Molecular and clinical studies
Paraneoplastische antistoffen : moleculaire en klinische studies
Paraneoplastic neurological syndromes (PNS) are remote effects of cancer. These are not caused by invasion of the tumor or its metastasis nor by other direct effects of the tumor or its treatment. PNS are rare, affecting less than 0.1% of all cancer patients. PNS have a subacute course, leaving the patient severely disabled in weeks to months. In most cases PNS precede the diagnosis of cancer.
The discovery of paraneoplastic antineuronal antibodies facilitated the diagnosis. ‘Well characterized onconeural antibodies’ are defined by recognizable patterns on rat brain immunohistochemistry and positive immunoblotting on recombinant antigen proteins. These are exclusively found in patients with cancer and include anti-Hu, Yo, CV2, Ri, Ma2 and amphiphysin. These antigens represent intracellular proteins, so in PNS damage is caused by cellular immune responses, explaining the poor response to immune modulating treatment and poor prognosis. We identified the anti-Tr antigen as the transmembrane protein Delta/ Notch-like epidermal growth factor-related receptor (DNER).
More recently a still growing number of autoantibodies directed against synaptic or neuronal cell-surface antigens has been identified, including mGluR1, NMDA, AMPA and GABA receptors. These autoantibodies have direct access to their target antigen and are potentially pathogenic. The associated clinical syndromes may be paraneoplastic or may represent an autoimmune encephalitis (without underlying tumor). Patients harboring autoantibodies directed against synaptic or neuronal cell-surface antigens respond favorably to immunotherapy with a good outcome in up to 80%.
This thesis focuses on paraneoplastic antineuronal antibodies and includes studies on new methods of autoantibody detection, identification of novel paraneoplastic antigen(s) and the description of clinical syndromes associated with newly detected paraneoplastic antibodies.