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Biomedical subjects

J N Whitaker

Publications and source records attributed to J N Whitaker.

At least 37 records · Page 2Linked to original sources
PubMed2000

Surgery for cervical spinal cord compression in patients with multiple sclerosis.

OBJECTIVE: The goal of this study was to investigate the clinical and paraclinical features, treatment, and outcomes of patients with multiple sclerosis (MS) and coexisting spinal cord compression secondary to either cervical spondylosis or cervical disc disease. Patients with MS commonly experience neurological disabilities that present as myelopathy associated with bladder dysfunction. For some patients with MS, however, this neurological deterioration may result from coexisting spinal cord compression attributable to either spondylosis or a herniated disc. Overlapping symptoms of the two conditions do not allow clear clinical determination of the underlying cause of worsening. METHODS: Patients with MS who underwent cervical decompression surgery were selected. Medical records were retrospectively reviewed, to collect data on their pre- and postoperative clinical courses. RESULTS: Nine women and five men with definite MS were selected for cervical decompression surgery to treat neurological deterioration considered to be at least partially attributable to spinal cord compression. The most common symptoms were progressive myelopathy (n = 13), neck pain (n = 11), and cervical radiculopathy (n = 10). Bladder dysfunction was notably absent among these patients with MS with moderate disabilities. Surgical intervention was frequently delayed because the neurological deterioration was initially thought to be attributable to MS. The majority of patients experienced either improvement or stabilization of their preoperative symptoms in the immediate postoperative period; three subjects (21%) maintained this improvement after a mean follow-up period of 3.8 years. No MS relapses, permanent neurological worsening, or serious complications resulting from surgery or general anesthesia were noted. CONCLUSION: Carefully selected patients with MS and cervical spinal cord compression secondary to either spondylosis or disc disease may benefit from surgical decompression, with minimal associated morbidity. Clinical features (especially neck pain and cervical radiculopathy) and magnetic resonance imaging may assist clinicians in differentiating between the two conditions and may guide appropriate treatment without undue delay.

Adult↗
PubMed2000

Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients.

Myelin basic protein (MBP), a candidate autoantigen in multiple sclerosis (MS), exists in different isoforms and charge isomers generated by differential splicing of exons and by a combination of posttranslational modifications, respectively. These various isoforms and charge isomers of MBP vary in abundance and most likely serve different functions during myelinogenesis and remyelination. The least cationic among the charge isomers of MBP is citrullinated and is referred to as MBP-C8. MBP-C8 is relatively increased in the population of MBP isomers in more developmentally immature myelin and in MS brain tissue. In a previous study, we found that MBP-C8-reactive T cells could be detected in CD4+ T cell lines (TCL) generated with MBP from both MS patients and normal controls. Here, we examined the frequency and peptide specificity of MBP-C8-specific TCL generated with MBP-C8 in MS patients and controls. Ten subjects grouped in five sets, each an MS patient and a control, were studied. In all cases, the MS patient had either a higher overall number of MBP-C8-responding lines, responded with greater sensitivity to the MBP-C8 antigen or both. Few lines responded to the MBP-C8 peptides but, if they did, they appeared to be specific to the carboxyl-half of the MBP-C8 molecule. Given the large amounts of citrullinated MBP in MS brain tissue, a preferential T cell response to MBP-C8 may be involved in the induction and perpetuation of this disease. Multiple Sclerosis (2000) 6 220 - 225

Adult↗
PubMed2000

Importance of paraclinical and CSF studies in the diagnosis of MS in patients presenting with partial cervical transverse myelopathy and negative cranial MRI.

