Autoantibody Synthesis Research Articles

Clinical and immunological parallels in periprosthetic infection after total large joints arthroplasty

Aim. To study peripheral blood lymphocytes and monocytes subpopulations and evaluate synthesis of serum autoantibodies in patients with periprosthetic infection after large joints arthroplasty.Methods. The study included 40 patients with infectious and inflammatory complications that developed at different times after knee or hip arthroplasty. All patients were divided into three groups according to the Coventry-Fitzgerald-Tsukayama classification. The number of cells expressing the CD3, CD4, CD8, CD19, CD14, CD16 and CD56 antigens, the expression of the activation markers HLA-DR, CD25 on lymphocytes and monocytes, the number of peripheral blood CD4+CD45RA+, CD4+CDRO+ cells, and the level of serum antibodies to double-stranded deoxyribonucleic acid (DNA) and anti-neutrophil antibodies were evaluated.Results. It is found that in acute development of infectious and inflammatory process in peripheral blood a significant increase in the number and functional activity of T-cells occur. For long-term low-grade infectious and inflammation process significant increase in the number of B-cells and memory T-cells, decrease in the number of naive T-cells are characteristic. Monocyte HLA-DR expression and the amount of B-lymphocytes correlate with the severity of inflammation. In seven patients elevated levels of antibodies to double-stranded DNA, in six - antineutrophil antibodies were revealed in blood serum.Conclusion. The assessment of lymphocytes subpopulations and the monocyte HLA-DR expression can be used as additional laboratory criteria for the diagnosis of infectious and inflammatory processes after large joints arthroplasty; the role of autoantibodies to double stranded DNA and anti-neutrophil antibodies, which were found in some patients, remains unclear.

Mitochondrial bioenergetics of immune cells in Type 1 diabetes

Abstract Mitochondrial (mito) bioenergetics of circulating cells change as a function of disease in Alzheimer’s, fibromyalgia, cancer, and Type 2 diabetes. We are exploring the use of mito-bioenergetics as a biomarker of Type 1 diabetes (T1D) progression and immune cell activation. T1D is a polygenic autoimmune disease in which an inflammatory leukocytic infiltrate into pancreatic islets results in destruction of insulin-producing β-cells. Autoantibody synthesis is currently used as a biomarker, but is a poor predictor of T1D since the majority of β-cells are destroyed prior to autoantibody seroconversion. We hypothesize that T1D is a chronic inflammatory disease in which conditions of oxidative stress will diminish the mitochondrial reserve capacity of immune cells and provide a surrogate marker for T1D. We compared mito-bioenergetics of murine immune cells derived from the spleen, pancreatic lymph node and bone marrow between diabetic and pre-diabetic Non-Obese Diabetic (NOD) mice. We show that mitochondrial reserve capacity is reduced in circulating CD4+ T cells from diabetic mice, but not in pre-diabetic mice during T1D progression. To explore the role of mitochondrial oxidative stress on diabetogenic CD4+ T cell effector responses, we used mito-TEMPO to scavenge mitochondrial reactive oxygen species (mROS). Mito-TEMPO reduced IFNγ synthesis in a primary recall assay by 0.24-fold and the combination of mito and cytosolic TEMPO increased Treg-associated IL-2 by 2.5-fold, suggesting that mROS have a causal role in modulating T cell effector responses critical for T1D pathology. We plan to perform human translational studies on mito-bioenergetics of PBMCs from recent onset T1D patients and further dissect the role of mROS on T1D.

SUPPRESSOR CELLS – THE BASIS OF IMMUNOPATHOGENESIS AUTOIMMUNE DISEASES

The issues of immune pathogenesis in autoimmune pathology are discussed in this review. The main attention is drawn to potential pathogenetic role of various suppressor cell populations, including T-regulatory cells, mesenchymal stem cells, myeloid lineage-derived suppressors. Homeostatic lymphocyte proliferation is considered to be of great importance for pathogenesis of autoimmune disorders. Recent data from literature suggest that the autoimmune diseases are characterized by reduced activity of the mentioned suppressor cell populations, thus being a possible prerequisite for development of autoaggressive clones of cytotoxic lymphocytes, increased synthesis of autoantibodies leading to evolving autoimmune pathology. It should be, however, noted, that all these processes are accompanied by changes in the immune system induced by homeostatic proliferation of lymphoid cells.

