CD20: a target antigen for immunotherapy of autoimmune diseases

This article reviews the role of CD20 antigen in B cell function and the effectiveness and limits of passive immunotherapy with anti-CD20 monoclonal antibody (Rituximab) in the treatment of autoimmune (or immune-mediated) diseases. Active immunotherapy is a more feasible way to control these chronic diseases. A peptide that mimics the CD20 epitope recognized by Rituximab is employed to stimulate the host immune response against CD20.     

Syk kinase as a treatment target for therapy in autoimmune diseases

Spleen tyrosine kinase (Syk) associates with a variety of immunoreceptors in myeloid and lymphoid cells. Syk initiates intracellular signaling once the receptor is engaged by its ligand. Blocking Syk may prove beneficial in interrupting the propagation of the abnormal immune response in both autoimmune and allergic diseases.     

Interleukin-23: as a drug target for autoimmune inflammatory diseases

Interleukin-23 (IL-23) is a member of the IL-12 family of cytokines with pro-inflammatory properties. Its ability to potently enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses. Emerging data demonstrate that IL-23 is a key participant in central regulation of the cellular mechanisms involved in inflammation. Both IL-23 and IL-17 form a new axis through Th17 cells, which has evolved in response to human diseases associated with immunoactivation and immunopathogeny, including bacterial or viral infections and chronic inflammation. Targeting of IL-23 or the IL-23 receptor or IL-23 axis is a potential therapeutic approach for autoimmune diseases including psoriasis, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. The current review focuses on the immunobiology of IL-23 and summarizes the most recent findings on the role of IL-23 in the pre-clinical and ongoing clinical studies.     

p38 MAPK as a potential therapeutic target for inflammatory osteolysis

Inflammatory osteolysis is a relatively frequent and incapacitating complication of rheumatoid arthritis and other inflammatory diseases, and is induced by accelerated osteoclast recruitment and activation in bone under the aegis of cytokines produced in the inflammatory environment. The success of antitumor necrosis factor-alpha and interleukin-1 therapy in correcting this condition highlights the central role of these cytokines in this process. Recent years have witnessed a revolution in understanding the molecular mechanism and pathogenesis of this family of diseases. It is now clear that p38 mitogen-activated protein kinase plays an essential role in the production of proinflammatory cytokines and cytokine-induced osteoclastogenesis, thus providing a potential therapeutic target for prevention of pathologic bone loss.     

CCR6-CCL20 axis as a therapeutic target for autoimmune diseases

Chemokine receptor CCR6 is expressed on various cells such as B cells, immature dendritic cells, innate lymphoid cells (ILCs), regulatory CD4 T cells, and Th17 cells. CCL20 is the only known high-affinity ligand that binds to CCR6 and drives CCR6⁺ cells' migration in tissues. CCL20 is mainly produced by epithelial cells, and its expression is increased by several folds under inflammatory conditions. Genome-wide association studies (GWAS) in patients with inflammatory bowel disease (IBD), psoriasis (PS), rheumatoid arthritis (RA), and multiple sclerosis (MS) showed a very strong correlation between the expression of CCR6 and disease severity. It has been shown that disruption of CCR6-CCL20 interaction by using antibodies or antagonists prevents the migration of CCR6 expressing immune cells at the site of inflammation and reduces the severity of the disease. This review discussed the importance of the CCR6-CCL20 axis in IBD, PS, RA, and MS, and recent advances in targeting the CCR6-CCL20 in controlling these autoimmune diseases.     

CD19 as a therapeutic target in a spontaneous autoimmune polyneuropathy

Spontaneous autoimmune polyneuropathy (SAP) in B7‐2 knock‐out non‐obese diabetic (NOD) mice is mediated by myelin protein zero (P0)‐reactive T helper type 1 (Th1) cells. In this study, we investigated the role of B cells in SAP, focusing on CD19 as a potential therapeutic target. We found that P0‐specific plasmablasts and B cells were increased in spleens of SAP mice compared to wild‐type NOD mice. Depletion of B cells and plasmablasts with anti‐CD19 monoclonal antibody (mAb) led to attenuation of disease severity when administered at 5 months of age. This was accompanied by decreased serum immunoglobulin (Ig)G and IgM levels, depletion of P0‐specific plasmablasts and B cells, down‐regulation/internalization of surface CD19 and increased frequency of CD4⁺ regulatory T cells in spleens. We conclude that B cells are crucial to the pathogenesis of SAP, and that CD19 is a promising B cell target for the development of disease‐modifying agents in autoimmune neuropathies.     

