Spontaneously occurring neutralizing antibodies against granulocyte-macrophage colony-stimulating factor in patients with autoimmune disease.
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There is increasing evidence that spontaneous anticytokine autoantibodies are associated with chronic infections and autoimmune diseases. We report the sporadic occurrence in autoimmune diseases of such autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine involved in inflammation and the regulation of proliferation, differentiation and function of granulocytic and monocytic cell lineages. In 41 of 425 patients tested, we found low to moderate levels of autoantibodies binding to GM-CSF in serum or plasma. These were most prevalent in patients with myasthenia gravis (MG). However, neutralizing autoantibodies against GM-CSF were very rare, being found in only three patients. Two had autoimmune MG, one with thymoma (Patient A) and the other (Patient B) with 'seronegative' MG, i.e. without the antiacetylcholine receptor autoantibodies characteristic of most MG patients, and a third (Patient D) had multiple sclerosis. Only very limited amounts of Patient A and Patient D serum/plasma were available for analysis and therefore further studies were carried out on the more plentiful samples from Patient B. The anti-GM-CSF autoantibodies of Patient B were predominantly polyclonal immunoglobulin G and strongly neutralized recombinant human (rh) GM-CSF derived from different expression systems. They had similar immunological and immunochemical characteristics to anti-GM-CSF antibodies that developed in immunocompetent colorectal carcinoma patients following (rh)GM-CSF therapy. In serial samples from Patient B, the anti-GM-CSF autoantibodies were undetectable from diagnosis at age 8 years until at least age 13, but then developed spontaneously during (temporary) withdrawal of immunosuppressive treatment. Their neutralizing activity has persisted since their first detection at age 15 years 1 month, and was at its highest level recently at age 17 years 7 months. There was no obvious association with other autoimmune phenomena, nor were any haematological deficiencies overtly manifested, suggesting that any loss of GM-CSF function may have been compensated for by other cytokines. (+info)
Interferon beta treatment for multiple sclerosis has a graduated effect on MRI enhancing lesions according to their size and pathology.
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OBJECTIVE: The ability of recombinant human interferon beta-1a (rh-IFN beta-1a) to suppress multiple sclerosis activity, evaluated from MRI, was assessed across a range of lesions enhancing at different gadolinium-DTPA (Gd) doses and with different sizes. METHODS: Every 4 weeks, standard dose (Sd; 0.1 mmol/kg Gd) and triple dose (Td; 0.3 mmol/kgGd) MRI were obtained from 18 patients with relapsing-remitting multiple sclerosis for 3 months before and 4 months after starting treatment with 44 microgram rh-IFN beta-1a subcutaneously, once a week. RESULTS: The total numbers of enhancing lesions were 145 and 126 on Sd scans and 278 and 192 on the Td scans obtained before and after treatment. The introduction of treatment decreased, on average, the rate of appearance of new enhancing lesions seen on Sd and Td scans by 37% (p<0.001). Treatment effects on new enhancing lesions seen on Td scans was, on average, 28% higher than on those seen on Sd scans. The distribution of lesion sizes on Td scans changed significantly during the treatment period (p=0.05), due to a marked decrease in the number of small lesions. CONCLUSIONS: The effect of 44 microgram rh-IFN beta-1a in reducing multiple sclerosis disease activity, as monitored by Gd enhanced MRI, is not homogeneous, but graduated according to the pathological characteristics and size of the lesions. (+info)
HLA-DPB1*0501-associated opticospinal multiple sclerosis: clinical, neuroimaging and immunogenetic studies.
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In order to clarify the relationship between the clinical phenotype and the human leucocyte antigen (HLA) in multiple sclerosis in Asians, 93 Japanese patients with clinically definite multiple sclerosis underwent clinical MRI and HLA-DPB1 gene typing studies. According to a neurological examination, 29 patients were classified as opticospinal multiple sclerosis, 17 as spinal multiple sclerosis and 47 as Western type multiple sclerosis showing the involvement of multiple sites in the CNS including either the cerebrum, cerebellum or brainstem. The opticospinal multiple sclerosis showed a significantly higher age of onset, higher expanded disability status scale scores and higher CSF cell counts and protein content than the Western type multiple sclerosis. On brain and spinal cord MRI, the opticospinal multiple sclerosis showed a significantly lower number of brain lesions, but a higher frequency of gadolinium-enhancement of the optic nerve and a higher frequency of spinal cord atrophy than in Western type multiple sclerosis. The frequency of the HLA-DPB1*0501 allele was found to be significantly greater in opticospinal multiple sclerosis (93%) than in healthy controls (63%, corrected P value = 0.0091 and relative risk = 7.9), but not in Western type multiple sclerosis (66%) or spinal multiple sclerosis (82%). The marked differences in the clinical and MRI findings as well as in the immunogenetic backgrounds between the opticospinal multiple sclerosis and Western-type multiple sclerosis together suggest that HLA-DPB1*0501-associated opticospinal multiple sclerosis is a distinct subtype of multiple sclerosis. (+info)
A longitudinal MR study of the presymptomatic phase in a patient with clinically definite multiple sclerosis.