Abstract B09: Fetuin-A, an emerging biomarker for breast and prostate cancer

Abstract We hypothesized that fetuin-A, a liver derived glycoprotein would be a useful biomarker to follow for the progression of prostate and breast cancer particularly in African American patients. For many years, conflicting reports have appeared in the literature regarding the role of fetuin-A in the progression of a number of solid tumors. The majority of the studies have reported that the serum levels of fetuin-A drops as tumors progress, suggesting a tumor suppressive role for the protein. We on the other hand, demonstrated that it is a significant tumor growth promoter in vitro. In the recent past, a number of laboratories, including ours, have indicated that fetuin-A is actively synthesized by high grade tumors. In the present study, we investigated the appearance of fetuin-A autoantibodies in the sera of 12 prostate and breast cancer patients, 60% of whom were African Americans. We demonstrated the presence of fetuin-A auto antibodies in all except two of the tumor serum specimens. Blood of normal tumor free individuals do not show fetuin-A autoantibodies. We also subjected tissue microarrays of prostate and breast tumors to immune-histochemical analysis of fetuin-A. Our data show a dramatic increase in the synthesis of fetuin-A in the TMA particularly in high grade tumors. Taken together, these results suggest that as tumors become more aggressive they may synthesize fetuin-A which then presents as a new antigen in the blood that provokes the synthesis of auto-antibodies, which could be a biomarker of advanced or metastatic disease. Furthermore, the study suggests that fetuin-A itself could be a significant surrogate marker of aggressive tumors of the prostate or breast particularly in African Americans. Citation Format: Gladys Nangami, Josiah Ochieng, Ebenezer Appah, Philip E. Lammers. Fetuin-A, an emerging biomarker for breast and prostate cancer. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B09.

Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society.

Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder of neuromuscular synaptic transmission. The clinical hallmark of MG consists of fluctuating fatigability and weakness affecting ocular, bulbar and (proximal) limb skeletal muscle groups. MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus. Impairment of central thymic and peripheral self-tolerance mechanisms in both cases is thought to favor an autoimmune CD4+ T cell-mediated B cell activation and synthesis of pathogenic high-affinity autoantibodies of either the IgG1 and 3 or IgG4 subclass. These autoantibodies bind to the nicotinic acetylcholine receptor (AchR) itself, or muscle-specific tyrosine-kinase (MuSK), lipoprotein receptor-related protein 4 (LRP4) and agrin involved in clustering of AchRs within the postsynaptic membrane and structural maintenance of the neuromuscular synapse. This results in disturbance of neuromuscular transmission and thus clinical manifestation of the disease. Emphasizing evidence from clinical trials, we provide an updated overview on immunopathogenesis, and derived current and future treatment strategies for MG divided into: (a) symptomatic treatments facilitating neuromuscular transmission, (b) antibody-depleting treatments, and (c) immunotherapeutic treatment strategies.

Patients with systemic lupus erythematosus have higher prevalence of thyroid autoantibodies: a systematic review and meta-analysis.

BackgroundThyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder and can be associated with other autoimmune endocrine disorders or non-endocrine diseases. Systemic lupus erythematosus is a prototypical autoimmune disorder with multifactorial etiology. The pathogenesis and development of the disease may result from a loss of immune tolerance and the resulting synthesis of autoantibodies against nuclear antigens. Autoimmune factors may be common features of both thyroid autoimmunity and systemic lupus erythematosus, making it likely that both conditions may coexist within some patients.Methods and FindingsA number of studies have investigated whether an association between thyroid autoimmunity and systemic lupus erythematosus exists. However, the results of these studies have been inconsistent. Furthermore, most of these studies have had relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is an association between systemic lupus erythematosus and thyroid autoimmunity. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and systemic lupus erythematosus by combining the primary data from all relevant studies. Literature databases were searched, including the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases, from January 1970 to May 2014. A total of 1076 systemic lupus erythematosus cases and 1661 healthy controls were included in this study. From these data, the odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated. The meta-analysis results showed that the prevalence of thyroid autoantibody positivity in patients with systemic lupus erythematosus was higher than in healthy controls (TgAb: OR = 2.99, 95% CI = 1.83–4.89; TPOAb: OR = 2.20, 95% CI = 1.27–3.82, respectively).ConclusionThe results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with systemic lupus erythematosus than in a control group.

