myelin-basic-protein and Arthritis--Rheumatoid

Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.

Topics: Amino Acid Sequence; Animals; Arthritis, Rheumatoid; Citrulline; Humans; Hydrolases; Molecular Sequence Data; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Protein Conformation; Protein Processing, Post-Translational; Protein-Arginine Deiminases

Topics: Animals; Antibodies; Arthritis, Rheumatoid; Autoimmune Diseases; Cytokines; Diabetes Mellitus, Experimental; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Mice, Transgenic; Multiple Sclerosis; Myelin Basic Protein; Th1 Cells; Th2 Cells; Time Factors

In experimental animal models of multiple sclerosis demyelinating antibody responses are directed against the myelin oligodendrocyte glycoprotein (MOG). We have investigated whether a similar antibody response is also present in multiple sclerosis patients. Using the recombinant human extracellular immunoglobulin domain of MOG (MOG-Ig) we have screened the sera and CSFs of 130 multiple sclerosis patients, 32 patients with other inflammatory neurological diseases (OIND), 30 patients with other non-inflammatory neurological diseases (ONND) and 10 patients with rheumatoid arthritis. We report that 38% of multiple sclerosis patients are seropositive for IgG antibodies to MOG-Ig compared with 28% seropositive for anti-myelin basic protein (MBP). In contrast, OIND are characterized by similar frequencies of serum IgG antibody responses to MOG-Ig (53%) and MBP (47%), whereas serum IgG responses to MOG-Ig are rare in ONND (3%) and rheumatoid arthritis (10%). Anti-MBP IgG antibodies, however, are a frequent finding in ONND (23%) and rheumatoid arthritis (60%). Our results provide clear evidence that anti-MOG-Ig antibodies are common in CNS inflammation. However, in OIND these antibody responses are transient, whereas they persist in multiple sclerosis. We demonstrate that the serum anti-MOG-Ig response is already established in early multiple sclerosis (multiple sclerosis-R0; 36%). In later multiple sclerosis stages frequencies and titres are comparable with early multiple sclerosis. In contrast, the frequency of anti-MBP antibodies is low in multiple sclerosis-R0 (12%) and increases during disease progression in relapsing-remitting (32%) and chronic progressive multiple sclerosis (40%), thus suggesting that anti-MBP responses accumulate over time. Finally we provide evidence for intrathecal synthesis of IgG antibodies to MOG-Ig in multiple sclerosis.

Topics: Adult; Arthritis, Rheumatoid; Autoantibodies; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulins; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Nervous System Diseases; Neuritis; Recombinant Proteins; Retrospective Studies

Rheumatoid arthritis (RA) has been associated with cognitive impairment and peripheral production of autoantibodies. Autoantibodies against central nervous system (CNS) proteins and S100 calcium-binding β (S100β) were found increased in diseases characterized by cognitive impairment like Alzheimer disease and Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). The aim of this study was to investigate the plasma levels of autoantibodies against myelin basic protein (anti-MBP), myelin oligodendrocyte glycoprotein (anti-MOG) and S100β, and their relationships with cognitive performance in RA patients. Twenty patients with active rheumatoid arthritis and 19 age-, sex-, and schooling-matched healthy controls were recruited. Multiple dimensions of cognitive function were evaluated by structured clinical questionnaires. Autoantibodies and S100β levels were assessed by ELISAs. Patients had significantly higher levels of anti-MBP IgG (17.51 ± 1.36 vs. 5.24 ± 0.53 ng/mL), anti-MOG IgG (5.68 ± 1.34 vs. 0.51 ± 0.49 ng/mL), and S100β protein (2.24 ± 0.50 vs. 0.47 ± 0.06) than controls (all p < 0.0001). After adjusting for potential confounders, RA group presented worse cognitive performance involving the working memory and executive functions such as inhibition, flexibility, and mental control in parallel to higher autoantibodies and S100β levels than healthy controls (all p < 0.001). Levels of anti-MBP were negatively associated with delayed verbal recall (DVR; r = -0.42, p = 0.005), Stroop Color-Word (r = -0.48, p = 0.004), and N-Back Total scores (r = -0.59, p < 0.0001) and positively with Trail Making Test B (TMB, r = 0.53, p = 0.001). Negative correlation was found between levels of anti-MOG and DVR (r = -0.64, p < 0.0001), N-Back Total scores (r = -0.35, p = 0.03), Stroop Color-Word (r = -0.51, p = 0.001), and positively with TMB (r = 0.50, p = 0.003). S100β levels were associated with DVR (r = -0.51, p = 0.002), TMB (r = 0.46, p = 0.008), Stroop Color-Word (r = -0.67, p < 0.0001), and N-Back Total (r = -0.52, p = 0.003). RA is associated with impaired cognitive performance associated with higher levels of CNS-related autoantibodies and S100β levels. Given the importance of myelin integrity to cognition, our data indicate that these autoantibodies may be harmful to proper cognitive function.

