Self-reactive Antibodies Research Articles

Autoimmune Diseases: An Introduction

The immune system recognizes and eliminates foreign agents, and protects the host against infection. Autoimmunity is a natural phenomenon where self-reactive antibodies and autoimmune cells are present in all individuals. A combination of genetic predisposition and environmental factors contribute to the development of autoimmune diseases. Autoantibodies attack structures within individuals that produce them. Autoimmunity is a major cause for a number of serious and fatal diseases. Presence of one autoimmune disease increases the chance for simultaneously developing other autoimmune diseases in the same person.

Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known outcomes or the potential for targeting these factors in SLE.

Current Management of Primary Immune Thrombocytopenia.

Primary immune thrombocytopenia is an autoimmune disorder of unknown cause affecting both children and adults. The low peripheral blood platelet count is caused by premature platelet destruction by self-reacting antibodies in addition to an impairment of platelet production. The disease is heterogeneous in its pathophysiology, clinical features and responses to treatment. To date, most of the treatments used have been immune-modulating drugs and these contribute to increased morbidity and mortality in patients. A new class of drugs, the thrombopoietin receptor agonists, has been developed for use in ITP. These have gone through randomised controlled trials in large numbers of patients with ITP. These drugs have high efficacy and are well tolerated. In addition, around 30% of patients receiving these drugs are able to stop them and maintain a safe or normal platelet count. Older treatments such as splenectomy are being used less than before, largely because of the introduction of the thrombopoietin receptor agonists. Currently there are trials underway evaluating novel therapies for ITP that will become available over the next few years once the trials are complete.

Evaluation of polyreactive monoclonal antibodies using HLA solid phase assays

It is well established that HLA antibodies play an important role in antibody-mediated rejection (AMR) and there is a growing body of literature demonstrating that non-HLA antibodies may also contribute to AMR. To study the source of non-donor specific HLA antibodies and self-reactive antibodies in patients with kidney graft loss, Porcheray et al. (Am J Transplant 2012; 12: 2088–2097) expanded immortalized polyreactive B-cell clones from a patient with kidney graft rejection and showed that some of these natural antibodies are cross-reactive to HLA and self-antigens. Gao et al. (Am J Transplant 2014; 14:1581–1591) also showed that the presence of IgG natural antibodies, with activity to apoptotic cells, correlates with late kidney allograft loss even after excluding patients with high reactivity to HLA. We have further characterized the HLA reactivity of 4 polyreactive B-cell clones isolated by Porcheray, Gao et al. using solid phase assays (Immucor, Inc.). We report here that while these clones do not react with HLA on the Immucor single antigen beads, they react to other HLA products, with some variation between different solid phase assays. Their reactivity appears to be enhanced upon denaturation, as judged by the monoclonal antibody 210.4, which reacts with denatured antigen, suggesting that they primarily react to cryptic epitopes. B. Ray: Employee; Company/Organization; Immucor.

Asymptomatic Plasmodium falciparum infection in children is associated with increased auto-antibody production, high IL-10 plasma levels and antibodies to merozoite surface protein 3.

BackgroundMechanisms of acquired protection to malaria in asymptomatic Plasmodium falciparum carriers are only partially understood. Among them, the role plays by the self-reactive antibodies has not been clarified yet. In this study, the relationship between repertoires of circulating self-reactive and parasite-specific immunoglobulin G (IgG), their correlation with cytokine levels, and their association with protection against malaria was investigated in asymptomatic Plasmodium falciparum-infected Gabonese children.MethodsThe diversity of P. falciparum-specific antibody repertoire was analysed using a protein micro-array immunoassay, the total auto-antibody repertoire by quantitative immunoblotting and circulating cytokine levels were measured by ELISA in endemic controls (EC) and P. falciparum-infected children from Gabon with asymptomatic (AM) or mild malaria (MM). The association of self- and parasite-specific antibody repertoires with circulating cytokines was evaluated using single linkage hierarchical clustering, Kruskal – Wallis tests and Spearman’s rank correlation.ResultsChildren with AM exhibited an IgG response to merozoite surface protein 3 (MSP3) but not to MSP1-19, although their levels of total P. falciparum-specific IgG were similar to those in the MM group. Moreover, the asymptomatic children had increased levels of autoantibodies recognising brain antigens. In addition, a correlation between IL-10 levels and parasite load was found in AM and MM children. These two groups also exhibited significant correlations between plasma levels of IL-10 and IFN-γ with age and with total plasma IgG levels. IL-10 and IFN-γ levels were also associated with auto-antibody responses in AM.ConclusionsAltogether, these results indicate that a self-reactive polyclonal response associated with increased IgG to MSP3 and high plasma levels of IL-10 and IFN-γ may contribute to protective immune mechanisms triggered in asymptomatic P. falciparum infection in Gabonese children.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0658-7) contains supplementary material, which is available to authorized users.