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We describe the dynamics and the nature of the presymptomatic phase of multiple sclerosis (MS) in a patient for whom MR abnormalities suggestive of MS were found before the development of clinical symptoms. The patient was monitored with serial monthly MR imaging of the brain and spinal cord for 5 months. Disease activity during the presymptomatic phase showed imaging characteristics comparable to that of early relapsing-remitting MS in terms of enhancing lesions, duration of enhancement, and new lesions depicted by T2-weighted imaging. Measurements derived from magnetization transfer imaging suggested that the amount and degree of tissue destruction within and outside the lesions revealed by T2-weighted imaging were mild. This, together with the fact that only one of the 43 new lesions that developed during the presymptomatic phase was located in a neurologically eloquent area, may be the reason why, for a relatively long period, the patient had no clinical manifestations of MS despite the marked MR findings of disease activity. (+info)
A common TCR V-D-J sequence in V beta 13.1 T cells recognizing an immunodominant peptide of myelin basic protein in multiple sclerosis.
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T cell responses to the immunodominant peptide (residues 83-99) of myelin basic protein are potentially associated with multiple sclerosis (MS). This study was undertaken to examine whether a common sequence motif(s) exists within the TCR complementarity-determining region (CDR)-3 of T cells recognizing the MBP83-99 peptide. Twenty MBP83-99-reactive T cell clones derived from patients with MS were analyzed for CDR3 sequences, which revealed several shared motifs. Some V beta 13.1 T cell clones derived from different patients with MS were found to contain an identical CDR3 motif, V beta 13.1-LGRAGLTY. Oligonucleotides complementary to the shared CDR3 motifs were used as specific probes to detect identical target CDR3 sequences in a large panel of T cell lines reactive to MBP83-99 and unprimed PBMC. The results revealed that, in contrast to other CDR3 motifs examined, the LGRAGLTY motif was common to T cells recognizing the MBP83-99 peptide, as evident by its expression in the majority of MBP83-99-reactive T cell lines (36/44) and PBMC specimens (15/48) obtained from randomly selected MS patients. The motif was also detected in lower expression in some PBMC specimens from healthy individuals, suggesting the presence of low precursor frequency of T cells expressing this motif in healthy individuals. This study provides new evidence indicating that the identified LGRAGLTY motif is preferentially expressed in MBP83-99-reactive T cells. The findings have important implications in monitoring and targeting MBP83-99-reactive T cells in MS. (+info)
Viral load and a locus on chromosome 11 affect the late clinical disease caused by Theiler's virus.
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Theiler's virus causes a persistent infection and a demyelinating disease of mice which is a model for multiple sclerosis. Susceptibility to viral persistence maps to several loci, including the interferon gamma locus. Inactivating the gene coding for the interferon gamma receptor makes 129/Sv mice susceptible to persistent infection and clinical disease, whereas inactivating the interferon gamma gene makes C57BL/6 mice susceptible to persistent infection but not to clinical disease. This difference in phenotype is due to the difference in genetic background. Clinical disease depends on high viral load and Tmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis. (+info)
Attachment device for side-biting cannula in stereotactic biopsy--technical note.
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An attachment device to fix a Sedan side-biting biopsy cannula to a stereotactic frame is described. The disadvantages of the biopsy cup forceps are resolved, and a relatively large amount of multiple specimens can be obtained along a single biopsy trajectory. This attachment device enables the side-biting cannula to follow a straight trajectory biopsy in various stereotactic frames. (+info)
Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler's virus-infected mice.
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The mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4(+) T cells targeting virally infected central nervous system-resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope-specific CD4(+) T cells via epitope spreading. Here we show that F4/80(+), I-A(s+), CD45(+) macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell-mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs. (+info)