Topics: Aged; Arthritis, Rheumatoid; Autoantibodies; Brazil; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; S100 Calcium Binding Protein beta Subunit

Citrullinated proteins have been suggested to play a critical role in the pathogenesis of multiple sclerosis (MS). Anticyclic citrullinated peptide (anti-CCP) antibody is used in the early diagnosis of rheumatoid arthritis (RA). The objective of this study was to investigate the presence of anti-CCP antibody in patients with MS compared to RA patients and healthy controls. Fifty patients with MS (38 females, 12 males; mean age 36.72 ± 8.82 years), 52 patients with RA (40 females, 12 males; mean age 40.87 ± 10.17 years), and 50 healthy controls (32 females, 18 males; mean age 38.22 ± 11.59 years) were included in this study. The levels of serum anti-CCP antibody were measured using an enzyme-linked immunosorbent assay (ELISA). The results of the study showed that anti-CCP antibody levels were significantly higher in RA patients versus MS or healthy controls (P < 0.001). Moreover, anti-CCP antibody was positive in 43 (83%) patients with RA, while it was negative in all MS patients as well as in all healthy controls. Also, no significant correlation was found between the anti-CCP levels and EDSS scores (r = -0.250). In conclusion, the results of this study did not support a positive association between serum anti-CCP antibody and MS.

Topics: Adult; Antibodies, Anti-Idiotypic; Arthritis, Rheumatoid; Central Nervous System; Citrulline; Early Diagnosis; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Peptides

Anti-citrullinated protein antibodies (ACPAs) are the serologic hallmark of rheumatoid arthritis. Functional studies on the role of ACPAs in experimental arthritis have yielded conflicting results, and therefore the present study was undertaken to assess systematically whether citrullinated proteins can really induce ACPAs and modulate arthritis in mice.. Balb/c, SJL, and DBA/1 mice were immunized with either native or citrullinated fibrinogen, myelin basic protein (MBP), and type II collagen (CII). ACPAs were detected with a peptide-based enzyme-linked immunosorbent assay (ELISA) and with Western blotting using fibrinogen as substrate. Arthritis was induced in mice by immunization with CII in Freund's complete adjuvant or by injection of anticollagen antibodies.. Analysis of the sera of mice immunized with citrullinated proteins revealed false-positive results with the citrulline peptide-based ELISA. In contrast, Western blot analysis using either citrullinated or native fibrinogen as substrate reliably detected ACPAs in Balb/c mice immunized with citrullinated fibrinogen, MBP, and CII. However, these ACPAs failed to induce or aggravate disease in Balb/c mice in the anticollagen antibody-induced arthritis model. Immunization with citrullinated fibrinogen induced ACPAs but did not lead to arthritis development in SJL and DBA/1 mice. In contrast, immunization with citrullinated CII failed to induce ACPAs or enhance disease in these strains in the collagen-induced arthritis model.. Mice can develop genuine ACPAs, but detection of ACPAs is highly dependent on strain, immunogen, immunization protocol, and detection assay. Murine ACPAs are not overtly pathogenic, since neither preexisting ACPAs nor the use of citrullinated collagen as immunogen modulates the clinical course of arthritis.

