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Biomedical subjects

J N Whitaker

Publications and source records attributed to J N Whitaker.

At least 55 records · Page 3Linked to original sources
PubMed1998

Myelin basic protein in cerebrospinal fluid and other body fluids.

Myelin basic protein (MBP) or a fragment thereof may enter cerebrospinal fluid (CSF) and other body fluids in an etiologically nonspecific fashion to provide information about the status of central nervous system (CNS) myelin damage. MBP immunochemically detected is referred to as MBP-like material (MBPLM). The clinical utility of the assay for MBPLM in CSF is to document the presence, continuation, or resolution of CNS myelin injury. The analysis of CSF for MBPLM is subject to many variables, among which are the antisera and the form of the assay utilized. The dominant epitope of CSF MBPLM is in the decapeptide of 80-89 from the intact MBP molecule of 170 residues. Normally, CSF has no detected MBPLM. Following an acute relapse of MS, MBPLM rises quickly in the range of ng/ml and rapidly declines and disappears. The presence of MBPLM in CSF in chronic and progressive phases of the disease is unusual, but it may sometimes be detected in low levels, depending on the assay used for detection. The level of CSF MBPLM is related to both the mass of CNS myelin damage and how recently it occurred. The level of CSF MBPLM rarely is elevated in optic neuritis. The level of CSF MBPLM is unrelated to CSF protein level, level of IgG, presence of oligoclonal bands or pleocytosis. CSF MBPLM has the potential of serving as a marker of therapeutic effectiveness in MS and does have predictive value for response to glucocorticoids given for worsening of disease. The detection of MBPLM in body fluids other than CSF would be of great value because of the resulting improved feasibility for objectively monitoring the natural history of MS and response to therapy. Studies on blood have yet to produce a valid assay of MBPLM. Urinary MBPLM, though different in its features from that in CSF, may provide a correlate, not with acute demyelination in MS as is the case for CSF, but with progression of disease.

Humans↗
PubMed1998

Myelin basic protein-like material in the urine of multiple sclerosis patients: relationships to clinical and neuroimaging changes.

Urinary myelin basic protein-like material (MBPLM) represents material which is cross-reactive with a cryptic epitope in peptide 84-89 of human myelin basic protein. While normally present at moderate levels in the adult, these levels rise higher in patients who have secondary progressive multiple sclerosis (MS). The increase in urine MBPLM correlates with the burden of disease detected by T2-weighted cranial magnetic resonance imaging. There is no correlation between urinary MBPLM and acute disease activity in relapsing-remitting MS. The first major need for improving the clinical utility of measurements of MBPLM in urine in MS patients is to delineate its exact chemical features so that assays may be improved and a potential biological role of the MBPLM better understood. The second major task is to apply the group data accumulated and apply them to individual patients. This could prove to be means to individually direct treatment and determine its effectiveness.

Adult↗
PubMed1998

A cross-reactive anti-myelin basic protein idiotope in cerebrospinal fluid cells in multiple sclerosis.

We wanted to find evidence of antibody to myelin basic protein (MBP) in patients with MS by detecting their shared usage of immunoglobulin genes. As demonstrated by the idiotopes (i.d.) of murine monoclonal antibody to peptides of MBP, there is limited use of the variable (V) region immunoglobulin genes for the immune response in mice to this encephalitogenic protein. Cross-reactive Ids have been detected across different murine strains and shared by T and B cells. One cross-reactive Id, designated as 845D3 Id, is located on the V region of kappa light chains of two murine monoclonal antibodies, one to MBP peptide 80-89 and the other to MBP peptide acetyl 1-9. To examine the occurrence of 845D3 Id in MS, we used the V region of a light chain (VL) of one of the monoclonal antibodies to probe the VL genes expressed in B cells in CSF of 50 patients (31 MS and 19 non-MS). The VL genes expressed in B cells found in CSF were amplified by polymerase chain reaction using universal human V-region primers. The 845D3 Id probe detected the Id+ V region in the CSF of 14 of 31 MS patients, 1 of 9 patients with other neurologic diseases, and 1 of 10 non-neurologic patients. The gene product was more common in but not restricted to CSF with oligoclonal bands. The presence in CSF of MS patients of a cross-reactive Id to different MBP peptides is indicative of an immune response to this encephalitogenic myelin protein in a segment of MS patients. These findings are also evidence for limited usage of V-region Ig genes in the immune response of humans to MBP and the possible importance of an Id network for MBP in demyelinating disease.

Adult↗
PubMed1998

Age-related changes in the level of urinary myelin basic protein-like material during childhood.

