Aspects of CNS lupus: mouse models of anti-NMDA receptor antibody mediated reactivity.

This chapter describes methods utilized in establishing a mouse model of neuropsychiatric lupus encompassing both cognitive and emotional dysfunction, and a model of the influence of maternal antibody on the developing brain. The antibody of interest binds the N-methyl-D: -aspartate receptor (NMDAR), a receptor for glutamate that is a major excitatory neurotransmitter in the brain involved in synaptic plasticity, in memory and learning, and in emotional responses.We introduce basic concepts of these models and provide protocols for the following: (1) the induction of anti-dsDNA, anti-NMDAR antibodies, (2) testing serum antibody titer by ELISA, (3) breaching blood brain barrier (BBB) integrity with LPS and epinephrine, (4) passive transfer of pathology by injecting human and mouse brain-reactive antibodies into adult mouse as well as injecting the antibody into gestating mice and transfer of antibody from dam to fetus, (5) blocking NMDAR-mediated pathogenicity in vivo, (6) evacuation of blood from the brain by cardiac perfusion to preserve the brain for histology, (7) evaluating injured/apoptotic neurons in brain histology, (8) preparing membrane-enriched brain -fractions for NMDAR analysis.

Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.

Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.

Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.

IL-6 contributes to an immune tolerance checkpoint in post germinal center B cells.

The generation of a B cell repertoire involves producing and subsequently purging autoreactive B cells. Receptor editing, clonal deletion and anergy are key mechanisms of central B cell tolerance. Somatic mutation of antigen-activated B cells within the germinal center produces a second wave of autoreactivity; but the regulatory mechanisms that operate at this phase of B cell activation are poorly understood.

Membrane trafficking events underlying axon repair, growth, and regeneration.

Two central challenges for the field of neurobiology are to understand how axons grow and make proper synaptic connections under normal conditions and how they repair their membranes and mount regenerative responses after injury. At the most reductionist level, the first step toward addressing these challenges is to delineate the cellular and molecular processes by which an axon extends from its cell body. Underlying axon extension are questions of appropriate timing and mechanisms that establish or maintain the axon's polarity, initiate growth cone formation, and promote axon outgrowth and synapse formation.

Enforced expression of the apoptosis inhibitor Bcl-2 ablates tolerance induction in DNA-reactive B cells through a novel mechanism.

How self tolerance is maintained during B cell development in the bone marrow has been a focal area of study in immunology. Receptor editing, anergy and clonal deletion all play important roles in the regulation of autoimmunity in the immature population. The mechanisms of tolerance induction in the periphery, however, are less well characterized.

Molecular mimicry in systemic lupus erythematosus.

Systemic lupus erythematosus is a multi-systemic autoimmune disease distinguished by the presence of various autoantibodies. Like most autoimmune diseases, systemic lupus erythematosus is believed to be induced by a combination of genetic, immunologic, and environmental factors, mainly infectious agents. Molecular mimicry between an infectious antigen and self-components is implicated as a pivotal mechanism by which autoimmune diseases such as systemic lupus erythematosus are triggered.

The role of B cells in lupus pathogenesis.

Autoantibodies clearly contribute to tissue inflammation in systemic lupus erythematosus. In order to therapeutically target B cells making pathogenic autoantibodies, it is necessary to identify their phenotype. It is also important to understand the defects in B cell repertoire selection that permit pathogenic autoreactive B cells to enter the immunocompetent B cell repertoire.

Phenotypic characterization of autoreactive B cells--checkpoints of B cell tolerance in patients with systemic lupus erythematosus.

DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE); DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood.

Polyreactive autoantibodies in systemic lupus erythematosus have pathogenic potential.

The present study was undertaken to determine whether germline encoded and polyreactive antibodies might be pathogenic and whether the breach of early tolerance checkpoints in systemic lupus erythematosus (SLE) might lead to a population of B cells expressing germline encoded antibodies that become pathogenic merely by class switching to IgG in a pro-inflammatory milieu. We demonstrate here that IgM, DNA-reactive antibodies obtained from lupus patients that are unmutated and display polyreactivity can bind to isolated glomeruli and exhibit neurotoxic potential. Thus, the IgM polyreactive repertoire in SLE includes antibodies that may acquire pathogenic function merely by undergoing class-switch recombination to become IgG antibodies.

Pathogenic autoantibodies in systemic lupus erythematosus are derived from both self-reactive and non-self-reactive B cells.

Previous studies have shown that both murine and human anti-double-stranded DNA (anti-dsDNA) antibodies can develop from non-DNA-reactive B cells and suggest a crucial role for somatic mutation in dsDNA binding. However, since only a limited number of human anti-dsDNA antibodies have been analyzed previously, we could not exclude other mechanisms for the generation of anti-dsDNA antibodies in patients with systemic lupus erythematosus (SLE). Therefore, we isolated IgM anti-dsDNA antibodies from peripheral blood B cells of a patient with SLE.

Molecular mimicry and auto-immunity.

The term "molecular mimicry" was coined by R. Damian in 1964, who was first to suggest that antigenic determinants of micro-organisms may resemble antigenic determinants of their host. Damian suggested that this similarity served as a defense mechanism of a microorganism from the host's immune system and prevented the development of immune response to the micro-organism, thereby protecting it from host defense.

B cell targeted therapy in autoimmunity.

Autoimmunity results from a break in self-tolerance involving humoral and/or cell-mediated immune mechanisms. Part of the pathological consequence of a failure in central and/or peripheral tolerance, results from survival and activation of self-reactive B cells. Such B cells produce tissue-damaging pathogenic autoantibodies, and subsequent formation of complement-fixing immune complexes that contribute to tissue damage.

