Proteins In Arthritis Research Articles

Type II Collagen-Specific B Cells Induce Immune Tolerance in Th1-Skewed, Th2-Skewed, and Arthritis-Prone Strains of Mice.

Antigen-specific regulatory T cells play key immune suppressive roles in autoimmune disease models and regulate the peripheral tolerance achieved via anterior chamber-associated immune deviation (ACAID). Articular cartilage has type II collagen (CII), which is a potent autoantigen protein in arthritis. There has not been much research on the clinical importance of CII-associated diseases. Moreover, the capability of CII to induce immune tolerance has not been previously assessed. We reported that delivery of CII either directly into the eye or via intravenous injection of CII-specific ACAID antigen presenting cells (APCs) can induce ACAID. Here, we hypothesized that peripheral tolerance can be induced following adoptive transfer of in vitro generated CII-specific ACAID B cells to naive mice. Delayed hypersensitivity (DTH) assays were used to assess the suppressive ability of adoptively transferred B cells. Immune responses of ACAID B cell-injected mice were significantly suppressed following challenges with CII as compared to positive controls. This effect was replicated in three different strains of mice (C57BL/6, BALB/c, and DBA/1). Thus, CII-specific ACAID B cells were able to induce immune tolerance in Th1-skewed, Th2-skewed, and arthritis-prone mice. ACAID B cell-mediated tolerance induced by CII could have therapeutic implications for the treatment of CII-mediated autoimmune diseases.

Context-dependent HOX transcription factor function in health and disease.

During animal development, HOX transcription factors determine the fate of developing tissues to generate diverse organs and appendages. The power of these proteins is striking: mis-expressing a HOX protein causes homeotic transformation of one body part into another. During development, HOX proteins interpret their cellular context through protein interactions, alternative splicing, and post-translational modifications to regulate cell proliferation, cell death, cell migration, cell differentiation, and angiogenesis. Although mutation and/or mis-expression of HOX proteins during development can be lethal, changes in HOX proteins that do not pattern vital organs can result in survivable malformations. In adults, mutation and/or mis-expression of HOX proteins disrupts their gene regulatory networks, deregulating cell behaviors and leading to arthritis and cancer. On the molecular level, HOX proteins are composed of DNA binding homeodomain, and large regions of unstructured, or intrinsically disordered, protein sequence. The primary roles of HOX proteins in arthritis and cancer suggest that mutations associated with these diseases in both the structured and disordered regions of HOX proteins can have substantial functional effects. These insights lead to new questions critical for understanding and manipulating HOX function in physiological and pathological conditions.

In vitro study on role of σB protein in avian reovirus pathogenesis.

Avian reoviruses, members of Orthoreovirus genus was known to cause diseases like tenosynovitis, runting-stunting syndrome in chickens. Among eight structural proteins, the proteins of S-class are mainly associated with viral arthritis but the significance of σB protein in arthritis is not established till date. In this infection pathological condition together with infection of joints often leads to arthritis because joints consists of cartilage which forms lubricating surface between two bones, and has limited metabolic, replicative and repair capacity.To establish the role of σB protein in arthritis, an in-vitro microarray study was conducted consisting four groups viz. virus infected and control; pDsRed-Express-N1-σB and empty pDs-Red transfected, CEF cells. With cut-off value as FC ≥2, p value <0.05, 6709 and 4026 numbers of DEGs in virus and σB, respectively were identified. The Ingenuity Pathway Analysis gave an idea about the involvement of σB protein in “osteoarthritis pathway”, which was activated with z-score with 3.151. The pathway “Role of IL-17A in arthritis pathway” was also enriched with –log (p-value) 1.64. Among total 122 genes involved in osteoarthritis pathway, 28 upregulated and 11 downregulated DEGs were common to both virus and σB treated cells. Moreover, 14 upregulated and 7 downregulated were unique in σB transfected cells. Using qRT-PCR for IL-1B, BMP2, SMAD1, SPP1 genes, the microarray data was validated. We concluded that during ARV infection σB protein, if not fully partially leads to molecular alteration of various genes of host orchestrating the different molecular pattern in joints, leading to tenosynovitis syndrome.