B Cell‐Targeted Therapy with Anti‐CD20 Monoclonal Antibody Reduced Secondary Tissue Damage and Enhanced Behavioral Recovery Following Experimental Spinal Cord Injury in Mice

Traumatic injury to the spinal cord activates B cells, which culminates in the synthesis of autoantibodies. The functional significance of this immune response is unclear. Antibodies produced after SCI caused pathology, in part by activating intraspinal complement and cells bearing Fc receptors. These data indicate that B cells, through the production of antibodies, affect pathology in SCI. There is increasing appreciation of the important role of B cells in spinal cord trauma and consequently, increasing interest in treating these disorders through B cell‐depletion therapy. The purpose of this study was to investigate the effects of anti‐CD20 mAb B cell depletion therapy within the first 24 hours of SCI.In this study, the T6‐T7 vertebrae in three groups of mice were injured by a 50‐g clip‐induced compression method, and the anti‐murine CD20 IgG2a antibody (clone 18B12, 1 mg/kg) was intravenously administered starting 1 hour and 6 hours postinjury. Animals were sacrified at 24 hours. The anti‐CD20 antibody treatment caused significant attenuation of leukocyte infiltration, reactive oxygen species‐associated enzymes, and secondary tissue damage. Basso‐Beattie‐Bresnahan (BBB) scores were significantly higher in anti‐CD20‐treated mice than controls 10 days postinjury. Our data demonstrate an important role of B cells which could possibly lead to B cell‐based strategies for the treatment of SCI.

ABATACEPT FOR RHEUMATOID ARTHRITIS: A NOVEL FORMULATION, NEW MECHANISMS, NEW POSSIBILITIES

Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease characterized by chronic inflammation of the synovial membrane of joints and by a wide spectrum of extra-articular (systemic) manifestations, with the pathological T cell activation that plays a key role in the pathogenesis of this disease. Therefore, the design of abatacept (ABC) that selectively inhibits T cell costimulation occupies a special place among various approaches to the pathogenetic therapy of RA. The review gives novel evidence for the efficacy and safety of its subcutaneous formulation and discusses its mechanism of action in suppressing the synthesis of autoantibodies and in restoring normal regulatory T cell function, etc. Mechanisms for the synergic action of ABC and methotrexate for RA and prospects for personified medicine in rheumatology are specially considered using the drug as an example.

New possibilities of pharmacotherapy for systemic lupus erythematosus: A place of belimumab

Systemic lupus erythematosus (SLE) is a multifactorial disease caused by complex interactions between the genetic and environmental factors underlying various innate and adaptive immunity disorders, including cytokine hyperproduction, abnormal B cell activation, impaired intracellular T-cell signaling, and defective apoptotic and necrotic cell clearance. A broad spectrum of genetic disorders associated with susceptibility to the disease and/or its definite variants has been identified. Our knowledge concerning the mechanisms of polyclonal B cell activation in SLE has advanced substantially. Various defects in the T cells regulating a B cell immune response have been detected. The development of genetic, epigenomic, transcriptomic, and proteomic technologies could identify a group of pathogenetically relevant cytokines, including BLyS (the B-lymphocyte stimulator is the most important component of cytokine-mediated regulation of B cell function, proliferation, and differentiation), interleukin (IL) 6, 17, 18, type 1 interferon, and tumor necrosis factor- α , which are involved in the development of visceral inflammation and damage. Large-scale clinical trials of different medications, primarily biological agents (BA), were conducted in patients with SLE. Rituximab (RTM) is the first BA to be used to treat this disease. Despite its official registration for the therapy of SLE, RTM is included in the EULAR, ACR, and Russia's Association of Rheumatologists guidelines for its treatment. Belimumab, a fully human recombinant IgG1λ monoclonal antibody, specially designed to treat SLE, prevents the interaction of pBLyS with the receptors of autoreactive transitional and naive B cells, giving rise to the suppression of B cell hyperresponsiveness, autoantibody synthesis in particular. In addition, BLyS block may cause decreased survival of B cells in the germinal centers of lymphoid organs, differentiation of memory B cells into autoantibody-producing cells, and synthesis of proinflammatory cytokines (IL-21, IL-17, and others) that play an important role in the immunopathogenesis of SLE. Despite its moderate efficacy, belimumab will be able to improve pharmacotherapy for this disease.

Current methods of treatment of true acantholytic pemphigus

Major stages of the pathogenesis of true acantholytic pemphigus are interpreted in terms of autoimmune pathology; therefore, treatment of this group of diseases remains pathogenetic and is aimed at suppressing the synthesis of autoantibodies against keratinocyte proteins. Treatment with the use of systemic glucocorticosteroids is currently the main method of treatment for true acantholytic pemphigus. To reduce the course dose of glucocorticosteroids, decrease the risk of adverse effect development and achieve long-term remission, further studies of disease pathogenesis and development of new treatment methods for reducing the doses of glucocorticosteroids are of great importance.