Patients presenting with isolated partial cervical myelopathy are at high risk for development of multiple sclerosis (MS), especially if lesions suggestive of demyelination are present on cranial magnetic resonance imaging (MRI). This risk is lower, though not precisely known, in patients whose cranial MRI is normal. This clinical issue was addressed by examining the role of paraclinical studies in establishing a diagnosis of MS at the time of initial presentation. Twelve consecutive patients, mean age of 32.2 years, seen over 6.5 years were identified prospectively and included in this study. Numbness was the presenting symptom in 11 of these patients. Symptoms completely resolved in nine patients regardless of treatment with glucocorticoids. Evoked potential (EP) and cerebrospinal fluid (CSF) examinations assisted in establishing a diagnosis of laboratory-supported definite (LSDMS) or clinically probable (CPMS) MS in six patients at the time of presentation. During a clinical follow-up period of 4.1 years, four developed recurrent neurologic deficits leading to the establishment of a diagnosis of clinically definite MS (CDMS). The presence of a solitary, non-specific lesion on cranial MRI resulted in an increased risk for the development of definite MS. In patients with a clinically isolated cervical partial transverse myelitis (TM) and normal cranial MRI, an accurate diagnosis of MS can usually be made. Revision of the diagnostic criteria for LSDMS is warranted. Multiple Sclerosis (2000) 6 312 - 316

Adolescent↗
PubMed2000

Cross-reactive idiotypy in cerebrospinal fluid immunoglobulins in multiple sclerosis.

The presence of oligoclonal bands in cerebrospinal fluid (CSF) in multiple sclerosis (MS) indicates a restricted heterogeneity of immunoglobulin (Ig). The portion of myelin basic protein encompassing residues 80-96 contains epitopes frequently recognized by T and B cells of MS patients. To define further this restricted heterogeneity and to direct further efforts to identify an antigenic target of CSF oligoclonal bands, the presence of idiotope (Id)-bearing antibodies sharing an Id with a murine monoclonal antibody to myelin basic protein peptide 80-89 was examined in the CSF of MS patients. CSF samples from 57 patients with clinically definite MS and 45 patients with other neurological diseases were standardized for amount of IgG and analyzed by immunoblotting for detection of Id-bearing antibodies. Id-bearing Ig was detected in the CSF of 79% of MS patients and 16% of other neurological disease patients. Further statistical analysis revealed an 84% specificity, an 86% positive predictive value, and a 76% negative predictive value of the test. The probability that a positive screening result indicated MS was 81%. Thus, antibodies containing a cross-reactive Id are present preferentially in the CSF of patients with MS compared with those with other neurological diseases. An immune network that has limited V region gene usage likely exists in the CSF and central nervous system of patients with MS and may provide evidence about antigens relevant to the pathogenesis of MS.

Adolescent↗
PubMed1999

Regulatory T cells in experimental allergic encephalomyelitis. II. T cells functionally antagonistic to encephalitogenic MBP-specific T cells show persistent expression of fasL.

Naive LEW rats and animals that have recovered from active or adoptive EAE contain a subset of T cells that inhibit EAE in secondary recipients and are lytic for MBP-reactive T cell lines in culture. Here we explore various features of these regulatory T cell populations (RTC) with respect to (1) their frequency in animals following immunization with syngeneic MBP-reactive cell lines, (2) their ability to inhibit proliferative responses by MBP-reactive cell lines in culture, (3) their ability to lyse MBP-specific target cells, and especially (4) their prolonged expression of high levels of FasL following activation in culture correlating with their lytic effects on A20, a FasL-sensitive mouse lymphoma cell line. Inhibition studies indicate that mAbs specific for MHC class I and MHC class II molecules inhibit lysis of syngeneic MBP-reactive target T cells, soluble Fas protein shows some inhibition, but none of these agents inhibits the lytic effects of activated RTC on the A20 cell line.

Animals↗
PubMed1999

Clinical and laboratory features of primary progressive and secondary progressive MS.

