muramidase and Autoimmune-Diseases

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

Topics: Autoimmune Diseases; DNA, Viral; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Muramidase; Nucleic Acid Hybridization; RNA, Messenger; RNA, Viral; Salivary Glands; Sjogren's Syndrome

Topics: Animals; Autoimmune Diseases; Biopsy; Colitis, Ulcerative; Colonic Diseases; Colonic Neoplasms; Diagnosis, Differential; Eye Manifestations; Humans; Lactose Intolerance; Liver Diseases; Milk; Muramidase; Prognosis; Psychophysiologic Disorders; Radiography; Sigmoidoscopy

Topics: Animals; Antibody Formation; Antigens; Autoimmune Diseases; Colitis, Ulcerative; Entamoeba histolytica; Humans; Hypersensitivity, Immediate; Intestinal Mucosa; Ischemia; Male; Milk; Muramidase

Topics: Animals; Antigen-Antibody Reactions; Autoimmune Diseases; Clinical Enzyme Tests; Colitis, Ulcerative; Feces; Humans; Intestinal Mucosa; Milk; Muramidase; Proteins; Psychophysiologic Disorders; Skin Tests

Th cells sensitized against autoantigens acquire pathogenicity following two sequential events, namely activation by their target Ag and a process named "licensing." In this study, we analyzed these processes in a transgenic mouse system in which TCR-transgenic Th cells specific to hen egg lysozyme (HEL) are adoptively transferred to recipients and induce inflammation in eyes expressing HEL. Our data show that the notion that the lung is the organ where "licensing" for pathogenicity takes place is based on biased data collected with cells injected i.v., a route in which most transferred cells enter via the lung. Thus, we found that when donor cells were activated in vitro and injected intraperitoneally, or were activated in vivo, they migrated simultaneously to the lung, spleen, and other tested organs. In all, tested organs donor cells undergo "licensing" for pathogenicity, consisting of vigorous increase in number and changes in expression levels of inflammation-related genes, monitored by both flow cytometry and microarray analysis. After reaching peak numbers, around day 3, the "licensed" donor cells migrate to the circulation and initiate inflammation in the HEL-expressing recipient eyes. Importantly, the kinetics of increase in number and of changes in gene expression by the donor cells were similar in lung, spleen, and other tested organs of the recipient mice. Furthermore, the total numbers of donor cells in the spleen at their peaks were 10- to 100-fold larger in the spleen than in the lung, contradicting the notion that the lung is the organ where "licensing" takes place.

Topics: Adoptive Transfer; Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; Disease Models, Animal; Flow Cytometry; Lung; Lymphocyte Activation; Mice; Mice, Transgenic; Muramidase; Spleen; T-Lymphocytes, Helper-Inducer

Increased serum levels of angiotensin converting enzyme and lysozyme are considered as inflammatory markers for diagnosis of sarcoidosis which is an autoimmune inflammatory disease. The purpose of this study is to evaluate the significance of differences in serum angiotensin converting enzyme and lysozyme levels of patients with ocular involvement of other autoimmune inflammatory and infectious diseases.. This is a prospective study involving patients with ankylosing spondylitis, behcet's disease, presumed sarcoidosis, presumed latent tuberculosis, presumed latent syphilis, and control group. The serum levels of angiotensin converting enzyme and lysozyme were analyzed by enzyme-linked immunosorbent assay. Bonnferoni analysis was used to assess pairwise comparisons between the groups.. There was a significant increase in serum angiotensin converting enzyme level in patients with presumed sarcoidosis compared to ankylosing spondylitis (p = 0.0001), behcet's disease (p = 0.0001), presumed latent tuberculosis (p = 0.0001), presumed latent syphilis (p = 0.0001), and control group (p = 0.0001). The increase in serum lysozyme level was significant for patients with presumed sarcoidosis with respect to ankylosing spondylitis (p = 0.0001), behcet's disease, (p = 0.0001) presumed latent tuberculosis (p = 0.001), presumed latent syphilis (p = 0.033), and control group (p = 0.0001).. Elevated serum angiotensin converting enzyme levels are significant for patients with presumed sarcoidosis compared to ocular involvement of other autoimmune diseases such as behcet's disease and ankylosing spondylitis, and ocular involvement of infectious diseases such as presumed latent tuberculosis and presumed latent syphilis. However, elevated serum lysozyme level might be also detected in ocular involvement of infectious diseases such as presumed latent tuberculosis and presumed latent syphilis.. NCT02627209. Date of registration: 12/09/2015.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Behcet Syndrome; Child; Communicable Diseases; Enzyme-Linked Immunosorbent Assay; Female; Humans; Latent Tuberculosis; Male; Middle Aged; Muramidase; Peptidyl-Dipeptidase A; Prospective Studies; Sarcoidosis; Spondylitis, Ankylosing; Syphilis

