Intrathecal IgG Production Research Articles

Cerebrospinal BAFF and Epstein–Barr virus-specific oligoclonal bands in multiple sclerosis and other inflammatory demyelinating neurological diseases

We measured circulating serum and cerebrospinal fluid (CSF) concentrations of B lymphocyte activating factor of the tumour necrosis factor superfamily (BAFF), and determined total and Epstein–Barr virus (EBV)-specific oligoclonal IgG bands (OCBs) in 43 patients with multiple sclerosis (MS), 23 patients with other inflammatory demyelinating neurological diseases, and 20 patients with non-inflammatory neurological diseases. Serum and CSF BAFF concentrations did not differ in the three studied groups. In MS, the highest BAFF concentrations were found in the CSF samples with more than 6 OCBs (233.1 ± 129.5 vs 79.2 ± 51.6 pg/mL in the samples with less than 7 OCBs, p < 0.0001). Irrespectively from BAFF levels, EBV-specific OCBs were detected in MS and in the other non-inflammatory and inflammatory demyelinating neurological diseases, with a similar frequency, and as a ‘mirror pattern’ in 30 of 33 EBV-specific OCB-positive cases (p < 0.0001). These results indicate that circulating CSF BAFF concentrations cannot help differentiate MS from other inflammatory demyelinating neurological diseases, but positively associates with the qualitative expression of elevated intrathecal IgG production in MS, and that the oligoclonal EBV-specific antibody response, when present, is mostly systemic in all the studied neurological patients, and not preferentially restricted to MS.

679 Cerebrospinal Fluid Oligoclonal Bands and Igg in Children

Introduction: Cerebrospinal fluid examination may be an essential aid in the diagnostic process of many neurological diseases in children as well as in adult patients The detection of oligoclonal bands and the assessment of IgG index contribute to information about the intrathecal production of oligoclonal IgG that may possibly occur in many neurological diseases This includes mainly demyelinating and inflammatory diseases, but elevated IgG index and/or positive oligoclonal bands can be detected also in other conditions, such as neoplastic disorders or neurometabolic diseases/ progressive encephalopaties (PE) Intrathecal immunoglobulin synthesis can be measured either quantitatively, using the IgG index, or /and qualitatively by oligoclonal bands detection. Material and methods: Cerebrospinal fluid and serum samples from 287 patients hospitalized in Child Neurology Department Medical University of Silesia in Katowice in the years 2000-2009 were analyzed The established diagnoses in examined group of patients included: demyelinating diseases (including MS, ADEM), neuroinfections (also neuroboreliosis), Guilliain -Barre syndrome (GBS), progressive encephalopathies, epilepsy, tumours of the central nervous system Agarose gel electrophoresis was used for detection of CSF oligoclonal bands. Results: Oligoclonal bands were detected in 108 In 50 patients with PE, in 39 children with neuroinfections, Guilliain-Barre syndrome -13, tumours-2 patients. Conclusions: Oligoclonal bands are important additional marker in different neurological disorders and can be used to confirm primary diagnosis.

Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis

To investigate chitotriosidase (CTTS) activity in serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients in relation to disease course and CSF markers for immune activation or inflammation. We studied 80 patients with relapsing-remitting MS (RRMS), 24 with secondary progressive MS (SPMS), 20 with primary progressive MS (PPMS) and 29 patients with other neurological disorders (OND). We measured CTTS activity and studied the correlation with CSF mononuclear cell count (MNC) and intrathecal IgG production. CTTS activity was significantly higher in CSF, but not in serum, from the total MS group compared with OND and controls. In RRMS and SPMS CTTS, index was increased compared with controls (RRMS, 0.10 +/- 0.21; SPMS, 0.10 +/- 0.15; controls, 0.021 +/- 0.020), but not in PPMS (0.061 +/- 0.052). CTTS index was higher in MS patients with elevated MNC or CSF-restricted oligoclonal IgG bands than in MS patients without these CSF findings. CTTS index is elevated in RRMS and SPMS. The CTTS index is related to CSF markers of inflammation or immune activation.

