Bodvar Vandvik

Oligoclonal Measles Virus-Specific IgG Antibodies Isolated from Cerebrospinal Fluids, Brain Extracts, and Sera from Patients with Subacute Sclerosing Panencephalitis and Multiple Sclerosis

Measles virus‐specific antibodies were isolated from sera, cerebrospinal fluids (CSF), and brain extracts of patients with subacute sclerosing panencephalitis (SSPE) and multiple sclerosis (MS) by absorption with measles antigens and subsequent acid elution of the antigen–antibody precipitates. Electrophoretically homogeneous measles antibodies were isolated from CSF or brain extracts in five patients with SSPE and in five out of seven patients with MS. Homogeneous IgG antibodies were also demonstrated in the sera from all SSPE patients and from three of the MS patients. The antibodies isolated from various control sera and from pooled CSF were electrophoretically heterogeneous. The results support the concept of a local synthesis in the nervous system of oligoclonal IgG antibodies to measles virus in all patients with SSPH and in some patients with MS. In SSPE, most or all oligoclonal IgG proteins of the CSF or brain carry measles antibody activities. In MS, only part of the oligoclonal IgG appears to be associated with measles antibody activity

HLA-DQA1 and HLA-DQB1 genes may jointly determine susceptibility to develop multiple sclerosis

Serologic DR typing and genomic DRB1, DQA1, DQB1, DPA1, and DPB1 typing using sequence-specific oligonucleotides were performed in 69 multiple sclerosis (MS) patients and 181 healthy controls on in vitro amplified DNA. The frequencies of DR2 as well as the DR2-associated DQA1*0102 and DQB1*0602 alleles were increased whereas DR7 was decreased among MS patients. The distribution of DR4 subtypes as well as DP alleles were similar in patients and healthy controls. All but one of 23 DR4-positive MS patients carried the DQB1*0302 allele, whereas five of five DR7-positive MS patients carried the DQB1*0303 allele. Of the MS patients, 99% compared to 79% of the controls carried DQA1 alleles encoding glutamine at residue 34, while 97% of the MS patients compared to 72% of the controls carried DQB1 alleles encoding DQ beta chains sharing long polymorphic stretches. A combination of such DQA1 and DQB1 alleles was carried by 96% of the MS patients and 60% of the controls, suggesting an association between MS and a combination of particular DQA1 alleles and DQB1 alleles. The corresponding DQ alpha beta heterodimers may have in common an ability to bind a particular peptide.

Patients with multiple sclerosis carry DQB1 genes which encode shared polymorphic amino acid sequences

Of 61 Norwegian multiple sclerosis patients tested, 59, i.e., 97%, were positive for at least one of the HLA specificities DR2, DR4, or DRw6. Typing with sequence-specific oligonucleotide probes revealed that the same 59 patients carried DR2-, DR4-, or DRw6-associated HLA-DQB1 genes which encode shared polymorphic amino acid sequences in the membrane-distal part of their HLA-DQ beta chains. This shared DQ beta polymorphism may explain previously reported DR associations and could thus be the primary HLA association in MS.

Multiple sclerosis: local synthesis of electrophoretically restricted measles, rubella, mumps and herpes simplex virus antibodies in the central nervous system.

An imprint electroimmunofixation (IEIF) technique was used to study measles, rubella, mumps, and herpes simplex virus antibodies in serum and concentrated cerebrospinal fluid (CSF) from ten patients with multiple sclerosis (MS). Electrophoretically restricted virus‐specific antibodies were detected in sera or CSF from nine of the ten patients. Comparison of the antibody patterns in matching serum and CSF samples indicated that electrophoretically restricted populations of antibody against one or more of the four viruses were produced locally in the central nervous system of nine patients. No association between the locally produced antibody populations and the oligoclonal IgG of the CSF could be demonstrated. The virus‐specific antibodies studied thus seem to constitute only a minor fraction of the total IgG of the CSF from MS patients.