Experimental autoimmune uveoretinitis (EAU) is a widely used experimental animal model of human endogenous posterior uveoretinitis. In the present study, we performed in vivo imaging of the retina in transgenic reporter mice to investigate dynamic changes in exogenous inflammatory cells and endogenous immune cells during the disease process.. Transgenic mice (C57Bl/6 J Cx 3 cr1 (GFP/+) , C57Bl/6 N CD11c-eYFP, and C57Bl/6 J LysM-eGFP) were used to visualize the dynamic changes of myeloid-derived cells, putative dendritic cells and neutrophils during EAU. Transgenic mice were monitored with multi-modal fundus imaging camera over five time points following disease induction with the retinal auto-antigen, interphotoreceptor retinoid binding protein (IRBP1-20). Disease severity was quantified with both clinical and histopathological grading.. In the normal C57Bl/6 J Cx 3 cr1 (GFP/+) mouse Cx3cr1-expressing microglia were evenly distributed in the retina. In C57Bl/6 N CD11c-eYFP mice clusters of CD11c-expressing cells were noted in the retina and in C57Bl/6 J LysM-eGFP mice very low numbers of LysM-expressing neutrophils were observed in the fundus. Following immunization with IRBP1-20, fundus examination revealed accumulations of Cx3cr1-GFP(+) myeloid cells, CD11c-eYFP(+) cells and LysM-eGFP(+) myelomonocytic cells around the optic nerve head and along retinal vessels as early as day 14 post-immunization. CD11c-eYFP(+) cells appear to resolve marginally earlier (day 21 post-immunization) than Cx3cr1-GFP(+) and LysM-eGFP(+) cells. The clinical grading of EAU in transgenic mice correlated closely with histopathological grading.. These results illustrate that in vivo fundus imaging of transgenic reporter mice allows direct visualization of various exogenously and endogenously derived leukocyte types during EAU progression. This approach acts as a valuable adjunct to other methods of studying the clinical course of EAU.

Topics: Animals; Autoimmune Diseases; CD11c Antigen; CX3C Chemokine Receptor 1; Disease Models, Animal; Disease Progression; Eye Proteins; Freund's Adjuvant; Luminescent Proteins; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multimodal Imaging; Muramidase; Peptide Fragments; Receptors, Chemokine; Retinal Vessels; Retinitis; Retinol-Binding Proteins; Time Factors; Uveitis

The interaction between TLRs and their cognate ligands triggers both the innate and adaptive immune systems, and thus can play a pivotal role in the defense against pathogen invasion. This work investigates the differentiation of naive CD4 cells into Th1 or Th17 phenotypes in mice treated with different TLR ligands. We use a model system in which naive transgenic cells specific to hen egg lysozyme are adoptively transferred into recipients that express hen egg lysozyme in the lens of the eye. The transferred naive T cells induce ocular inflammation only in recipients treated with TLR ligands. Treatment with LPS preferentially stimulated IL-17 production, whereas CpG oligodeoxynucleotide and polyinosinic:polycytidylic acid primarily stimulated Th1 cells. Peptidoglycan stimulated the two Th subpopulations equally. The preferential induction of Th1 or Th17 by the four ligands was detected in the spleen (where a major portion of the adoptively transferred cells homed) and in the eyes, where activated Th cells initiate inflammation. Analysis of the cytokines present in recipient mice suggests that Th1 induction is elicited by IL-12 and/or IFN-α, whereas Th17 generation is preferentially mediated by IL-6. Importantly, we show in this article that treatment with LPS selectively promoted in the recipient mice the generation of IL-6-producing activated B cells. An inverse correlation was found between the level of regulatory T cells and severity of inflammation induced by the donor cells. Taken together, our data show that specific TLR ligands differentially activate the immune system as evidenced by the generation of distinct Th phenotypes from naive CD4 cells.

Topics: Animals; Autoimmune Diseases; Chickens; Ligands; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; Peptidoglycan; Poly I-C; Th1 Cells; Th17 Cells; Toll-Like Receptor 2; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors

The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8+ CTLs and CD4+ Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen-specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease.

Topics: Animals; Antigen Presentation; Autoimmune Diseases; Cell Movement; Dendritic Cells; Disease Models, Animal; Glomerulonephritis; Kidney; Leukocytes, Mononuclear; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muramidase; Ovalbumin; Podocytes; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer

Synthetic oligodeoxynucleotides (ODN) expressing 'suppressive' TTAGGG motifs down-regulate a variety of proinflammatory and T helper type 1 (Th1)-mediated pathological immune responses. The ability of the archetypal suppressive ODN A151 to inhibit ocular inflammation was examined in two murine models: experimental autoimmune uveitis, induced by immunization with a retinal antigen, interphotoreceptor retinoid-binding protein (IRBP) and adoptively transferred ocular inflammation, induced by transferring Th1 cells specific to hen egg lysozyme (HEL) into recipient mice that express HEL in their eyes. A151 treatment suppressed the inflammation in both models. In addition, A151 inhibited IRBP-specific cytokine production and lymphocyte proliferation in mice immunized with IRBP. These findings suggest that suppressive ODN affects both afferent and efferent limbs of the immunopathogenic process and may be of use in the treatment of autoimmune ocular inflammation.

Topics: Adoptive Transfer; Animals; Autoimmune Diseases; Cell Proliferation; Cells, Cultured; Cytokines; Disease Models, Animal; Eye Proteins; Female; Immunosuppressive Agents; Inflammation Mediators; Lymphocyte Activation; Mice; Mice, Inbred Strains; Muramidase; Oligodeoxyribonucleotides; Retinol-Binding Proteins; Th1 Cells; Uveitis