Topics: Adjuvants, Immunologic; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Autoantibodies; Autoantigens; Citrulline; Collagen Type II; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; False Positive Reactions; Fibrinogen; Freund's Adjuvant; Genetic Predisposition to Disease; Immunotherapy, Active; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Myelin Basic Protein; Protein Processing, Post-Translational; Proteins

Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10(-8), OR 1.23, 95% CI: 1.14-1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease.

Topics: Antibodies; Arthritis, Rheumatoid; Case-Control Studies; Gene Expression Regulation; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Male; Myelin Basic Protein; Polymorphism, Single Nucleotide; Reproducibility of Results; Synovial Membrane; Transcription, Genetic

The antigen recognition pattern of immunoglobulin M (IgM) could, when directed against protein antigens, provide an indication of the antigenic moieties triggering new B cells. The half-life of IgM is short and memory B cells against T-cell-dependent protein antigens typically produce IgG and not IgM antibodies. In this study, we analyzed whether a difference exists between the fine specificity of IgM versus IgG anti-citrullinated protein antibodies (ACPAs).. We determined the fine specificity of IgM and IgG ACPAs in 113 ACPA-positive rheumatoid arthritis patients with IgM cyclic citrullinated peptide 2 (CCP2) levels above 100 AU/ml. Fine specificity was assessed by performing ELISA using citrullinated peptides derived from vimentin, fibrinogen-β, fibrinogen-α and α-enolase, as well as citrullinated proteins fibrinogen and myelin basic protein. The arginine counterparts were used as controls.. Recognition of defined citrullinated antigens by IgM ACPA was confined to samples that also displayed recognition by IgG ACPA. However, the IgM ACPA response displayed a more restricted antigen recognition profile than IgG ACPA (OR = 0.26, P < 0.0001).. Our data show that several defined citrullinated antigens are recognized only by IgG ACPA, whereas others are also recognized by IgM ACPA. These observations suggest that not all citrullinated antigens are able to activate new B cells despite concurrent recognition by IgG ACPA.

Topics: Amino Acid Sequence; Antibody Specificity; Arthritis, Rheumatoid; Enzyme-Linked Immunosorbent Assay; Epitopes; Fibrinogen; Humans; Immunoglobulin G; Immunoglobulin M; Molecular Sequence Data; Myelin Basic Protein; Peptides, Cyclic; Phosphopyruvate Hydratase; Protein Stability; Time Factors; Vimentin

Measles vaccine and porcine myelin basic protein were both found to ameliorate or abolish the symptoms of adjuvant arthritis (AA) in Lewis rats whether inoculated at the time of adjuvant administration or after the onset of arthritis. These results are consistent with clinical observations that measles infection can sometimes cause remission of juvenile rheumatoid arthritis. The fact that measles virus proteins and myelin basic protein have significant regions of homology allowed peptides based on these regions to be synthesized. A twenty-amino acid sequence exhibits significant anti-arthritic activity when inoculated into rats with pre-existing AA and it also prevented onset of AA when a single dose was preinoculated three weeks prior to AA induction. These data suggest the possibility of developing novel therapeutic vaccines against some forms of arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Freund's Adjuvant; Humans; Immunodominant Epitopes; Immunotherapy; Lower Extremity; Measles Vaccine; Myelin Basic Protein; Peptides; Rats; Rats, Inbred Lew; Severity of Illness Index; Structural Homology, Protein; Swine; Vaccination; Vaccines, Combined; Vaccines, Subunit; Viral Proteins