Molecular docking and dft studies of compounds identified from barleria cristata leaves to rheumatoid arthritis protein

Molecular docking and dft studies of compounds identified from barleria cristata leaves to rheumatoid arthritis protein

Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

Citrullination, the post-translational conversion of arginines to citrullines, may contribute to rheumatoid arthritis development given the generation of anti-citrullinated protein antibodies (ACPAs). However, it is not known which peptidylarginine deiminase (PAD) catalyzes the citrullination seen in inflammation. PAD4 exacerbates inflammatory arthritis and is critical for neutrophil extracellular traps (NETs). NETs display citrullinated antigens targeted by ACPAs and thus may be a source of citrullinated protein. However, PAD4 is not required for citrullination in inflamed lungs. PAD2 is important for citrullination in healthy tissues and is present in NETs, but its role in citrullination in the inflamed joint, NETosis and inflammatory arthritis is unknown. Here we use mice with TNFα-induced inflammatory arthritis, a model of rheumatoid arthritis, to identify the roles of PAD2 and PAD4 in citrullination, NETosis, and arthritis. In mice with TNFα-induced arthritis, citrullination in the inflamed ankle was increased as determined by western blot. This increase was unchanged in the ankles of mice that lack PAD4. In contrast, citrullination was nearly absent in the ankles of PAD2-deficient mice. Interestingly, PAD2 was not required for NET formation as assessed by immunofluorescence or for killing of Candida albicans as determined by viability assay. Finally, plasma cell numbers as assessed by flow cytometry, IgG levels quantified by ELISA, and inflammatory arthritis as determined by clinical and pathological scoring were all reduced in the absence of PAD2. Thus, PAD2 contributes to TNFα-induced citrullination and arthritis, but is not required for NETosis. In contrast, PAD4, which is critical for NETosis, is dispensable for generalized citrullination supporting the possibility that NETs may not be a major source of citrullinated protein in arthritis.

Cell penetrating recombinant Foxp3 protein enhances Treg function and ameliorates arthritis

Foxp3 is the master transcription factor for T regulatory (Treg) cell differentiation and function. This study aimed to test the therapeutic potential of cell penetrating recombinant Foxp3 protein in arthritis. Recombinant Foxp3 protein was fused to a cell penetrating polyarginine (Foxp3-11R) tag to facilitate intracellular transduction. In vitro Foxp3-11R treated CD4+ T cells showed a 50% increase in suppressive function compared with control protein treated cells. Severity of arthritis in Foxp3-11R treated mice was significantly reduced compared with those treated with a control protein. CD4+ T cells of lymph nodes and spleen from Foxp3-11R treated mice showed increased levels of Foxp3 expression compared with those of a control protein treated. These results demonstrated that Foxp3-11R can enhance T cell suppressive function and ameliorate experimental arthritis and suggest that cell penetrating recombinant Foxp3 is a potentially useful agent in therapy of arthritis.

RNAi mediated silencing of hnRNP-A2 decreases collagen-induced arthritis by inhibiting proliferation and cytokine production of cells of the mononuclear phagocytic system

BackgroundHeterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) belongs to a heterogenous family of nuclear proteins, importantly involved in mRNA trafficking, translational and transcriptional processes. Recent evidence let suggest that hnRNPs post-transcriptionally modulate...

ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor

ADAMTS-7, a metalloproteinase that belongs to ADAMTS family, is important for the degradation of cartilage extracellular matrix proteins in arthritis. Herein we report that ADAMTS-7 is upregulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. ADAMTS-7 potently inhibits chondrocyte differentiation and endochondral bone formation, and this inhibition depends on its proteolytic activity. The cysteine-rich domain of ADAMTS-7 is required for its interaction with the extracellular matrix, and the C-terminal four-thrombospondin motifs are necessary for its full proteolytic activity and inhibition of chondrocyte differentiation. ADAMTS-7 is an important target of canonical PTHrP signaling, since (i) PTHrP induces ADAMTS-7, (ii) ADAMTS-7 is downregulated in PTHrP null mutant (PTHrP-/-) growth plate chondrocytes, and (iii) blockage of ADAMTS-7 almost abolishes PTHrP-mediated inhibition of chondrocyte hypertrophy and endochondral bone growth. ADAMTS-7 associates with granulin-epithelin precursor (GEP), an autocrine growth factor that has been implicated in tissue regeneration, tumorigenesis, and inflammation. In addition, ADAMTS-7 acts as a new GEP convertase and neutralizes GEP-stimulated endochondral bone formation. Collectively, these findings demonstrate that ADAMTS-7, a direct target of PTHrP signaling, negatively regulates endochondral bone formation by associating with and inactivating GEP chondrogenic growth factor.