Both Th1 and Th17 T cell subsets can mediate inflammation, but the kinetics of the pathogenic processes mediated by these two subsets have not been investigated. Using an experimental system in which TCR-transgenic Th1 or Th17 cells specific for hen egg lysozyme induce ocular inflammation in recipient mice expressing eye-restricted hen egg lysozyme, we found important differences in the in vivo behavior of these two subsets. Th1 cells initially proliferated considerably faster and invaded the eye more quickly than their Th17 counterparts, but then disappeared rapidly. By contrast, Th17 cells accumulated and remained the majority of the infiltrating CD4(+) cells in the eye for as long as 25 days after transfer, mediating more long-lasting pathological changes. Unlike Th1, Th17 cells were highly resistant to restimulation-induced apoptosis, a major pathway by which autoimmune and chronically restimulated Th1 cells are eliminated. Th17 cells had reduced Fas ligand production and resistance to Fas-induced apoptosis, relative to Th1 cells, despite similar surface expression of Fas. Th17-induced ocular inflammation also differed from Th1-induced inflammation by consisting of more neutrophils, whereas Th1-induced disease had higher proportions of CD8 cells. Taken together, our data show that pathogenic processes triggered by Th17 lag behind those induced by Th1, but then persist remarkably longer, apparently due to the relative resistance of Th17 cells to restimulation-induced cell death. The long-lasting inflammation induced by Th17 cells is in accord with these cells being involved in chronic conditions in humans.

Topics: Adoptive Transfer; Animals; Apoptosis; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Eye; Fas Ligand Protein; fas Receptor; Flow Cytometry; Inflammation; Interleukin-17; Mice; Mice, Transgenic; Muramidase; T-Lymphocyte Subsets; Th1 Cells

Microbial products stimulate the immune system by interacting with Toll-like receptors (TLR) on antigen-presenting cells. This study examined the hypothesis that microbial products, which function as TLR ligands, are playing a major role in triggering pathogenic autoimmunity.. An experimental system was developed in which microbial TLR ligands were tested in vivo for their capacity to stimulate naïve CD4 cells specific against hen egg lysozyme (HEL) to become effector cells capable of inducing inflammation in eyes in which HEL is expressed. The ligands' mode of action was analyzed by determining their effects on the proliferation, acquisition of tissue-invading capacity, i.e. elevated CD49d and decreased CD62L expression, and production of interferon-gamma by the HEL-specific cells.. All the 7 tested TLR ligands triggered ocular inflammation in the experimental system used here, with pertussis toxin surpassing all other ligands in its activities. A correlation was found between the capacity of the ligands to trigger pathogenic immunity and to stimulate the proliferation, modification of cell surface and interferon-gamma production by T cells.. This study provides direct evidence to support the notion that microbial products are capable of triggering pathogenic autoimmunity.

Topics: Animals; Autoantigens; Autoimmune Diseases; Bacteria; Bacterial Toxins; CD4-Positive T-Lymphocytes; Disease Models, Animal; Integrin alpha2; Interferon-gamma; L-Selectin; Ligands; Mice; Mice, Transgenic; Muramidase; Polysaccharides, Bacterial; Toll-Like Receptors; Uveitis

Autoimmune uveoretinitis accounts for at least 10% of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4(+) TCR transgene. In this manner, we have tracked autoreactive CD4(+) T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4(+) T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.

Topics: AIRE Protein; Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; CD4-Positive T-Lymphocytes; Clonal Anergy; Eye Proteins; Mice; Mice, Transgenic; Muramidase; Pancreas; Retina; Retinitis; Retinol-Binding Proteins; Transcription Factors; Uveitis

A major hypothesis for the induction of autoimmunity invokes the enhanced display of previously hidden (cryptic) epitopes under inflammatory conditions leading to the activation of self-reactive T cells. However, there is meager data that directly validate the influence of specific immune mediators on the upregulation of the presentation of cryptic determinants in vivo. We tested the effect on well-defined cryptic epitopes of hen eggwhite lysozyme (HEL) of the availability locally of a cytokine (IL-2, IL-4, IL-6, IL-10, TNF-alpha or granulocyte-macrophage colony-stimulating factor) at the antigen delivery site, or of the pretreatment of the immunogen with a cathepsin (Cat B, D, L or S) prior to use in vivo. Each of the three mouse strains (H-2(b/d/k)) tested revealed a unique profile of T-cell reactivity to different cryptic epitopes of HEL in response to a particular cytokine or cathepsin. These results provide proof of principle for the reversal of crypticity of self-epitopes by immune mediators in the local milieu. Moreover, co-immunization with an antigen and a cytokine offers a simple and reliable tool for studying the role of cryptic epitopes in autoimmunity. Our results also strengthen the rationale for the use of inhibitors of cytokine/cathepsin activity in the treatment of autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cathepsins; Cytokines; Epitopes, T-Lymphocyte; Female; Immunodominant Epitopes; Mice; Mice, Inbred Strains; Muramidase

Microbial products are assumed to play a major role in triggering pathogenic autoimmunity. Recently accumulated data have shown that these products stimulate the immune system by interacting with TLRs, expressed on APCs. To examine the capacity of various TLR ligands to trigger pathogenic autoimmunity, we used a system in which naive CD4 cells, specific against hen egg lysozyme (HEL), are injected into recipient mice expressing HEL in their eyes. Only when stimulated, the naive cells acquire pathogenic capacity and induce ocular inflammation. Seven TLR ligands were tested in this system: lipoteichoic acid/peptidoglycan, zymosan, poly (I:C), LPS, pertussis toxin (PTX), flagellin, and CpG oligodeoxynucleotide. Treatment of recipient mice with HEL alone stimulated proliferation of the transferred cells, but no disease, whereas ocular inflammation did develop in recipient mice coinjected with HEL and any one of the seven TLR ligands. Inflammation induced by PTX surpassed by its severity those induced by all other tested TLR ligands and was accompanied by a dramatic increase in number of the transferred cells that acquired features of effector Th1 lymphocytes. Ocular inflammation and number of transferred cells in recipients injected with PTX and HEL were substantially reduced by treatment with Abs against IFN-gamma or IL-12, thus indicating the role of these cytokines in the PTX effect. Overall, our observations demonstrate that various TLR ligands are capable of triggering pathogenic autoimmunity and that PTX surpasses other microbial products in this activity, by stimulating excessive proliferation and polarization toward Th1 of naive T cells.

