Multisequence magnetic resonance imaging study of neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To investigate the relationship between magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy (H-MRS), and T2 relaxometry findings in patients with primary neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: The study group consisted of 24 female patients (mean age 36 years [range 23-65]) who had had a variety of neuropsychiatric symptoms that were judged to be due to NPSLE according to the criteria of the American College of Rheumatology. Patients with current active disease were excluded from participation. Quantitative MTI, DWI, H-MRS, and T2 relaxometry data were acquired in all patients, and the correlation coefficients were calculated. RESULTS: MTI results reflecting a decrease in homogeneity of cerebral parenchyma correlated significantly with H-MRS results representing axonal damage. MTI results also correlated significantly with DWI results reflecting increased diffusivity in the cerebral parenchyma. Finally, MTI results reflecting decreased cerebral homogeneity correlated significantly with increased T2 relaxation time, associated with either edema or gliosis. Increased T2 relaxation time correlated significantly with DWI results reflecting increased diffusivity. With the exception of the correlation between H-MRS and MTI findings, there was no significant correlation between H-MRS results and any other parameter. CONCLUSION: The selected study parameters represent different biologic features in the human brain and can be informative with regard to different pathologic processes in NPSLE. The demonstrated associations between MTI, DWI, H-MRS, and T2 data in patients with a history of NPSLE suggest that there is one pathogenesis and/or common neuropathologic outcome in NPSLE despite differences in clinical presentation.

Selective gray matter damage in neuropsychiatric lupus.

OBJECTIVE: Damage of brain parenchyma in patients with primary diffuse neuropsychiatric systemic lupus erythematosus (NPSLE) has been indicated by magnetization transfer imaging (MTI). However, the location of MTI abnormalities is unknown. This study was undertaken to assess the distribution of MTI abnormalities over gray matter (GM) and white matter (WM) in SLE patients with a history of NP symptoms without explanatory magnetic resonance imaging (MRI) evidence of focal disease. METHODS: MTI was performed in 24 female SLE patients with a history of diffuse NP symptoms and 24 healthy female controls. Magnetization transfer ratio (MTR) maps were calculated for GM and WM separately, and GM and WM MTR histograms were generated. Univariate and multivariate analyses with age as an additional covariate were performed on the histogram parameters peak location (PL), peak height (PH), and mean MTR. RESULTS: Compared with controls, significantly reduced PH (mean +/- SD 136 +/- 22 arbitrary units versus 151 +/- 13 arbitrary units) and mean MTR (33.3 +/- 1.0 percent units versus 33.6 +/- 0.5 percent units) were found in the GM of NPSLE patients (P = 0.002 and P = 0.033, respectively, in multivariate analyses). No significant differences were observed for WM MTR parameters. CONCLUSION: This is the first study to demonstrate, using MTI, that in SLE patients with a history of NP symptoms and without explanatory focal abnormalities on MRI, the GM is particularly affected. These findings support the hypothesis that neuronal injury may underlie central nervous system manifestations in NPSLE.

A neuroimaging follow up study of a patient with juvenile central nervous system systemic lupus erythematosus.

BACKGROUND: The course of central nervous system systemic lupus erythematosus (CNS-SLE) is largely unknown. New imaging techniques are available to assist in monitoring the disease course. OBJECTIVE: To report a case of juvenile CNS-SLE, in which magnetic resonance imaging (MRI) was used to assess disease activity. CASE REPORT: A 10-year-old female patient with SLE presented with convulsions; MRI and computed tomography (CT) of the cerebrum disclosed abnormalities. Despite adequate treatment, two years later she had a generalised convulsion, and MRI showed new lesions. MR spectroscopy (MRS) indicated neuronal loss, inflammation, and metabolically compromised tissue; magnetisation transfer imaging (MTI) showed an increase in whole brain lesion load. After exclusion of a malignancy, CNS-SLE was the most likely diagnosis, and cyclophosphamide pulses were administered. Initially, multiple sclerosis (MS)-like lesions regressed, but despite maximal immunosuppressive drugs, new lesions formed and disappeared. When immunosuppressive drugs had been stopped for six months MRI showed improved lesions and MTI histograms. DISCUSSION: In this case report, the anatomical substrate, metabolic aspect, neuroimaging, and clinical course of MS-like lesions in a child with CNS-SLE are described. The way in which radiological techniques can support clinical decision making in this young patient with progressive CNS-SLE is illustrated.

Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To investigate the relationship between quantitative estimates of global brain damage based on magnetization transfer imaging (MTI) and cerebral functioning, as measured by neurologic, psychiatric, and cognitive assessments, as well as disease duration in patients with a history of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: In a clinically heterogeneous group of 24 female patients (age range 19-65 years, mean age 35 years) with a history of NPSLE, the correlation values of several volumetric MTI measures and an estimate of cerebral atrophy, neurologic functioning (Kurtzke's Expanded Disability Status Scale [EDSS]), psychiatric functioning (the Hospital Anxiety and Depression Scale [HADS]), and cognitive functioning (cognitive impairment score [CIS] derived from the revised Wechsler Adult Intelligence Scale), as well as several measures of disease duration were assessed using Pearson's correlation coefficient. RESULTS: Quantitative volumetric estimates of global brain damage based on MTI and a measure of global brain atrophy correlated significantly with the EDSS, HADS, and CIS scores. No significant correlation was found between the quantitative estimates of global brain damage and the measures of disease duration. CONCLUSION: The results of this study demonstrate that volumetric MTI parameters and cerebral atrophy reflect functionally relevant brain damage in patients with NPSLE. Furthermore, the absence of a linear relationship between disease duration and results of volumetric MTI measures and atrophy suggests a complicated pattern of accumulating brain damage in patients with NPSLE.

Detection of cerebral involvement in patients with active neuropsychiatric systemic lupus erythematosus by the use of volumetric magnetization transfer imaging.

OBJECTIVE: To determine whether volumetric magnetization transfer imaging (MTI) histogram analysis can detect abnormalities in patients with active neuropsychiatric systemic lupus erythematosus (NPSLE) and to compare the MTI findings in patients with active NPSLE, chronic NPSLE, and multiple sclerosis (MS), as well as in normal control subjects. METHODS: Eight female and 1 male patient with active nonthromboembolic NPSLE (mean +/- SD age 39 +/- 9 years), 10 female patients with chronic NPSLE (age 33 +/- 11 years), 10 female patients with SLE and no history of NPSLE (non-NPSLE; age 34 +/- 11 years), 10 female patients with inactive MS (age 41 +/- 6 years), and 10 healthy control subjects (age 33 +/- 11 years) underwent MTL. Using the MTI scans, histograms were composed from which we derived a variety of parameters that quantitatively reflect the uniformity of the brain parenchyma as well as the ratio of cerebrospinal fluid to intracranial volume, which reflects atrophy. RESULTS: The magnetization transfer ratio (MTR) histograms in the non-NPSLE group and the healthy control group were similar, whereas those in the chronic NPSLE and MS groups were flatter. There was also flattening of the histograms in the active NPSLE group, but with a shift toward higher MTRs. CONCLUSION: Our results indicate that volumetric MTI analysis detects cerebral changes in the active phase of NPSLE. The abnormalities in the brain parenchyma of patients with chronic NPSLE produced MTI values that were the same as those in patients with inactive MS. MTI values in the active phase of NPSLE differed from those in the chronic phase, which might reflect the presence of inflammation. These preliminary results suggest that MTI might provide evidence for the presence of active NPSLE. MTI might also prove to be a valuable technique for monitoring treatment trials.

Unexpected rearrangement and expression of the immunoglobulin lambda1 locus in scid mice.

