Research Brief: Is Rare Amyloid Disorder Autoimmune Disease?

In a rare condition known as amyloid-β-related angiitis (ABRA), buildup of amyloid in the brain vasculature (cerebral amyloid angiopathy) is accompanied by swelling in the small- and medium-sized arteries of the cortices and in the membranes (leptomeninges) surrounding the brain. Previous studies suggested that ABRA is an autoimmune disorder, instigated by an immune reaction to Aβ. A case study offers new evidence to support this idea. In the February 20 Archives of Neurology, Nico Melzer and colleagues at the University Hospital Münster, Germany, report the first evidence of activated CD4+ T cells in the cerebral spinal fluid (CSF) of a patient with ABRA. Those activated cells were close to antigen-presenting cells that had engulfed Aβ.

"This is the first demonstration of activated T cells in ABRA cerebral spinal fluid," said Seth Love, University of Bristol, U.K., who was not involved in the study. Some previous case studies also offered evidence of autoimmunity in ABRA, Love noted. One revealed circulating memory B cells that reacted with Aβ, including some that reacted with Aβ aggregates in vessel walls and with plaques of a biopsy-confirmed ABRA patient (see Hermann et al., 2011), while Aβ antibodies showed up in the CSF of another patient with presumed ABRA (see Difrancesco et al., 2011). Antibodies to Aβ are found in human plasma and believed to be the basis for clinical improvement seen in small trials of intravenous immunoglobulin therapy for AD (see ARF related news story).

The current study describes a 67-year-old female patient who suffered two weeks of worsening headaches, disorientation, psychomotor slowing, frontal dysexecutive syndrome, and speech and motor impairments. A brain biopsy using a few cubic micrometers of tissue from the leptomeninges and cerebral cortex revealed the typical signs of ABRA—inflammatory infiltration in and around cortical and leptomeningeal arteries, thickening and splitting of vessel walls, acute thrombosis, microbleeds, and fibrinoid necrosis. Aβ had deposited in vessel walls, and the abundant cortical amyloid plaques contained activated microglia. Magnetic resonance imaging (MRI) revealed infiltration of foreign cells and bleeding of the leptomeninges. Flow cytometry showed more CD4+ cells in the CSF than is normal, and the presence of CD69 on those cells showed that about 18 percent of them were activated, compared to between 1 and 12 percent activation of CD4+ cells found in the 37 healthy controls. The paper does not report Aβ measurement in the CSF.

Increased protein in the CSF indicated a breach of the blood-brain barrier. Invading immune cells included T cells and macrophages. Many of the latter assumed an epithelioid or multinucleated giant cell appearance and contained deposits of Aβ. This suggested that these cells had engulfed Aβ and could present it as an antigen. CD4+ cells accounted for 80 percent of the lymphocytes in and around the vessels, and they hovered close to MHC class II-expressing microglia, epithelioid macrophages, and multinucleated giant cells. All these markers show that there was a pronounced T cell immune response "likely against the Aβ-engulfing and presenting microglia," Melzer told ARF in an e-mail. Since both cerebral amyloid angiopathy and AD lack that T cell immune response, they are not considered autoimmune diseases, he added.

In some cases of the rare disorder, patients respond well to immunosuppressive drugs such as steroids and cyclophosphamide. After treatment with both of these, the woman's MRI scans showed improvement in the inflammatory lesions in both the leptomeninges and cerebrum. Monitoring showed both reduced recruitment of CD4+ cells to the CSF and fewer activated CD4+ cells (down from 18 to 1 percent). Her headaches went away and executive function problems resolved.

"Our findings are in agreement with Aβ being the antigen of a CD4-mediated CNS inflammation around the vessel," said Melzer. "Knowing that it is an autoimmune disease and knowing a putative antigen is a rare combination." The finding of Aβ-directed immunity could explain why the brain parenchymas of people with ABRA contain few plaques compared with the brains of people with other Aβ-related disorders, such as AD. Though plaque clearance might seem helpful, the inflammatory reaction in people with ABRA overall is detrimental, the German scientists write.

Why ABRA occurs is unclear, as are many other questions about it, since there is little published information beyond a few case studies. Love pointed out that the condition is similar to the meningoencephalitis and perivascular inflammation that affected some patients in the Elan AN1792 trial, in which an immune response was induced by immunizing people against Aβ (see ARF related news story on Nicoll et al., 2003). "In some respects, these trial patients experienced the iatrogenic [treatment-induced] counterpart of a spontaneous autoimmune disease," said Seth Love. "A lot of the pathology is very similar."—Gwyneth Dickey Zakaib

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References

News Citations

  1. Toronto: In Small Trial, IVIg Slows Brain Shrinkage
  2. Trials and Tribulations—Autopsy Reveals Pros and Cons of AD Vaccine

Therapeutics Citations

  1. AN-1792

Paper Citations

  1. Hermann DM, Keyvani K, van de Nes J, Weimar C, Wiltfang J, Nitsch RM, Szodorai A. Brain-reactive β-amyloid antibodies in primary CNS angiitis with cerebral amyloid angiopathy. Neurology. 2011 Aug 2;77(5):503-5. PubMed.
  2. Difrancesco JC, Brioschi M, Brighina L, Ruffmann C, Saracchi E, Costantino G, Galimberti G, Conti E, Curtò NA, Marzorati L, Remida P, Tagliavini F, Savoiardo M, Ferrarese C. Anti-Aβ autoantibodies in the CSF of a patient with CAA-related inflammation: a case report. Neurology. 2011 Mar 1;76(9):842-4. PubMed.
  3. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.

Further Reading

Papers

  1. Scolding NJ, Joseph F, Kirby PA, Mazanti I, Gray F, Mikol J, Ellison D, Hilton DA, Williams TL, Mackenzie JM, Xuereb JH, Love S. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain. 2005 Mar;128(Pt 3):500-15. PubMed.
  2. Rigby H, Easton A, Bhan V. Amyloid β-related angiitis of the central nervous system: report of 3 cases. Can J Neurol Sci. 2011 Jul;38(4):626-30. PubMed.
  3. Jacobs DA, Liu GT, Nelson PT, Galetta SL. Primary central nervous system angiitis, amyloid angiopathy, and Alzheimer's pathology presenting with Balint's syndrome. Surv Ophthalmol. 2004 Jul-Aug;49(4):454-9. PubMed.
  4. Gray F, Vinters HV, Le Noan H, Salama J, Delaporte P, Poirier J. Cerebral amyloid angiopathy and granulomatous angiitis: immunohistochemical study using antibodies to the Alzheimer A4 peptide. Hum Pathol. 1990 Dec;21(12):1290-3. PubMed.
  5. Brotman DJ, Eberhart CG, Burger PC, McArthur JC, Hellmann DB. Primary angiitis of the central nervous system and Alzheimer's disease: clinically and pathologically evident in a single patient. J Rheumatol. 2000 Dec;27(12):2935-7. PubMed.

Primary Papers

  1. Melzer N, Harder A, Gross CC, Wölfer J, Stummer W, Niederstadt T, Meuth SG, Marziniak M, Grauer OM, Wiendl H. CD4+ T Cells Predominate in Cerebrospinal Fluid and Leptomeningeal and Parenchymal Infiltrates in Cerebral Amyloid β-Related Angiitis. Arch Neurol. 2012 Feb 20; PubMed.

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