Topics: Animals; Antibodies, Blocking; Autoantigens; Autoimmune Diseases; Cell Adhesion Molecules; Cell Differentiation; Cytokines; Interferon-gamma; Interleukin-12; Lens Diseases; Ligands; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; Pertussis Toxin; Resting Phase, Cell Cycle; Th1 Cells; Toll-Like Receptors

We analysed and compared electrophoretic tear proteins patterns of healthy subjects and patients with different autoimmune diseases associated with secondary Sjogren's syndrome.. Tears were collected using the Schirmer's method. Proteins were separated by sodium-dodecyl sulfate polyacrylamide gel electrophoresis. The lanes were stained by Coomassie blue and/or silver.. Lactoferrin, albumin, lipocalin and lysozyme were found to be the main components being identified using molecular weight markers.. Electrophoretic analysis of tear proteins patterns is a fast, reproducible and simple method which provides information about the possibility of lacrimal gland involvement in auto-immune diseases.

Topics: Anti-Infective Agents; Autoimmune Diseases; Carrier Proteins; Cysteine Proteinase Inhibitors; Electrophoresis, Gel, Two-Dimensional; Eye Proteins; Humans; Lactoferrin; Lipocalin 1; Muramidase; Sjogren's Syndrome; Tears

We analysed and compared electrophoretic tear protein patterns of healthy subjects and patients with different autoimmune diseases associated with secondary Sjogren's syndrome.. Tears were collected using the Schirmer's method. Proteins were separated by sodium-dodecyl sulfate poliacrylamide gel electrophoresis. The lanes were stained by Coomassie blue and/or silver.. Lactoferrin, albumin, lipocalin and lysozyme were found to be the main components being identified using molecular weight markers.. Electrophoretic analysis of tear proteins patterns is a fast, reproducible and simple method which provides information about the possibility of lacrimal gland involvement in autoimmmune diseases.

Topics: Albumins; Anti-Infective Agents; Autoimmune Diseases; Carrier Proteins; Case-Control Studies; Electrophoresis, Polyacrylamide Gel; Eye Proteins; Humans; Lactoferrin; Lipocalin 1; Muramidase; Sensitivity and Specificity; Sjogren's Syndrome; Tears

To evaluate the effects of an interleukin 1 receptor antagonist (IL-1RA) on the development of immune-mediated ocular inflammation in mice.. Recombinant, human, nonglycosylated IL-1RA (anakinra [kineret]) was tested for its inhibitory effects in 2 systems: (1) experimental autoimmune uveitis induced by interphotoreceptor retinoid-binding protein in B10.A mice using routine procedures and evaluated by clinical and histological examination, and (2) ocular inflammation in mice induced by transfer of hen egg lysozyme-specific T cells to hen egg lysozyme-transgenic mice. Treatment with IL-1RA included daily subcutaneous injections of the drug, at 300 and 500 mg/kg, or phosphate-buffered saline as control.. Mean +/- SE experimental autoimmune uveitis scores of histological ocular changes of the mice at day 14 postimmunization with interphotoreceptor retinoid-binding protein were 1.5 +/- 0.3 in control mice; 1.0 +/- 0.4 in 300-mg/kg anakinra-treated mice; and 0.5 +/- 0.2 in 500- mg/kg anakinra-treated mice (P = .004). There was a corresponding decrease in the cellular immune response and cytokine production of immune cells in treated mice. Suppression of ocular inflammation by anakinra in the transfer system was also observed (P = .04).. Human IL-1RA suppresses immune-mediated ocular inflammation in mice, affecting both the afferent and efferent components of the pathogenic immune response.Clinical Relevance Systemic administration of IL-1RA may have clinical application in the management of patients with uveitis.

Topics: Adoptive Transfer; Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Eye Proteins; Female; Immunity, Cellular; Immunosuppression Therapy; Immunotherapy, Adoptive; Injections, Subcutaneous; Interleukin 1 Receptor Antagonist Protein; Lymphocyte Activation; Mice; Mice, Transgenic; Muramidase; Recombinant Proteins; Retinol-Binding Proteins; Sialoglycoproteins; Th1 Cells; Uveitis

