Bernd Krone

Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS). Recent reports proposed an increased EBV-targeted humoral immune response in MS, which appears to be more pronounced in pediatric patients. However, little is known about the CNS-derived antibody production against EBV in patients with MS. The objective of this study was to assess the frequency and intensity of intrathecal antibody production against EBV as compared to other neurotropic viruses in pediatric and adult onset MS. In cohorts of 43 childhood, 50 adult onset MS patients, 20 children and 12 adults with other CNS disorders, paired CSF and serum samples were studied. Frequency and intensity of intrathecal antibody production against EBV as compared to measles, rubella, varicella zoster (VZV) and herpes simplex virus (HSV) were analyzed by determination of virus-specific CSF-to-serum Antibody Indices (AI). Intrathecally synthesized EBV antibodies were detectable in 26% pediatric and 10% adult onset MS patients, compared to frequencies ranging in both groups from 10 to 60% for the other viruses. Median AIs for EBV were lower than those for all other viruses, with more than twofold higher median AI for measles, rubella and VZV. The EBV-targeted humoral immune response in the CNS is only part of the intrathecal polyspecific antibody production in MS, directed against various neurotropic viruses. Our results do not rule out the possibility that EBV is involved in the pathogenesis of MS by triggering diverse cellular immune mechanisms, but they argue against a direct pathogenic role of EBV-targeted humoral immune response within the CNS.

Common infectious agents in multiple sclerosis: a case–control study in children

Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein—Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS. Multiple Sclerosis 2008; 14: 136—139. http://msj.sagepub.com

Ein neues antifungisches β-lactam-antibioticum der clavam-reihe

Abstract The novel β-lactam-antibiotic (-)-2-(2-hydroxyethyl)clavam ( 1 ) originales from cultures of Streptomyces antibioticus. The structure is shown by spectroscopic and degradative methods.

Improved Serological Diagnosis Stresses the Major Role of Campylobacter jejuni in Triggering Guillain-Barré Syndrome

ABSTRACT Guillain-Barré syndrome (GBS) is a postinfectious autoimmune polyradiculoneuropathy. The most frequent antecedent pathogen is Campylobacter jejuni, followed by cytomegalovirus. However, more than 40% of GBS cases currently cannot be attributed to triggering events. This might be due to the shortcomings of the serological assays used for diagnosing infections, in particular for C. jejuni. In our study investigating 36 patients with acute GBS, standard serological methods identified the triggering viral or bacterial etiology in only 25% of cases. However, using a highly specific enzyme-linked immunosorbent assay based on two recombinant outer antigens encoded by C. jejuni genes Cj0017 (P39) and Cj0113 (P18), we found serological evidence of a preceding C. jejuni infection in 80.6% of the patients but in only 3.5% of the controls. We conclude that the role of C. jejuni in triggering GBS has been greatly underestimated.

Is the risk of multiple sclerosis related to the 'biography' of the immune system?

Multiple sclerosis (MS) with onset in childhood offers a unique opportunity to study the infectious background of this disease but the immune reactions against infectious agents in such children have only recently been investigated. These and other epidemiological studies strongly implicate involvement of one or more infectious agents in the aetiology of MS, with Epstein-Barr virus (EBV) being the prime candidate. Rather than being the actual cause of MS, it is more probable that these agents are involved in the development of immunoregulatory pathways. These pathways, if disturbed by hygiene-related factors including an altered sequence of infections, may generate and maintain a deficit within the immunological network that facilitates, to particular early events in the development of MS, preceding the onset of MS disease by years or a decade. A framework that can serve as a guide for further epidemiological, immunologic and molecular biologic investigations is formulated. This approach may shed light on the complex natural history of MS and may lead to rational preventive and therapeutic strategies. It is possible that, in the future, MS could be prevented by vaccination against EBV in early childhood; the framework is of relevance to the design of an appropriate type of vaccine.

Infection, inflammation and cancer.

Erdmann et al.remark that, in contrast to autoimmune diseases, there havebeen few studies on the hygiene hypothesis in relation tocancer. This is undoubtedly true, but there are some impor-tant and illustrative examples that point to possible preven-tive strategies based on currently available vaccines. Theseexamples relate principally to leukaemia and melanoma, andthere is evidence that the risk of both diseases is reduced byvaccination early in life with bacille Calmette–Gue´rin (BCG).In the case of leukaemia it has been shown in severalstudies, recently summarised in a meta-analysis,

Multiple Sclerosis: Are Protective Immune Mechanisms Compromised by a Complex Infectious Background?