The role of Wnt proteins in arthritis

Wnt proteins regulate organ development, tumorigenesis and bone homeostasis, among other functions. The binding of Wnt proteins to plasma membrane receptors on mesenchymal cells induces the differentiation of these cells into the osteoblast lineage and thereby supports bone formation. Wnts are also key signaling proteins in joint remodeling processes. Active Wnt signaling contributes to osteophyte formation and might have an essential role in the anabolic pattern of joint remodeling that is observed in ankylosing spondylitis and osteoarthritis. By contrast, blockade of Wnt signaling facilitates bone erosion and contributes to catabolic joint remodeling, a process that is observed in rheumatoid arthritis. This Review summarizes current knowledge of the molecular regulation of joint remodeling associated with chronic arthritis, focusing on the role of the Wnt proteins and their inhibitors. It also addresses the role of Wnt in determining the differences in clinical presentation of inflammatory arthropathies and discusses implications for future therapy.

Antibodies to citrullinated proteins in arthritis: pathology and promise

The purpose of this review is to describe how the current knowledge of antibodies to citrullinated protein antigens in rheumatoid arthritis and related conditions emerged; to discuss the diagnostic and prognostic value associated with antibodies to citrullinated protein antigens as a biomarker; and most importantly for this review, to discuss the potential pathogenetic significance of these antibodies. Antibodies to citrullinated protein antigens have evolved from being mainly a diagnostic marker, to being recognized as something that can help us understand fundamental etiologic and pathogenetic features of rheumatoid arthritis. Fundamental in this context is the finding that rheumatoid arthritis can be divided into two distinct subsets by means of presence or absence of antibodies to citrullinated protein antigens. Thus, several genetic as well as environmental risk factors differ between these two variants of rheumatoid arthritis. From analysis of these genetic and environmental risk factors, new testable hypotheses have been produced concerning triggering of antibodies to citrullinated protein antigens, and potential pathogenicity of antibodies to citrullinated protein antigens and accompanying immune reactions. The implications of the findings are that antibodies to citrullinated protein antigens can be used for early and precise diagnosis of a subset of rheumatoid arthritis with worse prognosis than other polyarthritides, and that a new basis is formed for etiologic and pathogenetic studies of antibodies to citrullinated protein antigens-positive rheumatoid arthritis.

Mechanisms of Disease: the role of high-mobility group protein 1 in the pathogenesis of inflammatory arthritis

High-mobility group protein 1 (HMG1) is a nonhistone nuclear protein that is a prototype of a dual-function alarmin whose immune activity is dependent upon its cellular location. Inside the cell, HMG1 binds to DNA and has a role in transcriptional regulation. Outside the cell, HMG1 acts as a cytokine and has activities that resemble those of tumor necrosis factor. The cytokine activities of HMG1 become manifest when this protein translocates from the nucleus to the cytoplasm and, eventually, into the external milieu; this translocation occurs during cell activation and cell death. Given its cytokine activity, HMG1 has been implicated in the pathogenesis of a broad range of immune-mediated diseases including arthritis. The role for this protein in arthritis was established by observations of the expression of HMG1 in synovial tissue of patients with rheumatoid arthritis as well as in the joints of animals used to model arthritis. Furthermore, in the mouse model of collagen-induced arthritis, treatment with antibodies to HMG1 or to an inhibitory domain of HMG1 can attenuate joint inflammation and damage. These studies identify a novel pathway in the pathogenesis of inflammatory arthritis, as well as a new target for biologic therapy.

Proinflammatory S100 proteins in arthritis and autoimmune disease

Proinflammatory S100 proteins in arthritis and autoimmune disease

Citrullinated Proteins in Arthritis; their Presence in Joints and Effects on Immunogenicity

Autoantibodies directed against citrulline‐containing proteins have an impressive specificity of nearly 100% in RA patients and a suggestive involvement in the pathogenesis. The targeted epitopes are generated by a post‐translational modification catalysed by the calcium‐dependent enzyme peptidyl arginine deaminase that converts the positively charged arginine to polar but uncharged citrullin. The aim of this study was to analyse the presence of citrulline in the joints at different time points of collagen‐induced arthritis in DA rats by immunohistochemistry and to investigate how immunogenicity and arthritogenicity was affected by citrullination of rat serum albumin (RSA) and collagen type II (CII). Our results indicate that citrulline could be detected in joints of arthritic animals, first appearance at the onset of disease and increasing as disease progressed into a chronic state. Unimmunized animals or time points before clinical signs of arthritis were negative. By morphology, we state that some infiltrating macrophages as well as the cartilage surface stain positive for citrulline, while the major source of citrullinated proteins appears to be fibrin depositions. A specific Cit‐RSA T‐cell response was observed in animals challenged by citrullinated RSA, no response was recorded when RSA was used as a stimulus. The IgG analysis reveals not only a response towards the modified protein but also cross‐reactivity to native RSA. No T‐cell or B‐cell response was noted in animals injected with unmodified RSA. Cit‐CII induced a disease with higher incidence and earlier onset than did the native counterpart. We conclude that, in contrast to the human disease, citrulline does not seem to appear before clinical signs. As inflammation proceeds, citrulline is detected specifically in the joints. All other organs investigated were negative. We also conclude that citrullination of a protein can break tolerance and increase its arthritogenic properties.