CpG oligodeoxynucleotides (ODN) are synthetic DNA sequences that mimic bacterial DNA, and bind to the TLR9 receptor. The cells that express TLR9, B cells and dendritic cells, are stimulated by CpG ODN and induce innate and acquired immune responses. Because CpG ODN induce antigen-independent immune activation there has been much interest in the possibility that they may break self tolerance. To test this hypothesis we used a tolerance model with hen egg lysozyme (HEL)-transgenic (Tg) mice, anti-HEL Ig-Tg mice and double (Dbl)-Tg mice injected with CpG ODN alone or together with HEL self antigen. When cultured in vitro, tolerant B cells responded to CpG ODN in a similar way as the non-tolerant Ig-Tg B cells in terms of cell proliferation, NFkappaB activation and CD69 expression. Despite these potent in vitro stimulatory effects of CpG ODN alone, HEL-Tg mice injected with CpG ODN alone, or in combination with low dose antigen (4 microg HEL), surprisingly did not produce any detectable anti-HEL Ab. However, HEL-Tg or Dbl-Tg mice immunized with CpG ODN plus higher doses of self antigen showed strong antigen-specific humoral responses. Surprisingly, control non-CpG ODN also had partial activity for breaking tolerance and inducing autoantibody production when administered in combination with self antigen, though not when used alone. Despite the production of high titers of anti-HEL Ab in the immunized HEL-Tg mice, no evidence of autoimmune disease was detected. We conclude that immunization with CpG or control ODN in the presence of a high dose of exogenous self antigen, but not treatment with ODN alone, can break tolerance to self antigen without inducing autoimmune disease in this system.

Topics: Animals; Animals, Genetically Modified; Antibody Formation; Autoantibodies; Autoimmune Diseases; CpG Islands; DNA; Immune Tolerance; Mice; Muramidase; Oligodeoxyribonucleotides

Nasal instillation is an effective method for inducing antigen-specific immune tolerance. However, it is not clear how a tolerization scheme established in one mouse strain will perform when used in a mouse of a different haplotype.. To compare the antigen-specific recall responses in four mouse strains--BALB/c, C57BL/6, NOD, and B10.PL--that were pretreated nasally with 50 micrograms of hen egg-white lysozyme prior to parenteral immunization with homologous antigen.. Mice were nasally treated with a prototype antigen, HEL, and then immunized with the same antigen emulsified in complete Freund's adjuvant. Spleens and lymph nodes were assayed for T cell proliferation measured by tritiated thymidine incorporation. Cytokine production was measured using ELISPOT assay. Serum antibody response to HEL was measured using an enzyme-linked immunosorbent assay.. Proliferative recall responses to HEL in B10.PL, C57BL/6, and BALB/c were greatly reduced compared to control mice, but non-obese diabetic mice were resistant to the tolerization regime. Despite their susceptibility to nasally induced suppression, the mechanisms responsible for tolerance induction differed in BALB/c and C57BL/6 mice.. Our findings demonstrate that while mucosal contacts with specific antigen consistently affect the outcome of subsequent exposure to the same antigen, the observed response will vary non-predictably, depending on the genetic background of the animal.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Epitopes; Haplotypes; Immune Tolerance; Immunity, Mucosal; Immunization; Instillation, Drug; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Muramidase; Nasal Mucosa; T-Lymphocytes

Ocular inflammation leads to vision loss through the destruction and scarring of delicate tissues along the visual axis. To identify inflammatory mediators involved in this process, we used real time RT-PCR to quantify the expression of mRNA transcripts of 34 cytokines, 26 chemokines, and 14 chemokine receptors at certain time points during T cell-mediated ocular inflammation. We induced disease by adoptive transfer of Ag-specific Th1 or Th2 cells into recipients expressing the target Ag in their eyes. We also compared the mediator expression patterns seen in adoptive transfer-induced inflammation with that seen in mouse eyes developing experimental autoimmune uveoretinitis. In addition, we used laser capture microdissection to examine chemokine mRNA production by both retinal pigment epithelium cells and infiltrating leukocytes in inflamed eyes. Major findings included the following: 1) Three patterns of expression of the inflammation-related molecules were seen in recipients of adoptively transferred Th cells: preferential expression in Th1 recipients, or in Th2 recipients, or similar expression in both recipient groups. 2) In experimental autoimmune uveoretinitis, the inflammatory mediator expression pattern largely paralleled that seen in Th1-induced disease. 3) Both retinal pigment epithelium and infiltrating leukocytes expressed chemokine transcripts in distinct, but overlapping patterns in inflamed eyes. 4) Interestingly, transcripts of multiple cytokines, chemokines, and chemokine receptors were constitutively expressed in high levels in mouse eyes. Seven of these molecules have not been previously associated with the eye. These data underscore the multiplicity of mediators that participate in the pathogenesis of eye inflammation and point to upstream cytokines as potential therapeutic targets.

Topics: Adoptive Transfer; Animals; Autoimmune Diseases; Cell Movement; Chemokines; Cytokines; Kinetics; Mice; Mice, Transgenic; Muramidase; Pigment Epithelium of Eye; RNA, Messenger; Th1 Cells; Th2 Cells; Transcriptional Activation; Uveitis

Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.

Topics: Adoptive Transfer; Animals; Arthritis, Experimental; Autoimmune Diseases; Bacterial Proteins; Chaperonin 60; Chaperonins; Concanavalin A; Disease Susceptibility; Environment, Controlled; Epitopes, T-Lymphocyte; Housing, Animal; Immunity, Innate; Immunodominant Epitopes; Incidence; Injections, Intraperitoneal; Injections, Intravenous; Intestinal Mucosa; Lymphocyte Activation; Male; Muramidase; Mycobacterium tuberculosis; Peptide Fragments; Rats; Rats, Inbred F344; Severity of Illness Index; Species Specificity; Spleen; T-Lymphocytes