OBJECTIVE: To compare the clinical and laboratory features of primary progressive (PP) and secondary progressive (SP) MS, to evaluate the role of CSF and urine myelin basic protein-like material (MBPLM) in differentiating PP from SP MS, and to assess the utility of urine MBPLM as a surrogate marker of disease activity in progressive MS. BACKGROUND: The current categorization of subtypes of MS is based solely on clinical and temporal characteristics of the disease. Laboratory markers are needed that can differentiate reliably the subtypes of MS and serve as surrogate markers of disease progression. METHODS: Clinical and paraclinical data of 51 PPMS and 140 SPMS patients were reviewed retrospectively. CSF and urine MBPLM were measured using a double-antibody radioimmunoassay. RESULTS: PPMS was more likely to present with progressive myelopathy (p < or = 0.001) after the age of 40 years (p = < or = 0.001), and it affected men relatively more often than SPMS (male-to-female ratio, 1:1.7 versus 1:3.2 respectively). Ambulatory assistance was required by PP patients more often and earlier than in those with SPMS. The incidence of abnormal CSF, evoked potential, and cranial MRI studies was similar in the two groups. Spinal cord MRI abnormalities were noted significantly more often in SP disease. There was an insignificant trend of higher CSF MBPLM in SPMS compared with PPMS. Urine MBPLM and MBPLM/creatinine were significantly higher in SPMS than in PPMS. However, the values of urine MBPLM and MBPLM/creatinine at the initial visits of patients with PPMS and SPMS were not significantly different. Urine MBPLM/creatinine was significantly higher in both PPMS and SPMS compared with normal control subjects. No correlation was found between urine MBPLM and disease duration or between urine MBPLM and clinical disability. There was no correlation between urine MBPLM/creatinine and either disease duration or clinical disability. CONCLUSIONS: These findings provide additional evidence of the differences in PPMS and SPMS, notably in the associated changes in MBPLM in urine, and also suggest a possible role for urine MBPLM in identifying patient cohorts. The high urine MBPLM levels in progressive MS patients indicate a potential role of this marker for assessing responsiveness to therapeutic interventions.

Adult↗
PubMed1999

Alanine-substituted peptide ligands differ greatly in their ability to activate autoreactive T-cell subsets specific for the wild-type peptide.

Alanine-substituted peptide ligands (APLs) have the potential to reduce or block autoreactive T-cell activation. Most previous investigations aimed at either identification of the amino acid residue within a peptide ligand that is critical for T-cell activation or characterization of inhibitory APLs have analyzed the effects of APLs on one, or a limited number, of T-cell lines. In this study, we compared the effects of a panel of peptides on the proliferative and activation responses of one T-cell line as well as the effects of one peptide on the responses of a panel of T-cell lines. This study reveals that the T cells that comprise the T-cell population that responds to a specific peptide are heterogeneous in that an APL may fail to induce a response in some of these T cells although it is capable of inducing a response in the others. Moreover, APLs can induce T-cell activation, in terms of production of IL-2 and/or TNF-alpha, in the absence of appreciable cell proliferation. Indeed, despite being poor stimulators in proliferation assays, most APLs readily induce production of TNF-alpha. Our results demonstrate that the net outcome of APL treatment in vivo represents the sum of diverse effects, which may not be revealed completely by limited and randomly chosen in vitro assays.

Alanine↗
PubMed1999

Rapid release and unusual stability of immunodominant peptide 45-89 from citrullinated myelin basic protein.

Myelin basic protein (MBP) exists in a population of isoforms and isomers. The 18.5 kDa MBP-C1, the main human adult isoform, has 170 residues and is relatively unmodified, whereas the same isoform can be citrullinated on six arginine residues to create the MBP-C8 (MBP Cit6) isomer. MBP Cit6 dominates in MS brain, accounting for 45% rather than 25% of the population of MBP isomers. In the fulminant form of MS, known as Marburg's Disease, 18 of the 19 arginines in MBP are citrullinated (MBP Cit18). Citrullination of MBP could lead to instability of myelin or limited remyelination. In this investigation, the susceptibilities to degradation by cathepsin D of MBP Cit6 and MBP-C1, both from normal and MS brain tissue, and Marburg MBP Cit18 were compared. The pattern of digestion was similar, and no differences of corresponding isomers in normal and MS brain were noted. However, normal MBP Cit6 was degraded 10-fold more rapidly than MBP-C1, and MBP Cit18 was degraded even more rapidly. MBP peptide 45-89 was preserved regardless of isomer type or source. Its generation was directly related to the citrulline content of the MBP substrate being 4 times faster in normal MBP Cit6 and 35 times faster in Marburg MBP Cit18 than in normal MBP-C1. Peptide 45-89 from a citrullinated MBP exhibited more deamidation, and, regardless of source, showed an alpha-helix structure in a lipid mimetic environment. We postulate that the generation of MBP peptides, including those that are dominant and encephalitogenic, is directly related to deimination of arginine to citrulline in MBP.

Brain↗
PubMed1999

Urinary myelin basic protein-like material in patients with multiple sclerosis during interferon beta-1b treatment.