P2X7 receptor: A potential therapeutic target for autoimmune diseases

P2X7 receptor (P2X7R), a distinct ligand-gated ion channel, is a member of purinergic type 2 receptor family with ubiquitous expression in human body. Previous studies have revealed a pivotal role of P2X7R in innate and adaptive immunity. Once activated, it will meditate some vital cascaded responses including the assembly of nucleotide-binding domain (NOD) like receptor protein 3 (NLRP3) inflammasome, non-classical secretion of IL-1β, modulation of cytokine-independent pathways in inflammation such as P2X7R- transglutaminase-2 (TG2) and P2X7R-cathepsin pathway, activation and regulation of T cells, etc. In fact, above responses have been identified to be involved in the development of autoimmunity, specifically, the NLRP3 inflammasome could promote inflammation in massive autoimmune diseases and TG2, as well as cathepsin may contribute to joint destruction and degeneration in inflammatory arthritis. Recently, numerous evidences further suggested the significance of P2X7R in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), etc. In this review, we will succinctly discuss the biological characteristics and summarize the recent progress of the involvement of P2X7R in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.     

Amino acid metabolism as drug target in autoimmune diseases

In mammals, amino acid metabolism has evolved to control immune responses. Autoimmune diseases are heterogeneous conditions that involve the breakdown of tolerogenic circuitries and consequent activation of autoreactive immune cells. Therefore, critical enzymes along amino acid degradative pathways may be hijacked to keep in check autoimmunity. We examined here current knowledge of indoleamine 2,3-dioxygenase 1 (IDO1) and arginase 1 (ARG1), the main enzymes catabolizing tryptophan and arginine, respectively, in organ-specific and systemic autoimmune diseases as well as in the development of autoantibodies to therapeutic proteins. At variance with neoplastic contexts, in which it is known to act as a pure immunosuppressive molecule, ARG1 exhibited a protective or pathogenetic profile, depending on the disease. In contrast, in several autoimmune conditions, the bulk of data indicated that drugs capable of potentiating IDO1 expression and activity may represent valuable therapeutic tools and that IDO1-based immunotherapeutic protocols could be more effective if tailored to the genetic profile of individual patients.     

MicroRNA-22-3p as a novel regulator and therapeutic target for autoimmune diseases

MicroRNAs (miRNAs) are a class of noncoding RNAs and have emerged as critical regulators of gene expression. Some miRNAs play important roles in regulating the function of the immune system and are involved in the pathogenesis of autoimmune diseases. Recent studies suggested that microRNA-22-3p (miR-22-3p) was able to regulate the function of several types of immune cells and may be involved in the development of autoimmune diseases. We systematically reviewed relevant literatures to provide a comprehensive review of the possible roles of miR-22-3p in autoimmune diseases. Published studies suggest that miR-22-3p can act as a novel regulator of autoimmune diseases via several pathways. More studies are needed to further elucidate the exact roles of miR-22-3p in autoimmune diseases. Treatment strategy targeting miR-22-3p is also a promising therapy for autoimmune diseases.     

Inflammatory molecules: a target for treatment of systemic autoimmune diseases

Inflammation is a process to protect the host against infection and danger signals. However, many pathologic conditions, including autoimmune diseases, are sustained by perpetual activation of the inflammatory process. In the past few years our knowledge about the molecular basis of inflammation have been uncovered and now much is known about the primary role of pro-inflammatory cytokines such as IL-1 and TNF. In the early '90s, anti-cytokine therapies started and confirmed the primary role of TNF in autoimmune diseases, such as rheumatoid arthritis, Crohn's Disease and psoriasis. Increasing understanding of the role of inflammatory mediators in inflammation and diseases is opening new avenues for the treatment of inflammatory-based diseases through selective targeting of cytokines and lipid mediators.     

Therapeutic potential of CD1d-restricted invariant natural killer T cell-based treatment for autoimmune diseases

CD1d-restricted invariant natural killer T (iNKT) cells are a unique subset of T cells that recognize glycolipid antigens presented by the CD1d molecule. iNKT cells participate in various kinds of immunoregulation due to a potent ability to produce a variety of cytokines. Recent advances in studies of novel synthetic glycolipid ligands has led to new strategies to manipulate the pleiotropic functions of iNKT cells. The molecular mechanism of selective cytokine production by glycolipid ligands will be discussed. We will also focus on the possible therapeutic application of such ligands for the clinical treatment of various autoimmune diseases.     

