Oligoclonal immune response in cerebral cavernous malformations. Laboratory investigation.

OBJECT: Mechanisms of cerebral cavernous malformation (CCM) pathogenesis include genetic predisposition in some cases, but other factors are likely to be involved in lesion proliferation and clinical manifestations. Given the unique antigenic milieu of CCMs, there may be a characteristic immune response in these lesions. We hypothesize that the immunoglobulin (Ig) fraction in CCMs reflects an oligoclonal immune response not present in paired sera from the same patients or in other types of cerebrovascular malformations. METHODS: Surgically excised lesions from five patients with CCMs, three patients with arteriovenous malformations (AVMs), and four normal brain control specimens obtained at autopsy were homogenized and extract tested for IgG clonality by isoelectric focusing in parallel with each patient's serum. RESULTS: The authors detected B cells in all three lesions examined, and plasmacytes in two out of three lesions examined. Four of five extracts of homogenized CCMs showed an oligoclonal pattern of IgG distinct from the polyclonal pattern seen in those patients' sera. Immununoglobulin G oligoclonality was not seen in AVMs or control brain specimens. CONCLUSIONS: The results of isoelectric focusing studies showed that CCM lesions had oligoclonal patterns of IgG unrelated to peripheral blood contamination, indicating selective synthesis of IgG within the lesions. This finding probably reflects a clonal expansion of B cells and/or plasmacytes in CCMs, an event that might be antigen-driven or a potential marker of inflammation.

Concepts and hypotheses: inflammatory hypothesis in the pathogenesis of cerebral cavernous malformations.

OBJECTIVE: Cerebral cavernous malformations (CCMs) affect more than one million Americans, predisposing them to a lifetime risk of hemorrhagic stroke and epilepsy. A potential role of the immune response in this disease has not been postulated previously but is compelling given the unique antigenic milieu of CCM lesions with sequestered thrombi and a leaky blood-brain barrier and the numerous examples of immune modulation of angiogenesis in other disease states. The objective of this article is to reveal novel observations about apparent immune responses in CCM lesions excised from human patients and to outline the potential pathobiological significance of these observations, specific hypotheses for future research, and potential clinical implications. METHODS: We reviewed data from differential gene expression revealing several immunoglobulin and other related genes markedly upregulated within human CCM lesions. Other observations are presented revealing infiltration of antibody-producing B lymphocytes and plasma cells in CCM lesions. We also present recent data demonstrating fivefold enrichment of gamma globulin to albumin ratio in a human lesion compared with serum from the same patient and oligoclonality of IgG in four of five CCM lesions, but not in paired sera from the same patients or in control specimens. RESULTS: We describe ongoing research aiming to characterize cellular and humoral components of the immune response in CCMs and initiating investigation into its clonality by isoelectric focusing on the predominant immunoglobulin isotypes isolated from the lesion, in comparison to the patient's serum, and by the distribution of lengths of complementary-determining region 3 of the immunoglobulin heavy chain genes in messenger ribonucleic acid 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. CONCLUSION: Immune response could play a role in or represent a potential marker of CCM lesion proliferation and hemorrhage or could otherwise contribute to lesion phenotype. The ongoing 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 research would stimulate future experiments to identify autoimmune or extrinsic antigenic triggers involved in CCM disease.

Increased CD4+ T cells during acute attack of Ménière's disease.

OBJECTIVE: We aimed to investigate if there is an alteration in CD4 and CD8 T-cell populations and in CD25 and CD49d activation antigens linked to these cells during an acute attack of Ménière's disease (MD). MATERIAL AND METHODS: Patients with MD who met the American Academy of Otolaryngology-Head and Neck Surgery criteria for the disease and healthy controls were enrolled in this study. Blood samples were collected during an acute attack of MD and when the disease was in its quiescent phase. RESULTS: 16 patients with MD and nine healthy controls were enrolled. The percentage of CD4 (T helper) cells was significantly increased during an acute attack of MD compared to that in healthy controls and in patients in the quiescent phase (71% vs 58% and 59%, respectively; p < 0.05). The increase in activation antigens was not statistically significant. CONCLUSION: To our knowledge this is the first demonstration of an increase in CD4 cells during an acute attack of MD. Further investigation is required to clarify the role of T cells in the pathogenesis of the disease.