Development Of Autoimmune Inflammation Research Articles

Hidradenitis suppurativa: definition, epidemiology, etiology, diagnosis (part 1)

Hidradenitis suppurativa (HS) is a chronic recurrent skin disease characterized by development of autoimmune inflammation in the infundibulum of the hair follicle and apocrine sweat glands located in the axillary, inguinal, anogenital regions, submammary folds, near the areola of mammary glands and the umbilical region. HS is difficult to treat and has an extremely negative impact on the quality of life. HS is separated into a distinct clinical entity fundamentally different in etiopathogenesis from acute bacterial hidradenitis. The exact prevalence of HS is unknown, it varies greatly in different studies ranging from 0.03 to 4% in general population. The detection of IL-1β, IL-23, and IL-17 in the lesions indicates the key role of autoimmune inflammation involving Th17-lymphocytes in the pathogenesis of HS. Risk factors include smoking, obesity, mechanical friction, genetic predisposition. The diagnosis of HS relies on three obligatory criteria: characteristic distribution, typical morphology of the lesions and relapsing, chronic disease course. There is no “gold standard” in assessing the severity of the disease, since all available scoring systems have many limitations, therefore many questions regarding this disease remain unsolved at present — from terminology and clear and most objective assessment criteria for the severity of the process to the development of native clinical guidelines.

The role of macrophages in the development of neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative disease of the central nervous system with an autoimmune mechanism of development. It is known that along with T- and B-lymphocytes, cells of the innate immune system also play a significant role in the pathogenesis of MS. Macrophages are central to the functioning of the innate immune response and, depending on the phenotype, have pro-and anti-inflammatory properties. In the central nervous system, resident macrophages form microglia capable of presenting antigens and producing cytokines and, depending on phenotype, may participate in the development of autoimmune inflammation or maintaining immunological tolerance. The brief report presents data on the participation of macrophages in the pathogenesis of experimental autoimmune encephalomyelitis and MS. In addition, current methods of modulation of macrophage functions for the treatment of MS are discussed.

The combined effect of nuclear and mitochondrial genomes on the risk of developing multiple sclerosis

Multiple sclerosis (MS) is a severe chronic CNS disease characterized by autoimmune inflammation, demyelination, and neurodegeneration. The interaction of mitochondrial and nuclear genomes is shown to be important in the formation of a predisposition to many diseases.Objective: to analyze the association of MS with the carriage of biallelic combinations, including as components the polymorphisms of three genes of mitochondrial DNA (mtDNA) and those of 16 nuclear genes, the products of which are involved in the functioning of the immune system and may participate in the development of autoimmune inflammation in MS; and, if these combinations are identified, to determine the nature of an interaction between their components. Patients and methods. The investigation enrolled 540 MS patients and 406 control group individuals; all were Russians. The mitochondrial genome was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. APSampler software was used for multilocus association analysis. Results and discussion. The investigators identified five biallelic combinations that were associated with MS (p=0.0036–0.022) and possessed protective properties (odds ratio (OR) 0.67–0.75). The mitochondrial component of the identified combinations was the polymorphisms m.4580 (rs28357975), m.13368 (rs3899498), and m.13708 (rs28359178) mtDNA; the nuclear component was CXCR5 (rs523604), TNFRSF1A (rs1800693), and CD86 (rs2255214) gene polymorphisms. The interaction between the components of the identified combinations was additive. Conclusion. The data obtained in the Russian population suggest that the combined contribution of the mitochondrial and nuclear genomes may affect the risk of developing MS.