OBJECTIVE: To examine the developmental profile of myelin basic protein-like material (MBPLM) in urine. If urinary MBPLM exhibits a developmental profile corresponding to that of forebrain myelination, certain inferences should follow deviations from normal. Thus, MBPLM might provide a marker for monitoring the neurodevelopmental status in infants at risk for adverse outcomes. BACKGROUND: MBPLM in different immunochemical forms is detectable in human CSF and urine, presumably a result of myelin basic protein (MBP) catabolism. Urinary MBPLM has been used successfully as a marker of disease status in adults with MS. Urinary MBPLM increases in MS patients changing from a relapsing-remitting to a progressive course, possibly reflecting attempted or failed remyelination. Scant information exists concerning the presence or specific levels of urinary MBPLM during infancy and childhood when myelination is most active. METHODS: MBPLM was assayed in 402 urine specimens from 398 infants and children ranging in age from birth to 17 years according to previously described methods. RESULTS: MBPLM is detectable in urine from newborns, although at substantially lower levels than in adults (157.3 +/- 83.9 ng/mg creatinine). Whether expressed as nanograms per milliliter urine or nanograms per milligram creatinine, MBPLM levels are lower (p < 0.05) from birth through 12 months and greater (p < 0.05) between ages 2 to 8 years than in adults. CONCLUSION: Human urinary MBPLM exhibits a developmental profile that parallels the onset of normal myelination and exceeds normal adult values through early childhood. Thus, urinary MBPLM could serve as a useful marker of myelination in the developing child.

Adolescent↗
PubMed1997

Quantitative assessment of myelin basic protein-reactive T cell entry to the central nervous system by using oligonucleotide probes complementary to VDJ junctional sequences of rat TCR beta-chain.

The VDJ junctional region represents the most diverse part of the antigenic TCR. We have previously reported that of 200 sequenced TCR beta-chains of rat MBP-reactive T cells, rarely did two share sequence homology over the entire CDR3 region. In this study, we demonstrate that sequences of the TCR CDR3 region are excellent clonotypic markers for rat MBP-reactive T cell clones and oligonucleotide probes complementary to the CDR3 region of three T cell clones specifically recognized the TCR from which they were derived, but failed to recognize syngeneic T cells that express a similar TCR beta-chain or T cells that share both V beta and J beta usage. To explore this observation, we determined the ability of MBP-reactive T cell clones to enter the CNS. We were able to show that some MBP-reactive T cell clones have an augmented ability to enter the CNS and that fully-activated T cells have a higher penetrating activity than their less-activated T cell counterparts.

Amino Acid Sequence↗
PubMed1997

Expression of chemokine genes in rat glial cells: the effect of myelin basic protein-reactive encephalitogenic T cells.

Chemokine gene expression and chemokine activity appear to be major components of the immunopathological processes of inflammation and autoimmunity. To initiate an investigation of the role of chemokines in the pathogenesis of autoimmune inflammatory demyelination, we examined the expression of mRNA transcripts encoding four prominent chemokines, IP-10, MIP-1 alpha, MCP-1, and RANTES, in encephalitogenic rat MBP-reactive T cells, astrocytes, and microglia. Astrocytes and microglia, whether as lines or as freshly isolated cells, did not constitutively express IP-10 and MCP-1 mRNA but could be induced with LPS to also produce MIP-1 alpha and RANTES. MBP-reactive T cells were induced with MBP to produce abundant levels of MIP-1 alpha, MCP-1, and RANTES mRNA in different temporal profiles but did not express IP-10 mRNA. In an MHC-II restricted fashion, the antigen-activated MBP-reactive T cells also induced glial cells to express all four chemokines, with the chemokine gene expression greatest following T-cell interactions with MHC-compatible glia. Treatment of glial cells with TNF-alpha and IFN-gamma induced only IP-10, indicating that the expression of chemokine genes other than IP-10 requires a combination of different cytokines or direct cell-cell contact between T cells and glia. Quantitative assays revealed that activated astrocytes, the dominant glia of the CNS, express higher levels of chemokine transcripts than transcripts of the major proinflammatory cytokines TNF-alpha and IFN-gamma. These results underscore the prominent but complex expression of chemokines by cellular component of inflammatory demyelinating lesions.

Animals↗
PubMed1997

Immunological effects of an arginine side chain contaminating synthetically prepared peptides.