OBJECTIVES: To determine levels of urinary myelin basic protein-like material (MBPLM) in patients with multiple sclerosis (MS) openly treated with interferon beta-1b and to correlate these with clinical changes. BACKGROUND: Levels of urinary MBPLM correlate with the presence of the progressive phase of MS and with the disease burden detected on T2-weighted, cranial magnetic resonance imaging. Measurement of urinary MBPLM level may be a feasible test for monitoring or predicting response to therapeutic measures. DESIGN AND METHODS: In a prospective study at one site, 166 patients with MS (131 with relapsing-remitting [RR] and 35 with secondary progressive [SP] disease) were treated for a minimum of 1 year and up to 3 years with interferon beta-1b and underwent assessment for neurologic disability (Expanded Disability Status Scale and Scripps Neurological Rating Scale) and change in disease subtype. Urine samples were obtained at 1219 of 1378 clinic visits, and urinary MBPLM level was determined and related to creatinine level to adjust for renal function. RESULTS: Statistical analysis using the general linear models procedure confirmed previous findings that the level of urinary MBPLM related to urinary creatinine level (MBPLM/creatinine) was higher (P<.001) in patients with SP than RR MS. Of the 131 patients with RR MS, SP disease developed in 13 during the observation period. Compared with those in the RR group, the RR to SP group had a higher level (P<.001) of urinary MBPLM and did not differ from the SP group. CONCLUSIONS: The level of urinary MBPLM is higher in SP MS than RR MS but not in RR MS that converts to SP MS. Level of urinary MBPLM may permit the examination of treatment tested to prevent RR disease from becoming progressive.

Adjuvants, Immunologic↗
PubMed1999

Regulatory T cells in experimental allergic encephalomyelitis. III. Comparison of disease resistance in Lewis and Fischer 344 rats.

Rats of the Fischer 344 (F344) strain are resistant to experimental allergic encephalomyelitis (EAE) induced by active immunization with guinea pig myelin basic protein (MBP) in complete Freund's adjuvant whereas Lewis (LEW) rats are susceptible even though both strains share the same I-A-like class II alleles of the MHC RT1.B locus. To determine factors that might contribute to this difference in disease susceptibility, we have compared in these two strains (1) the frequency of MBP-reactive T cells in the lymph nodes and spleens of MBP-immunized animals, (2) the dominant MBP epitopes recognized by responding T cells, (3) the ability of MBP-reactive T cells to enter the central nervous system (CNS), and (4) the frequency of CD8+ regulatory T cells (RTC) whose activity is functionally antagonistic to MBP-reactive T cells. The results indicate that MBP-reactive T cell numbers are similar in MBP-immunized F344 and LEW rats, they both recognize p68-88 as the dominant encephalitogenic epitope of MBP, and MBP-reactive T cells isolated from immunized rats and adoptively transferred to naive animals are similarly effective in penetrating the blood-brain barrier and entering the CNS, leading to pathogenesis in EAE. However, the frequency of RTC that functionally inhibit MBP-reactive T cells is greater in F344 rats.

Animals↗
PubMed1999

Highly related immunoglobulin light chain sequences in different multiple sclerosis patients.

Although immunoglobulin G and free light (L) chains of oligoclonal origin in cerebrospinal fluid (CSF) are the most common immunologic abnormalities in multiple sclerosis (MS), it is unknown whether homologous CSF L chain sequences are present in different individuals with MS. Using Southern blotting, a particular kappa (kappa) L chain variable region (V) probe was recently found to hybridize to Vkappa cDNA from CSF B cells from almost one half of the MS patients tested but only 10% of normal or other neurologic disease controls [Zhou, S.-R., Maier, C.C., Mitchell, G.W., LaGanke, C.C., Blalock, J.E., Whitaker, J.N., 1998. A cross-reactive idiotope in cerebrospinal fluid cells in multiple sclerosis: further evidence for the role of myelin basic protein. Neurology 50, 411-417.] Here, we report that this likely results from remarkable sequence similarity in certain Vkappa from CSF B cells from different individuals with MS. The high degree of sequence homology even extended to all three complementarity determining regions (CDR) which in part form an antibody combining site. In addition, marked sequence homology was observed between the light chains from the MS patients and those from certain mouse antibodies against myelin basic protein (MBP). The results establish, in principle, that the same or very similar kappa light chain variable regions can be shared between CSF B lymphocytes from different individuals with MS as well as with certain antibodies against MBP.