Молекулярно-генетическое исследование рассеянного склероза

Рассеянный склероз - это хроническое воспалительное демиелинизирующее заболевание центральной нервной системы многофакторной природы. Цель настоящего исследования состояла в проведении анализа ассоциаций с заболеванием полиморфных маркеров в генах, продукты которых предположительно участвуют в патогенезе заболевания, а также идентифицированных в результате проведения полногеномных исследований, в популяциях башкир, русских и татар, проживающих в Республике Башкортостан. В результате проведенного исследования нами получены данные, подтверждающие ассоциацию с рассеянным склерозом генов, продукты которых участвуют в развитии аутоиммунного воспаления центральной нервной системы. Multiple sclerosis is a chronic inflammatory demyelinating disorder of central nervous system of multifactorial origin. Genome-wide association studies identified 700 polymorphic genetic variants associated with multiple sclerosis. The aim of the current study was to analyse associations of the polymorphic markers in genes involved in the pathogenesis of the disease and those identified by genome-wide association studies in the populations of Bashkirs, Russians, and Tatars from the Republic of Bashkortostan (Russian Federation). The study group was comprised of 644 patients with multiple sclerosis and 1408 control group individuals. Genotyping of 35 polymorphic genetic markers was performed using allele-specific PCR and PCR followed by restriction fragment length polymorphism analysis. The data obtained in our study confirm the association with multiple sclerosis of the genes involved in the development of autoimmune inflammation in central nervous system.

Autoimmune/inflammatory syndrome induced by adjuvants

The development of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is associated with the hyperergic reaction of the human immune system. The development of autoimmune inflammation is preceded by contact with internal or external trigger factors (adjuvants) of immune disorders. ASIA is associated with an individual genetic predisposition that is probably associated with the carriage of HLA-DRB1*01 or HLA-DRB4. The paper presents five possible options for the impact of adjuvants in the pathogenesis of autoimmune disorders. It gives diagnostic criteria for the syndrome, as well as its clinical, laboratory and morphological manifestations. Emphasis is laid on the importance of morphological changes in the diagnosis of autoimmune disorders. The spectrum of morphological changes in ASIA is extensive. The tissues show signs of immune inflammation, such as lymphohistiocytic infiltration, granulomatous inflammation, and scleroderma-like changes. The characteristic feature is the regression of clinical, laboratory, and morphological manifestations after adjuvant removal.

Maturation and cytokine production potential of dendritic cells isolated from rheumatoid arthritis patients peripheral blood and induced in vitro

BackgroundSince dendritic cells (DC) are involved in the development of autoimmune inflammation, researchers consider DC both as target cells for specific therapy of rheumatoid arthritis (RA) and as candidate cells for the development of cell-based methods to treat autoimmune diseases. The development of treatment strategies requires comprehensive research into the quantitative and qualitative characteristics of DC subtypes both ex vivo from RA patients and in vitro, to determine the possibility of inducing functionally mature DC in RA. ObjectiveTo study the phenotypic and functional properties of myeloid (mDC) and plasmacytoid (pDC) DC isolated from the peripheral blood of patients with RA and induced in vitro. Materials and methodsBlood samples were obtained from RA patients and healthy donors. Immature DC in the whole blood and in vitro induced DC were characterized by the positive expression of CD80, CD83, CCR7, IL-10, IL-4, IL-12 and IFN-α. R848 and lipopolysaccharide were used to determine DC maturation ability. From PBMCs of RA patients and health donors DCs with myeloid (imDC) and plasmacytoid (ipDC) phenotype were induced. ResultsThe relative count of mDC in the peripheral blood between studied groups did not differ. pDC count was significantly lower for RA patients. DC from RA patients were characterized by low expression levels of CD80 and CD83 on both populations cells and high expression of CCR7 only on pDC. An increase in pDC producing IL-12 and IFN-α and a decrease in mDC and pDC producing IL-4 and IL-10 were shown in RA. imDC and ipDC obtained from RA patients according to their phenotype and cytokine profile did not differ from those obtained from healthy donors. ConclusionsThere is an imbalance between subpopulations of DC in the peripheral blood of RA patients. DC of RA patients are less mature. The data suggest the involvement of DC in RA pathogenesis and confirm DC participation in balance shift towards Th1-type immune responses. At the same time, in vitro induced RA DC are phenotypically and functionally competent.