To determine the role of expanded CD4(+)CD28(null) T cells in multiple sclerosis and rheumatoid arthritis pathology, these cells were phenotypically characterized and their Ag reactivity was studied. FACS analysis confirmed that CD4(+)CD28(null) T cells are terminally differentiated effector memory cells. In addition, they express phenotypic markers that indicate their capacity to infiltrate into tissues and cause tissue damage. Whereas no reactivity to the candidate autoantigens myelin basic protein and collagen type II was observed within the CD4(+)CD28(null) T cell subset, CMV reactivity was prominent in four of four HC, four of four rheumatoid arthritis patients, and three of four multiple sclerosis patients. The level of the CMV-induced proliferative response was found to be related to the clonal diversity of the response. Interestingly, our results illustrate that CD4(+)CD28(null) T cells are not susceptible to the suppressive actions of CD4(+)CD25(+) regulatory T cells. In conclusion, this study provides several indications for a role of CD4(+)CD28(null) T cells in autoimmune pathology. CD4(+)CD28(null) T cells display pathogenic features, fill up immunological space, and are less susceptible to regulatory mechanisms. However, based on their low reactivity to the autoantigens tested in this study, CD4(+)CD28(null) T cells most likely do not play a direct autoaggressive role in autoimmune disease.

Topics: Adult; Aged; Antigens, Differentiation; Arthritis, Rheumatoid; Autoantigens; CD28 Antigens; Cell Differentiation; Collagen Type II; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Autoimmunity to chondrocyte-producing proteins has been reported in patients with osteoarthritis (OA) as well as in those with rheumatoid arthritis (RA). To answer whether or not OA-specific autoimmunity exist, we performed screening of chondrocyte-producing autoantigens by two-dimensional electrophoresis and Western blotting with each of 20 OA and 20 RA serum samples. We identified an apparently OA-specific autoantigen spot with a molecular mass of 52 kDa and a Isoelectric point of 4.1 as fibulin-4 by mass fingerprinting. By preparing recombinant proteins of fibulin-4, we determined prevalence of the autoantibodies to fibulin-4 in 92 patients with OA, 67 patients with RA, 40 patients with systemic lupus erythematosus, and 43 patients with systemic scleroderma. As a result, the IgG type anti-fibulin-4 autoantibodies were detected in 23.9% of sera from patients with OA, in 8.9% of sera from patients with RA, in 2.5% of sera from patients with systemic lupus erythematosus, and in 9.3% of sera from patients with systemic scleroderma. Furthermore, we immunized DBA/1J, ICR, BALB/c, and C57BL/6 mice with the recombinant fibulin-4 proteins to investigate arthritogenecity of fibulin-4. As a result, mild synovitis was detected in all of the four strains. In addition, we demonstrated expression of fibulin-4 in chondrocytes at both mRNA and protein levels in vivo and in vitro by RT-PCR, Western blotting, and immunohistochemistry. Taken together, fibulin-4, expressed in chondrocytes and recognized as an autoantigen mainly in OA rather than in RA, may play pathogenic roles in OA.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Animals; Arthritis, Rheumatoid; Autoantigens; Chondrocytes; Extracellular Matrix Proteins; Female; Humans; Immunoglobulin G; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Middle Aged; Molecular Sequence Data; Myelin Basic Protein; Osteoarthritis; Recombinant Fusion Proteins; Scleroderma, Systemic; Synovitis