Is intrathecal anti-CD20 an option to target compartmentalized CNS inflammation in progressive MS?

B cells have gained enormous attention in the treatment of multiple sclerosis (MS). While our earlier pathogenic understanding of its cause primarily focused on B cell–derived plasma cells producing self-reactive antibodies, more recent findings support the theory that B cells themselves substantially contribute to MS pathogenesis. This conceptual change was primarily triggered by the empirical observation that anti-CD20–mediated B-cell depletion is effective in the treatment of relapsing-remitting MS (RRMS). Clearly exceeding the initial expectations, IV rituximab led to a rapid and lasting halt in the formation of new CNS lesions in patients with RRMS.1 Its further humanized successor ocrelizumab,2 as well as the human anti-CD20 antibody ofatumumab,3 confirmed these encouraging findings. The clinical efficacy of anti-CD20 provided greater appreciation of the fact that antigen-specific B cells are important antigen-presenting cells (APCs),4,5 most likely due to their unique capability to directly bind larger conformational antigens at very low concentrations via their B-cell receptor. Furthermore, B cells could be identified as a major source of proinflammatory cytokines,6 activating other APCs and fostering development of encephalitogenic T cells, jointly consolidating the concept that in RRMS, B cells exert distinctive pathogenic properties that can be targeted by systemic anti-CD20 treatment.

Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies.

Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.

Targeting pathogenic postischemic self-recognition by natural IgM to protect against posttransplantation cardiac reperfusion injury.

Natural IgM antibodies represent a class of innate pattern recognition receptors that recognize danger-associated molecular patterns expressed on stressed or dying cells. They play important roles in tissue homeostasis by disposing of prenecrotic cells and suppressing inflammation. However, ischemic insult leads to a pathogenic level of IgM binding and complement activation, resulting in inflammation and injury. We investigate the role of self-reactive IgM in the unique setting of transplantation where the donor organ undergoes both cold and warm ischemia and global ischemic insult. By transplanting hearts from wild-type donor mice into antibody-deficient mice reconstituted with specific self-reactive IgM monoclonal antibodies, we identified neoepitopes expressed after transplantation and demonstrated a key role for IgM recognition of these epitopes in graft injury. With this information, we developed and characterized a therapeutic strategy that exploited the postischemia recognition system of natural antibodies. On the basis of neoepitope identification, we constructed an anti-annexin IV single-chain antibody (scFv) and an scFv linked to Crry, an inhibitor of C3 activation (scFv-Crry). In an allograft transplantation model in which recipients contain a full natural antibody repertoire, both constructs blocked graft IgM binding and complement activation and significantly reduced graft inflammation and injury. Furthermore, scFv-Crry specifically targeted to the transplanted heart and, unlike complement deficiency, did not affect immunity to infection, an important consideration for immunosuppressed transplant recipients. We identified pathophysiologically important epitopes expressed within the heart after transplantation and described a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches.

