Identity of the Purkinje cell cytoplasmic antibody type 2 autoantibody antigen is finally revealed

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Excerpt

Paraneoplastic neurological syndromes (PNS) are associated with cancer. These syndromes can affect the central nervous system (eg, encephalomyelitis, limbic or brainstem encephalitis, and optic neuritis), the peripheral nervous system (eg, subacute sensory neuropathy), and the neuromuscular junction (eg, Lambert–Eaton myasthenic syndrome and dermatomyositis).1 Proper recognition of onconeural antibodies can be very useful, because PNS may antecede cancer diagnosis.2
Neuronal loss and inflammation are early hallmarks for PNS and are associated with the appearance of several antibodies directed against nuclear (antineuronal nuclear antibody types 1 and 2) or cytoplasmic proteins like collapsin response mediator protein 5 (CRMP5) and amphiphysin. These antibodies can be found both in serum and cerebrospinal fluid (CSF). Purkinje cell cytoplasmic antibody type 2 (PCA‐2) was originally described in patients with signs of lung cancer.3 Until now, the identity of the antigen recognized by the PCA‐2 antibody remained obscure. However, a new study from Sean Pittock's group published in the February issue of Annals of Neurology unravels the identity of the PCA‐2 antibody antigen, which corresponds to the microtubule‐associated protein 1B (MAP1B).
MAP1B stabilizes and regulates microtubule dynamics in neurons. It is present in both the central and peripheral nervous system, and is also expressed in oligodendrocytes. MAP1B expression is high during the development of the nervous system. During adulthood, MAP1B expression decreases except in regions showing high neuronal plasticity.4 Mouse models lacking MAP1B display several abnormalities in the structure of their nervous system, which are related to deficiencies in neuronal migration, axonal guidance, and growth cone formation. In addition, neurite outgrowth and branching, dendritic spine formation, and synaptic transmission are also abnormal in the central and peripheral nervous systems.4
In the February issue of Annals of Neurology Gadoth and colleagues5 characterized the PCA‐2 autoantibody using biochemical, molecular, and histological approaches, and evaluated >100 serum and human CSF samples from the Mayo Clinic Neuroimmunology Laboratory. Samples were further evaluated using mass spectroscopy to unequivocally assign MAP1B as the main antigen for the PCA‐2 antibody. Interestingly, these results also show that the PCA‐2 antibody reacts to a lesser extent with the highly homologous protein MAP1A, and other microtubule‐associated proteins such as MAP2A and/or B. The binding region for the PCA‐2 antibody in MAP1B spans the microtubule‐binding domain of MAP1B, which is fairly conserved in MAP1A. The authors also ruled out the possibility that the PCA‐2 autoantibody may recognize other cytoskeleton polymers such as neurofilaments or actin microfilaments. Patients whose tumors expressed the PCA‐2 antigen displayed a variety of neurological disorders, with peripheral neuropathy being the most prevalent condition.
MAP1B in the peripheral nervous system is associated with neurite outgrowth in dorsal root ganglia and sciatic nerve neurons, and also with peripheral nerve regeneration.6 Neural regeneration is highly dependent on cytoskeleton dynamics. Thus, antibodies targeting elements linked to the cytoskeleton could impact the potential regenerative capacity of nerve cells. For example, it has been recently proposed that inhibition of microtubule detyrosination could be a suitable strategy to support nerve regeneration in human patients.7 Interestingly, MAP1B interacts with the enzyme tubulin tyrosine ligase, which enhances microtubule tyrosination.8 Also, systemic administration of drugs that moderately stabilize microtubules such as epothilone B enhance axonal growth even in the presence of an environment that inhibits axonal outgrowth.9
In most of the patients' samples used in this study, other neural antibodies such as those against CRMP5 and voltage‐gated calcium channels were identified along with the presence of MAP1B IgG. CRMP5 belongs to the family of collapsing‐response mediator proteins. Notably, CRMP5 protein functions are also related with the regulation of neuronal cytoarchitecture. Neurons derived from CRMP5 knockout mice display abnormal dendritic development.
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