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2.  Neuropsychiatric lupus and auto-antibodies against ionotropic glutamate receptor (NMDAR) 
Almost half of lupus patients will experience neuropsychiatric symptoms during the course of their disease. The etiology of the neuronal damages are still uncertain and probably multiple. Auto-antibodies reactive with brain have been postulated to play a role. The observation of pathogenic auto-antibodies binding the NR2A and NR2B subunits of the ionotropic glutamate receptor (NMDAR) illustrates this hypothesis.
First studies showed that 40% of lupus patients possess serum titers of anti-NR2A/B antibody, but the presence of these auto-antibodies is not always associated with the occurrence of neuronal damages or neuropsychiatric symptoms. Nevertheless, their presence is observed in the cerebro-spinal fluid (CSF) of one half of the patients suffering from neurolupus. The presence in the serum of these auto-antibodies anti-NR2A/B of the NMDAR is preliminary to their presence in the CSF where their deleterious effect is observable. Their entry into the brain is dependent on a breach of the blood brain barrier (BBB).
In conclusion, the serum titer of auto-antibodies against NR2A/B subunits is an indication of the potential for neuro-psychiatric manifestations during the course of the disease.
PMCID: PMC2976813  PMID: 20605660
lupus; neuropsychiatry; autoantibodies; NMDAR; DNA
3.  Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus 
Journal of internal medicine  2011;269(1):36-44.
Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that can mediate tissue damage in multiple organs. The underlying aetiology of SLE autoantibodies remains unknown, and treatments aimed at eliminating B cells, or limiting their function, have demonstrated limited therapeutic benefit. Thus, the current therapies for SLE are based on the concept of nonspecific immunosuppression and consist of nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, anti-malarials and cytotoxic drugs, all of which have serious adverse side effects including organ damage. The major auto-specificity in SLE is double-stranded (ds) DNA. Many anti-dsDNA antibodies cross-react with non-DNA antigens that may be the direct targets for their pathogenic activity. Studying anti-dsDNA antibodies present in SLE patients and in animal models of lupus, we have identified a subset of anti-dsDNA antibodies which is pathogenic in the brain as well as in the kidney. We have recently demonstrated that specific peptides, or small molecules, can protect target organs from antibody-mediated damage. Thus, it might be possible to treat the aspects of autoimmune disease without inducing major immunosuppression and ensuing infectious complications.
PMCID: PMC3069637  PMID: 21158976
autoantibodies; systemic lupus erythematosus; therapeutic strategy
5.  Functional magnetic resonance imaging of working memory impairment after traumatic brain injury 
OBJECTIVES—To examine patterns of brain activation while performing a working memory task in persons with moderate to severe traumatic brain injury (TBI) and healthy controls. It is well established that working memory is an area of cognition that is especially vulnerable to disruption after TBI. Although much has been learned about the system of cerebral representation of working memory in healthy people, little is known about how this system is disrupted by TBI.
METHODS—Functional magnetic resonance imaging (fMRI) was used to assess brain activation during a working memory task (a modified version of the paced auditory serial addition test) in nine patients with TBI and seven healthy controls.
RESULTS—Patients with TBI were able to perform the task, but made significantly more errors than healthy controls. Cerebral activation in both groups was found in similar regions of the frontal, parietal, and temporal lobes, and resembled patterns of activation found in previous neuroimaging studies of working memory in healthy persons. However, compared with the healthy controls, the TBI group displayed a pattern of cerebral activation that was more regionally dispersed and more lateralised to the right hemisphere. Differences in lateralisation were particularly evident in the frontal lobes.
CONCLUSIONS—Impairment of working memory in TBI seems to be associated with alterations in functional cerebral activity.

PMCID: PMC1737512  PMID: 11459886
6.  Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation 
Speed of information processing was assessed in patients with multiple sclerosis and healthy controls using both an auditory and visual task designed to control for accuracy of performance across groups. After controlling for accuracy of performance, patients with multiple sclerosis were found to have significantly slower speed of information processing relative healthy controls, irrespective of the modality of stimulus presentation (auditory or visual). When given an adequate amount of time to process information, however, the patients performed similarly to controls. These results suggest that persons with multiple sclerosis experience deficits specifically in processing speed but not performance accuracy. Results are discussed in terms of rehabilitative guidelines for the cognitive improvement of persons with multiple sclerosis.

PMCID: PMC1736611  PMID: 10519876
7.  Lupus-specific antibodies reveal an altered pattern of somatic mutation. 
Journal of Clinical Investigation  1997;100(10):2538-2546.
