Mohammad K. Sharief

Association between Tumor Necrosis Factor-α and Disease Progression in Patients with Multiple Sclerosis

BACKGROUND Cachectin, or tumor necrosis factor-alpha (TNF-alpha), is a principal mediator of the inflammatory response and may be important in the pathogenesis and progression of multiple sclerosis, an inflammatory disease of the central nervous system. METHODS In a 24-month prospective study, we used a sensitive enzyme-linked immunosorbent assay to determine levels of TNF-alpha in cerebrospinal fluid and serum in 32 patients with chronic progressive multiple sclerosis and in 20 with stable multiple sclerosis and 85 with other neurologic diseases. An attempt was made to relate TNF-alpha levels with the degree of disability of the patients with multiple sclerosis and with their neurologic deterioration during the 24 months of observation. RESULTS High levels of TNF-alpha were found in the cerebrospinal fluid of 53 percent of the patients with chronic progressive multiple sclerosis and in none of those with stable multiple sclerosis (P less than 0.001). TNF-alpha was detected in the cerebrospinal fluid of 7 percent of the controls (P less than 0.01) with other neurologic disease. In patients with chronic progressive multiple sclerosis, mean TNF-alpha levels were significantly higher in the cerebrospinal fluid than in corresponding serum samples (52.41 vs. 11.88 U per milliliter; range, 2 to 178 vs. 2 to 39; P less than 0.001). In these patients, cerebrospinal fluid levels of TNF-alpha correlated with the degree of disability (r = 0.834, P less than 0.001) and the rate of neurologic deterioration (r = 0.741, P less than 0.001) before the start of the study. Cerebrospinal fluid levels also correlated with the increase in neurologic disability after 24 months of observation (r = 0.873, P less than 0.001). CONCLUSIONS These data provide evidence of intrathecal synthesis of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease. Our results suggest that TNF-alpha may reflect histologic disease activity in multiple sclerosis and could be used to monitor outcomes or responses to therapy.

IV immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barré syndrome

Background: Treatment with human IV immunoglobulin (IVIg) modifies the course of Guillain-Barré syndrome (GBS), but its specific mode of action is unknown. Cellular interactions mediated through the release of cytokines play a role in the pathogenesis of GBS and may be regulated by IVIg therapy. Objective: To delineate possible immunoregulatory mechanisms of IVIg in patients with GBS. Methods: Circulating levels of the proinflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, were assayed in 21 patients with GBS before and serially after IVIg therapy. Comparisons were made with serum concentration of the anti-inflammatory cytokines, soluble TNF-α receptor and IL-10. Serial measurements were also performed in 12 untreated patients with relatively mild disease and 7 patients treated by plasma exchange. Results: Circulating levels of TNF-α and IL-1β decreased after treatment with IVIg but remained relatively high in untreated patients and in those treated by plasma exchange. Clinical improvement in patients treated with IVIg was associated with a reduction in unbound TNF-α during the acute phase of the illness. Circulating levels of anti-inflammatory cytokines were not affected by IVIg treatment. Conclusion: Data presented here suggest a novel mechanism of action of IVIg that involves selective modulation of circulating proinflammatory cytokines.

Elevated serum levels of tumor necrosis factor-α in Guillain-Barré syndrome

Activated T lymphocytes and macrophages play a putative role in the pathogenesis of Guillian-Barre syndrome. Both cell types secrete tumor necrosis factor-α, a cytokine that has well-recognized toxi effects on myelin, Schwann cells, and endothelial cells. We determined serum and cerebrospinal fluid concentrations of tumor necrosis factor α in 26 patients with Guillain-Barre syndrome, 27 patients with other polyneuropathies, 30 patients with neurological diseases of the central nervous system, and 14 helthy control subjects. Markedly increased serum levels were detected in 14 patients(54%) with Guillian-Barre syndrome and to a significantly lesser extent, in patients with other polyneuropathies (26%) and in neurological control subjects(23%). Tumor necrosis factor-α was not detected in the cerebrospinal fluid of patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome correlated directly with disease severity and these concentrations returned to normal in parallel with clinical recovery. These findings emphasize the complexity of the immune response in patients with Guillain-Barre syndrome and suggest that tumor necrosis factor-αL may be important in the pathogenesis of peripheral demylination in this disorder.