Stress has been implicated as a factor in the pathogenesis of autoimmune disorders. In order to determine the effect of adrenergic stress on immune responses in vivo, C57BL/6 (B6; H-2b) mice, which respond weakly to hen-egg lysozyme (HEL), were immunized on day 0 with HEL (50-200 microg s.q.) and subsequently injected with epinephrine (EPI; 0.1-0.5 mg/kg s.q.) daily for up to 10 days. Controls included A/J mice (H-2k) which respond strongly to HEL. In some experiments, B6 mice were depleted of CD4+ or CD8+ lymphocytes by monoclonal antibody treatment in vivo, prior to immunization with HEL, and injection with EPI. On day 10, single cell suspensions of draining lymph nodes (LN) and spleen were examined for immune phenotype, proliferative responses to HEL, and lymphokine production. Minimal specific proliferative responses were detected in B6 mice compared to A/J mice. However, lymphocyte proliferation increased in HEL-immunized EPI-treated B6 mice but not in the A/J mice. IL-2-mediated proliferation and IL-2 secretion were both increased in the HEL-immunized EPI-treated B6 mice. The depletion of CD8+ but not CD4+ lymphocytes in vivo abrogated the effects of EPI, whereas adoptive transfer of naive CD8+ splenocytes to the CD8-depleted mice restored specific responses in the HEL-immunized EPI-treated animals. We conclude that EPI augments antigen-specific T-cell responses to HEL in B6 mice by a CD8+ T-cell-dependent mechanism.

Topics: Adoptive Transfer; Animals; Antigens; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chickens; Disease Models, Animal; Epinephrine; Female; Immunization; Interleukin-2; Lymphocyte Activation; Lymphocyte Depletion; Lymphokines; Mice; Mice, Inbred A; Mice, Inbred C57BL; Muramidase; Stress, Physiological

In this study an indirect ELISA with patients' sera was performed using human collagen type II, double- (dsDNA) and single-stranded DNA (ssDNA), thyroid microsomal antigen, insulin and lysozyme as antigens. Since many preoperated otosclerotic patients demonstrated the signs of myringosclerosis (n=7). they were classified separately and compared with otosclerotic patients without myringosclerosis (n=28), with healthy controls (n=42) and with patients with tympanosclerosis (n=5) of other origin. The otosclerotic patients had serum antibodies to antigens tested similar to normal controls. However, elevated antibody levels to human collagen type II, dsDNA and ssDNA were observed only in patients with a disease duration between 3 and 5 years as compared to other otosclerotic patients. The same duration association was observed in the level of the total serum alkaline phosphatase activity. These observations would suggest that the enzymatic bone resorption is the driving force in human otosclerosis. Elevated serum autoantibodies during tissue reparation in the otosclerotic stage may be a transient response to sustained excess antigen turnover in the primary lesion.

Topics: Adolescent; Adult; Analysis of Variance; Autoantibodies; Autoantigens; Autoimmune Diseases; Collagen; DNA; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin; Iodide Peroxidase; Iron-Binding Proteins; Least-Squares Analysis; Male; Middle Aged; Muramidase; Otosclerosis; Time Factors

Hybrid F1 mice derived from inbred parental mouse strains are extensively used as animal models of human autoimmune diseases and transplantation. It is generally believed that with regard to immunologic studies, hybrid F1 mice behave in a consistent manner, equivalent to any other inbred mouse strain. In this study, we report that in comparison to inbred parental strains, individual hybrid F1 mice revealed a broad heterogeneity of proliferative response to the immunodominant determinants within hen eggwhite lysozyme (HEL). Of five parental strains tested, individual mice of three strains responding to only a few dominant HEL determinants (B6, BALB/c, and B10.PL) showed quite homogeneous patterns of response, whereas two mouse strains responsive to several determinants of HEL revealed either relative homogeneity (CBA/J mice) or heterogeneity (SJL mice) of response. However, in SJL mice, responses to major, dominant determinants of HEL were quite consistent. On the contrary, regardless of the consistency of response of parental strains, all three of F1 mice [[B6 x BALB/c]F1, [B6 x CBA/J]F1, and [SJL x B10.PL]F1] revealed significantly greater heterogeneity of response, which even involved the major, dominant determinants of HEL. We attribute the above heterogeneity of response to the competitive as well as aleatory nature of the interaction between various factors, including the coexistence of different MHC (parental as well as hybrid MHC) molecules, determinant capture, and the T cell repertoire. These results have important implications for studies on autoimmunity, infection, and vaccine design in human populations, where heterozygosity is the norm rather than the exception.

Topics: Animals; Autoimmune Diseases; Chickens; Crosses, Genetic; Egg White; Epitopes, T-Lymphocyte; Female; Immunodominant Epitopes; Infections; Injections, Subcutaneous; Lymph Nodes; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred Strains; Muramidase; Peptides; T-Lymphocyte Subsets

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.

Topics: Animals; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Clonal Anergy; Complement C3; Complement C4; Complement System Proteins; fas Receptor; Female; Immune Tolerance; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; Receptors, Complement 3b; Receptors, Complement 3d

The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.