ROLE OF TOLL-LIKE RECEPTORS AND THEIR ENDOGENOUS LIGANDS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS: A REVIEW OF LITERATURE

Despite great advances in the study of the pathogenesis of rheumatoid arthritis (RA), which could design a radically new class of fundamentally sound therapeutic agents, many immunological aspects remain fully unstudied. The role of innate immunity mechanisms in the development of autoimmune inflammation is one of the important issues in the pathogenesis of not only RA, but also all rheumatic diseases. The discovery of pattern recognition receptors (PRRs) has allowed fundamental immunology to make a great stride toward understanding how these mechanisms are implemented. The study of membranous and endosomal Toll-like receptors (TLRs), the most extensive and well-studied group of PRRs, is a promising area of modern rheumatology. It is significant to note that some molecular agents, the presence of which in tissue is associated with its damage, are able to stimulate TLRs. They have received the name damage-associated molecular patterns (DAMPs). The paper provides a review of the literature on the mechanisms of TLR-mediated signaling pathways, on different aspects of a role of individual TLRs and DAMPs in the induction and maintenance of autoimmune inflammation in RA, and on prospects for targeted therapy aimed at inhibiting some TLRs and DAMPs.

Modern view on the role of serotonergic system in the regulation of autoimmune inflammation, perception of pain and emotional sphere (review of references)

The article is dedicated to the review of references related to the influence of serotonergic system on the development of autoimmune inflammation. We analysed the data indicating the role of serotonin receptor gene 5-HT2A polymorphism in the development of rheumatic arthritis (RA). We also showed some findings concerning the importance of serotonergic system in regulation of pain syndrome of various origin and demonstrated the significance of gene polymorphism associated with serotonin in regulation of psycho-emotional sphere.

Role of interleukin-6 in the development of atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Coronary vascular events caused by atherosclerosis are one of the leading causes of death in RA. The review gives the results of studies of the role of interleukin-6 (IL-6) in the development of autoimmune inflammation and cardiovascular diseases. The link between IL-6, inflammation, and blood lipid spectrum is considered. Attention is focused on the lipid-lowering and pleiotropic effects of statins. There is information of the effects of IL-6 receptor inhibitors (Tocilizumab – TCZ)) on blood lipid levels in RA. The implication of IL-6 in the pathogenesis of atherosclerosis in RA and the effects of TCZ on the development and progression of atherosclerosis need future investigations.

AB0055 Rho a protein and erk/jnk pathways regulate il-23 production by tlr2 in synovial macrophages from patients with rheumatoid arthritis

BackgroundTLR2 expression upon application of TNF-a, IL-1b, and LPSin synovial fibroblasts from joints of RA patients (1, 2).IL-23 is involved in autoimmune diseases such as RA and psoriasis, in which...

TNF-α impairs differentiation and function of TGF-β-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway

Deficiency in the TGF-β-induced regulatory T (iTreg) cell differentiation is associated with compromised immune homeostasis and plays a key role in many autoimmune diseases. Therapeutic intervention to enhance in situ iTreg differentiation has become a promising treatment modality for autoimmune diseases. Here we describe that the development of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE) is associated with selective impairment of iTreg differentiation largely due to the increased production of TNF-α. The neutralization of TNF-α markedly increases iTreg differentiation, leading to the amelioration of EAE, whereas the depletion of iTreg cells abolishes the therapeutic effect of an anti-TNF-α antibody. The inhibition of iTreg differentiation by TNF-α is mediated through a signaling cascade involving the induction of TNF receptor II (TNFR2) expression and the activation of Akt. The activated Akt in turn interacts with Smad3, resulting in the inhibition of TGF-β-induced Smad3 phosphorylation and consequently the reduction of p-Smad3 results in the decreased binding to the specific binding site of the foxp3 promoter, and finally foxp3 transcription itself. Interestingly, this regulatory pathway is iTreg cell specific as TNF-α does not activate Akt in naturally occurring regulatory T cells, therefore conferring a selective effect of TNF-α and its antagonism on iTreg cells. The study sheds new light on the critical role and underlying mechanism of TNF-α in the regulation of iTreg differentiation and provides a novel rationale for TNF-α antagonistic therapy for autoimmune diseases.