The immunological background of multiple sclerosis (MS) manifests as an altered reactivity against a diverse range of infections, particularly with the Epstein-Barr virus. Although this could be only an epiphenomenon of a more generalised dysfunction of the immune system in MS, it is also possible that a complex infectious background forms the basis of a specific immune dysregulation finally causing the disease. It is thus suggested that the complex infectious background bears the key for an understanding of the immune pathogenesis of the disease. It appears probable that improved standards of hygiene cause regulatory defects in the immune system, allowing the abnormal expression of human endogenous retroviral (HERV) genes. On the basis of epidemiological observations we describe how a failure of expansion or an eclipse of a subfraction of self-antigen-specific CD8+ T cells mediating immune repair, and a deleterious mode of action of HERV gene products, could underlie the pathogenesis of MS.

Immunotherapy for malignant melanoma - Tracing Ariadne's thread through the labyrinth

A working group (FEBIM) within the European Organisation for Research and Treatment of Cancer undertook extensive studies on the possible association of infectious diseases and the risk of malignant melanoma. These studies provided evidence that several infectious diseases and also some vaccines including the anti-tuberculosis vaccine, BCG, derived from Mycobacterium bovis, confer a significant level of protection against this form of cancer. In recent years, the importance of immunoregulatory networks in the establishment of tolerance to tumour antigens and the key role of the innate immune system in the development of such networks have been recognised. The molecular patterns of micro-organisms activate pattern recognition receptors on antigen presenting cells and determine the qualitative nature of the ensuing immune response. Bacteria in the actinomycetales family, notably members of the genus Mycobacterium, exhibit particularly powerful adjuvant activity and profoundly affect underlying patterns of immune reactivity. In particular, there is growing evidence that a heat-killed preparation of a strain of Mycobacterium vaccae is able to down-regulate patterns of immune reactivity that favour the tumour and to induce those that lead to anti-cancer immune responses. The results of preliminary clinical observations with melanoma patients, and published studies on other cancers, point to the need for more formal clinical trials.

Paradigms in multiple sclerosis: time for a change, time for a unifying concept

It has recently been suggested that, rather than being an autoimmune disease, multiple sclerosis (MS) is an example of a neurocristopathy, a pathological process resulting from a faulty development of the neural crest. Whilst several characteristics of the disease suggest a neurocristopathy, other aetiological factors require consideration, including hygiene-related factors that alter the immune responses to common pathogens resulting in an eclipse of immune reactivity that could protect against MS, the possible role of human endogenous retroviruses (HERVs) in pathogenesis and autoimmune phenomena, HLA polymorphism, vitamin D levels before and after birth and immune repair mechanisms. A postulated aetiological factor in MS, associated with altered vitamin D metabolism and abnormal HERV expression, is a long-lasting disturbed redox regulation in the biosynthesis of a melanoma-like melanin pigment. Although intensive further studies on melanin pigments in nerve tissue in MS are required, the known properties of a pathological form of such pigments in melanoma could explain a number of observations in MS, including the impact of light, UV-light, and vitamin D, and could explain the clinical manifestations of MS on the basis of an oscillating process of oxidative charge and discharge of the pigments and a threshold phenomenon with a change of the quasi-catalytic function of the pigment from destroying reactive oxygen radicals or species to transforming them to more harmful long-persisting highly reactive species. Taken together with the consequences of an adaptive process in partly demyelinated neurons, resulting in an increase in number of mitochondria, and the impact of stressful life events, these conditions are necessary and sufficient to explain the disease process of MS with its spatial (plaques) and temporal (attacks and remissions) characteristics. This suggested unifying concept of the pathogenesis of MS may open perspectives for prevention, diagnosis and therapy. In particular, prevention may be achieved by vaccinating against Epstein-Barr virus in early childhood.

Enhanced transcription of the s-adenosylhomocysteine hydrolase gene precedes Epstein-Barr virus lytic gene activation in ganglioside-stimulated lymphoma cells

Abstract Stimulation of Epstein-Barr virus (EBV) genome-positive Burkitt lymphoma cells with the ganglioside IV3NeuAc-nLcOse4Cer leads to the induction of cell differentiation processes and activates the EBV lytic viral cycle. In cells of the Burkitt lymphoma line Raji differential expression of host cell genes was analysed in the early phase (150 min) post stimulation with the ganglioside to display the cell activities that precede the activation of the EBV lytic cycle using the differential display reverse transcription-polymerase chain reaction technique. Multiple fragment cDNAs derived from control cells and ganglioside-stimulated cells were amplified using random primers and displayed via polyacrylamide gel electrophoresis. The expression pattern of 8,400 bands was analysed. Eleven differentially expressed fragment cDNAs were reamplified and identified by nucleotide sequencing. Six of these could be identified as coding for proteins that may take part in virus reactivation and differentiation. The most striking finding was the induction of s-adenosylhomocysteine hydrolase (AHCY) expression. The cellular enzyme AHCY plays an important role in transmethylation reactions controlling the replication of several viruses. Thus, an involvement in EBV replication can be suggested.