The F4 idiotype is a heavy chain determinant expressed almost exclusively on IgG immunoglobulins and is highly associated with specificity for double-stranded DNA. Since high-titered F4 expression is present predominantly in sera of patients with systemic lupus erythematosus (SLE), we thought F4+ IgG antibodies might constitute a useful subset of immunoglobulins in which to investigate lupus-specific alterations in variable (V) region gene expression or in the process of somatic mutation. This molecular analysis of F4+ B cell lines generated from lupus patients demonstrates that despite the strong association of F4 reactivity with specificity for native DNA, there is no apparent VH gene restriction. Furthermore, VH gene segments encoding these antibodies are also used in protective immune responses. An examination of the process of somatic mutation in F4+ antibodies showed no abnormality in frequency of somatic mutation nor in the distribution of mutations in complementarity-determining regions or framework regions. However, there was a decrease in targeting of mutations to putative mutational hot spots. This subtle difference in mutations present in these antibodies may reflect an intrinsic defect in mutational machinery or, more likely, altered state of B cell activation that affects the mutational process and perhaps also negative selection.
PMCID: PMC508454  PMID: 9366568
8.  The double edged sword of the immune response: mutational analysis of a murine anti-pneumococcal, anti-DNA antibody. 
Journal of Clinical Investigation  1996;97(10):2251-2259.
Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury. Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both dsDNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall. While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders.
PMCID: PMC507304  PMID: 8636404
9.  Molecular analysis of the human immunoglobulin V lambda II gene family. 
Journal of Clinical Investigation  1994;94(2):532-538.
The 8.12 idiotype characterizes a subpopulation of anti-DNA antibodies in patients with systemic lupus erythematosus (SLE). The idiotype is present on lambda light chains and has previously been shown to be exclusively encoded by V lambda II light chains. RFLP analysis of the V lambda II gene family has shown the family to consist of 10 to 15 members. Thus far, the sequences of seven V lambda II germline genes are reported in the literature with one of these a pseudogene. To identify the V lambda II genes that encode 8.12 positive antibodies and to further characterize the V lambda II family, germline V lambda II clones were derived from a patient with SLE. Two libraries were constructed: a genomic DNA library and a library of PCR-derived V lambda II gene products obtained using a conserved V lambda II leader region primer and a primer for the nonamer region 3' of the coding sequence. We now describe seven new germline genes, two of which are pseudogenes. Comparison of V lambda II germline genes to sequences of 8.12 positive light chains produced by EBV-transformed B cell lines show that all 8.12 positive light chains are encoded by a limited number of highly homologous members of the V lambda II family. 8.12 negative V lambda II encoded light chains also derive from a limited number of V lambda II genes, suggesting that only a subset of the apparently available V lambda II genes are commonly expressed.
PMCID: PMC296127  PMID: 8040307
10.  Cardiac alpha-myosin heavy chains differ in their induction of myocarditis. Identification of pathogenic epitopes. 
Journal of Clinical Investigation  1993;92(6):2877-2882.
BALB/c mice develop autoimmune myocarditis after immunization with mouse cardiac myosin, whereas C57B/6 mice do not. To define the immunogenicity and pathogenicity of cardiac myosin in BALB/c mice, we immunized mice with different forms of cardiac myosin. These studies demonstrate the discordance of immunogenicity and pathogenicity of myosin heavy chains. The cardiac alpha-myosin heavy chains of BALB/c and C57B/6 mice differ by two residues that are near the junction of the head and rod in the S2 fragment of myosin. Myosin preparations from both strains are immunogenic in susceptible BALB/c as well as in nonsusceptible C57B/6 mice; however, BALB/c myosin induces a greater incidence of disease. To further delineate epitopes of myosin heavy chain responsible for immunogenicity and disease, mice were immunized with fragments of genetically engineered rat alpha cardiac myosin. Epitopes in the region of difference between BALB/c and C57B/6 (residues 735-1032) induce disease in both susceptible and nonsusceptible mice. The data presented here demonstrate that pathogenic epitopes of both mouse and rat myosin residue in the polymorphic region of the S2 subunit. In addition, these studies suggest that polymorphisms in the autoantigen may be part of the genetic basis for autoimmune myocarditis.
PMCID: PMC288490  PMID: 7504694
11.  Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype. 
Journal of Clinical Investigation  1991;87(5):1519-1525.