Features of intrathecal immunoglobulins in patients with multiple sclerosis

We have analyzed immunoglobulin (Ig) isotypes and IgG subclasses in cerebrospinal fluid (CSF) and serum of patients with multiple sclerosis (MS) and other neurological diseases to determine whether different Ig isotype patterns correlate with clinical or paraclinical findings and CSF B cell populations. Intrathecal IgG1 synthesis was elevated in MS patients. An increased intrathecal IgM production was found in patients with a higher cerebral MRI lesion burden, whereas other clinical and paraclinical parameters were not associated with a specific Ig isotype or subclass profile. Finally, intrathecal IgG production (IgG1 and IgG3) correlated with the presence of mature B cells and plasma blasts.

Soluble Class 1 antigens (sHLA) in CSF and serum of patients with HIV infection

sHLA are secreted by B and T lymphocytes upon activation. These antigens are present in serum and cerebrospinal fluid (CSF). The establishment of a sHLA index, IH = (CSF sHLA/serum sHLA)/(CSF albumin/serum albumin) helped us to define that values above 9.7 reflect an intrathecal synthesis of these proteins. IH was significantly increased in a group of patients with intrathecal production of IgG against HIV-1 (HIV) and directly correlated with the synthesis of such antibodies. Therefore, IH seems to be an index of lymphocyte activation in CNS.

CSF follow-up in HIV-1 infection: intrathecal production of HIV-specific and unspecific IGG, and beta-2-microglobulin increase with duration of HIV-1 infection.

Ninety-nine sequential cerebrospinal fluid (CSF) samples from 28 human immunodeficiency virus-1 (HIV-1)-infected patients were analyzed during the follow-up of 9 months to 4 years. Intrathecal synthesis of HIV-antibodies and IgG (p < 0.01), and the levels of beta-2-microglobulin (beta 2m) in the CSF (p < 0.05) and serum (p < 0.01) increased with duration of HIV-1 infection. No effect of duration of HIV-1 infection was observed on the individual CSF white cell counts and the levels of blood-brain-barrier (BBB) permeability. In 13 patients with HIV-1-associated central nervous system (CNS) disease, the effect of duration was seen as an increase of the individual beta 2m levels in serum (p < 0.01). Moreover, 7 of 9 patients who developed neurological disease or showed its progression during the study increased the level of beta 2m in the CSF. All of them increased the level of beta 2m in serum. In 15 neurologically healthy subjects, the effect of duration was expressed as an increase of the level of individual beta 2m in CSF (p < 0.05) and intrathecal IgG synthesis (p < 0.01). In the AIDS group, the level of beta 2m in the CSF increased, but in less severe stages the dependency of the individual CSF parameters on disease duration was not found. Our results indicate that elevated levels of beta 2m in CSF and serum appear to predict progression of neurological and systemic diseases, respectively. Elevated beta 2m in the CSF of clinically intact individuals may indicate subclinical neurological disease caused by HIV-1.(ABSTRACT TRUNCATED AT 250 WORDS)

CSF immune variables in patients with narcolepsy

Cerebrospinal fluid (CSF) and serum from 15 patients with narcolepsy were examined regarding presence of oligoclonal bands on isoelectric focusing, IgG index elevation as indicator of intrathecal IgG production and CSF/serum albumin ratios. Two of 15 patients (13%) showed oligoclonal IgG bands in CSF, one of whom had increased IgG index. Slight disturbance of blood-brain-barrier function as reflected by elevated CSF/serum albumin ratios was present in 4 other patients. The frequency of oligoclonal IgG bands in CSF from patients with narcolepsy is within the range of what is found in other neurological, non-inflammatory diseases. These findings do not support the hypothesis of an immune-mediated pathogenesis of narcolepsy.

Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65 in patients with stiff person syndrome

Most patients with stiff person syndrome (SPS) display intrathecal synthesis of oligoclonal and high-avidity IgG against the 65 kDa isoform of glutamic acid decarboxylase (GAD65 IgG), but little is known about the mechanisms driving this immune response. We hypothesized that GAD65-specific T cells accumulating in the central nervous system drive the intrathecal GAD65 IgG production. Accordingly, we were able to clone HLA-DR or DP restricted GAD65-specific T cells from the cerebrospinal fluid (CSF) of all three patients with, but not in one patient without substantial intrathecal production of GAD65 IgG. The CSF T cells recognized four GAD65 epitopes, which were unique to each patient. In two patients, identical or closely related GAD65-specific CSF T cell clones were expanded in vivo. In contrast to the findings in CSF, only one GAD65-specific T cell clone could be raised from the blood of one single patient. Cysteine in amino acid position 474, which is important for enzymatic function of GAD65, was critical for recognition of GAD65 474–484 by HLA-DP restricted CSF T cells. We conclude that GAD65-specific T cells and clonally expanded GAD65-specific B cells coexist intrathecally, where they may collaborate in the synthesis of GAD65 IgG.