Amino Acid Sequence↗
PubMed1999

Regulatory T cells in experimental allergic encephalomyelitis. I. Frequency and specificity analysis in normal and immune rats of a T cell subset that inhibits disease.

We have shown previously that administration of myelin basic protein (MBP)-reactive T cells to naive Lewis rats induces not only autoimmune encephalomyelitis (EAE) but also a near total resistance to subsequent disease. By isolating the effector cells that are responsible for the resistance, we demonstrated that disease protection paralleled with increased numbers of a CD8+ regulatory T cell (RTC) subset and that co-injection of this RTC subset with encephalitogenic T cells aborted the pathogenic activity of the latter cells. Here, we show that a radio-sensitive splenic population of RTC also exists in naive rats that can be recruited and activated to inhibit the onset of secondary episodes of adoptive EAE. In co-transfer experiments, this protective RTC subpopulation can be isolated to neutralize the pathogenic activity of stimulatory MBP-reactive T cells in vivo. We show that the frequency of RTC with specificity for MBP-reactive T cells in naive rats is two orders of magnitude higher than the frequency of MBP-specific precursors, the activity of RTC increases substantially with age and RTC frequencies increase as a consequence of immunization with MBP-reactive cells lines. In specificity studies, we show that RTC isolated from naive rats and RTC from animals primed with one MBP-reactive cell line show cross-reactive responses to a variety of different MBP-reactive T cell lines. However, following repeated stimulation with a given MBP line, these RTC display a more limited, clonotypic response to the selecting line and assume a uniform CD8 phenotype. Finally, functional studies with RTC indicate that proliferative and lytic specificities do not necessarily correlate and that activated rat RTC are especially lytic for a Fas-sensitive murine cell line.

Adoptive Transfer↗
PubMed1998

Reciprocal stimulation between TNF-alpha and nitric oxide may exacerbate CNS inflammation in experimental autoimmune encephalomyelitis.

Nitric oxide (NO) and TNF-alpha are both highly active pleotypic modulators of cell function that are abundantly generated during inflammation. Experiments in animal systems have linked the generation of NO and TNF-alpha to autoimmune pathogenesis, and blockade of either NO or TNF-alpha has been shown to impede disease development. In this study, we show that NO and TNF-alpha can act mutually to stimulate each other's production. While IFN-gamma alone induces NO release from microglia, astrocytes are provoked into significant NO production only by a combination of IFN-gamma and TNF-alpha. Since both TNF-alpha and NO are abundantly generated during T-glial cell interaction, we asked whether and how NO affects TNF-alpha production. Using an in vitro system in which TNF-alpha secretion is induced in MBP-reactive T cells by co-culture with syngeneic astrocytes, we observed that the efficiency of TNF-alpha secretion was markedly increased, in a dose-dependent fashion, by addition of micromolar concentrations of a chemical generator of NO donor, sodium nitroprusside (SNP). Similarly, low concentrations of SNP significantly enhanced the IL-2 dependent growth of MBP-reactive T cells. These results suggest that autoimmune pathogenesis initiated by inflammatory responses within the CNS may result in part from a vicious cycle in which TNF-alpha and NO mutually provoke each other's production.

Animals↗
PubMed1998

Citrullinated myelin basic protein induces experimental autoimmune encephalomyelitis in Lewis rats through a diverse T cell repertoire.

An increased proportion of citrullinated MBP (MBP-C8) occurs in the brains of multiple sclerosis (MS) patients. In this study, MBP-C8 from guinea pig (GP) brains was isolated and found encephalitogenic in Lewis rats upon immunization. An encephalitogenic T cell line selected with MBP-C8 preferentially reacted with MBP-C8 over unmodified MBP. This T cell line responded weakly to the dominant encephalitogenic epitope, GP-MBP peptide 70-88, and did not display restricted TCR beta-chain usage (such as Vbeta88.2). The distinctive features of MBP-C8 were also demonstrated by its ability to reinduce active EAE in 70% of rats which had recovered from unmodified MBP induced EAE. These findings raise the possibility that citrullinated MBP may elicit a different pathogenic T cell repertoire for the recurrent phases of inflammatory demyelination.