This study describes a methodology for generating stable, cloned, EBV-transformed IgG- and IgM-producing human B cell lines. Using these lines we have characterized immunoglobulin V gene utilization in an anti-DNA-associated idiotypic system. The 31 anti-DNA-associated idiotype is encoded preferentially by the VK1 gene family, and, in all probability, reflects a germ line gene-encoded framework determinant. Analysis of these lines indicates that the DNA-binding antibodies produced by B cell lines from SLE patients may differ from DNA binding myeloma proteins and from natural autoantibodies.
PMCID: PMC295231  PMID: 1708781
12.  Antibodies elicited by pneumococcal antigens bear an anti-DNA--associated idiotype. 
Journal of Clinical Investigation  1991;87(3):842-846.
There is evidence in both murine and human lupus that the production of anti-DNA antibodies may be triggered by environmental antigens. To explore this further, we studied the serum of 10 nonautoimmune individuals immunized with a polyvalent pneumococcal polysaccharide vaccine. All 10 patients showed a rise in the titer of antipneumococcal antibodies bearing an anti-DNA-associated idiotype. The antipneumococcal response was specific as no idiotypic antitetanus antibodies were detected. Furthermore, no anti-DNA antibodies were present in postvaccination sera. The molecular analysis of antipneumococcal and anti-DNA antibodies bearing a common idiotype will help elucidate how foreign antigen might lead to the production of anti-DNA antibodies in susceptible individuals.
PMCID: PMC329872  PMID: 1999497
13.  Molecular characterization of a somatically mutated anti-DNA antibody bearing two systemic lupus erythematosus-related idiotypes. 
Journal of Clinical Investigation  1990;85(5):1401-1409.
We report the molecular characterization of 2A4, an IgG, DNA-binding antibody bearing the 3I and F4 idiotypes which are associated with anti-DNA antibodies in serum of patients with systemic lupus erythematosus (SLE). The antibody is produced by an EBV-transformed B cell line derived from a patient with multiple myeloma whose myeloma protein is also an IgG, 3I-reactive, F4-reactive, DNA-binding immunoglobulin, although the 2A4 antibody does not itself represent the myeloma protein. The 2A4 heavy chain is encoded by a VH4 gene, a D-D gene fusion and the JH6 gene; the light chain is derived from a Vk1 gene and the Jk2 gene. This is the first human antibody shown to have a CDR3 encoded by a D-D fusion. DNA sequence analysis of the 2A4 VH gene together with a Southern blot of genomic DNA probed with a 2A4 VH-specific oligonucleotide strongly suggest it to be somatically mutated. The data provide evidence that human autoantibodies can be products of somatically mutated genes and suggest that the 2A4 antibody may reflect the selective pressure of antigen.
PMCID: PMC296585  PMID: 2110188
14.  Arthritis and antinuclear antibodies (ANA) with inherited deficiency of the sixth component of complement (C6). 
Annals of the Rheumatic Diseases  1986;45(5):431-434.
We report here the case of a woman with joint pains found to have antinuclear antibodies and undetectable serum haemolytic complement. Investigation of her and her family members showed an inherited deficiency of C6.
PMCID: PMC1001906  PMID: 3487293
15.  Evidence for immunoglobulin Fc receptor-mediated prostaglandin2 and platelet-activating factor formation by cultured rat mesangial cells. 
Journal of Clinical Investigation  1988;82(3):936-944.
The possibility of Fc-dependent uptake of IgG immune complexes was examined in subcultured rat mesangial cells free of monocytes. 195Au-labeled colloidal gold particles were coated either with BSA only or with BSA followed by rabbit anti-BSA-IgG or the F(ab')2 fragment of the IgG. Mesangial cells preferentially took up 195Au particles covered with BSA-anti-BSA-IgG over those covered with BSA or the F(ab')2 fragment. This uptake was a time-dependent and saturable process inhibitable by sodium azide or cytochalasin B. Using phase-contrast microscopy in the light reflectance mode, it was established that essentially all mesangial cells took up IgG-coated gold particles. By electron microscopy the process was shown to consist of vesicular uptake with delivery to endosomes. Mesangial binding-uptake of the IgG-covered particles was associated with stimulation of PGE2 synthesis and production of platelet-activating factor, a lipid mediator of inflammation. To characterize the potential Fc receptor for IgG we used the rosetting technique with sheep red blood cells coated with IgG subclass-specific mouse monoclonal antibodies. 50% of mesangial cells exhibited rosetting with red cells coated with mouse IgG2a, whereas negligible rosetting was observed with IgG2b or IgG1. Competition experiments confirmed the specificity of IgG2a binding. We conclude that cultured rat mesangial cells exhibit specific receptors for IgG and that occupancy of Fc receptors results in endocytosis and is associated with generation of PGE2 and platelet-activating factor. These observations may be of significance for immune-mediated glomerular diseases.