The side chain, 4-methoxy-2,3,6-trimethylbenzenesulphonyl (Mtr), is a protective group coupled to arginine to mask the omega-nitrogen, in order to protect the guanidino function during peptide synthesis by the 9-fluorenylmethoxycarbonyl (Fmoc) procedure (Walker, 1994). This group is removed at the completion of peptide synthesis; however, the cleavage process can be incomplete. We have found that animals injected with a mixed population of pure, i.e. unmodified, and Mtr-containing MBP peptides have an immunodominant humoral response to the Mtr-bearing peptide. This response is dependent on the characteristics of the MBP peptide involved. For two MBP peptides, the Mtr-containing peptide had increased binding to antibody over pure peptide. For two other peptides, only the Mtr-containing peptide bound antibody while the unmodified peptide did not. In a separate system involving a polyclonal response to an unrelated peptide from beta2-microglobulin (beta2 m), the dominance of the Mtr group was also evident. These results provide further evidence that a small side chain on a single amino acid in a peptide can markedly alter the immunogenicity and antigenicity of that peptide for antibody reactivity. This evidence emphasizes the need for a critical awareness of each component of peptide synthesis and its potential to alter the immunoreactivity of the final product.

Amino Acid Sequence↗
PubMed1997

Nonactivated astrocytes downregulate T cell receptor expression and reduce antigen-specific proliferation and cytokine production of myelin basic protein (MBP)-reactive T cells.

Astrocytes express variable levels of MHC class II antigens depending on their activation status or exposure to certain cytokines, notably IFN-gamma. When they are induced to express higher surface densities of MHC class II molecules, astrocytes are capable of stimulating syngeneic myelin basic protein (MBP)-reactive T cells to proliferate at a modest rate and to secrete proinflammatory cytokines, such as TNF-alpha, in response to antigen. In the present investigation evidence is presented that uninduced astrocytes, whether fresh or established as clones, on which surface MHC class II molecules are expressed at a very low density, promote an antigen-dependent reduction of TCR on the surface of syngeneic T cells. Accompanying this effect on the TCR is an induction of T cell hyporeactivity and little or no production of proinflammatory cytokines. These observations suggest that the ability of the astrocyte, through varying their surface MHC class II molecules, can control the effect of antigen-induced T cell responses. In their normal state of low MHC II expression astrocytes are expected to induce no or partial, rather than full, activation of autoreactive T cells that enter the CNS, resulting in T cell hyporeactivity. Since astrocytes usually diminish the production of proinflammatory cytokines by T cells that enter the CNS, the status and control of MHC class II expression on astrocytes should be important determinants of the suppression or enhancement of in situ immune responses in the CNS.

Animals↗
PubMed1997

Inhibition of allergic encephalomyelitis in marmosets by vaccination with recombinant vaccinia virus encoding for myelin basic protein.

A primary demyelinating form of experimental allergic encephalomyelitis (EAE) resembling human multiple sclerosis (MS) occurs in Callithrix jacchus marmosets following immunization with human white matter. Participation of a T-cell immune response against myelin basic protein (MBP) in this disease model is supported by observations of increased reactivity against MBP in PBMC and of adoptive transfer of an inflammatory form of EAE by MBP-reactive T-cells. To evaluate the effects of ectopic presentation of MBP on marmoset EAE, animals were vaccinated prior to induction of EAE by subcutaneous injection of attenuated strains of vaccinia virus genetically engineered to contain either the entire coding sequence for human MBP (vT15) or the equine herpes virus glycoprotein gH gene (vAbT249). Vaccination with vT15 was followed by transient cytoplasmic and surface membrane expression of MBP in circulating PBMC (15-45 days). The onset of clinical EAE after immunization (pi) was markedly delayed in vT15-vaccinated animals (37-97 days pi, n = 4) compared to vAbT249-vaccinated controls (14-18 days pi, n = 3). Proliferative responses against MBP but not against vaccinia antigens or phytohemagglutinin were suppressed in protected animals. Thus, development of attenuated live viruses carrying genes for myelin antigens could be useful for induction of immunologic tolerance and for modulation of autoimmune demyelination.

Animals↗
PubMed1996

Active immunization with complementary peptide PBM 9-1: preliminary evidence that it modulates experimental allergic encephalomyelitis in PL/J mice and Lewis rats.