GAD65 IgG autoantibodies in stiff person syndrome: clonality, avidity and persistence

Persistent intrathecal production of IgG autoantibodies against glutamic acid decarboxylase 65 (GAD65 IgG) and oligoclonal IgG of undetermined specificity has been reported in stiff person syndrome (SPS). To chart the avidity and clonal patterns of GAD65 IgG, we performed scatchard plot of binding characteristics and isoelectric focusing-immunoblot of cerebrospinal fluid (CSF) and serum from five SPS patients. Oligoclonal GAD65 IgG bands, predominantly restricted to the IgG1 subclass, were detected in CSF and serum in all patients. The distribution of GAD65-specific IgG bands in serum and CSF revealed intrathecal synthesis of oligoclonal GAD65 IgG in all five patients, whilst radioimmunoassay demonstrated intrathecal synthesis of GAD65 IgG in four. The binding avidity of GAD65 IgG from CSF was more than 10 times higher than in serum in two of the patients but did not differ substantially in the remaining three. These differences were not related to symptom severity. The pattern of oligoclonal GAD65 IgG bands in CSF and serum in three patients examined remained unchanged for up to 7 years after symptom debut. This study confirms the persistent systemic and intrathecal production of GAD65-specific IgG in SPS, and further shows that this immune response is oligoclonal and mediated by a stable population of affinity maturated B cell clones.

CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions

CCL19 and CCL21 bind to CCR7, which is crucial for both inducing an immune response and establishing immunological tolerance. We report that in the normal human brain CCL19, but not CCL21, is transcribed, and detectable as a protein in tissue lysates and in cerebrospinal fluid. In both active and inactive multiple sclerosis (MS) lesions CCL19 transcripts were elevated. In cerebrospinal fluid from MS and OIND patients CCL19 protein was increased. In relapsing–remitting and secondary progressive MS patients CCL19 correlated with intrathecal IgG production. This study suggests that CCL19 plays a role in both the physiological immunosurveillance of the healthy CNS and the pathological maintenance of immune cells in the CNS of MS patients.

Assessment of the IgG index in dogs by indirect immunoenzimatic assays as diagnostic tool for inflammatory diseases of central nervous system

The IgG index measures the intrathecal immunoglobulin production and it is a useful tool for diagnosis of inflammatory diseases involving the central nervous system. This index is based on the precise quantification of albumin and IgG in canine cerebrospinal fluid and serum. Here, we report the development of an indirect competitive ELISAs for the detection of both antigens. Thirty-two dogs were included in this study, divided into three experimental groups. Group A was composed of 22 healthy animals, as determined by standard clinical examination. In group B, six animals, presented neurological pathologies associated with endogenous IgG production and, in group C four animals presented neurological diseases or symptoms not associated with intrathecal IgG production. Cerebrospinal fluid and serum samples were obtained from these animals. As expected, by using the indirect ELISAs proposed here, the IgG indexes obtained in healthy animals (A) were 0.371 ± 0.252 (SD). In B and C, the values (3.002 ± 1.897; 0.36 ± 0.306, respectively), were in agreement with the pathologic conditions of the individuals in each group. Thus, the immunometric competition ELISA methods proposed here allow the discrimination of abnormal intrathecal IgG production, in a variety of inflammatory pathologic conditions of the central nervous system.

The Immunological Basis for Treatment of Multiple Sclerosis

During the last few years, the concept of multiple sclerosis (MS) as a pure inflammatory disease mediated by myelin reactive T cells has been challenged. Neither the specificity nor the mechanisms triggering or perpetuating the immune response are understood. Genetic studies have so far not identified therapeutic targets outside the HLA complex, but epidemiological and immunological studies have suggested putative pathogenetic factors which may be important in therapy or prevention, including the Epstein-Barr virus and vitamin D. Advances in the treatment of MS have been reached by manipulating the immune response where the pathogenesis of MS intersects experimental autoimmune encephalomyelitis, most recently by blocking T-cell migration through the blood-brain barrier. Antigen-specific approaches are effective in experimental models driven by a focused immune response against defined autoantigens, but MS may not fit into this concept. Novel candidate autoantigens which are not constitutively expressed in the brain, such as protein alpha-B crystallin or IgG V-region idiotopes, as well as evidence of pathogenetic heterogeneity and complexity, suggest that treating MS by tolerizing the immune system against an universal MS antigen may be a fata morgana. Further characterization of MS subtypes may lead to individualized treatment. However, shared immunological features, such as intrathecal production of oligoclonal IgG, suggest that potential therapeutic targets may be shared by most MS patients.