PMCID: PMC303605  PMID: 3166467
16.  Suppression of anti-DNA antibody synthesis in vitro by a cross-reactive antiidiotypic antibody. 
Journal of Clinical Investigation  1987;79(3):997-1000.
An understanding of the regulatory mechanisms that govern the humoral immune response will be facilitated by the availability of techniques for the measurement of specific antibody production in vitro. We have developed an enzyme-linked immunosorbent assay system for the measurement of in vitro anti-DNA antibody production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus. Using this technique, the PBMC from 74% of serologically active SLE patients produced levels of anti-DNA antibodies that were greater than 2 SD above the mean of 18 +/- 9 IU/ml for normal subjects. Furthermore, the addition of 3I, a monoclonal anti-idiotypic antibody that recognizes a cross-reactive determinant on anti-DNA antibodies, was shown to specifically inhibit anti-DNA production in vitro.
PMCID: PMC424259  PMID: 3493261
17.  Familial systemic lupus erythematosus. Presence of a cross-reactive idiotype in healthy family members. 
Journal of Clinical Investigation  1985;76(2):731-736.
Sera of 27 members of 3 human kindreds with familial systemic lupus erythematosus (SLE) were examined for expression of a cross-reactive idiotype present on anti-DNA antibodies of SLE patients. By radioimmunoassay, serum samples from 6 of 8 SLE patients and 15 of 19 family members had high-titered reactivity with the antiidiotype, 3I. Isoelectric focusing and Western blot analysis of 3I-reactive bands revealed two patterns of reactivity: either a pattern of bands present at pH 5-7, or bands present at pH 5-7 with additional bands present at pH 7-8.5. Cationic bands were found to correlate with the presence of anti-DNA antibodies, indicating that immunoglobulin charge may be a factor in determining specificity for DNA. Millipore filter analysis revealed anti-DNA antibodies in sera of 4 of 8 SLE patients and 2 of 19 family members without SLE. In 2 additional SLE patients and 2 additional family members, anti-DNA antibodies were revealed when sera were analyzed under conditions that dissociate immune complexes. This study indicates that expression of an idiotype associated with anti-DNA antibodies is significantly increased in relatives of SLE patients and usually occurs in the absence of anti-DNA activity.
PMCID: PMC423889  PMID: 3875631
18.  HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-6Chigh inflammatory monocytes in murine sepsis survivors 
Journal of Internal Medicine  2013;274(4):381-390.
More than 500,000 hospitalized patients survive severe sepsis annually in the USA. Recent epidemiological evidence, however, demonstrated that these survivors have significant morbidity and mortality, with 3-year fatality rates higher than 70%. To investigate the mechanisms underlying persistent functional impairment in sepsis survivors, here we developed a model to study severe sepsis survivors following cecal ligation and puncture (CLP).
Sepsis was induced in mice by CLP and survivors were followed for twelve weeks. Spleen and blood were collected and analyzed at different time points post-sepsis.
We observed that sepsis survivors developed significant splenomegaly. Analysis of the splenic cellular compartments revealed a major expansion of the inflammatory CD11b+ Ly-6CHigh pool. Serum high-mobility group box 1 (HMGB1) levels in the sepsis surviving mice were significantly elevated for 4-6 weeks after post-sepsis, and administration of an anti-HMGB1 monoclonal antibody significantly attenuated splenomegaly as well as splenocyte priming. Administration of recombinant HMGB1 to naive mice induced similar splenomegaly, leukocytosis and splenocyte priming as observed in sepsis survivors. Interestingly analysis of circulating HMGB1 from sepsis survivors by mass spectroscopy demonstrated a stepwise increase of reduced form of HMGB1 (with known chemo-attractant properties) during the first 3 weeks, followed by disulphide form (with known inflammatory properties) 4-8 weeks after CLP.
Our results indicate that prolonged elevation of HMGB1 is a necessary and sufficient mediator of splenomegaly and splenocyte expansion, as well as splenocyte inflammatory priming in murine severe sepsis survivors.
PMCID: PMC4223507  PMID: 23808943
anti-HMGB1; CD11b+ Ly-6Chigh; HMGB1; sepsis survivors; splenomegaly

Results 1-18 (18)