In this Letter, Dominic Grün and Sagar have been added to the author list (affiliated with Max-Planck-Institute of Immunology and Epigenetics (MPI-IE), Freiburg, Germany). The author list, 'Author ...contribution' and 'Acknowledgements' sections have been corrected online. See accompanying Amendment.
Aims
Natalizumab is a humanized monoclonal antibody specific for CD49d receptors of integrins. It inhibits the entry of inflammatory cells into the central nervous system and is approved for the ...treatment of relapsing‐remitting multiple sclerosis (MS). Several lines of evidence indicate an involvement of B cells and plasma cells in MS pathogenesis. However, treatment with the natalizumab analogon PS/2 immunoglobulin G (IgG) has so far only been investigated in T cell‐mediated animal models of MS. Due to the importance of B lineage cells in the pathogenesis of MS, the objective of the present study has thus been to analyse the effects of PS/2 IgG in a mouse model of MS with T and B cell cooperation (OSE mice).
Methods
OSE mice were treated with the natalizumab analogon PS/2 IgG either at disease onset or after peak of disease. Treatment was also performed with PS/2 F(ab′)2 fragments.
Results
PS/2 IgG treatment improved the clinical outcome and decreased spinal cord demyelination and immune cell infiltration if given early in the disease course. Treatment increased blood leukocytes and resulted in a partial internalization of CD49d in T and B cells. The therapeutic effects of PS/2 IgG injections were independent of the Fc fragment as F(ab′)2 injections were equally beneficial. In contrast, PS/2 IgG was not effective when given late in the disease course.
Conclusions
Results indicate that natalizumab may also be beneficial in MS with B cell‐driven immunopathogenesis.
Early natalizumab analogon treatment in a mouse model of multiple sclerosis (MS) with T and B cell co‐operation leads to improved clinical outcome, decreased spinal cord demyelination and reduced inflammatory cell infiltration indicating that natalizumab may be beneficial in MS with B cell‐mediated pathogenesis.
Genitalia are among the fastest evolving morphological traits as evidenced by their common function as diagnostic traits in species identification. Even though the main function of genitalia is the ...successful transfer of spermatozoa, the presence of diverse structures that are obviously not necessary for this suggests that genitalia are a target of sexual selection. The male genitalia of many spider species are extremely complex and equipped with numerous sclerites, plates and spines whose functions are largely unknown. Selection on male genitalia may be particularly strong in sexually cannibalistic spiders, where mating success of males is restricted to a single female. We investigated the copulatory mechanism of the sexually cannibalistic orb weaving spider
Argiope bruennichi by shock freezing mating pairs and revealed a complicated interaction between the appendices and sclerites that make up the male gonopods (paired pedipalps). The plate that covers the female genital opening (scape) is secured between two appendices of the male genital bulb, while three sclerites that bear the sperm duct are unfolded and extended into the female copulatory opening. During copulation, females attack and cannibalise the male and males mutilate their genitalia in about 80% of cases. Our study demonstrates that (i) genital coupling is largely accomplished on the external part of the female genitalia, (ii) that the mechanism requires an interaction between several non-sperm-transferring structures and (iii) that there are two predetermined breaking points in the male genitalia. Further comparative work on the genus
Argiope will test if the copulatory mechanism with genital mutilation indeed is an adaptation to sexual cannibalism or if cannibalism is a female counter adaptation to male monopolisation through genital plugging.
One approach to improving efficacy in MS therapy is to identify medications that provide additive or synergistic benefit in combination. Orally administered cholesterol-lowering HMG-CoA reductase ...inhibitors (known as statins), which exhibit immunomodulatory properties and are effective in treatment of the MS model EAE, are being tested in MS. As atorvastatin can enhance protective Th2 responses and has a different mechanism of action than glatiramer acetate (GA), a parenterally administered immunomodulatory agent approved for MS treatment, we tested whether the combination of these agents could be beneficial in EAE. Combination therapy using suboptimal doses of atorvastatin and GA prevented or reversed clinical and histologic EAE. Secretion of proinflammatory Th1 cytokines was reduced--and conversely Th2 cytokine secretion was increased--in these mice, but not in mice treated with each drug alone at the same doses. Monocytes treated with the combination of suboptimal doses of atorvastatin and GA secreted an antiinflammatory type II cytokine pattern and, when used as APCs, promoted Th2 differentiation of naive myelin-specific T cells. Our results demonstrate that agents with different mechanisms of immune modulation can combine in a synergistic manner for the treatment of CNS autoimmunity and provide rationale for testing the combination of atorvastatin and GA in MS.
BACKGROUND Multiple sclerosis (MS) is a heterogeneous autoimmune disease of the central nervous system. The identification of 4 different immunopathological subtypes of MS raises the question of ...whether these subtypes represent different patient subgroups that can be distinguished according to their leading mechanism of myelin destruction or whether this is a stage-dependent process in the development of lesions in a given patient. OBJECTIVE To document intraindividual immunopathological and radiological homogeneity of 2 different lesions in a single patient with relapsing-remitting MS over time. DESIGN Case report. SETTING A neuropathological referral center for inflammatory demyelinating diseases of the central nervous system. PATIENT A 49-year-old woman with clinically definite relapsing-remitting MS. MAIN OUTCOME MEASURES Radiological and immunopathological analysis of MS lesions. RESULTS Identical pathological findings in 2 different MS lesions separated by more than 2 years were identified. These lesions displayed similar and distinct radiological features on cranial imaging. CONCLUSIONS In this patient we were able to show the same antibody/complement-mediated lesion pathological findings with compatible identical ring enhancement on T1-weighted magnetic resonance images and hypointense rims on T2-weighted images after an interval of 26 months. Our observations support the concept of intraindividual homogeneity of a given immunopathological MS subtype.Arch Neurol. 2008;65(11):1527-1532-->
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