Intrathecal immune response in patients with the post-polio syndrome.

Background. The syndrome of progressive muscular atrophy decades after acute paralytic poliomyelitis (post-polio syndrome) is not well understood. The theory that physiologic changes and aging cause the new weakness does not explain the immunologic abnormalities reported in some patients. An alternative explanation is persistent or recurrent poliovirus infection. Methods. We assessed the intrathecal antibody response to poliovirus and intrathecal production of interleukin-2 and soluble interleukin-2 receptors in 36 patients with the post-polio syndrome and 67 controls (including 13 who had had poliomyelitis but had no new symptoms and 18 with amyotrophic lateral sclerosis). Intrathecal antibody responses to measles, mumps, herpes simplex, and varicella-zoster viruses were also determined. Results. Oligoclonal IgM bands specific to poliovirus were detected in the cerebrospinal fluid of 21 of the 36 patients with the post-polio syndrome (58 percent) but in none of the control group (P < 0.0001). In quantitative studies there was evidence of increased intrathecal synthesis of IgM antibodies to poliovirus only among the patients with the post-polio syndrome; there was no increased synthesis of IgM to measles, mumps, herpes simplex, or varicella-zoster viruses. The patients with post-polio syndrome had significantly higher mean (+/- SD) cerebrospinal fluid levels of interleukin-2 and soluble interleukin-2 receptors than the controls (8.1 +/- 5.3 vs. 1.4 +/- 0.8 U per milliliter and 159.6 +/- 102.9 vs. 10.7 +/- 6.2 U per milliliter, respectively). The intrathecal synthesis of IgM antibodies to poliovirus correlated with the cerebrospinal fluid concentrations of interleukin-2 (P < 0.0005) and soluble interleukin-2 receptors (P < 0.001). Conclusions. An intrathecal immune response against poliovirus is present in many patients with the post-polio syndrome. In some of these patients the recrudescence of muscle weakness may be caused by persistent or recurrent infection of neural cells with the poliovirus.

Infection-associated encephalopathies: their investigation, diagnosis, and treatment.

Reduced level of consciousness is a common clinical finding in acutely sick patients. In the majority of cases a cause for the encephalopathy is readily identifiable,whilst in a minority the aetiology is more difficult to ascertain.Frequently the onset of encephalopathy is associated with, or follows, infection. The mechanisms through which infection leads to encephalopathy are diverse. They range from direct microbial invasion of the brain or its supporting structures, to remote, infectiontriggered mechanisms such as acute disseminated encephalomyelitis. Most common however, is the encephalopathy caused through a remote effect of systemic sepsis—septic encephalopathy.This article discusses the clinical presentation and underlying pathogeneses of the acute encephalopathies associated with infection, aiming to aid both their recognition and treatment.

Elevated serum levels of tumor necrosis factor-alpha in Guillain-Barré syndrome.

Activated T lymphocytes and macrophages play a putative role in the pathogenesis of Guillian-Barre syndrome. Both cell types secrete tumor necrosis factor-α, a cytokine that has well-recognized toxi effects on myelin, Schwann cells, and endothelial cells. We determined serum and cerebrospinal fluid concentrations of tumor necrosis factor α in 26 patients with Guillain-Barre syndrome, 27 patients with other polyneuropathies, 30 patients with neurological diseases of the central nervous system, and 14 helthy control subjects. Markedly increased serum levels were detected in 14 patients(54%) with Guillian-Barre syndrome and to a significantly lesser extent, in patients with other polyneuropathies (26%) and in neurological control subjects(23%). Tumor necrosis factor-α was not detected in the cerebrospinal fluid of patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome correlated directly with disease severity and these concentrations returned to normal in parallel with clinical recovery. These findings emphasize the complexity of the immune response in patients with Guillain-Barre syndrome and suggest that tumor necrosis factor-αL may be important in the pathogenesis of peripheral demylination in this disorder.

