muramidase and Lupus-Erythematosus--Systemic

The appearance of autoantibodies in autoimmune diseases such as lupus suggests that B-cell tolerance to self is breached. Hence it becomes important to unravel the precise cellular and molecular mechanisms that are responsible for violations in various B-cell tolerance checkpoints in autoimmune diseases. B-cell immunoglobulin or B-cell receptor transgenic models have been of immense aid in uncovering many of these key tolerance checkpoints during normal B-cell development. By breeding these transgenic models onto mice that are engineered to lack or hyperexpress various B-cell molecules, including signaling intermediates, researchers have delineated the role of these molecules in B-cell tolerance. These transgenic models have also been useful in delineating the impact of various lupus prone genomes and lupus susceptibility loci on B-cell tolerance. This review focuses on some of the more well-studied B-cell receptor transgenic models and the lessons they have taught us over the past two decades.

Topics: Animals; Apoptosis; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cytokines; Histocompatibility Antigens Class I; Immune Tolerance; Immunoglobulins; Intracellular Signaling Peptides and Proteins; Lupus Erythematosus, Systemic; Mice; Mice, Transgenic; Muramidase; Receptors, Antigen, B-Cell

It is becoming well accepted that innate immunity serves as a natural adjuvant in enhancing and directing the adaptive immune response. In this review, I have discussed how the complement system, a major mediator of innate immunity, links the two systems. The recent availability of knockout mice bearing selective deficiencies in the critical complement proteins and receptors has allowed formal demonstration of the importance of complement in enhancement of humoral immunity. Characterization of the mice has also uncovered mechanisms for maintaining survival of activated B cells within the lymphoid compartment. For example, co-ligation of the CD21/CD19/Tapa-1 receptor with the BCR not only reduces the threshold for B cell follicular survival but provides a unique signal for survival in the germinal centers. In addition complement receptors are critical for localization of antigen and C3d ligand to FDCs for maintenance of long-term B cell memory. A surprise that has come from analysis of the deficient mice is that complement is also important in negative selection of B lymphocytes. This observation provides new insight to a long-standing enigma that the major predisposing factor in lupus is deficiency in complement C1q or C4. The seeming contradiction of dual role for complement in both B cell activation and tolerance is reconciled by the hypothesis that natural IgM provides a mechanism to selectively identify self-antigens that are highly conserved and cross-react with microbial ones such as DNA and nuclear proteins. Thus, the importance of complement in tolerance to self-antigens is restricted to those self-antigens that are evolutionary conserved, and they are identified by natural antibody. The future should hold further surprises as to the intricate interactions between the complement system and acquired immunity.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Antigens; Autoimmune Diseases; Chickens; Chimera; Clonal Deletion; Complement Activation; Complement C3; Complement System Proteins; Dendritic Cells, Follicular; Female; Guinea Pigs; Humans; Immune Tolerance; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Models, Immunological; Muramidase; Receptors, Antigen, B-Cell; Receptors, Complement; Receptors, Complement 3b; Receptors, Complement 3d

The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.

Topics: Animals; Autoantibodies; B-Cell Activating Factor; B-Lymphocytes; Immune Tolerance; Lupus Erythematosus, Systemic; Mice; Mice, Transgenic; Muramidase; T-Lymphocytes

The susceptibility locus for the autoimmune disease lupus on murine chromosome 1, Sle1z/Sle1bz, and the orthologous human locus are associated with production of autoantibody to chromatin. We report that the presence of Sle1z/Sle1bz impairs B cell anergy, receptor revision, and deletion. Members of the SLAM costimulatory molecule family constitute prime candidates for Sle1bz, among which the Ly108.1 isoform of the Ly108 gene was most highly expressed in immature B cells from lupus-prone B6.Sle1z mice. The normal Ly108.2 allele, but not the lupus-associated Ly108.1 allele, was found to sensitize immature B cells to deletion and RAG reexpression. As a potential regulator of tolerance checkpoints, Ly108 may censor self-reactive B cells, hence safeguarding against autoimmunity.

Topics: Animals; Antigens, Ly; Autoantigens; B-Lymphocytes; Bone Marrow Cells; Cell Death; Cell Line, Tumor; Cells, Cultured; Clonal Anergy; Clonal Deletion; Genetic Predisposition to Disease; Immune Tolerance; Lupus Erythematosus, Systemic; Mice; Mice, Transgenic; Multifactorial Inheritance; Muramidase; Receptors, Antigen, B-Cell; Spleen; Transfection