Anti-vascular endothelial growth factor receptor (VEGFR) 2 autoantibody identification in glioblastoma patient using single B cell-based antibody gene cloning

Antibody direct cloning from single B cells is simple and efficient and has been successful in antibody identification of infectious diseases. However, although a recent whole-exome sequencing revealed abundant heterogeneic mutation accumulation in cancers, identification and synthesis of autoantibodies against specific cancer-associated antigens is still difficult in cancer patients owing to the very small number of B cells producing autoantibodies. In the present study, to identify autoantibodies targeting tumor antigens, we measured the titer of autoantibodies in high-grade glioma patients’ plasma and identified two patients with elevated autoantibodies to a few transmembrane proteins. Specific B cells producing autoantibody against vascular endothelial growth factor receptor (VEGFR) 2 were immunostained with labeled protein and anti-human IgG antibody, and then collected by a single cell sorter. Finally, 22 antibody genes were successfully identified using direct IgG cloning from single B cell mRNA, and two antibody clones were found to have significant VEGFR2-specific binding affinity.The current direct human IgG gene cloning technique for identifying human antibodies derived from IgG-memory B cells avoids time-consuming procedures such as phage display-based antibody-library screening, and therefore may be applicable to identifying human autoantibodies in a variety of disorders including cancers even when antibody elevation is not detected because of a very small number of memory B cells.

AB0493 Association between antiviral igm antibodies and myositis autoantibodies in patients with autoimmune myositis in bulgarian population

BackgroundConsiderable evidences indicate that the viruses may be important environmental factors in the pathogenesis of the connective tissue diseases – systemic lupus erythematodes, systemic sclerosis, myositis, etc.1 Viruses activate a...

Prescience of a Surgeon in 1980

ThyroidVol. 23, No. 6 Letters to the EditorPrescience of a Surgeon in 1980Sandra M. McLachlanSandra M. McLachlanSearch for more papers by this authorPublished Online:6 Jun 2013https://doi.org/10.1089/thy.2012.0636AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Prescience of a Surgeon in 1980." , 23(6), pp. 773–774FiguresReferencesRelatedDetails Volume 23Issue 6Jun 2013 InformationCopyright 2013, Mary Ann Liebert, Inc.To cite this article:Sandra M. McLachlan.Prescience of a Surgeon in 1980.Thyroid.Jun 2013.773-774.http://doi.org/10.1089/thy.2012.0636Published in Volume: 23 Issue 6: June 6, 2013Online Ahead of Editing: January 25, 2013PDF download

Discoveries in the pathophysiology of neuropsychiatric lupus erythematosus: consequences for therapy

Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder characterized by the presence of several autoantibodies, including anti-double-stranded DNA. Neuropsychiatric (NP)LE contributes to the prognosis of SLE, and is divided into 19 NPLE syndromes. Its mechanisms are mediated through autoantibodies, complement components, and cytokines. The pathophysiology and diagnosis of NPLE are diverse and complicated. Recent studies have shown that several autoantibodies cross-react with human brain tissue and cause NPLE symptoms in SLE. It is known that in mice, depression and hippocampus-related memory impairment are induced by anti-ribosomal P antibody and anti-NR2 antibody, respectively. In a BMC Medicine research article, Kivity et al. demonstrated novel work showed that the 16/6 Id antibody impaired visual memory and spatial memory by causing hippocampal injury in mice. Given differences in the cross-reactivity of each autoantibody with the nervous system, the clinical features might be different and diverse in NPLE. Identification of autoantibody targets could lead to the development of novel therapies. Investigators and clinicians should consider not only the inhibition of autoantibody synthesis but also the protection of neuronal cells in the treatment strategy for NPLE.See related Research article: http://www.biomedcentral.com/1741-7015/11/90

Macrophage scavenger receptor 1 (Msr1) promotes autoantibody-mediated arthritis by impairing B cell tolerance (171.18)

