For many years the group has been interested in aspects of immune regulation in MS involving natural CD4+CD25+FOXP3+ regulatory T cells (Treg).
Natural Regulatory T cells in Multiple Sclerosis
We were able to show that Treg isolated from patients with MS harbor reduced numbers of naive cells within circulating effector and regulatory T-cell subsets, thereby prompting diminished functional Treg activity. A role of premature immunosenescence is strengthened by results showing that (1) CD4+ T cells from MS patients express markedly lower levels of IL-7Rα on their cell surface than those from healthy persons of the same age, thereby affecting frequencies of naive and RTE-Treg and, consequently, Treg function; (2) frequencies of circulating dual-receptor Treg designating cells released from the thymus are reduced in MS; and (3) homeostatic abnormalities are also detectable in pediatric patients. In line with this idea, patient-derived Treg comprise disproportionately increased numbers of non-inhibitory cells when assessed with regard to their potential to suppress calcium signals in adjacent conventional T cells (Tconv) at the single-cell level (see Fig.1). This distinguishing feature correlates with diminished quantities of naive Treg subtypes. Complementary studies have shown that Treg are not abundant in the inflamed CNS and are prone to pharmacological modulation in the systemic compartment.
Further studies focusing on the role of B cells in MS have revealed that B lymphocytes undergo unique compartmentalized redistribution in peripheral blood and cerebrospinal fluid (CSF) during active MS. Long-term treatment with disease-modifying agents was found to differentially affect B-cell homeostasis. B-cell diapedesis across the blood-CSF barrier is currently under investigation.
|Figure 1: Single-cell Ca2+ live imaging in classified T lymphocytes. Color-coded details of an ongoing Ca2+ imaging experiment at a single measurement point. Warmer colors (yellow/red) indicate high Ca2+ influx while colder colors (blue/pink) indicate low Ca2+ influx in TCR-triggered CD4+ T cells.|
Neuromyelitis Optica and Aquaporin-4 Antibodies
Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system of putative autoimmune etiology which mainly affects the optic nerves and spinal cord. Recently, a distinct serum reactivity was discovered in NMO (termed NMO-IgG) and astrocytic aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Previous and ongoing efforts have focused on the development and evaluation of immunoassays to improve the diagnostic sensitivity of AQP4-Ab testing as well as on the prognostic and pathogenic impact of this autoantibody in NMO and related disorders. As 20% of patients with NMO remain seronegative for NMO-IgG/AQP4-Ab, we are currently searching for further disease-related autoantibodies and their respective target autoantigens.
|Figure 2: Binding of serum NMO-IgG/AQP4-Ab to adult mouse cerebellum as demonstrated by immunohistochemistry (A) and to the surface of cultured human embryonic kidney cells (HEK293) transfected with AQP4 as demonstrated by immunocytochemistry (A, inset). Magnified images show staining of the microvasculature (B), the Virchow-Robin spaces (C), and the pia mater (D). Bound IgG was visualized using a goat anti-human IgG secondary antibody labeled with fluorescein isothiocyanate.|
Autoantibody-associated neurological disorders other than NMO
The focus of this project is the diagnostic and pathophysiological role of autoantibodies in disorders of the central and peripheral nervous system other than NMO. We have discovered novel autoantibodies in patients with autoimmune cerebellar ataxia and Susac syndrome, a rare microangiopathy of the retina, inner ear and brain.
History of Neuroscience
This project focuses on the history of neuroscience in the 18th and 19th centuries, with a special interest in neuroimmunology.