To identify defects in B cell tolerance that may contribute to the production of autoantibodies in New Zealand Black (NZB) mice, we crossed soluble hen egg white lysozyme (sHEL) and anti-HEL Ig transgenes (Ig Tg) onto the NZB background. In this study, we have examined one of the first checkpoints involved in maintenance of peripheral B cell tolerance, follicular exclusion and elimination of self-reactive B cells in the absence of T cell help. Freshly isolated anti-HEL Ig Tg B cells were labeled with CFSE, adoptively transferred into sHEL recipients, and the fate of self-reactive anti-HEL Ig Tg B cells was followed using flow cytometry and immunofluorescence microscopy. Although anti-HEL Ig Tg B cells from NZB mice are appropriately excluded from B cell follicles in NZB sHEL recipient mice, they demonstrate aberrant survival, proliferation, and generation of anti-HEL Ab-producing cells. This abnormal response results from an intrinsic defect in NZB B cells, requires the presence of CD4(+) T cells, and is facilitated by the splenic environment in NZB mice. Thus, NZB mice have immune defects that interact synergistically to allow autoreactive B cells to become activated despite the presence of tolerizing autoantigens.

Topics: Adoptive Transfer; Animals; Autoantibodies; B-Lymphocyte Subsets; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Division; Cell Survival; Chickens; Crosses, Genetic; Immunoglobulin Heavy Chains; Interphase; Lupus Erythematosus, Systemic; Lymphocyte Activation; Major Histocompatibility Complex; Mice; Mice, Inbred C57BL; Mice, Inbred NZB; Mice, Transgenic; Muramidase; Self Tolerance; Transgenes

We have investigated the individual role of FcgammaR and CR, as well as their cooperation, in mediating the oxidative burst and degranulation of neutrophils of Brazilian systemic lupus erythematosus (SLE) patients. Neutrophils were stimulated with the immune complexes (IC)-IgG or -F(ab')2, opsonized or not with normal or SLE human serum. The oxidative burst was decreased in neutrophils of active SLE patients compared to healthy controls when this response was mediated by FcgammaR and/or CR, while the degranulation was unaffected. The SLE hypocomplementemia did not affect the oxidative burst mediated only by CR. FcgammaRII and CR1 expression on neutrophils of active SLE patients was reduced, while the expression of FcgammaRIII and CR3 was unaffected. These results suggest that the different FcgammaR and CR may be involved or cooperate in different ways in the mediation of the oxidative burst and the degranulation. Moreover, the decreased oxidative burst of neutrophils of active SLE patients may not depend only on SLE hypocomplementemia for IC opsonization. These observations are directed at the understanding of how each of these immune system components (FcgammaR, CR and complement) influences the precise biological neutrophil responses both in physiological and pathological conditions. Since the Brazilian population comprises many races, these results are important because they are directed at a specific population of SLE patients.

Topics: Brazil; Cell Degranulation; Female; Gene Expression; Hemolysis; Humans; Immunoglobulin G; Luminescent Measurements; Lupus Erythematosus, Systemic; Male; Muramidase; Neutrophils; Receptors, Complement; Receptors, IgG; Respiratory Burst

This investigation was designed to determine and compare the distribution pattern of anti-neutrophil cytoplasmic antibodies (ANCA) in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in the presence or absence of periodontal disease.. Sera of 30 patients with SLE and 30 with RA were tested for ANCA utilizing an indirect enzyme immunosorbent assay (ELISA) directed to a neutrophil granular extract and 6 neutrophil granule proteins. A control group of 20 healthy individuals showing neither evidence of periodontal disease nor systemic compromise was also included in this study.. For RA, the number of ANCA-positive sera was very low but was evenly distributed among patients with and without periodontitis. Conversely, a high number of ANCA-positive sera in SLE was found mostly in individuals presenting periodontal compromise. A statistically significant association between ANCA and periodontitis in SLE patients was found (P <0.005, chi square test).. A marked difference in the number and distribution of ANCA with respect to periodontitis between RA and SLE was found. Hyperresponsiveness of B cells and polyclonal B activation to periodontopathic bacteria in SLE might be accountable for the high numbers of ANCA and the close association observed between those autoantibodies and periodontitis in SLE.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Autoantigens; B-Lymphocytes; Bacteria; Cathepsin G; Cathepsins; Chi-Square Distribution; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lactoferrin; Leukocyte Elastase; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Middle Aged; Muramidase; Myeloblastin; Neutrophils; Periodontitis; Peroxidase; Serine Endopeptidases