T Cells from Multiple Sclerosis Patients Recognize Multiple Epitopes on Self‐IgG

The highly diversified variable regions of immunoglobulin (Ig) molecules contain immunogenic determinants denoted idiotopes. We have previously reported that T cells from multiple sclerosis (MS) patients recognize IgG from autologous cerebrospinal fluid (CSF), and mapped a T-cell epitope to an IgG idiotope. To test the ability of CSF IgG molecules to elicit a broad polyclonal T-cell response in MS, we have analysed T-cell responses in the blood and CSF against idiotope peptides spanning complementarity determining region (CDR) 3 and somatic mutations within the variable regions of monoclonal CSF IgG. Consistent with a diversified idiotope-specific T-cell repertoire, CD4(+) T cells from both patients recognized several idiotope peptides presented by HLA-DR molecules. Mutations were critical for T-cell recognition, as T cells specific for a mutated CDR1 peptide did not recognize corresponding germline-encoded peptides. One T-cell clone recognized both an idiotope peptide and the B-cell clone expressing this idiotope, compatible with endogenous processing and presentation of this idiotope by B cells. These results suggest that mutated CSF IgG from MS patients carry several T-cell epitopes, which could mediate intrathecal IgG production and inflammation in MS through idiotope-driven T-B-cell collaboration.

Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF

We investigated the correlation of antimyelin oligodendrocyte glycoprotein-(anti-MOG) and anti-myelin basic protein antibodies (anti-MBP) in serum of CIS patients with inflammatory signs in MRI and in CSF and, as previously suggested,the incidence of more frequent and rapid progression to clinically definite MS (CDMS). 133CIS patients were analysed for anti-MOG and anti-MBP (Western blot). Routine CSF and cranial MRI (quantitatively and qualitatively) measures were analyzed. 55 patients had a follow-up of at least 12 months or until conversion to CDMS. Patients with anti-MOG and anti-MBP had an increased intrathecal IgG production and CSF white blood cell count(p = 0.048 and p = 0.036). When anti-MBP alone, or both antibodies were present the cranial MRI showed significantly more T2 lesions (p = 0.007 and p = 0.01,respectively). There was a trend for more lesion dissemination in anti-MBP positive patients (p = 0.076).Conversely, anti-MOG- and/or anti-MBP failed to predict conversion to CDMS in our follow-up group (n = 55). Only in female patients with at least one MRI lesion (n = 34) did the presence of anti-MOG correlate with more frequent (p = 0.028) and more rapid (p = 0.0209) transition to CDMS. Presence of anti-MOG or anti-MBP or both was not significantly associated with conversion to CDMS in our CIS cohort. However, patients with anti-MOG and anti-MBP had higher lesion load and more disseminated lesions in cranial MRI as well as higher values for CSF leucocytes and intrathecal IgG production. Our data support a correlation of anti-MOG and anti-MBP to inflammatory signs in MRI and CSF. The prognostic value of these antibodies for CDMS, however, seems to be less pronounced than previously reported.

Isoelectric focusing is superior to immunofixation electrophoresis in diagnosing CNS inflammation

A sensitive method to detect intrathecal IgG production is important in diagnosing inflammatory central nervous system (CNS) diseases, including multiple sclerosis (MS). To compare cerebrospinal fluid (CSF) electrophoresis with isoelectric focusing (IEF), immunofixation-peroxidase electrophoresis (IFPE) and high-resolution agarose electrophoresis with protein-staining (HRAGE). Paired serum and CSF samples from 307 consecutive patients attending a general neurology clinic were examined with IEF, IFPE and HRAGE. Clinical diagnosis was based on review of the patients' medical records after an average of 4 years. The sensitivity for detecting any inflammatory (autoimmune or infectious) CNS disease (52 patients) was 67% for IEF, 50% for IFPE and 29% for HRAGE. The sensitivity for detecting MS (14 patients) was 93%, 86% and 29% respectively. The sensitivity for detecting clinically isolated syndrome (eight patients) was 75%, 25% and 13% respectively. The number of oligoclonal bands in IEF was higher in inflammatory than in non-inflammatory neurological diseases or symptoms, but similar in MS and other inflammatory diseases. IEF is the method of choice in diagnosing intrathecal IgG synthesis.

