A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the Degree of Master of Medicine. J o h a n n e s b u r g 1988 / Infections can cause autoantibody production. The purpose of this study was to determine the prevalence of autoantibodies in chronic mycobacterial infections in Johannesburg. Sera from 41 leprosy patients and from 49 untreated and 73 treated tuberculosis patients were tested for rheumatoid factor, antibodies against a panel of nuclear antigens, anticardiolipin antibodies and syphilis serology. The antinuclear antibody was positive in 7.3% of the leprosy group, 6.1% of the untreated TB group and 15% of the treated tuberculosis patients (p=0.0125). Antinuclear antibody positivity correlated with duration of treatment (p=0.025). The antinuclear antibody titres were low and there was no specific pattern. / IT2018

abstract: Systemic lupus erytematosus (SLE) is an autoimmune disease where the immune system is reactive to self antigens resulting in manifestations like glomerulonephritis and arthritis. The immune system also affects the central nervous system (known as CNS-SLE) leading to neuropsychiatric manifestations such as depression, cognitive impairment, psychosis and seizures. A subset of pathogenic brain-reactive autoantibodies (BRAA) is hypothesized to bind to integral membrane brain proteins, affecting their function, leading to CNS-SLE. I have tested this BRAA hypothesis, using our lupus-mouse model the MRL/lpr mice, and have found it to be a reasonable explanation for some of the manifestations of CNS-SLE. Even when the MRL/lpr had a reduced autoimmune phenotype, their low BRAA sera levels correlated with CNS involvement. The correlation existed between BRAA levels to integral membrane protein and depressive-like behavior. These results were the first to show a correlation between behavioral changes and BRAA levels from brain membrane antigen as oppose to cultured neuronal cells. More accurate means of predicting and diagnosing lupus and CNS-SLE is necessary. Using microarray technology I was able to determine peptide sets that could be predictive and diagnostic of lupus and each specific CNS manifestation. To knowledge no test currently exists that can effectively diagnose lupus and distinguish between each CNS manifestations. Using the peptide sets, I was able to determine possible natural protein biomarkers for each set as well as for five monoclonal BRAA from one MRL/lpr. These biomarkers can provide specific targets for therapy depending on the manifestation. It was necessary to investigate how these BRAA enter the brain. I hypothesized that substance P plays a role in altering the blood-brain barrier (BBB) allowing these BRAA to enter and affect brain function, when bound to its neurokinin-1 receptor (NK-1R). Western blotting results revealed an increase in the levels of NK-1R in the brain of the MRL/lpr compared to the MRL/mp. These MRL/lpr with increased levels of both NK-1R and BRAA displayed CNS dysfunction. Together, these results demonstrate that NK-1R may play a role in CNS manifestations. Overall, the research conducted here, add to the role that BRAA are playing in CNS-lupus. / Dissertation/Thesis / Ph.D. Molecular and Cellular Biology 2011

Abstract Increased prevalence of anticardiolipin antibodies (aCL) and antinuclear antibodies (ANA) and changes in serum immunoglobulin concentrations have been reported in patients with epilepsy. The purpose of this study was to determine the presence of aCL, ANA, anti-B2 glycoprotein I -antibodies (anti-B2-GPI), antimitochondrial antibodies (AMA), immunoglobulin A, G and M serum concentrations and the presence of IgA and IgG class antigliadin antibodies (AGAbA and AGAbG), transglutaminase antibodies (tTGAbA) and antiendomysial antibodies (EMA) in a cohort of 1386 adult patients treated for epilepsy in the Oulu University Central Hospital during the years 1996–7 and in a reference population obtained from the Population Register Centre and matched for age, gender and municipality of residence. The effects of co-morbidity, medications, age, gender and different epilepsy attributes on the occurrence of the immunological parameters studied as well as the possible interrelations of these parameters were studied. There was no difference in the presence of aCL or ANA between the patients and the reference subjects. In patients, aCL were associated with long duration of epilepsy and poor seizure control. Low IgA serum concentrations were more common in patients with epilepsy, particularly those using phenytoin. Unspecific AMA were more common among the epilepsy patients. The prevalence of coeliac disease (CD)-related antibodies was similar in patients with epilepsy and in the reference population. AGAbA were associated with primary generalised epilepsy. No significant interrelations between the immunological markers were found. These findings suggest that patients with epilepsy do not have an increased prevalence of autoantibodies as a result of their disease. Various factors such as genetic traits and epilepsy attributes may independently affect the presence of each individual immunological marker.

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine

Thesis (M. D.)--University of Hong Kong, 2007. / Also available in print.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Texas at El Paso, 2008. / Title from title screen. Vita. CD-ROM. Includes bibliographical references. Also available online.

The recent history of autoimmune neurology is marked by the discovery of many central nervous system (CNS) antibody-mediated diseases. These disorders are caused by antibodies that target important proteins expressed in the neuronal surface, which are believed to be directly pathogenic. These antibodies are immunoglobulin G (IgG) isotype and, as such, have the potential to cross the placenta during gestation. Foetal exposure to CNS-targeting antibodies could alter developing neuronal circuits, leading to disease. However, the consequences of exposure to these antibodies during neurodevelopment has hardly been considered. To study the relationship between maternal antibodies towards neuronal surface proteins and neurodevelopmental disorders in the foetus a dual approach was undertaken. First, pregnancy serum samples from mothers of children later diagnosed with a neurodevelopmental disorder and from mothers of children with typical development were screened for the presence of neuronal surface antibodies. Next, the effects of pathogenic neuronal surface antibodies in the offspring were assessed in a maternal-to-foetal transfer mouse model. Antibodies to neuronal surface proteins in the gestational serum, particularly CASPR2 antibodies, were found to associate with an increased risk of mental retardation and disorders of psychological development in the progeny. The animal model showed that mice exposed in utero to CASPR2 antibodies have long term behavioural sequelae and histological findings suggestive of abnormalities in brain development. These findings support a model in which maternal antibodies towards foetal neuronal proteins cause long-term behavioural deficits and permanent abnormalities at the cellular and synaptic level in a subset of children with neurodevelopmental disorders.

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