Abrogation of peripheral tolerance in transgenic mice that express a uniform B-cell receptor may create a powerful tool to examine the molecular mechanisms that underlie the autoimmune response in B cells. Here we report that processes that induce a systemic lupus erythematosus-like syndrome in normal mice, namely chronic graft vs host reaction, trigger systemic autoimmunity in a well-established transgenic mice model of B cell receptor peripheral tolerance. The induction of graft vs host reaction in mice that carry both a rearranged B cell Ag receptors specific for hen egg lysozyme and expressing chronically circulating hen egg lysozyme Ag resulted in induction of high and sustained levels of circulating anti-hen egg lysozyme autoantibodies and glomerulonephritis with proteinuria. This was associated with marked changes in expression of cell-surface proteins, such as CD23 and complement receptor 2. B cells from the graft vs host-induced mice could proliferate in vitro in response to self-Ag, and upon stimulation with anti-IgD demonstrated rapid phosphotyrosine phosphorylation of specific proteins, which could not be induced in the anergic double transgenic B cells. Conversely, loss of tolerance was not associated with a higher induction in the level of Syk kinase phosphorylation following stimulation with anti-IgD. Taken collectively, these data establish that 1) processes that induce a systemic lupus erythematosus-like syndrome in normal mice can abrogate peripheral tolerance in transgenic mice expressing self-tolerized B cells, and that 2) loss of tolerance in this model is associated with marked changes in surface expression of B cell coreceptors as well as with selective changes in IgD-induced signaling by discrete tyrosine-phosphoproteins, but not Syk kinase.

Topics: Animals; Autoantibodies; Autoantigens; B-Lymphocytes; Disease Models, Animal; Enzyme Precursors; Graft vs Host Reaction; Immune Tolerance; Immunoglobulin D; Immunoglobulin M; Intracellular Signaling Peptides and Proteins; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphocyte Activation; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; Phosphoproteins; Phosphotyrosine; Protein-Tyrosine Kinases; Receptors, Antigen, B-Cell; Self Tolerance; Syk Kinase

A B lymphocyte hyperactivity syndrome resembling systemic lupus erythematosus characterizes mice lacking the src-family kinase Lyn. Lyn is not required to initiate B cell antigen receptor (BCR) signaling but is an essential inhibitory component. lyn-/- B cells have a delayed but increased calcium flux and exaggerated negative selection responses in the presence of antigen and spontaneous hyperactivity in the absence of antigen. As in invertebrates, genetic effects of loci with only one functional allele can be used to analyze signaling networks in mice, demonstrating that negative regulation of the BCR is a complex quantitative trait in which Lyn, the coreceptor CD22, and the tyrosine phosphatase SHP-1 are each limiting elements. The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex.

Topics: Animals; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Autoantigens; Autoimmunity; B-Lymphocytes; Cell Adhesion Molecules; Female; Intracellular Signaling Peptides and Proteins; Lectins; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muramidase; Phenotype; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases; Quantitative Trait, Heritable; Radiation Chimera; Receptors, Antigen, B-Cell; Sialic Acid Binding Ig-like Lectin 2; Signal Transduction; src-Family Kinases

Lysozyme was administered to 57 patients with lupus erythematosus (LE) for 10 days according to 4 schemes: Group 1 (n = 10)--30 mg of lysozyme 3 times a day sublingually; Group 2 (n = 10)--100 mg daily i.m.; Group 3 (n = 10)--100 mg twice a day i.m.; Group 4 (n = 27)--100 mg 3 times a day i.m. After a course of lysozyme therapy patients with discoid and disseminated LE were prescribed delagil, those with systemic LE were administered corticosteroid hormones in moderate doses or presocyl. The treatment was well tolerated, only 2 (3.5%) patients developed toxicoderma. The results evidence that lysozyme efficacy is not inferior to that of levamisole but this agent is better tolerated. Clinical and paraclinical efficacy was higher in Groups 1 and 4; cellular, humoral, and local immunity parameters, as well as the characteristics reflecting the inflammatory processes evidence positive changes developing as a result of lysozyme therapy, these changes persisting in the majority of cases during further combined treatment. Therapy with low doses of lysozyme is indicated for patients with the immune status disorders mainly. If changes in the nonspecific resistance predominate, the scheme used in Group 4 is advisable.

Topics: Adult; Chronic Disease; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Immunoglobulins; Leukocyte Count; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Male; Middle Aged; Muramidase; Remission Induction; Time Factors

This paper reports preliminary evidence suggesting that measurements of free light-chain Ig (FLIg) in urine may represent quantitative markers of in vivo polyclonal B-cell activation. Thus, longitudinal levels of urinary FLIg in patients with systemic lupus erythematosus (SLE) may be used to track or monitor the in vivo immunopathologic B-cell activity of SLE and be helpful in predicting a disease relapse. Our findings showed that dramatic rises in urinary FLIg occurred during asymptomatic intervals that preceded by 4-8 weeks the first symptomatic signs of acute SLE relapse. These results suggest that a sizable lead time may exist between the occurrence of immunopathologic B-cell stimulation and the resultant symptoms and tissue damage of immune complex-induced acute inflammation. In these studies the measurement of urinary FLIg was accomplished by an indirect method using ng-sensitive radioimmunoassays (RIAs) that measured isotypic IgG, IgA, IgM, total kappa-Ig, and total lambda-Ig. As a control for the assessment of renal tubular function and the excretion of low molecular weight proteins in SLE patients, longitudinal measurements of beta-2-microglobulin (B2M) and lysozyme were made using a novel solid-phase 3H-biotin RIA technique.