Immunomodulation of experimental pulmonary fibrosis by intravenous immunoglobulin (IVIG).

Objectives: To assess the immunomodulatory effect of intravenous immunoglobulin (IVIG) using an experimental model of bleomycin-induced pulmonary fibrosis.

Methods: Pulmonary fibrosis was induced in C57BL/6 mice by direct intratracheal injection of bleomycin. Mice were treated with IVIG 1 week prior to (prevention protocol), or 10 days following bleomycin injection, when the disease was in progress.

Outcome of patients with scleroderma admitted to intensive care unit. A report of nine cases.

Objective: Patients with systemic rheumatic disease constitute a small percentage of admissions to the medical intensive care units (ICUs). Systemic sclerosis (SSc) is one of the rheumatic diseases that together with secondary complications may lead to a critical illness requiring hospitalization in the ICU. We present the features, clinical course and outcome of critically ill patients with scleroderma that were admitted to the ICU.

Autoimmunity to protective molecules: is it the perpetuum mobile (vicious cycle) of autoimmune rheumatic diseases?

Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload and might be involved in the initiation of an autoimmune response. The C1q protein and mannose-binding lectin are activators of the complement system. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein and serum amyloid P, and the long pentraxin family member, pentraxin 3, all of which are involved in innate immunity and in acute-phase responses.

Mechanisms of disease: atherosclerosis in autoimmune diseases.

Atherosclerosis is a pathologic process affecting blood vessels, which leads to the development of cardiovascular disease. The immune system is involved in atherogenesis and in the pathogenesis of atherosclerosis. Several autoimmune rheumatic conditions, including rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome, are characterized by enhanced atherosclerosis and consequently higher cardiovascular morbidity and mortality rates.

Intravenous immunoglobulin and fibrosis.

Fibrosis is a pathological process that includes scar formation and overproduction of extracellular matrix by the connective tissue as a response to tissue damage. Pathologies include pathological scarring as colloid and hypertrophic scars in the skin, cirrhosis of liver and gallbladder, pulmonary and bone-marrow fibrosis, and scleroderma. The molecular process is not different from normal formation of connective tissue and extracellular matrix in the normal organs.

Toward molecular targeting with specific intravenous immunoglobulin preparation.

Intravenous immunoglobulin (IVIg) is used successfully for therapy of inflammatory and autoimmune diseases, especially in cases of conventional therapy resistance. Within the broad spectrum of immunoregulatory activities of IVIg in vitro and in vivo, the anti-idiotypic activity neutralizing the related idiotypes is one of the main mechanisms. Furthermore, IVIg addresses integrins associated with inflammation and immune response thrombosis, such as the RGD (Arg-Gly-Asp) motif, expressed on a large number of cell surface and matrix proteins.

From rheumatic fever to Libman-Sacks endocarditis: is there any possible pathogenetic link?

The heart lesions of rheumatic fever and the heart involvement in antiphospholipid syndrome (APS), have different clinical pictures. Yet, there are several common characteristics linking both diseases: 1) central nervous system (CNS) and heart involvement; 2) molecular mimicry between the a pathogen and the origin of the disease; 3) cross reacting antibodies between the pathogen and self molecules; 4) endothelial cell activation in the 'crime-area' i.e.

Infection, vaccines and other environmental triggers of autoimmunity.

The etiology of autoimmune diseases is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Most often autoimmunity is not followed by clinical symptoms unless an additional event such as an environmental factor favors an overt expression. Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune mosaic.

The homogeneous multiplexed system--a new method for autoantibody profile in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method. We analyzed the presence of elevated titers of anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Jo1, anti-centromere, anti-Scl-70, anti-histone, and anti-dsDNA antibodies in 199 serum samples (113 SLE patients, 86 healthy donors).

Libman-Sacks endocarditis associated with antiphospholipid syndrome and infection.

Introduction: Antiphospholipid syndrome (APS) is a systemic autoimmune disease, associated not only with a hypercoagulable state and recurrent fetal loss but with many diverse clinical manifestations including heart involvement, neurological manifestations, as well as skin, kidney and hematologic abnormalities. Cardiac manifestations include coronary by-pass graft and angioplasty occlusions, cardiomyopathy, cyanotic congenital heart disease, intracardiac thrombus and complications of cardiovascular surgery. The valvular heart disease was defined as Libman-Sacks nonbacterial endocarditis.

Antiphosphatidylserine antibodies and reproductive failure.

Some cases of reproductive failure with autoimmune background are characterized by the involvement of autoantibodies. This occurs mainly in patients having systemic lupus erythematosus or antiphospholipid syndrome. The autoantibodies associated with reproductive failure include: a) antibodies which directly bind phospholipid (e.

Autoantibodies associated with reproductive failure.

Autoimmune factors are involved in some of the cases of reproductive failure. These factors entail several autoantibodies, especially in patients having systemic lupus erythematosus (SLE) or the antiphospholipid syndrome (APS). These autoantibodies include mainly antibodies directed to phospholipid such as cardiolipin, phosphatidylserine, phosphatidylethanolamine or phospholipids binding glycoproteins such as beta2glycoprotein-I, annexin V, prothrombin and protein-Z.

Beta-2-glycoprotein-I, infections, antiphospholipid syndrome and therapeutic considerations.

Evidence supports the association between infectious agents, antiphospholipid syndrome (APS), and the presence of antiphospholipid antibodies and anti-beta2-glycoprotein-I (beta2GPI) antibodies. Several mechanisms have been proposed to explain the role of bacteria/viruses in induction of an autoimmune condition, such as molecular mimicry between structures of a pathogen and self antigen and bystander activation or bacterial/viral superantigens. Protein databases reveal high homologies between the beta2GPI-related synthetic peptides and infectious agents.