Demonstration of Electrophoretically Restricted Virus‐Specific Antibodies in Serum and Cerebrospinal Fluid by Imprint Electroimmunofixation

A sensitive technique for the electrophoretic characterization of virus‐specific antibodies is described, Electrophoretically separated Ig is allowed to diffuse into a virus‐antigen containing gel. The antibodies hound to viral antigen are then demonstrated by 125I‐labelled rabbit anti‐human Ig and autoradiography. Electrophoretically restricted antibodies against measles, rubella, mumps or herpes simplex viruses were demonstrated in some normal sera. The antibody patterns of normal cerebrospinal fluids (CSF) closely resembled those of the matching sera. A selective increase of oligoclonal antibodies was demonstrated in CSF from patients with infection of the central nervous system (CNS) caused by any of the four viruses. We propose that the method may be used to demonstrate local synthesis in the CNS of antibodies against viral or other antigens.

Mumps meningitis: specific and non-specific antibody responses in the central nervous system.

Intrathecal production of oligoclonal mumps‐specific IgG was demonstrated in nine out of 10 children with mumps meningitis by imprint immunofixation (IIF) of sera and cerebrospinal fluids (CSF) separated by agarose electropheresis and by thin‐layer electrofocusing. Four of the patients had intrathecal mumps antibody synthesis demonstrable also by conventional serological tests.

Progressive rubella virus panencephalitis: synthesis of oligoclonal virus-specific IgG antibodies and homogeneous free light chains in the central nervous system.

The occurrence of oligoclonal IgG and homogeneous free lambda light chains in the cerebrospinal fluid (CSF) of a patient with progressive rubella virus panencephalitis is reported. Fractions of oligoclonal IgG corresponding to those of the CSF occurred also in the serum.

Intrathecal synthesis of virus-specific oligoclonal IgG, IgA and IgM antibodies in a case of varicella-zoster meningoencephalitis☆

Varicella-zoster (VZ) virus meningoencephalitis was diagnosed in a 72-year-old man without other clinical signs of VZ infection, on the basis of intrathecal virus-specific IgG, IgA and IgM antibody responses demonstrated by imprint immunofixation (IIF) and by serological analyses of serum and CSF. The intrathecally produced antibodies displayed oligoclonal characteristics. The intrathecal production of VZ-IgG and -IgA antibodies persisted throughout the observation period of 20 months, while that of VZ-IgM antibodies was not detectable later than 3 months after onset. Part of the intrathecally produced VZ-IgG and -IgA antibody populations, but no IgM antibodies, were shown to cross-react with herpes simplex virus. Oligoclonal IgG bands were demonstrated in the CSF throughout the observation period. The bulk of the IgG bands was shown to represent VZ-specific antibodies.

Intrathecal complement activation in neurological diseases evaluated by analysis of the terminal complement complex

The terminal complement complex (TCC) was determined in plasma and cerebrospinal fluid (CSF) from 208 neurological patients. Elevated CSF TCC levels were observed in higher frequencies in patients with infectious diseases (80%), radiculoneuritis (62%), multiple sclerosis (30%), and miscellaneous autoimmune diseases (27%) than in patients with miscellaneous non-inflammatory diseases (2-13%). The plasma level of TCC was significantly increased only in the infectious group. No positive correlation was observed between the plasma and the CSF TCC concentration in the whole patient population nor in subgroups divided according to blood-brain barrier function. Furthermore, the CSF TCC concentration did not correlate with the serum/CSF albumin ratio or with CSF total protein concentration when this was below 1.0 g/l. It is concluded that an elevated TCC concentration in CSF reflects intrathecal complement activation and that quantification of TCC in CSF may be a valuable supplement in the examination of neurological diseases.

IgG1 Subclass Restriction of Oligoclonal Measles Virus‐Specific IgG Antibodies in Patients with Subacute Sclerosing Panencephalitis and in a Patient with Multiple Sclerosis

A restriction to the IgG1 subclass was demonstrated for measles virus‐specific IgG antibodies isolated from the sera of five patients with subacute sclerosing panencephalitis, from the cerebrospinal fluid of one of the patients, and from brain extract from a sixth patient. A predominance of IgG1 was also observed in measles antibodies isolated from the serum and brain extract of a patient with multiple sclerosis. Evidence is presented that the IgG1 restriction is associated with the occurrence of oligoclonal measles antibodies in these patients. A similar restriction to the IgG1 subclass was not observed in measles antibodies isolated from the serum of a measles‐convalescent child or from pooled normal serum and IgG.