IL-6 and CCL2 levels in CSF are associated with the clinical course of MS: Implications for their possible immunopathogenic roles

Biological markers would provide valuable tools for tracking disease activity, immunopathological processes or therapeutic efficacy in MS. In this study we analysed a panel of Th 1/Th 2 cytokines and the chemokine CCL2 in serum and CSF from MS patients and healthy controls. Increased levels of IL-6 ( p < 0.05) and decreased levels of CCL2 ( p < 0.001), with the lowest levels during acute relapses, was found in CSF from patients with relapsing–remitting MS. CSF levels of CCL2 correlated with indices for intrathecal IgG production and the CSF level of the neurofilament light protein, a marker for axonal damage, indicating a immunopathogenic role for CCL2.

HIV?induced chorea

Sirs: Neurological disorders cooccur with the acquired immunodeficiency syndrome (AIDS) in approximately 30–50 % of AIDS patients [1], e. g. HIV-1-associated dementia (HAD) [2]. Movement disorders, mostly due to Toxoplasmosis abscesses but also with other rare causes, appear in 2–3 % of these patients [2, 3]. We describe a 32-year-old HIV-infected patient with chorea, which in all probability was caused by HAD. The generalized, but asymmetric (left > right) involuntary movements of the trunk and the extremities in our patient had progressed over the preceding 6 months. The CD4 cell count was 310 cells/μl and the patient received highly active antiretroviral treatment and also pyrimethamine as a secondary prophylaxis for cerebral toxoplasmosis, which had occurred 3 years before. At that time minor cognitive deficits had suggested mild HAD, but all symptoms had improved during closely monitored treatment. The current brain MRI showed marked frontal atrophy with white matter hyperintensities in the T2and proton-density (PD) weighted images (see Fig. 1 A and B). Compared with an MRI examination 2 years previously, these findings had worsened. However, the structure and signaling of the basal ganglia were not pathological. The SPECT binding study with 187 MBq 123Iodine-IBZM (binding to postsynaptic dopamine-D2 receptor) revealed a significant reduction on the right and a slight reduction on the left in the striatum (Fig. 1 C). The SPECT binding study with 188 MBq 123Iodine-DaTSCAN (binding on presynaptic dopamine transporter) showed a bilateral (right > left) reduction that was pronounced in the posterior striatum (Fig. 1 D). The PET examination with 132 MBq 18F-FDG (FDG PET) indicated that glucose utilization had significantly decreased in the right temporal, frontomesial, parietal, and central cortex as well as bilaterally in the hippocampus (right > left). The striati showed no abnormalities, but the FDG uptake in the left thalamus was slightly reduced (Fig. 1 E). CSF analysis revealed only a mildly increased CSF WBC count (7 cells/μl) and increased intrathecal IgG production. PCRs for varicella zoster virus, JC virus, and cytomegalovirus were negative. Huntington’s chorea was excluded by genetic examination. The chorea in our patient was associated with an asymmetric (right > left) dysfunction of the dopaminergic system, which is compatible with the asymmetric clinical presentation and comparable to patients with Huntington’s disease [4]. MRI and FDG PET examination, however, revealed no clear pathologies in the region of the basal ganglia. The SPECT findings suggest an asymmetric encephalopathic involvement of the basal ganglia, most probably the anatomo-clinical correlate of chorea in our patient. Interestingly, HAD worsened clinically with the appearance of chorea, but the patient’s mental status did not obviously deteriorate. FDG PET showed reduced glucose metabolism bilaterally in the hippocampus, frontomesially, parietally, and centrally, and MRI revealed an increase of white matter hyperintensities that conformed with slowly progressive HAD. HAD [5, 6] typically presents with subcortical dementia combined with slight motor disturbances, but a significant involvement of the basal ganglia during HAD has also been documented in immunohistochemical [7–9], neuroradiological [10, 11], MRI spectroscopic [12], and CSF studies [9, 13]. Ours is the first report of a dedicated SPECT study of the nigrostriatal dopaminergic system. Although a rare clinical manifestation of HAD, HIV-associated chorea should be considered in young patients who present with chorea but lack a family history of movement disorders. Dedicated SPECT studies of the nigrostriatal dopaminergic system may help establish the diagnosis of HAD-associated chorea and also provide a more detailed documentation of basal ganglia involvement. The reported SPECT abnormalities are, however, not specific for HAD-associated chorea.

Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.

Chronic intrathecal immunoglobulin (Ig) production is a hallmark of multiple sclerosis characterized by the presence of oligoclonal IgGs and, in addition, polyspecific recognition of different pathogens such as measles, rubella and herpes zoster virus. While the antigen specificity of the oligoclonal IgGs in multiple sclerosis is largely unknown, the oligoclonal IgGs arising during CNS infectious diseases are reactive against the specific pathogen. Recently, a link between Chlamydia pneumoniae and multiple sclerosis has been claimed. To test the possible role of C. pneumoniae in multiple sclerosis, we analysed (i) whether there is intrathecal IgG production against C. pneumoniae in multiple sclerosis and (ii) if the oligoclonal IgGs in the CSF of multiple sclerosis patients recognize C. pneumoniae. By studying paired serum-CSF samples from 120 subjects (definite multiple sclerosis, 46; probable multiple sclerosis, 12; other inflammatory neurological diseases, 35; other neurological diseases, 27) by enzyme-linked immunosorbent assay, we found that 24% of all patients with definite multiple sclerosis, but only 5% of patients with other inflammatory or non-inflammatory diseases, produced IgGs specific for C. pneumoniae intrathecally (definite multiple sclerosis versus other inflammatory neurological diseases: P = 0.027). The presence of intrathecal IgGs to C. pneumoniae was independent of the duration of disease and relatively stable over time. The major CSF oligoclonal IgG bands from multiple sclerosis patients with an intrathecal Ig production to C. pneumoniae did not react towards purified elementary bodies and reticulate bodies of C. pneumoniae on affinity-mediated immunoblot following isoelectric focusing (IEF-western blots). In contrast, the IgGs in the CSF of control patients with neuroborreliosis strongly reacted with their specific pathogen, Borrelia burgdorferi, by IEF-western blot analysis. Concomitant analysis of the CSF of 23 patients with a nested polymerase chain reaction for C. pneumoniae was negative in all cases. Together, our findings strongly suggest that the immune response to C. pneumoniae is part of a polyspecific intrathecal Ig production, as is commonly observed with other pathogens. This argues against a specific role for C. pneumoniae in multiple sclerosis.

Oligoclonal T cell repertoire in cerebrospinal fluid of patients with inflammatory diseases of the nervous system

OBJECTIVETo evaluate the T cell receptor β chain variable region (TCRBV) gene usage ex vivo in CSF cells and peripheral blood mononuclear cells (PBMCs) collected from patients with autoimmune and...

Blood–brain barrier function in cerebral malaria and CNS infections in Vietnam

The intraerythrocytic parasite Plasmodium falciparum induces the life-threatening neurologic syndrome of cerebral malaria (CM) from within cerebral blood vessels, without entering the brain parenchyma. 1) To assess the use of CSF as an indicator of specific pathologic processes occurring in the brain during CM; 2) to compare this with other neurologic and infectious diseases to understand the distinct pathogenic features of CM; 3) to test the hypothesis that CM involves a specific functional breakdown of the blood-brain barrier (BBB). 1) Radial immunodiffusion assays to detect albumin and IgG in matched plasma and CSF samples as indicators of BBB integrity and intrathecal IgG production; and 2) ELISA for soluble intracellular adhesion molecule-1 and sE-selectin, the cytokines tumor necrosis factor-alpha and transforming growth factor-beta1, and the matrix metalloproteinase MMP-9, to detect cellular activation and inflammatory responses within the brain. Albumin and IgG indices implied only minimal degree of BBB breakdown in a few cases of CM, with most remaining within the normal range. In contrast, cryptococcal, tubercular, and acute bacterial meningitis produced detectable changes in the composition of the CSF and evidence of BBB breakdown. CM appears to involve only subtle functional changes in BBB integrity with minimal intraparenchymal inflammatory responses compared with other neurologic infections. This focuses attention on local events within and around the cerebral microvasculature in CM, rather than indicating widespread parenchymal disease.