Topics: Adult; B-Lymphocytes; beta 2-Microglobulin; Biomarkers; Female; Humans; Immunoglobulin Light Chains; Immunosorbents; Lupus Erythematosus, Systemic; Male; Middle Aged; Muramidase; Prognosis; Radioimmunoassay; Time Factors

The effect of lysozyme on intraglomerular immune complex deposition was examined in NZB/W F1 mice undergoing unilateral nephrectomy. Unilateral nephrectomy enhanced the glomerular immune complex deposition and glomerular lesions, which were suppressed by repeated intraperitoneal injections of lysozyme, in spite of unaltered serum anti-DNA antibody titers. DNA binding to the glomerular basement membrane (GBM) examined in vitro and that to glomeruli examined in vitro were also suppressed by lysozyme. An increased survival rate and decreased proteinuria were also induced by this basic protein. The mechanisms of the ameliorative effect were studied in vitro. DNA was bound to the GBM only in the presence of serum, plasma, or fibronectin. A similar inhibitory effect on DNA binding was also obtained by another polycation, hexadimethrine, in place of lysozyme. The in vitro findings suggest that DNA binding to the GBM is mediated by fibronectin, and that lysozyme electrostatically inhibits this binding, thereby possibly reducing the in situ DNA-anti-DNA complex formation in the GBM.

Topics: Albuminuria; Animals; Antigen-Antibody Complex; Autoantibodies; Basement Membrane; DNA; Fibronectins; In Vitro Techniques; Kidney Glomerulus; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Muramidase

The Fc receptor mediated reaction, the beta-glucuronidase and the lactic dehydrogenase activities of monocytes and the serum lysozyme level were tested together with the circulating immune complex content of patients with systemic lupus erythematosus. Simultaneously with the increasing FC receptor-mediated reaction and the elevated enzyme activities of patient monocytes, the secretion of lysozyme and the immune complex content of the sera were higher than those of the controls. A positive correlation was demonstrated between the Fc receptor-mediated reaction, the beta-glucuronidase activity, the lysozyme secretion and the immune complex content of the sera. Thus, the monocytes of patients appeared to be activated by the circulating immune complexes.

Topics: Antigen-Antibody Complex; Female; Glucuronidase; Humans; L-Lactate Dehydrogenase; Lupus Erythematosus, Systemic; Male; Monocytes; Muramidase; Receptors, Fc

Topics: Adolescent; Adult; Behcet Syndrome; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Muramidase; Neutrophils; Oxygen

The authors describes four cases of lupus erythematosus (LE) diagnosed during the course of a medication toxicodermia, which was always acute and variable in its severity (in one case it concerned a Lyell's syndrome). The lupus affection was made evident by the toxicodermia and lupic manifestations may regress spontaneously after recovery from the skin disorder. This emphasizes the value of clinical and biological testing for the presence of LE in severe cases of toxicodermia in women, more particularly immunofluorescent studies of the basal structures in the cutaneous lesions.

Topics: Adult; Aged; Ampicillin; Aprindine; Drug Eruptions; Female; Humans; Lupus Erythematosus, Systemic; Muramidase; Procainamide; Sulfasalazine; Thiamphenicol

Topics: Animals; Antibodies, Viral; Arteritis; Colitis, Ulcerative; Crohn Disease; Cytomegalovirus; Food Hypersensitivity; Humans; Immunity, Cellular; Lupus Erythematosus, Systemic; Mice; Milk; Muramidase; Rabbits; RNA Viruses

Topics: Arthritis, Rheumatoid; Electrophoresis; Humans; Kidney Diseases; Kidney Function Tests; Kidney Glomerulus; Kidney Tubules; Leukemia; Lupus Erythematosus, Systemic; Multiple Myeloma; Muramidase; Neoplasms; Proteinuria

Topics: Blood Protein Electrophoresis; Chemical Phenomena; Chemistry; Dermatitis; Electrophoresis; Eye Manifestations; Female; Humans; Lupus Erythematosus, Systemic; Middle Aged; Muramidase; Tears

Topics: Anti-Infective Agents, Local; Antiviral Agents; Dermatologic Agents; Humans; Lupus Erythematosus, Systemic; Muramidase

Topics: Anti-Infective Agents, Local; Antiviral Agents; Dermatologic Agents; Humans; Lupus Erythematosus, Systemic; Muramidase