson’s disease (PD). Clinical trials in PD have shown over the last decade that AAV is a safe and suitable vector for gene therapy but that it also is a vehicle that can benefit significantly from improvement in specificity and potency. This review provides a concise collection of the state-of-the-art for synthetic capsids and their utility in PD. We also summarize what therapeutical strategies may become feasible with novel engineered vectors, including genome editing and neuronal rejuvenation.

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Multiobjective Optimization and Artificial Immune Systems

Handbook of Research on Artificial Immune Systems and Natural Computing ◽

10.4018/978-1-60566-310-4.ch001 ◽

2011 ◽

pp. 1-21 ◽

Cited By ~ 7

Author(s):

Fabio Freschi ◽

Carlos A. Coello Coello ◽

Maurizio Repetto

Keyword(s):

Immune System ◽

Multiobjective Optimization ◽

State Of The Art ◽

Optimization Algorithms ◽

Artificial Immune Systems ◽

The State ◽

Review Of The Literature ◽

Artificial Immune ◽

Immune Systems

This chapter aims to review the state of the art in algorithms of multiobjective optimization with artificial immune systems (MOAIS). As it will be focused in the chapter, Artificial Immune Systems (AIS) have some intrinsic characteristics which make them well suited as multiobjective optimization algorithms. Following this basic idea, different implementations have been proposed in the literature. This chapter aims to provide a thorough review of the literature on multiobjective optimization algorithms based on the emulation of the immune system.

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Viral Infections and Autoimmune Disease: Roles of LCMV in Delineating Mechanisms of Immune Tolerance

10.20944/preprints201907.0134.v2 ◽

2019 ◽

Author(s):

Georgia Fousteri ◽

Amy Dave Jhatakia

Keyword(s):

Immune System ◽

Autoimmune Disease ◽

Viral Infections ◽

Molecular Mimicry ◽

Short Review ◽

Hygiene Hypothesis ◽

Organ Damage ◽

Lymphocytic Choriomeningitis ◽

Immune Deviation ◽

Viral Pathogen

Viral infections are a natural part of our existence. They can affect us in many ways that are the result of the interaction between the viral pathogen and our immune system. Most times the resulting immune response is beneficial for the host. The pathogen gets cleared thus protecting our vital organs with no other consequences. Conversely, the reaction of our immune system against the pathogen can cause organ damage (immunopathology) or lead to autoimmune disease. To date, there are several mechanisms for virus-induced autoimmune disease, including molecular mimicry and bystander activation, in support of the “fertile field” hypothesis, terms defined in our review. On the flip side, viral infections have been associated with protection from autoimmunity through mechanisms that include Treg invigoration and immune deviation, in support of the “hygiene hypothesis”, also defined here. Infection with lymphocytic choriomeningitis virus (LCMV) is one of the prototypes showing that the interaction of our immune system with viruses can either accelerate or prevent autoimmunity. Studies using mouse models of LCMV have helped conceive and establish several concepts that we today know and explain how viruses can lead to autoimmune activation or induce tolerance. Some of the most important mechanisms established during the course LCMV are described in this short review.

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Development and validation of the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214764 ◽

2019 ◽

Vol 78 (6) ◽

pp. 807-816 ◽

Cited By ~ 8

Author(s):

Nava Ferdowsi ◽

Molla Huq ◽

Wendy Stevens ◽

Marie Hudson ◽

Mianbo Wang ◽

...

Keyword(s):

Clinical Trials ◽

Systemic Sclerosis ◽

Short Form ◽

Damage Index ◽

Clinical Importance ◽

Organ Damage ◽

Physical Component Summary Score ◽

Summary Score ◽

Data Set ◽

Mortality And Morbidity

ObjectiveWe sought to develop the first Damage Index (DI) in systemic sclerosis (SSc).MethodsThe conceptual definition of ‘damage’ in SSc was determined through consensus by a working group of the Scleroderma Clinical Trials Consortium (SCTC). Systematic literature review and consultation with patient partners and non-rheumatologist experts produced a list of potential items for inclusion in the DI. These steps were used to reduce the items: (1) Expert members of the SCTC (n=331) were invited to rate the appropriateness of each item for inclusion, using a web-based survey. Items with >60% consensus were retained; (2) Using a prospectively acquired Australian cohort data set of 1568 patients, the univariable relationships between the remaining items and the endpoints of mortality and morbidity (Physical Component Summary score of the Short Form 36) were analysed, and items with p<0.10 were retained; (3) using multivariable regression analysis, coefficients were used to determine a weighted score for each item. The DI was externally validated in a Canadian cohort.ResultsNinety-three (28.1%) complete survey responses were analysed; 58 of 83 items were retained. The univariable relationships with death and/or morbidity endpoints were statistically significant for 22 items, with one additional item forced into the multivariable model by experts due to clinical importance, to create a 23-item weighted SCTC DI (SCTC-DI). The SCTC-DI was predictive of morbidity and mortality in the external cohort.ConclusionsThrough the combined use of consensus and data-driven methods, a 23-item SCTC-DI was developed and retrospectively validated.

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