The idiotype (Id) of T cells and possibly antibodies are involved in an Id network that may immunoregulate experimental allergic encephalomyelitis (EAE). Thus, the adoptive EAE in PL/J mice responding to myelin basic protein (MBP) peptide acetyl 1-9 can be modulated by monoclonal antibody (mAb) anti-Id generated by immunization with a peptide of inverted hydropathy to MBP peptide 1-9, designated as PBM 9-1. A cross-reactive Id between species can be recognized on the T cell receptor (TCR) of Vb8.2 restricted T cells in either PL/J mice or Lewis rats. The present study was undertaken to examine the vaccine effect of PBM 9-1 presented in the form of a multiple antigen peptide (MAP) to induce active immunity against active EAE in Lewis rats and active or adoptive EAE in PL/J mice. MAP-PBM 9-1 induced an antibody response in both Lewis rats and PL/J mice, but more in the former. A low level of anti-Id antibody, including a low level of reactivity with specific but not control T cells, was also detected in the sera collected before induction of or after recovery from EAE. Active immunization with MAP-PBM 9-1 had a protective effect on relapses of adoptive EAE in PL/J mice and could prevent active EAE in Lewis rats. A relationship was noted between the titer of serum anti-PBM 9-1 Ab and the protective effect of active immunization in Lewis rats. Although the mechanism of effect remains to be clarified, these results suggest that MAP-PBM 9-1 is a nonencephalitogenic candidate for protection against inflammatory demyelination.

Amino Acid Sequence↗
PubMed1996

Murine V lambda x and V lambda x-containing antibodies bind human myelin basic protein.

Myelin basic protein (MBP) is highly immunogenic and a known autoantigen capable of inducing experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis. We have previously described a murine monoclonal antibody (mAb), F28C4, directed against the encephalitogenic MBP peptide acetyl (Ac) 1-9, which contains a V lambda x light chain. Considering the rarity of V lambda x usage, we determined whether other Abs having V lambda x light chains shared similar antigen (Ag) specificity. We screened a panel of V lambda x-containing monoclonal and polyclonal Abs, of unknown specificity for reactivity with MBP. All such Ab, but not heavy chain isotype matched controls, bound MBP but were not polyreactive with other potential self Ags. The binding of a recombinant form of V lambda x alone to MBP demonstrated the important contribution of the V lambda x light chain to the reaction. With the exception of mAb F28C4 which recognizes MBP Ac1-9, the epitope specificity of all other V lambda x-bearing Abs was localized to MBP residues 25-34. These results demonstrate a unique association between V lambda x expression and MBP reactivity. Given that V lambda x shares sequence homology with T cell receptors (TCR) from encephalitogenic T lymphocytes, these results imply a potential role for V lambda x in the pathogenesis of EAE.

Amino Acid Sequence↗
PubMed1996

Evaluation of multiple sclerosis by 1H spectroscopic imaging at 4.1 T.

The authors report on high-field (4.1 T) magnetic resonance 1H spectroscopic imaging studies on eight patients with relapsing remitting multiple sclerosis (mean expanded disability status scale (EDSS) 1.0) and eight normal controls. Using T1-weighted imaging to determine lesion position, the authors found the ratios of choline/N-acetyl (NA) compounds and creatine/NA were increased significantly in the multiple sclerosis (MS) patients relative to controls in lesioned tissue, adjacent to lesion, far removed from lesions as well as in periventricular tissue. The gray matter creatine/NA was mildly increased (P < 0.01) in the MS patients, whereas the elevated gray-matter ratio of choline/NA was of borderline significance (P = 0.13). A more detailed comparison of white-matter and mean gray-matter metabolite values indicates that creatine is increased greatest in areas far from lesions. This is in contrast to choline, which was greatest in lesions, and NA, which was smallest in lesions. It is postulated that the creatine increase may reflect an astrocytic (gliotic) or oligodendrocytic remyelinating process. The increased choline most likely reflects varying levels of inflammation and membrane turnover, whereas the NA decrease is representative of axonal dysfunction or loss.

Adult↗
PubMed1996

Preferential association of V lambda x light chains with gamma 2a heavy chains in naturally occurring human myelin basic protein reactive antibodies.

Active immunization with myelin basic protein (MBP) induces experimental allergic encephalomyelitis (EAE) in a variety of animal species, including rats and mice. We have previously described the ability of the newly described mouse lambda (lambda) variable (V) region V lambda x, to confer MBP reactivity to an Ab. In this report, we have evaluated the heavy (H) chain isotype distribution of V lambda x-bearing Abs in normal mouse serum. We demonstrate a biased H chain isotype association with V lambda x light (L) chains with a skewing towards gamma 2a and 2b isotypes. The IgG2a restriction in normal mouse Igs is even more evident in V lambda x-containing Abs that bind MBP. This was confirmed by the ability of purified polyclonal IgG2a Abs to bind MBP and the finding that most or all of the IgG2a Abs that bind MBP seem to harbor a V lambda x L chain. The specificity of naturally-occurring V lambda x-bearing Abs with MBP can be localized to a particular epitope encompassing residues 25-34 of the MBP molecule. Furthermore, virtually all of the reactivity of V lambda x-containing Abs with MBP peptide 25-34 is associated with the gamma 2a isotype. Collectively, these results suggest that the interaction of V lambda x with MBP seems to be facilitated by an association with gamma 2a which may reflect preferred VH usage by this isotype. Such unique pairing of particular H chains with V lambda x L chains in Abs that bind MBP may be indicative of a new B-cell component involved in the pathogenesis of EAE.