Increased cellular expression of the caspase inhibitor FLIP in intrathecal lymphocytes from patients with multiple sclerosis

Failure of Fas-mediated apoptosis of potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis. The intracellular protein FLIP, a naturally occurring caspase-antagonist, is a potent inhibitor of the Fas signalling pathway that may block Fas-mediated apoptosis of activated lymphocytes. This study reports specific overexpression of both long and short forms of FLIP in intrathecal lymphocytes from patients with multiple sclerosis. The overexpression of FLIP is independent of cellular expressions of Fas receptor or the anti-apoptotic protein Bcl-2. These results provide a better understanding of some of the intrinsic immunoregulatory mechanisms that are involved in multiple sclerosis.

Intrathecal synthesis of IgM in neurological diseases: A comparison between detection of oligoclonal bands and quantitative estimation

Immunoglobulin (Ig) M concentration in cerebrospinal fluid (CSF) was measured in 30 reference subjects to determine reference ranges which were up to 0.41 mg/l for CSF IgM, 0.06 for IgM index, and 9 x 10(-4) mg/l for the Reiber empirical formula. Intrathecal IgM synthesis was then studied in 159 patients with different neurological diseases both by detecting CSF oligoclonal IgM bands and by determining the IgM index and Reibers intrathecal IgM production values. At the same time, the state of blood-CSF barrier was evaluated in all patients by CSF polyacrylamide gel electrophoresis and by CSF/serum albumin ratio. Oligoclonal IgM bands were present mainly in patients with intrathecal humoral immune response, e.g. multiple sclerosis, other inflammatory nervous diseases, and infections of the central nervous system. Quantitative IgM ratios were, however, elevated in conditions not associated with local humoral immune response. Furthermore, quantitative ratios were elevated in patients with damaged blood-CSF barriers. Oligoclonal IgM bands are thus considered to be the most useful tool in detecting intrathecal synthesis of IgM.

Significance of CSF immunoglobulins in monitoring neurologic disease activity in Behçet's disease

We examined the intrathecal production of immunoglobulins (Ig) G, A, and M in 16 patients with Behçets disease, 13 of whom have CNS involvement, and in 40 neurologic controls. Oligoclonal IgA and IgM bands were mainly detected in CSF samples from patients with active neuro-Behçets disease and were documented to disappear when neurologic manifestations remit. Oligoclonal IgG bands, however, were not related to disease activity and were also found in some neurologic controls. High immunoglobulin index values were detected in both active and quiescent diseases and were high in some patients with impaired blood-CSF barriers. The study presented here demonstrates that CSF oligoclonal IgA and IgM may be helpful in monitoring CNS disease activity in neuro-Behçets and could be useful in understanding the pathogenesis of this disease.

The relationship of interleukin-2 and soluble interleukin-2 receptors to intrathecal immunoglobulin synthesis in patients with multiple sclerosis

The in vivo relationship of interleukin-2 (IL-2) to the local humoral immune response within the central nervous system (CNS) in patients with multiple sclerosis (MS) is hitherto largely unknown. Intrathecal levels of IL-2 and soluble IL-2 receptors (sIL-2R) were correlated to the local CNS synthesis of immunoglobulin G, A, D, and M isotypes in 70 patients with clinically definite MS. Levels were also determined in 19 normal control subjects to establish normal reference limits. High cerebrospinal fluid levels of IL-2 and sIL-2R were detected mainly in patients with acute relapsing-remitting MS and were significantly higher than corresponding serum levels. Intrathecal levels of IL-2 significantly correlated with local CNS synthesis of IgD and IgM, while no correlation was found with either IgG or IgA. Similarly, intrathecal sIL-2R levels significantly correlated with local CNS production of IgD and IgM, but not IgG or IgA. These findings further extend previous reports and also suggest that IL-2 and sIL-2R are involved in the early intrathecal humoral immune response in MS.