Topics: Animals; Antibody Specificity; Antigens, CD19; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocyte Subsets; Chickens; Clonal Anergy; Complement C3d; Crosses, Genetic; Humans; Immune Tolerance; Immunoglobulin D; Immunoglobulin M; Inflammation; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; Receptors, Antigen, B-Cell; Receptors, Complement 3d; Signal Transduction

Mice homozygous for the lymphoproliferation (lpr) mutation, which disrupts expression of the Fas cell surface molecule, develop an autoimmune syndrome with a spectrum of autoantibodies resembling human SLE. It is not known how the loss of Fas leads to autoantibody production. To study the fate of autoreactive B cells in lpr/lpr mice, C57BL/6 (B6) strain transgenic mice expressing hen egg lysozyme (HEL) as a model autoantigen in soluble or membrane-bound forms and carrying HEL-specific Ig (Ig) transgenes were mated onto the congenic B6-lpr/lpr background. Despite the absence of Fas, elimination of self-reactive lpr/lpr B cells recognizing membrane-bound autoantigen occurred as efficiently as in autoreactive B cells bearing the wild-type (+/+) Fas gene. Functional inactivation of autoreactive B cells binding soluble HEL also occurred normally in most young lpr/lpr animals. Nevertheless, breakdown of B cell tolerance to soluble lysozyme occurred in one of eight young lpr/lpr animals and in four of seven old animals with lymphadenopathy. Interestingly, the presence of the rearranged Ig transgenes markedly delayed the onset of lymphadenopathy. These results demonstrate that Fas is not an essential molecule in the biochemical pathways mediating autoreactive B cell elimination or inactivation. The breakdown of tolerance observed in a considerable fraction of older animals nevertheless confirms that autoantibody production in this model of SLE involves a defect in active censoring of autoreactive B cells. The possible basis for that defect is discussed.

Topics: Animals; Autoimmune Diseases; B-Lymphocytes; Blotting, Southern; Bone Marrow Cells; Egg Proteins; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Lymph Nodes; Mice; Mice, Mutant Strains; Mice, Transgenic; Muramidase; Radiation Chimera; Self Tolerance

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

Topics: Animals; Autoimmune Diseases; Histocompatibility Antigens Class II; Immunization; Lymphocyte Activation; Major Histocompatibility Complex; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Transgenic; Muramidase; Peptide Fragments; T-Lymphocytes

Production of autoantibodies, which characterizes most autoimmune diseases, is normally avoided by active elimination or functional inactivation (anergy) of B and T lymphocytes bearing receptors for self antigens. The mechanisms leading to the escape of self-reactive clones from these normal tolerance mechanisms in autoimmune diseases nevertheless remain obscure. Here, we demonstrate that clonal anergy in B lymphocytes is a reversible process, and that silenced self-reactive B cells can be reactivated under particular conditions to give rise to vigorous antibody responses. Reactivation of anergic lymphocytes may explain many examples of transient autoimmune reactions in normal individuals, and may under pathological conditions be important in the development of chronic autoimmune disease.

Topics: Animals; Antibody Formation; Autoimmune Diseases; B-Lymphocytes; Immune Tolerance; Immunoglobulin M; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; Spleen; T-Lymphocytes, Helper-Inducer

Diabetes in the non-obese diabetic (NOD) mouse is a multigenic autoimmune disease and is possibly controlled by three recessive loci, including one that is linked to the major histocompatibility complex (MHC). The first external domain of the Class II MHC I-A beta chain in these mice is unique and has been suggested as being responsible for autoimmunity. The I-A alpha chain in these mice is I-A alpha d, and they lack the expression of I-E molecules. We have investigated immune responses to various Ir gene control antigens in NOD mice to determine the influence of the NOD Ia and particularly the I-A beta chain. We find that sheep insulin is highly immunogenic while other insulins are weakly immunogenic in these mice. Hen egg lysozyme, pigeon cytochrome C and the synthetic polypeptide Poly 18, Poly EYK(EYA)5 antigen produce good antibody responses. Apart from H-2d, NOD are the only mice where Poly 18 antigen is immunogenic. In these mice Poly 18 induced good T-cell proliferative response, which was inhibited by anti-Ia antibody, and the mice were able to respond to tyrosine-containing polypeptide Poly EYA but not to the phenylalanine-containing antigen Poly EFA. We also found that synthetic peptide 48-60 of the NOD I-A beta chain is highly immunogenic in syngeneic NOD mice both for T cells and B cells. Using an I-A beta chain-specific monoclonal antibody, we are able to prevent induction of diabetes when the antibody was administrated in prediabetic, young mice. Our results suggest that the immune response to various antigens and autoimmune diabetes in NOD mice is directly influenced by the I-A beta chain.

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Formation; Autoimmune Diseases; Chickens; Columbidae; Cytochrome c Group; Diabetes Mellitus, Experimental; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Histocompatibility Antigens Class II; Immunization; Insulin; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Mice; Mice, Mutant Strains; Molecular Sequence Data; Muramidase; Peptide Fragments; T-Lymphocytes

A feature common to many animal models of autoimmune disease, for example, experimental allergic encephalomyelitis, experimental autoimmune myasthenia gravis and collagen-induced arthritis, is the presence of self-reactive T cells in healthy animals, which are activated to produce disease by immunization with exogenous antigen. It is unclear why these T cells are not deleted during ontogeny in the thymus and, having escaped tolerance induction, why they are not spontaneously activated by self-antigen. To investigate these questions, we have examined an experimental model in which mice are tolerant to an antigen despite the presence of antigen-reactive T cells. We find that the T cells that escape tolerance induction are specific for minor determinants on the antigen. We propose that these T cells evade tolerance induction because some minor determinants are only available in relatively low amounts after in vivo processing of the whole antigen. For the same reason, these T cells are not normally activated but can be stimulated under special circumstances to circumvent tolerance.