The women's health initiative: a potential resource for future studies of autoimmune diseases

The women's health initiative observational and clinical trials cohort is one of the largest and most carefully characterized group of postmenopausal women who have undergone long-term follow-up. Although outcome assessment has focused on the outcomes of CVD, cancer, and fractures, a wealth of data have been collected, which could form the basis for researchers interested in autoimmune diseases to begin important studies. Baseline and follow-up blood samples and DNA samples are available upon application to the study's Design and Analysis Committee and publications can be planned based on the current dataset upon application to the Publications and Presentations Committee. In both of these cases, one of the principal investigators from the 40 clinical centers or the Central Coordinating Center would need to be involved as a collaborator. Upon obtaining appropriate IRB approval, it could be possible to recontact women to collect additional information to verify outcomes or obtain further follow-up data. In addition to the WHI, the National Institutes of Health have funded a number of other large cohort studies that could be of use for researchers of autoimmune diseases. These include several longitudinal studies of diabetes funded by the NIDDK and several other large cardiovascular cohorts funded by the National Heart, Blood and Lung institute (e.g. ARIC, CARDIA and CHS. In addition, the national Cancer Institute has funded studies of large cohorts of Whites, Blacks, Hispanics, and American Indians in the United States. In all these studies, individuals have undergone baseline assessment for environmental and lifestyle risk factors and are being followed for long-term health outcomes. Given the time and expense devoted to the Women's Health initiative and these other studies, it would be of great value if researchers interested in a wide variety of chronic diseases would make use of these rich sources of data.     

Carbonic anhydrase III: a new target for autoantibodies in autoimmune diseases

The objective of this study was to identify new autoantibodies that could be useful for the diagnosis of rheumatoid arthritis (RA) using immunoblotting on synovial membrane proteins which represent the best source of candidate RA autoantigens. A new target protein with a molecular weight of 26 kDa was found to be recognized by autoantibodies in RA sera and was identified using MALDI-TOF mass spectrometry and second-dimension electrophoresis as carbonic anhydrase III (CAIII). Three similar protein spots at 26 kDa were recognized by both human sera and monoclonal antibody (mAb) directed against CAIII on immunoblotting using the human recombinant CAIII. Interestingly, CAIII expression within the synovial membrane was not observed in non-RA patients and was differentially expressed among RA patients. The sensitivity of these new autoantibodies for RA, using an immunoenzymatic technique, was 17%. Specificity was high when comparing non-autoimmune diseases (100%), while it was found to be weak (67%) when comparing some other autoimmune diseases, and particularly systemic lupus erythematosus (SLE). In conclusion, this study demonstrates that these new autoantibodies against CAIII are not restricted to RA. However the expression of CAIII in the synovial membrane of RA warrants further investigation of the pathophysiological relevance of this finding.     

BAFF: a local and systemic target in autoimmune diseases

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF‐R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation‐inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)‐6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.     

Heart fatty acid binding protein as a potential diagnostic marker for neurodegenerative diseases

The diagnosis of neurodegenerative diseases with dementias requires several different test approaches and often remains uncertain. Using a proteomic approach it was shown in nine patients that heart fatty acid binding protein (H-FABP) might be a biomarker for Creutzfeldt-Jakob disease (CJD). The aim of our study was to evaluate whether H-FABP is a biomarker for the differential diagnosis of dementias. Therefore we measured H-FABP in cerebrospinal fluid (CSF) and serum of patients having CJD, dementia with Lewy-bodies (DLB), Alzheimer's disease (AD) and in non-demented control (NDC) patients. H-FABP levels in CSF and serum of CJD patients are increased compared to non-demented controls. Levels of H-FABP were significantly higher in CJD patients compared to AD and DLB in CSF. However, discrimination between CJD and AD was not possible in serum. Interestingly, highest levels of H-FABP were found in serum of DLB patients. Our results suggest that H-FABP might be a useful biomarker for the differentiation between the dementias examined if levels in CSF and serum are determined in parallel.     

NLRP3: A promising therapeutic target for autoimmune diseases

NLRP3, a member of nucleotide-binding domain-(NOD) like receptor family, can be found in large varieties of immune and non-immune cells. Upon activation, the NLRP3, apoptosis-associated speck-like protein (ASC) and pro-caspase-1 would assemble into a multimeric protein, called the NLRP3 inflammasome. Then the inflammasome promotes inflammation (through specific cleavage and production of bioactive IL-1β and IL-18) and pyroptotic cell death. Previous studies have indicated the importance of NLRP3 in regulating innate immunity. Recently, numerous studies have revealed their significance in autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc) and inflammatory bowel disease (IBD). In this review, we will briefly discuss the biological features of NLRP3 and summarize the recent progression of the involvement of NLRP3 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.     

Pentraxin 3: A promising therapeutic target for autoimmune diseases

Pentraxin 3 (PTX3) is a prototypic humoral soluble pattern recognition molecule that exerts a pivotal role in innate immune response and inflammation, as well as in tissue damage and remodeling. Recently, emerging evidence has revealed that PTX3 is involved in the occurrence and development of various autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), systemic sclerosis (SSc), inflammatory bowel disease (IBD), multiple sclerosis (MS) and psoriasis, etc. In this review, we have succinctly summarized the complex immunological functions of PTX3 and mostly focused on recent findings of the pleiotropic activities played by PTX3 in the pathogenesis of autoimmune diseases, aiming at hopefully offering possible future therapeutic alternatives.