In severe combined immunodeficient (scid) mice, V(D)J recombination is severely impaired due to a recessive mutation (scid). Thus, we were surprised to find in this study that Vlambda1-Jlambda1 rearrangement is routinely detectable in scid fetal liver, adult bone marrow, and spleen in the apparent absence of completed VH-DJH and Vkappa-Jkappa rearrangements. Particularly surprising, we found the level of Vlambda1-Jlambda1 rearrangement in scid fetal liver to be comparable to that in fetal liver of wild-type mice. The majority of scid Vlambda1-Jlambda1 rearrangements contained abnormal deletions at the VJ junction, consistent with the known effect of scid. However, approximately 15% of Vlambda1-Jlambda1 rearrangements lacked abnormal deletions. Productive lambda1 transcripts resulting from in-frame rearrangements were readily detectable in scid adult bone marrow and spleen, consistent with our ability to detect lambda1-expressing cells by flow cytometry in the spleens of bcl-2-transgenic scid mice. Strikingly, lambda1 transcripts from individual scid mice often showed VJ junctional sequences with the same recurring palindromic (P) additions of three, four, or five nucleotides. To account for these findings, we suggest that (a) nonhomologous end joining of Vlambda1 and Jlambda1 coding ends in fetal B lineage cells may not be (severely) impaired by scid; (b) recurring P additions in scid lambda1 transcripts may reflect certain molecular constraints imposed by scid on the resolution of Vlambda1 and Jlambda1 hairpin coding ends; and (c), scid lymphocytes with productively rearranged Vlambda1 and Jlambda1 elements may differentiate into recombinase-inactive cells and emigrate from bone marrow to spleen.

Evidence of central nervous system damage in patients with neuropsychiatric systemic lupus erythematosus, demonstrated by magnetization transfer imaging.

OBJECTIVE: The clinical symptoms of neuropsychiatric systemic lupus erythematosus (NPSLE) are usually reversible, but whether the associated brain damage is also reversible is still a matter of debate. Since magnetization transfer imaging (MTI) is more sensitive than conventional magnetic resonance imaging (MRI) in demonstrating brain damage, it has become a useful tool in the detection and quantification of diffuse brain disorders such as multiple sclerosis. In this study, MTI was applied to investigate whether central nervous system (CNS) damage is present in patients with a history of NPSLE. METHODS: Eleven female patients with a history of NPSLE and no previous or concurrent primary neurologic or psychiatric disease (ages 17-49 years), 11 female patients with SLE without a history of NPSLE (non-NPSLE; ages 15-51 years), and 10 healthy female controls (ages 17-47 years) underwent MTI. From these MTI scans, quantitative data on the uniformity of the brain parenchyma and atrophy were derived. RESULTS: One NPSLE and 1 non-NPSLE patient were excluded from this study due to infarctions detected with conventional MRI. MTI measures normalized for intracranial volume, reflecting abnormalities of the brain parenchyma as well as atrophy, were lower (P < 0.001) in the NPSLE group than in both control groups. A higher (P < 0.005) mean ratio of cerebrospinal fluid to intracranial volume, indicative of atrophy, was present in the NPSLE group compared with either the non-NPSLE patients or healthy controls. Still, the MTI measures solely reflecting uniformity of the brain parenchyma (normalized for brain volume) were also significantly (P < 0.001) lower in the NPSLE patients than in both control groups. CONCLUSION: This study demonstrates that using MTI, CNS damage can be demonstrated in patients with a history of NPSLE. MTI might, therefore, be an alternative and sensitive tool to detect brain injury in NPSLE, and might also be useful in studying the natural history of the disease.

Differential effect of an Ig mu transgene on development of pre-B cells in fetal and adult SCID mice.

Progression of pro-B lymphocytes to the pre-B stage depends on the expression of a pre-B cell receptor (pre-BCR), consisting of an Ig mu H chain, Ig surrogate light chain, and associated signal transducing chains. Mice that are unable to express a pre-BCR show an arrest of B cell development at the pro-B stage. Such is the case for severe combined immune deficient (SCID) mice in which mu chains are not made because of a defect in V(D)J recombination. When mu chains are made, as in SCID mice bearing a functional mu transgene, then B cell differentiation can proceed to the pre-B stage. However, as reported here, a mu transgene (M54) that promotes development of SCID pre-B cells in adult bone marrow fails to do so in fetal liver. We suggest that a pre-BCR containing the M54 mu chain cannot signal progression of pro-B cells to the pre-B stage in the fetal liver microenvironment.