Abstract Peripheral tolerance is achieved through several mechanisms, including induction of the hyporesponsive state of anergy in potentially autoreactive lymphocytes. The class A macrophage scavenger receptor, Msr1, is reported to participate in the maintenance of immunological tolerance by performing functions such as the clearance of apoptotic debris and the tonic sampling of self-antigens. We evaluated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in the K/BxN TCR transgenic model (Msr1-/- K/BxN) decreased the incidence and severity of arthritis. However, arthritis induced by transfer of arthritogenic autoantibodies was unimpaired in naïve mice lacking Msr1, suggesting that Msr1 deficiency in K/BxN mice affected the pathogenic events preceding autoantibody synthesis. Indeed, antibodies against the key autoantigen in this model, glucose 6-phosphate isomerase (GPI), were undetectable in Msr1-/- K/BxN mice, despite the presence of an expanded population of GPI-specific B cells. We did not observe any defect in T cell numbers or function. We hypothesized that Msr1 might control the availability of autoantigen and found that Msr1-/- macrophages displayed impaired uptake of GPI. Taken together, these data suggest a model in which deficiency of Msr1 can lead to a higher concentration of soluble autoantigens, resulting in B cell anergy and protection from autoimmune disease.

Autoimmune stiff person syndrome and related myelopathies: Understanding of electrophysiological and immunological processes

Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS.

Need for a paradigm shift in therapeutic approaches to CNS injury

Irreversible damage to the nervous system can result from many causes including trauma, disruption of blood supply, pathogen infection or neurodegenerative disease. Common features following CNS injury include a disruption of axons, neuron death and injury, local B-cell and microglial activation, and the synthesis of pathogenic autoantibodies. CNS injury results in a pervasive inhibitory microenvironment that hinders regeneration. Current approaches to eliminate the inhibitory environment have met with limited success. These results argue for a paradigm shift in therapeutic approaches to CNS injury. Targeting CNS cells (neurons, oligodendrocytes and astrocytes) themselves may drive CNS repair. For example, our group and others have demonstrated that autoreactive antibodies can participate in aspects of CNS regeneration, including remyelination. We have developed recombinant autoreactive natural human IgM antibodies with the therapeutic potential for CNS repair in several neurologic diseases

Effects of immunization with Streptococcus mutans surface antigens in auto-reactivity of BALB/c mice

AbstractBALB/c mice were hiperimmunized with surface antigens of Streptococcus mutans, GS5 strain. The immunization increased significantly anti-heart and anti-myosin IgG, free and present in immunecomplexes. In Western-blotting, the autoantibodies displayed a notable reactivity with cardiac myosin and cardiac tissue proteins, mainly with a 35 kDa peptide. The histological analysis of hearts demonstrated absence of significant damage in valves and myocardium, and immunohistochemistry showed absence of antibodies linked in cardiac tissue. The treatment with cyclophosphamide was able to reduce autoantibody levels but did not alter de histological aspect of heart. These findings demonstrated that surface antigens S. mutans, GS5 strain, were able to induce autoantibody synthesis without potential to initiate cardiac damage.

Bases patogénicas de la terapia dirigida a las células B en el lupus eritematoso sistémico (LES)

Recent success of B-cell targeted therapies in rheumatoid arthritis suggests their potential efficacy for other auntoantibody-mediated autoimmune diseases. Currently, multiple agents directed toward different B-cell specific targets are under development. Although the best strategy is yet to be defined, multiple functional inhibitors or cytolitic agents such as anti-CD20 or anti-CD19 are available. According to studies in RA, the most likely mechanism of action of rituximab (anti-CD20) consists of a secondary reduction in local (synovial) or systemic autoantibody producing short-lived plasma cells. According to this data, it is expected that these therapies will be efficacious in SLE, were B-cell enhanced function and autoantibodies play relevant pathogenetic roles. Clinical trials confirm B-cell effects, delayed activity on autoantibody synthesis, and most importantly, the feasibility of these therapies to treat SLE. However, there are no sufficient data confirming their therapeutic value when added to convencional therapy. Although multiple open trials suggest that rituximab might be useful for refractory manifestations of SLE, more controlled trials are needed in order to establish the indications and strategies of its use in SLE.

B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice

Traumatic injury to the mammalian spinal cord activates B cells, which culminates in the synthesis of autoantibodies. The functional significance of this immune response is unclear. Here, we show that locomotor recovery was improved and lesion pathology was reduced after spinal cord injury (SCI) in mice lacking B cells. After SCI, antibody-secreting B cells and Igs were present in the cerebrospinal fluid and/or injured spinal cord of WT mice but not mice lacking B cells. In mice with normal B cell function, large deposits of antibody and complement component 1q (C1q) accumulated at sites of axon pathology and demyelination. Antibodies produced after SCI caused pathology, in part by activating intraspinal complement and cells bearing Fc receptors. These data indicate that B cells, through the production of antibodies, affect pathology in SCI. One or more components of this pathologic immune response could be considered as novel therapeutic targets for minimizing tissue injury and/or promoting repair after SCI.