Topics: Animals; Autoimmune Diseases; Dose-Response Relationship, Immunologic; Epitopes; Immune Tolerance; Immunologic Memory; Lymphocyte Activation; Mice; Muramidase; Oligopeptides; T-Lymphocytes

Topics: Animals; Antigens; Autoimmune Diseases; B-Lymphocytes; Immune Tolerance; Mice; Mice, Transgenic; Muramidase; Receptors, Antigen, B-Cell; T-Lymphocytes

Immunological tolerance has been demonstrated in double-transgenic mice expressing the genes for a neo-self antigen, hen egg lysozyme, and a high affinity anti-lysozyme antibody. The majority of anti-lysozyme B-cells did not undergo clonal deletion, but were no longer able to secrete anti-lysozyme antibody and displayed markedly reduced levels of surface IgM while continuing to express high levels of surface IgD. These findings indicate that self tolerance may result from mechanisms other than clonal deletion, and are consistent with the hypothesis that IgD may have a unique role in B-cell tolerance.

Topics: Animals; Antibodies; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Female; Genes, Immunoglobulin; Hybridomas; Immune Tolerance; Immunoglobulin D; Immunoglobulin M; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muramidase; T-Lymphocytes

A wide variety of tests for the detection of circulating immune complexes (IC) has been proposed by different authors, but there is very little to no information concerning the performance of IC screening assays in samples known to contain in vivo-formed IC. The purpose of our investigation was to compare the behavior of a non-specific assay, the PEG-IgG screening test for IC, with an antigen-specific assay in serum samples sequentially obtained from rabbits to which we induced acute serum sickness. Five animals were used in the study; we were able to detect an increase of IC constituted by the heterologous antigen (human serum albumin) and corresponding antibodies in all, and in 4 animals the results of the PEG-IgG assay closely correlated with the results of the antigen-specific assay (rho values between 0.975 and 1.00). The 4 animals in which IC showed a definite peak by both assays developed proteinuria and IC deposits at the glomerular level, while the animal that failed to develop IC detectable by the PEG-IgG test remained normal throughout the study. These results demonstrate the ability of the PEG-IgG test to detect in vivo-formed IC and suggest that the IC detected by this test have pathogenic potential.

Topics: Acute Disease; Albuminuria; Animals; Antigen-Antibody Complex; Autoimmune Diseases; Disease Models, Animal; Immunoglobulin G; Longitudinal Studies; Muramidase; Polyethylene Glycols; Proteinuria; Rabbits; Serum Sickness

A neutrophil monolayer system was used to study the effects of uric acid on neutrophil-aggregate interactions important in rheumatoid inflammation. No effect on immunoglobulin G aggregate phagocytosis was seen, but hyperuricaemic levels of uric acid were associated with an enhancement of phagocytosis-induced release of the azurophilic granular enzyme beta-glucuronidase. A trinitrophenyl-coupled mononuclear leucocyte rheumatoid factor plaque-forming assay was utilised to study uric acid effects on polyclonal activation of immunocompetent cells. Low levels of uric acid enhanced and high levels suppressed this system. Hyperuricaemia may enhance some aspects of rheumatoid inflammation, while uric acid may modulate an important component of rheumatoid autoimmunity.

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Cells, Cultured; Glucuronidase; Humans; Immunoglobulin G; Leukocytes; Models, Biological; Muramidase; Neutrophils; Phagocytosis; Rheumatoid Factor; Uric Acid

Topics: Adolescent; Adult; Autoimmune Diseases; Female; Humans; Male; Mikulicz' Disease; Muramidase; Parotid Gland; Parotitis; Sjogren's Syndrome

Rectocolitis remains, at the present time, in spite of the large amount of work carried out, a condition of which the cause and the physiopathological mechanism are unknown: none of the theories proposed has been confirmed by the facts; none has made it possible to propose an effective therapeutic regimen. The diagnosis of haemorrhagic rectocolitis rests solely on an assembly of clinical, radiological, and anatomological findings, together with findings on progress of the disease; none of these findings taken separately being pathognomonic. Because of this it is essential in cases of inflammatory colic disorders to analyse critically these different elements before affirming the diagnosis that is often arrived at too easily. Different affections, even apart from Crohn's disease (parasitic, microbial, and iatrogenic affections, etc) may, in fact, give rise to radiological and clinical pictures close to those of haemorrhagic rectocolitis.

Topics: Autoimmune Diseases; Colitis; Colon; Crohn Disease; Diagnosis, Differential; Endoscopy; Gastrointestinal Hemorrhage; Genotype; Humans; Hypersensitivity; Infections; Intestinal Diseases, Parasitic; Intestinal Mucosa; Muramidase; Proctocolitis; Psychophysiologic Disorders; Radiography

Topics: Adult; Autoantibodies; Autoimmune Diseases; Chronic Disease; Colitis; Complement System Proteins; Female; Humans; Male; Middle Aged; Muramidase; Properdin

Topics: Animals; Arthritis, Infectious; Autoimmune Diseases; Cell Wall; Chymotrypsin; Freund's Adjuvant; Glycolipids; Injections, Intradermal; Leg; Male; Mice; Muramidase; Mycobacterium; Mycobacterium bovis; Mycobacterium tuberculosis; Rats; Trypsin; Tuberculin; Waxes

Topics: Antigen-Antibody Reactions; Autoimmune Diseases; Cerebrovascular Circulation; Cerebrovascular Disorders; Muramidase; Time Factors

Topics: Autoimmune Diseases; Conjunctiva; Estradiol; Humans; Keratoconjunctivitis; Microscopy, Electron; Muramidase; Rose Bengal; Xerophthalmia