Cervical spondylarthrotic myelopathy with early onset in Down's syndrome: five cases and a review of the literature.

Progressive walking difficulties and bladder dysfunction may be attributed to Alzheimer disease or atlanto-axial subluxation in people with Down's syndrome (DS). The present authors describe five patients with DS suffering from the above symptoms as a result of cervical spondylarthrotic myelopathy. Clinical and radiological data were collected from all patients with DS who underwent surgery for cervical spondylarthrotic myelopathy at the Leiden University Medical Centre during the period between 1991 and 1995. Five patients with DS (four males and one female) were identified. Their mean age at diagnosis was 42 years. The main clinical features were weakness of the arms and legs, ataxic gait, hyperreflexia and bilateral Babinski signs. Radiological examination showed spondylarthrosis, compression of the spinal cord and myelomalacia. The mean delay in diagnosis was 3 years. All five individuals showed clinical stabilization after laminectomy. Cervical spondylarthrotic myelopathy seems a rather frequent disorder in DS, occurring at a relatively young age. Early diagnosis may prevent irreversible neurological deficits.

Extended duration of DH-JH rearrangement in immunoglobulin heavy chain transgenic mice: implications for regulation of allelic exclusion.

Here we show that suppression of VH-DJH rearrangement in mice bearing a mu heavy (H) chain transgene (mu-tg mice) is associated with an extended period of DH-JH rearrangement, the first step of Immunoglobulin H chain gene rearrangement. Whereas DH-JH rearrangement is normally initiated and completed at the pro-B cell stage, in mu-tg mice it continues beyond this stage and occurs most frequently at the small (late) pre-B stage. Despite ongoing DH-JH rearrangement in late pre-B cells of mu-tg mice, VH-DJH rearrangement is not detectable in these cells. We infer that the lack of VH-DJH rearrangement primarily reflects tg-induced acceleration of B cell differentiation past the stage at which rearrangement of VH elements is permissible. In support of this inference, we find that the normal representation of early B lineage subsets is markedly altered in mu-tg mice. We suggest that the effect of a productive VH-DJH rearrangement at an endogenous H chain allele may be similar to that of a mu-tg; i.e., cells that make a productive VH-DJH rearrangement on the first attempt rapidly progress to a developmental stage that precludes VH-DJH rearrangement at the other allele (allelic exclusion).

Subunit composition of pre-T cell receptor complexes expressed by primary thymocytes: CD3 delta is physically associated but not functionally required.

Maturation of immature CD4-CD8- (DN) thymocytes to the CD4+CD8+ (DP) stage of development is driven by signals transduced through a pre-T cell receptor (TCR) complex, whose hallmark is a novel subunit termed pre-T alpha (pT alpha). However, the precise role of pre-TCRs in mediating the DN to DP transition remains unclear. Moreover, progress in understanding pre-TCR function has been hampered thus far because previous attempts to demonstrate expression of pT alpha-containing pre-TCRs on the surface of normal thymocytes have been unsuccessful. In this report, we demonstrate for the first time that pT alpha-containing pre-TCR complexes are expressed at low levels on the surface of primary thymocytes and that these pre-TCR complexes comprise a disulfide-linked pT alpha-TCR-beta heterodimer associated not only with CD3-gamma and -epsilon, as previously reported, but also with zeta and delta. Interestingly, while CD3-delta is associated with the pre-TCR complex, it is not required for pre-TCR function, as evidenced by the generation of normal numbers of DP thymocytes in CD3-delta-deficient mice. The fact that any of the signaling components of the pre-TCR are dispensable for pre-TCR function is indeed surprising, given that few pre-TCR complexes are actually expressed on the surface of primary thymocytes in vivo. Thus, pre-TCRs do not require the full array of TCR-associated signaling subunits (gamma, delta, epsilon, and zeta), possibly because pT alpha itself possesses signaling capabilities.