Animals↗
PubMed1996

Cerebrospinal fluid myelin basic protein-like material in acute monosymptomatic optic neuritis.

INTRODUCTION: Cerebrospinal fluid (CSF) may provide markers of severity and outcome of optic neuritis. MATERIAL AND METHODS: We examined the CSF from 29 patients with acute monosymptomatic optic neuritis (AMON) for content of myelin basic protein-like material (MBPLM) and correlated the levels with results of cranial magnetic resonance imaging. The length of the time from onset of AMON to the time of CSF collection did not exceed four weeks. RESULTS: Only two patients (7%), one of whom developed an acute myelopathy one month after AMON, showed an elevated value of CSF MBPLM. No MBPLM was detected in 6 patients (21%), and other 21 (72%) had detectable levels of MBPLM but below the upper limit of normal of 0.1 ng/ml. The value of MBPLM was not significantly correlated with the interval to CSF sampling from onset of AMON or with severity of decreased visual acuity. The highest values of CSF MBLPM were observed among patients with severely decreased visual acuity and among patients with an abnormal MRI (13 of 27 i.e. 48%). CONCLUSIONS: CSF MBPLM was rarely abnormal in AMON. However, CSF MBPLM may have potential value in reflecting disease activity, as the highest values were obtained among patients with CSF sampled soon after the maximum visual dysfunction was reached, with severe visual impairment, and with an abnormal MRI.

Acute Disease↗
PubMed1996

Management of patients receiving interferon beta-1b for multiple sclerosis: report of a consensus conference.

Results of a double-blind, placebo-controlled study in ambulatory patients with relapsing-remitting MS showed that interferon beta-1b reduced the rate of exacerbations by one-third compared with placebo and limited new disease activity in the brain as evidenced by MRI. Interferon beta-1b, administered subcutaneously at a dosage of 0.25 mg (8 million IU) every other day is indicated for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1b may help a wider range of patients, but it should be prescribed only for patients with a diagnosis of clinically definite or laboratory-supported definite MS. The decision to treat a patient with interferon beta-1b should be individualized; that is, based on each patient's clinical presentation and course of MS. The most common adverse effects include (1) injection-site reactions and (2) flu-like symptoms, which are generally manageable and usually abate after the first few months of treatment. Spasticity may increase. Patients with severe depression or suicidal ideation should be monitored carefully, and symptomatic treatment should be pursued. Interferon beta-1b is contraindicated in pregnant and nursing women. Interferon beta-1b is effective in reducing the progression of total disease burden as seen on MRI in patients with MS. Its use is relatively straightforward and generally does not require alteration in the symptomatic treatment of MS. Patient education and support remain the mainstays of maintaining compliance through the early phases of therapy.

Female↗
PubMed1996

Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial.

The Optic Neuritis Treatment Trial (ONTT) is a prospective study of corticosteroid treatment of acute optic neuritis (ON), with subsequent longitudinal follow-up to determine development of clinically definite multiple sclerosis (CDMS). We analyzed the CSF of 83 patients with clinically isolated ON who underwent lumbar puncture within 24 hours of enrollment into the ONTT to determine the value of CSF changes in ON, especially regarding diagnostic utility, immunologic changes, MRI correlations, and progression to CDMS. All patients had baseline MRI scans graded for changes typical of MS. CSF measurements included immunoglobulin G (IgG) synthesis, IgG ratio, myelin basic protein, IgG kappa light chains, and oligoclonal banding. No patients had their diagnosis or management altered as a result of CSF findings. Except for oligoclonal bands, few patients showed any abnormalities on CSF tests, and no tests correlated with the 2-year development of CDMS. Oligoclonal banding, present at baseline in 11 of 13 patients who developed CDMS, did predict progression to CDMS, but this was not independent of MRI abnormalities. Two patients with oligoclonal bands and a normal MRI did progress to CDMS. We conclude that CSF analysis may not be necessary in the routine evaluation of patients presenting with a typical clinical profile of acute ON, and that most CSF tests add little additional information to MRI results for predicting the 2-year development of CDMS. However, the precise role of oligoclonal banding in the analysis of such patients awaits longer follow-up of this cohort.

Administration, Oral↗