Animals↗
PubMed1998

Cell death mediated by Fas-FasL interaction between glial cells and MBP-reactive T cells.

Apoptosis in T cells that have penetrated into the central nervous system (CNS) may be important for the physiological control of T cells with potentially dangerous reactivities to CNS antigens; such control may be dysfunctional in animals suffering from experimental autoimmune encephalomyelitis (EAE). In this study we examined the expression of Fas and FasL genes both in myelin basic protein (MBP)-reactive T cells and in glial cells and the susceptibility of these cells to death induced by Fas/FasL interaction. Both Fas and FasL gene expression is detectable in glial cells and MBP-reactive T cells. Cell death is not unidirectional: when T cells interact with glial cells death can be induced in the former or in the latter population. The ability to induce death of Fas-expressing cells varies greatly among different lines of MBP-reactive T cells, as does resistance to death induction by cells expressing FasL. Moreover, the ability of T cells both to deliver and to resist death signals is a function of their activation status: T cells freshly activated transmit a stronger apoptotic signal to Fas-positive target cells and are also more resistant to FasL-induced suicide. Soluble form of FasL provides a convenient titratable means of delivering death signals via Fas. However, comparison of the susceptibility of different targets to soluble FasL and to FasL expressed on the surface of a transfected glial line revealed differences, suggesting that signals arising from Fas/FasL interaction may be modulated by additional cell-surface molecules.

Animals↗
PubMed1998

The role of regulatory T cells in Lewis rats resistant to EAE.

Adult Lewis (LEW) rats are highly susceptible to experimental autoimmune encephalomyelitis (EAE), induced actively by immunization with guinea pig (GP) myelin basic protein (MBP) in complete Freund's adjuvant or adoptively transferred with activated T lymphocytes reactive to GP MBP peptide 68-88. Once LEW rats recover from active EAE or when given MBP in incomplete Freund's adjuvant (IFA), they become resistant to further attempts to induce active or passive EAE. In this study, we examined whether such EAE-resistant rats after MBP-IFA immunization have reduced frequencies of MBP-reactive T cells, whether these T cells are anergized, and whether the activity of regulatory T cells is increased to the event that they prevent activation of MBP-specific T cell subpopulations. By limiting dilution analyses (LDA) of unfractionated splenic T cells, the levels of MBP-reactive T cells in EAE-resistant rats appeared to be approximately 5% of the levels in EAE-susceptible rats. However, a subsequent analysis of CD4+ enriched T cell populations, depleted of the CD8 subset, showed similar frequencies of MBP-reactive cells in susceptible and resistant LEW rats. Not only were the frequencies on LDA altered by suppressor cells, but also LDA comparisons based on cell proliferation and cytokine production as indicators of MBP reactive cell frequencies gave markedly different results. We conclude that MBP-reactive T cells in this model of EAE-resistant LEW rats are hyporeactive to MBP as the result of an increased activity of a regulatory subset of CD8+ T cells. These results also demonstrate that the quantitation of MBP-reactive CD4+ T cells by LDA is strongly influenced by the presence of functionally antagonistic CD8+ T cells, which cause an underestimation of responder T cell frequencies, and by the method of detecting T cell reactivity.

Animals↗
PubMed1998

Current immunotherapy in multiple sclerosis.

The underlying pathophysiology of multiple sclerosis is presumed to be autoimmune in nature. Attempts to find an effective treatment for this common disease of the central nervous system have primarily focused on immune-mediated therapies, both immunosuppressive and immunomodulatory. The wide variety of immunological abnormalities detected in multiple sclerosis and its animal model, experimental allergic encephalomyelitis, has prompted the testing of a diverse array of drugs to be used for treatment. Recent successes in the treatment of relapsing-remitting multiple sclerosis with interferon beta and glatiramer acetate have renewed interest in and raised expectations for the effective control of this neurological disorder. Improved methodology in clinical trials, the development of surrogate markers and the availability of novel therapies bode well for more rapid advances.

Animals↗