T-cell regulation in the pathogenesis of autoimmune diseases

Evidence suggests that chronic inflammation in several human autoimmune diseases, such as rheumatoid arthritis (RA), is mediated by activated Th1 cells. Delineation of the regulatory mechanisms controlling a Th1-biased human immune reaction and its pathologic potential is, therefore, a critical step in the understanding of chronic autoimmune inflammation. We analyzed T-cell subsets from patients with RA with regard to their regulatory capacity for Th1 inflammation. Flow cytometric analysis of freshly isolated peripheral blood (PB) and synovial fluid (SF) T cells revealed that rheumatoid inflammation is characterized by the absence of Th2 cells and their cytokines. Moreover, resting T cells from patients with RA expressed an impaired ability to differentiate into Th2 effectors with a potential to downmodulate Th1 inflammation. Thus, altered Th2 cell differentiation might contribute to the imbalance in favor of inflammatory Th1 cells in RA. Whereas Th2 cytokines, such as IL-4, play essential roles in regulating the development and perpetuation of Th1-mediated autoimmune responses, a novel subset of regulatory CD4 T cells that express CD25 on their surface and perform their suppressor function on the development of autoimmune inflammation by cytokine-independent mechanisms has recently been described in animals and humans. However, their in vivo role in human inflammation is largely elusive. We identified CD4CD25pos T cells in the PB and the SF of patients with active RA. Importantly, CD4CD25pos T cells from both RA PB and RA SF exerted potent suppressive activity as proliferation of autologous peripheral blood mononuclear cells was significantly inhibited by the presence of CD4CD25pos T cells compared with proliferation in the presence of CD4CD25neg T cells. CD4CD25 regulatory T-cell-mediated inhibition of the proliferation was abrogated by addition of exogenous IL-2, a characteristic of CD4CD25 regulatory T cells in animals. Moreover, RA CD4CD25 T cells had a markedly decreased proliferative capacity in response to anti-CD3 monoclonal antibody, suggesting an anergic phenotype typical for CD4CD25 regulatory T cells. Together, the data indicate that, in contrast to immunomodulatory Th2 effectors, CD4CD25pos T cells with potent suppressive potential are present in rheumatoid inflammation. The data further suggest that CD4CD25pos regulatory T cells are involved in the continuous regulation of the developing human Th1 inflammation in vivo. However, their activity appears to be insufficient to silence the chronic immune response in RA.

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis.

The complement system is important in the development of autoimmune inflammation, including rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Complement receptor 1 (CR1) is involved in regulation of complement activity. Studies on models of autoimmunity have demonstrated that soluble CR1 (sCR1) is a potent therapeutic agent. The present study was thus undertaken to investigate the feasibility of antiinflammatory gene therapy to prevent CIA by delivery of genes encoding truncated sCR1 (tsCR1) and dimeric tsCR1-Ig. Syngeneic fibroblasts or arthritogenic splenocytes, engineered to express tsCR1 using retrovirus-mediated gene transfer, were injected into DBA/1 recipients that had been immunized with bovine type II collagen (CII). In separate experiments, naked DNA containing tsCR1 and tsCR1-Ig genes was injected intramuscularly into the immunized animals. The clinical development of arthritis was monitored, anti-CII levels measured, and antigenic T cell response studied. Affinity-purified tsCR1-Ig was assayed for its inhibitory effect on the alternative complement pathway in mouse serum. Treatment of CII-immunized mice with the tsCR1-expressing cells inhibited development of CIA, reduced anti-CII antibody levels, and inhibited T cell response to CII in vitro. Intramuscular injections of DNA encoding the CR1 genes prevented the progression of disease. Furthermore, compared with full-length sCR1, purified tsCR1-Ig was more active in inhibiting the murine alternative complement pathway. Our findings demonstrated that tsCR1 and tsCR1-Ig, when delivered via gene therapy, had a beneficial effect on autoimmune inflammation. These results indicate that targeting the complement system in RA patients may be of clinical importance.