Cerebral cavernous malformations (CCMs) affect more than 1 million Americans, predisposing them to a lifetime risk of hemorrhagic stroke and epilepsy. Immunoglobulin and other related genes are markedly upregulated within human CCM lesions. Preliminary work suggests the infiltration of B lymphocytes and plasma cells within the lesions. A potential role of the immune response in this disease has not been postulated previously, but would be compelling, given the unique antigenic milieu of CCM lesions with sequestered thrombi and leaky blood-brain barrier, and the numerous examples of immune modulation of angiogenesis in other disease states. It could explain, in part, why some CCM lesions remain biologically dormant, while others proliferate with serious clinical consequences. This pilot proposal will characterize cellular and humoral components of the immune response in CCMs and initiate investigation into its clonality. The hypotheses to be tested are that CCM lesions are associated with immunoglobulin-producing B cells and plasma cells and that the immune response in CCMs is oligoclonal.
Specific Aim 1 proposes to characterize the predominant immunoglobulin isotype and distribution of inflammatory cells in CCM lesions, including lesions with and without recent aggressive clinical behavior.
Specific Aim 2 proposes to determine whether the immunoglobulins in CCMs are oligoclonal, as in response to specific antigenic trigger. Oligoclonality shall be assessed by isoelectric focusing of the predominant immunoglobulin isotypes isolated from the lesion, in comparison to the patient's serum, and by the distribution of lengths of complementary- determining regions 3 (CDR3) of the immunoglobulin heavy chain genes in mRNA isolated from lesions and from pooled plasma cells and B cells laser captured from CCMs, in comparison to peripheral lymphocytes from the blood of the same patients. LAY STATEMENT ON

Public Health Relevance

Immune response could play a role in or represent a potential marker of cerebral cavernous malformation lesion proliferation and hemorrhage. The proposed pilot studies will generate preliminary data for future research aimed at comparing the immune response in quiescent versus clinically aggressive CCM lesions. An oligoclonal immune response shown in this pilot study would stimulate future research to identify autoimmune or extrinsic antigenic triggers involved in CCM disease. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Golanov, Eugene V
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Northshore University Healthsystem
United States
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Shi, Changbin; Shenkar, Robert; Du, Hongyan et al. (2009) Immune response in human cerebral cavernous malformations. Stroke 40:1659-65
Pham, Martin; Gross, Bradley A; Bendok, Bernard R et al. (2009) Radiosurgery for angiographically occult vascular malformations. Neurosurg Focus 26:E16
Shenkar, Robert; Shi, Changbin; Check, Irene J et al. (2007) Concepts and hypotheses: inflammatory hypothesis in the pathogenesis of cerebral cavernous malformations. Neurosurgery 61:693-702;discussion 702-3