CTCF-binding elements 1 and 2 in the Igh intergenic control region cooperatively regulate V(D)J recombination

Ig heavy chain (IgH) variable region exons are assembled from V, D, and J gene segments during early B-lymphocyte differentiation. A several megabase region at the "distal" end of the mouse IgH locus (Igh) contains hundreds of V(H)s, separated by an intergenic region from Igh Ds, J(H)s, and constant region exons. Diverse primary Igh repertoires are generated by joining Vs, Ds, and Js in different combinations, with a given B cell productively assembling only one combination. The intergenic control region 1 (IGCR1) in the V(H)-to-D intergenic region regulates Igh V(D)J recombination in the contexts of developmental order, lineage specificity, and feedback from productive rearrangements. IGCR1 also diversifies IgH repertoires by balancing proximal and distal V(H) use. IGCR1 functions in all these regulatory contexts by suppressing predominant rearrangement of D-proximal V(H)s. Such IGCR1 functions were neutralized by simultaneous mutation of two CCCTC-binding factor (CTCF)-binding elements (CBE1 and CBE2) within it. However, it was unknown whether only one CBE mediates IGCR1 functions or whether both function in this context. To address these questions, we generated mice in which either IGCR1 CBE1 or CBE2 was replaced with scrambled sequences that do not bind CTCF. We found that inactivation of CBE1 or CBE2 individually led to only partial impairment of various IGCR1 functions relative to the far greater effects of inactivating both binding elements simultaneously, demonstrating that they function cooperatively to achieve full IGCR1 regulatory activity. Based on these and other findings, we propose an orientation-specific looping model for synergistic CBE1 and CBE2 functions.

Islamic Fasting and Presentations of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology, characterized by symmetric peripheral polyarthritis. The disease is characterized by increased immune and inflammatory responses due to a complex interaction between genes and environment, which leads to accumulation of immune cells in the synovial tissue, causing matrix destruction and damage to bone and cartilage (1). Both B and T cells as well as monocytes can be seen with increasing tendency with the disease progression. The pathogenesis of RA is built upon the concept that self-reactive antibodies and T cells drive the chronic inflammatory response. T cells are activated and thus they proliferate and release cytokines. B Cells produce rheumatoid factor immunoglobulin M (IgM) and other antibodies. Monocytes produce pro-inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which induce proliferation and activation of the synovium tissue (2, 3). Furthermore, prostaglandin E2 (PGE2), collagenase and other matrix metallo-proteinases are released (3). All the mechanisms of the disease and complications of its treatment can reduce patients’ quality of life and cause psychiatric diseases and sleep disorders, leading to patient dissatisfaction (4). Some studies showed that fasting decreases the immune and inflammatory responses and affects both hormonal and cellular immune responses (1, 5, 6). Fasting decreases the serum concentration of TNF-α (1, 7), IL-1 (1), IL-6 (1, 7), insulin-like growth factor 1 (IGF-1) (7), rheumatoid factor (RF), IgM and immunoglobulin G (IgG) (8), leukocytes and leukotrienes (1), complements (8, 9), and the ability of neutrophils to produce cytotoxic metabolites and release enzymes (9). Fasting also decreases the erythrocyte sedimentation rate (ESR) (10) and C-reactive protein (CRP) (10). Figure 1 shows schematic laboratory findings of RA and Ramadan fasting effects on inflammatory and immune responses (Figure 1).

VH replacement in primary immunoglobulin repertoire diversification

The genes encoding the variable (V) region of the B-cell antigen receptor (BCR) are assembled from V, D (diversity), and J (joining) elements through a RAG-mediated recombination process that relies on the recognition of recombination signal sequences (RSSs) flanking the individual elements. Secondary V(D)J rearrangement modifies the original Ig rearrangement if a nonproductive original joint is formed, as a response to inappropriate signaling from a self-reactive BCR, or as part of a stochastic mechanism to further diversify the Ig repertoire. VH replacement represents a RAG-mediated secondary rearrangement in which an upstream VH element recombines with a rearranged VHDHJH joint to generate a new BCR specificity. The rearrangement occurs between the cryptic RSS of the original VH element and the conventional RSS of the invading VH gene, leaving behind a footprint of up to five base pairs (bps) of the original VH gene that is often further obscured by exonuclease activity and N-nucleotide addition. We have previously demonstrated that VH replacement can efficiently rescue the development of B cells that have acquired two nonproductive heavy chain (IgH) rearrangements. Here we describe a novel knock-in mouse model in which the prerearranged IgH locus resembles an endogenously rearranged productive VHDHJH allele. Using this mouse model, we characterized the role of VH replacement in the diversification of the primary Ig repertoire through the modification of productive VHDHJH rearrangements. Our results indicate that VH replacement occurs before Ig light chain rearrangement and thus is not involved in the editing of self-reactive antibodies.