Citrullinated proteins in arthritis: presence in joints and effects on immunogenicity

Citrullinated proteins in arthritis: presence in joints and effects on immunogenicity

Induction of tolerance with intranasal administration of human cartilage gp-39 in DBA/1 mice: amelioration of clinical, histologic, and radiologic signs of type II collagen-induced arthritis.

Human cartilage glycoprotein 39 (HC gp-39) was recently identified as a candidate autoantigen in the pathogenesis of rheumatoid arthritis. In the present studies, we investigated the capacity of HC gp-39 to interfere in clinical disease induced by an unrelated autoantigen, type II collagen (CII), by the induction of cross-tolerance. DBA-1j/Bom mice were immunized with bovine CII/complete Freund's adjuvant and were given intraperitoneal booster injections of CII on day 21. Tolerance was induced via the intranasal pathway with either the disease-inducing antigen (CII), a control antigen (ovalbumin), or HC gp-39 either before priming with CII or near the day of the booster injection. Arthritis was monitored visually, and joint pathology was examined histologically and radiologically. In addition, CII antibody levels in serum were analyzed by enzyme-linked immunosorbent assay. In contrast to treatment before priming, intranasal application of HC gp-39 after immunization markedly suppressed disease activity and prevented joint destruction, whereas application of ovalbumin or CII was ineffective. Interference of HC gp-39 with the immune response to CII was demonstrated by decreased anti-CII antibody levels. The combined data indicate that intranasal treatment with HC gp-39 may trigger modulatory or regulatory mechanisms that interfere with the expression of disease in murine collagen-induced arthritis. HC gp-39 is the first cross-tolerance-inducing protein in arthritis that down-modulates a spectrum of disease features when given in a semitherapeutic protocol.

INTERLEUKIN-1 RECEPTOR ANTAGONIST: Role in Biology

The interleukin-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular isoform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellular forms have been cloned, and some of the functional cis-acting DNA regions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The tissue distribution of IL-1Ra in mice indicates that sIL-1Ra is found predominantly in peripheral blood cells, lungs, spleen, and liver, while icIL-1Ra is found in large amounts in skin. Studies in transgenic and knockout mice indicate that IL-1Ra is important in host defense against endotoxin-induced injury. IL-1Ra is produced by hepatic cells with the characteristics of an acute phase protein. Endogenous IL-1Ra is produced in numerous experimental animal models of disease as well as in human autoimmune and chronic inflammatory diseases. The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease. Treatment of human diseases with recombinant human IL-1Ra showed an absence of benefit in sepsis syndrome. However, patients with rheumatoid arthritis treated with IL-1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage.

Stress proteins, infection, and immune surveillance

Prokaryotic and eukaryotic cells respond to potentially damaging stimuli such as elevated temperature by increasing the synthesis of a family of proteins collectively known as stress proteins. The major stress proteins (also known as heat shock proteins) are among the most highly conserved and abundant proteins found in nature. Stress proteins have been shown to be among the dominant antigens recognized in immune responses to a broad spectrum of pathogens. Recent reports indicate that immune responses against stress proteins can be highly crossreactive and can even involve anti-self reactivity. Some of these reports implicate immune responses to stress proteins in arthritis. Others suggest that healthy individuals may have the capacity to respond to self stress protein determinants in a manner that could help eliminate their own cells that are infected, transformed, or otherwise stressed. The purpose of this review is to bring together observations on the nature of stress proteins, the antigenicity of stress proteins, and the relationship between stress protein antigens and autoimmunity. The Stress Response and Stress Proteins One to two dozen proteins are induced in response to a range of different stresses, including heat shock, nutrient deprivation, oxygen radicals, and metabolic disruption. The best studied of these stresses is heat shock (reviewed in Lindquist and Craig, 1988), in which a sudden increase in temperature induces the increased synthesis of heat shock proteins (hsp’s). The heat shock response is the most highly conserved genetic system known. Because many of the heat shock proteins are also induced by other stresses, we refer to them here as stress proteins. The stress proteins are remarkable in their evolutionary conservation. For example, the hsp90, hsp70, and hsp60 proteins are found in all prokaryotes and eukaryotes. Pairwise comparison of hsp70 sequences from almost any two organisms reveals that about half of the amino acid residues are identical, and many of the remaining residues are similar. Hsp90 and hsp60 are similarly highly conserved. Indeed, these are among the most highly conserved proteins known. The major stress proteins occur at low to moderate levels in cells that have not been stressed but accumulate to very high levels in stressed cells. The most striking example of this is E. coli hsp60, which accounts for 1.6% of total M inireview