Rheumatoid arthritis (RA) is a diffuse connective tissue disease and a multi-system disorder with inflammatory process affecting joints in the first place. RA is found in 1 to 3% of population; the first signs of it are usually found in people aged 35 to 50. Neurological pathology in RA is manifested by cervicocranialgia, cervical myelopathy, pathological changes in the upper cervical spine, and cerebral disorders. However, exact mechanisms of the development of central nervous system (CNS) lesions in RA have not been presented. The aim of this study was to clarify the pathophysiological mechanisms and clinical peculiarities of cerebral disturbances in RA. The subjects were 42 female patients, who underwent clinical, neurological, clinicolaboratory, immunological, and clinicophysiological examination. Subjective and objective symptoms were studied; the following syndromes of CNS pathology were distinguished: initial manifestations of cerebral functional insufficiency; disseminated cerebral micro symptoms; focal cerebral lesion. These disorders were accompanied by changes in biochemical parameters which evidenced the presence of connective tissue destruction and immune inflammation. Immunological tests revealed elevation of the level of myelin basic protein antibodies, which correlated with the degree of neurological disturbances and the duration of the disease. The level of myeloperoxidase was elevated, but the degree of this elevation did not depend on the degree of the cerebral disorder and displayed a negative correlation with the duration of the disease. The results of the study demonstrate primary lesion of small vessels in RA--secondary vasculitis followed by demyelinization of CNS white substance. Thus, three forms of cerebrovascular pathology, caused by acute or chronic cerebral vascular insufficiency in RA can be distinguished: initial manifestations of cerebral circulation insufficiency; discirculatory encephalopathy; transient cerebral circulation disturbances and cerebral stroke.

Topics: Adult; Aged; Antibodies; Arthritis, Rheumatoid; Cerebrovascular Disorders; Cervical Vertebrae; Electroencephalography; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Neuralgia; Peroxidase

In the present study, we examined the therapeutic effects of T-614 (3-formylamino-7-methylsulfonylaminoxy-4H-1-benzopyran-4-one), a new anti-rheumatic drug, on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). T-614 dose-dependently suppressed the development of active EAE induced in Lewis rats by immunization with myelin basic protein (MBP) when administered for 2 weeks starting on the day of immunization (day 0 to 14). Amelioration of clinical signs was also obtained by the treatment at the effector phase (day 7 to 14) of the disease. Furthermore, T-614 treatment of recipient rats that had received MBP-sensitized lymphoid cells resulted in suppression of the clinical severity of EAE. Immunohistological examination revealed that the number of TCR alpha beta-expressing T cells and the extent of MHC class II expression in the spinal cord of rats treated with T-614 was markedly reduced. In vitro study using MBP-specific T cells showed that the addition of T-614 inhibited the proliferative responses of T cells and the production of pro-inflammatory cytokines such as IFN-gamma, IL-6 and TNF produced by T and accessory cells. Taken together, these findings imply that T-614 suppresses the development of EAE by inhibiting the proliferation of autoreactive T cells and pro-inflammatory cytokine production not only by T cells but also by macrophages/microglia. This may be attributable to the result that T-614 is more effective at the effector phase rather than the induction phase. Thus, this drug has a potential value for the treatment of various T cell-mediated autoimmune diseases including multiple sclerosis (MS) as well as rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Benzopyrans; Encephalomyelitis, Autoimmune, Experimental; Interferon-gamma; Interleukin-1; Interleukin-6; Macrophages; Microglia; Myelin Basic Protein; Rats; Rats, Inbred Lew; Spinal Cord; Sulfonamides; T-Lymphocytes; Tumor Necrosis Factor-alpha

The OX-40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)-specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE). An OX-40 immunotoxin was used to target and eliminate MBP-specific T cells within the central nervous system without affecting peripheral T cells. When injected in vivo, the OX-40 immunotoxin bound exclusively to myelin-reactive T cells isolated from the CNS, which resulted in amelioration of EAE. Expression of the human OX-40 antigen was also found in peripheral blood of patients with acute graft-versus-host disease and the synovia of patients with rheumatoid arthritis during active disease. The unique expression of the OX-40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4+T cells that does not require prior knowledge of the pathogenic autoantigen.

Topics: Animals; Arthritis, Rheumatoid; CD4-Positive T-Lymphocytes; Cell Separation; Encephalomyelitis, Autoimmune, Experimental; Humans; Immunotoxins; Myelin Basic Protein; Rats; Rats, Inbred Lew; Receptors, OX40; Receptors, Tumor Necrosis Factor; Ricin; T-Lymphocyte Subsets; Tumor Necrosis Factor Receptor Superfamily, Member 7