Development of B cells in scid mice with immunoglobulin transgenes: implications for the control of V(D)J recombination.

The inability of scid pro-B cells to progress to the pre-B and B cell stages is believed to be caused by a defective recombinase activity that fails to resolve chromosomal breaks resulting from attempted V(D)J recombination. In support of this model, we report that certain immunoglobulin transgenes, specifically those which strongly inhibit endogenous VH-to-DJH and V kappa-to-J kappa rearrangement in wild-type mice, allow scid pro-B cells to progress to the pre-B and B cell stages. This rescue of scid B cell differentiation is associated with a dramatic reduction in expression of the recombination activation genes, RAG1 and RAG2, and with reduced transcription of the kappa locus.

Analysis of the defect in DNA end joining in the murine scid mutation.

Murine severe combined immune deficiency (scid) is marked by a 5,000-fold reduction in coding joint formation in V(D)J recombination of antigen receptors. Others have demonstrated a sensitivity to double-strand breaks generated by ionizing radiation and bleomycin. We were interested in establishing the extent of the defect in intramolecular and intermolecular DNA end joining in lymphoid and nonlymphoid cells from scid mice. We conducted a series of studies probing the ability of these cells to resolve free ends of linear DNA molecules having various biochemical end configurations. We find that the stable integration of linear DNA into scid fibroblasts is reduced 11- to 75-fold compared with that in normal fibroblasts. In contrast, intramolecular and intermolecular end joining occur at normal frequencies in scid lymphocytes and fibroblasts. This normal level of end joining is observed regardless of the type of overhang and regardless of the requirement for nucleolytic activities prior to ligation. The fact that free ends having a wide variety of end configurations are recircularized normally in scid cells rules out certain models for the defect in scid. We discuss the types of DNA end joining reactions that are and are not affected in this double-strand break repair defect in the context of a hairpin model for V(D)J recombination.

[Cows with swollen anus and vulva as a husbandry problem]. / Koeien met opgezette anus en vulva als bedrijfsprobleem.

An acute farming problem is described. The symptoms were poor intake of concentrates, swelling of the anus and vulva, and decreased milk production. Research results show that pig premix was incorporated into the concentrate for dairy cows. Which component of the concentrate was responsible for the symptoms remains to be established.

The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination.

Pre-B and pre-T cell lines from mutant mice with severe combined immune deficiency (scid mice) were transfected with plasmids that contained recombination signal sequences of antigen receptor gene elements (V, D, and J). Recovered plasmids were tested for possible recombination of signal sequences and/or the adjacent (coding) sequences. Signal ends were joined, but recombination was abnormal in that half of the recombinants had lost nucleotides from one or both signals. Coding ends were not joined at all in either deletional or inversional V(D)J recombination reactions. However, coding ends were able to participate in alternative reactions. The failure of coding joint formation in scid pre-B and pre-T cells appears sufficient to explain the absence of immunoglobulin or T cell receptor production in scid mice.

Transcription of unrearranged antigen receptor genes in scid mice.

The scid mouse mutant is severely deficient in lymphocytes; cells of the B or T lymphocyte lineage cannot be detected by either serological or functional assays. However, as shown here, germ-line transcripts of B cell immunoglobulin (Ig) constant and variable region genes and of T cell receptor (TCR) genes are detectable in lymphopoietic tissues of scid mice, as well as B and T lineage-specific lambda 5 and T3 delta transcripts. We conclude that B and T lineage-committed cells do arise in scid mice and that their Ig and TCR genes are accessible to enzymes involved in their recombination. This suggests that scid impairs lymphopoiesis at the stage at which antigen receptor genes normally undergo rearrangement.