Serum and synovial fluid proteins in arthritis.

Synovial fluid isgenerally considered tobe a dialysate ofplasma towhichmucinhasbeenadded during itspassage through thesynovial membrane (RopesandBauer,1953).The proteins ofthe serumandsynovial fluid havebeenshowntobe qualitatively identical (Schmid andMacNair, 1956) andtheconcentrations ofthevarious proteins in synovial fluid probably depend uponthefollowing factors: (1)Themolecular weights ofthevarious protein fractions; thesmaller albumin molecules achievingrelatively higher concentrations inthenormal synovial fluid thanthelarge globulin molecules (Decker, McKenzie, McGuckin, andSlocumb, 1959).

THE FORMOL-GEL REACTION IN BLOOD OF PATIENTS WITH CHRONIC RHEUMATOID DISEASES

Article1 December 1940THE FORMOL-GEL REACTION IN BLOOD OF PATIENTS WITH CHRONIC RHEUMATOID DISEASESC. WESLER SCULL, PH.D., RALPH PEMBERTON, M.D., F.A.C.P.C. WESLER SCULL, PH.D.Search for more papers by this author, RALPH PEMBERTON, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-14-6-993 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptINTRODUCTIONStudies conducted in this laboratory on the protein fractions in the sera of arthritics clearly show that moderate and sometimes marked hyperglobulinemia is a significant feature among certain classes of arthritic subjects.6Associated with the increase in serum globulin there is an elevation in the fibrinogen of the corresponding plasma. These results are in substantial agreement with observations made by Aldred-Brown and Monroe1and by Davis.3Recognition of the presence of these features in a given case is of practical importance, inasmuch as an elevation in the level of the globulin or fibrinogen in the blood shows the presence...Bibliography1. ALDRED-BROWNMONROE GRJM: The plasma protein and non-protein nitrogen and sedimentation rate in chronic rheumatic disorders, Quart. Jr. Med., 1935, iv, 269-277. Google Scholar2. BING J: The formol-gel reaction and other globulin reactions, Acta med. Scand., 1937, xci, 336-356. Google Scholar3. DAVIS JS: Protein studies in atrophic (rheumatoid) and hypertrophic arthritis, Jr. Lab. and Clin. Med., 1936, xxi, 478-490. Google Scholar4. GIBSONKERSLEY HJGD: Gout, Med. Press and Circ., 1934, cxcvi, 5164. Google Scholar5. GIBSONRICHARDSON HJEW: The formol-gel test (aldehyde reaction) in chronic rheumatism, Acta Rheumatol., 1938, x, 30-33. Google Scholar6. SCULLBACHPEMBERTON CWTFR: The serum proteins in arthritis, ANN. INT. MED., 1939, xii, 1463-1472. Google Scholar7. WISEGUTMAN CRAB: The formol-gel reaction: a convenient preliminary test for hyperglobulinemia, Am. Jr. Med. Sci., 1937, cxciv, 263-270. CrossrefGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Philadelphia, Pennsylvania*Received for publication June 18, 1940.From the Abington Memorial Hospital, Abington, Pa.The expenses of this investigation were defrayed in part by a grant in memory of Alexander B. Coxe. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe Formol-Gel Test on Plasma and Serum in Rheumatic Cases: Correlation Studies and a Suggestion that Non-Rouleaux-Forming Pathological Globulins may be of Significance in Rheumatism 1 December 1940Volume 14, Issue 6Page: 993-1000KeywordsBloodBlood plasmaFibrinogenGlobulinsHyperglobulinemiaMemoryPlasma proteinsResearch laboratoriesSerum proteins ePublished: 1 December 2008 Issue Published: 1 December 1940 PDF downloadLoading ...