Human-derived natural antibodies: biomarkers and potential therapeutics.

The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy.

Utility of autoantibodies as biomarkers for diagnosis and staging of neurodegenerative diseases.

Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of autoimmune diseases. They are found in the blood of all human sera, regardless of age, gender, or the presence or absence of disease. While the underlying reason for their ubiquity remains unknown, it has been hypothesized that they participate in the clearance of blood-borne cell and tissue debris generated in both healthy and diseased individuals on a daily basis. Although much evidence supports this debris clearance role, recent studies also suggest a causal role for autoantibodies in disease. This chapter first presents well-known examples of autoimmune diseases that emphasize a direct causal role for autoantibodies and then discusses the veritable explosion of evidence now supporting their involvement in a wide variety of other diseases, including cancers and several types of neurological and neurodegenerative diseases. Lastly, translational strategies that take advantage of the "cause and/or effect" role of autoantibodies and recent technological advancements in their detection to exploit autoantibodies as sensitive and specific biomarkers useful for the detection and diagnosis of disease are outlined. Their use in the diagnosis and staging of Alzheimer's and Parkinson's diseases is presented, and future applications in clinical medicine and basic science are highlighted.

Both Tumor Necrosis Factor Receptor Signaling Pathways Contribute to Mortality but not to Splenomegaly in Generalized Lymphoproliferative Disorder

The phenotypical consequences of a combined deficiency of the Fas-Fas Ligand (FasL) and one or both Tumor Necrosis Factor (TNF) signaling pathways were investigated. Mice, which expressed a non-functional FasL suffered from a pathological accumulation of both B and T cells leading to splenomegaly and lymphadenopathy and, depending on the genetic background, pathogenic self-reactive antibodies (generalized lymphoproliferative disorder (gld)-phenotype). If mice additionally lacked TNF, they displayed a significantly ameliorated gld-phenotype while TNF Receptor-1-deficient gld mice (B6.gld.TNFR1−/−) displayed a more severe phenotype. To complement this combination, we also generated TNF Receptor-2-deficient gld mice (B6.gld.TNFR2−/−). Both double knockouts followed in their splenic structure the respective TNFR contribution to the phenotype. TNFR1−/− mice showed an absence of B cell follicles in the spleen while TNFR2−/− mice were comparable to WT mice. In general, we demonstrated a strong contribution of both TNFR signaling pathways to the symptoms of gld with the notable exception of splenomegaly where only TNFR1−/− played a role.

Nanorobotic investigation identifies novel visual, structural and functional correlates of autoimmune pathology in a blistering skin disease model.

There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg) 3. We demonstrate that pathogenic (blister-forming) anti-Dsg3 antibodies, distinct from non-pathogenic (non-blister forming) anti-Dsg3 antibodies, alter the structural and functional properties of keratinocytes in two sequential steps - an initial loss of cell adhesion and a later induction of apoptosis-related signaling pathways, but not full apoptotic cell death. We propose a “2-Hit” model for autoimmune disruption associated with skin-specific pathogenic autoantibodies. These data provide unprecedented details of autoimmune processes at the tissue level and offer a novel conceptual framework for understanding the action of self-reactive antibodies.

STEALTH ADAPTED VIRUSES AND THE ALTERNATIVE CELLULAR ENERGY (ACE) PATHWAY IN ALZHEIMER'S DISEASE

STEALTH ADAPTED VIRUSES AND THE ALTERNATIVE CELLULAR ENERGY (ACE) PATHWAY IN ALZHEIMER'S DISEASE

Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.

The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5'-phosphate-binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.

P03-027 - A brief Case report on specific undiagnosed condition, whose provisional diagnosis on the basis of provisional lab investigation proved as one of the component of autoinflammatory disorder

The autoinflammatory syndromes are a newly recognized group of immune disorders that lack the high titers of self-reactive antibodies and T cells characteristic of classic autoimmune disease. , patients with these illnesses experience unprovoked inflammatory disease in the absence of underlying infection.(Curr Top Microbiol Immunol. 2006;305:127-60). In the category of autoinflamation this disease is a a lesion particularly known as CRMO or chronic recurrent mutifocal osteomylitis a rare condition in which bones have an lesion, inflammation and pain but without a focus of infection .the result of its inheritance pattern is still being debated and the distinguishing feature from the autoimmune pattern is still not clear. It is classified as an auto inflammatory disease due to its recurrent out breaks and lack of any known pathogen.this disease tends to range from 4 to 14 years of age and 10 years as median. As by current statistics it occur 1:1000000 and primarly in girls with a 5:1 ratio. CRMO may similar to a painful bone lesion such as arthritis , RF , bacterial osteomylitis ,ewings sarcoma, lymphoma, eosinophilic granuloma or LAH. When all the prevoious illness are ruled out and a bone biopsy turns negative for any known cancer CRMO is usually diagnosed. As such the common medication given for reducing the inflammation are such as NSAIDS and steroids, antibiotics are not prescribed as there is no evident focus of infection. Congenital dyserthropoitic anaemia and CRMO , uncommon childhood diseases an association with sweet syndrome may be interelated .( journal of paediatrics 115 (5, part 1):730-4. Dol10.1016/S0022-3476(89)80650. A retrospective review of autoinflamatory diseases in Saudi children at rheumatology clinic showed that of the 34 children with a mean age 118 months , consanguinity was present in 40 %. And in which FMF 50%, CRMO 23.5%, EOS 8.8%, MWS 6 %.(Ann Saudi med . 2012 ;32(1);43-8(ISSN;0975-4466). CRMO is sometimes associated with palmoplantar pustulosis and frequent relapses may be present with remission lasting for 4-16 weeks. The most distal case if the affected series . classical Xray diagnosis reveled skeletal changes consistent with appearance of acute or chronic heamoatogenic osteomylits.morphologically CRMO begins as an acute inflammatory process either predominance of PMN leucocytes, with occasionally form absesses and osteoclastic bone resorption. At a later stage it may present as lymphocytes and inflamatoty infiltrate and occasional granulomatous foci and signs of new bone formation.

Neurotoxic or Neuroprotective? Current Controversies in SCI-Induced Autoimmunity

Controversy exists regarding the autoimmune response that has been observed following traumatic spinal cord injury (SCI). It is not clear if this represents a protective response by the immune system to prevent further tissue damage, a pathological reaction of the immune system to central nervous system antigens released by the injury, or a combination of both. Experimental evidence indicates that B cells produce auto-antibodies following SCI and that the presence of self-reactive antibodies is associated with tissue damage. Conversely, other studies suggest T cell activity at the site of the injury promotes tissue regeneration. Vaccination with dendritic cells exposed to central nervous system (CNS) antigens dramatically improves recovery of motor function in spinal cord injured rats. Further research is required to determine the nature of post-SCI B cell and T cell responses and to establish efficacy of dendritic cell vaccination therapy in clinical studies. This information is critical for the development of therapies to either suppress or promote immune responses following neurotrauma to improve neurological outcomes.

Soluble human CD83 ameliorates lupus in NZB/W F1 mice

In the present study we explored the immunomodulatory potential of prokaryotically expressed soluble CD83 in the treatment of murine lupus using the NZB/W F1 mouse model. Therefore female NZB/W F1 lupus mice were treated either with sCD83 or PBS for 4 weeks. sCD83 treated mice showed a significantly delayed onset of anti-dsDNA autoantibody production when compared with the control group. Importantly, during the treatment period with sCD83 none of the mice showed elevated levels of anti-dsDNA autoantibodies. In addition, NZB/W F1 mice which received sCD83 displayed lower concentrations of anti-histone IgG autoantibodies. Furthermore, there was no difference in total IgG antibodies, indicating a modulatory role for sCD83 in the production of self-reactive antibodies without decreasing total IgG. These results indicate that administration of sCD83 has profound immune-modulatory effects on the induction of autoantibodies in NZB/W F1 lupus mice and may thus be a promising approach to interfere with autoimmunity in SLE and other autoantibody-driven diseases.