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(Stroke. 1996;27:1155-1162.)
© 1996 American Heart Association, Inc.

Articles

Immune Reactions Associated With Cerebral Amyloid Angiopathy

Masahito Yamada, MD; Yoshinori Itoh, MD; Masayuki Shintaku, MD; Junichiro Kawamura, MD; Olafur Jensson, MD; Leifur Thorsteinsson, PhD; Naomi Suematsu, MD; Masaaki Matsushita, MD Eiichi Otomo, MD

the Department of Neurology, Tokyo Medical and Dental University (M.Y.); Departments of Internal Medicine (Y.I., E.O.) and Pathology (N.S.), Yokufukai Geriatric Hospital; Department of Pathology, Osaka Red Cross Hospital (M.S.); Department of Neurology, Kobe City General Hospital (J.K.); Department of Psychiatry, University of Tokyo (M.M.) (Japan); and the Blood Bank, National University Hospital, Reykjavik, Iceland (O.J., L.T.).

Correspondence to Dr Masahito Yamada, Department of Neurology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan. E-mail m-yamada.nuro@med.tmd.ac.jp.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Cerebral amyloid angiopathy (CAA) occasionally coexists with cerebral vasculitis. An immune system may influence deposition or degradation of the amyloid in cerebral blood vessels. The purpose of this study was to elucidate immune reactions associated with CAA.

Methods In 11 elderly patients with sporadic CAA, 2 patients with Icelandic familial CAA, and 2 patients with CAA and granulomatous angiitis, the cerebrovascular amyloid proteins and infiltrating inflammatory cells were analyzed immunohistochemically.

Results In both sporadic CAA (ß-protein amyloid angiopathy) and Icelandic familial CAA (cystatin C amyloid angiopathy), leptomeningeal and cortical vessels were associated with an increase or activation of monocyte/macrophage lineage cells. In the cases of CAA with granulomatous angiitis, the vascular amyloid was of ß-protein and associated with infiltration of many monocyte/macrophage lineage cells, which included multinucleated giant cells containing the amyloid in the cytoplasm as well as T cells composed of CD4⁺ and CD8⁺ subsets. Amyloid P component, which was reported to be a common component of amyloid deposits and to prevent phagocytic proteolysis of amyloid fibrils of ß-protein, was negative for the vascular amyloid in a case of CAA with granulomatous angiitis but positive in the others.

Conclusions In both the ß-protein and cystatin C amyloid angiopathies, cerebrovascular amyloid deposition was associated with an increase or activation of monocyte/macrophage lineage cells. Prominent reactions of monocyte/macrophage lineage cells admixed with CD4⁺ and CD8⁺ T cells (granulomatous angiitis) were occasionally associated with ß-protein angiopathy. In some of these cases, the absence of amyloid P component might be related to pathogenesis of the granulomatous reaction.

Key Words: amyloid • angiitis • cerebrovascular disorders • immunohistochemistry

	Introduction

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Cerebral amyloid angiopathy occasionally coexists with cerebral vasculitis, including granulomatous angiitis (giant cell arteritis) of the brain.^{1 2 3 4 5 6 7 8 9 10 11 12 13} Some speculate that the angiitis may cause amyloid deposition^{4 11} ; alternatively, others consider that vascular amyloid deposition may secondarily induce a granulomatous (giant cell) reaction.^{6 9 10} Causal relationships between CAA and angiitis remain to be determined. In some patients with CAA and granulomatous angiitis, corticosteroid or immunosuppressive therapy resulted in clinical improvement,^{8 12} suggesting that clarification of a CAA-related immune response is important from clinical as well as pathogenetic points of view.

Generally, inflammation is not apparent in CAA, although some perivascular mononuclear cells are observed in the CAA-associated vascular changes, including hyaline changes and fibrinoid degeneration.^{14 15} Cerebral blood vessels are associated with resident histiocytic cells (perivascular cells or perivascular macrophages); these cells are immunophenotypically indistinguishable from hematogenous macrophages and have immunologic functions in the perivascular region.^{16 17 18} An ultrastructural study of cerebral vessels with amyloid deposits in Alzheimer's disease suggested that perivascular cells and perivascular microglia may engage in amyloid fibril formation.¹⁹ An immune system may influence deposition or degradation of the amyloid in cerebral blood vessels.

The purpose of this study was to characterize an immune response associated with CAA. Using immunohistochemical analyses, we revealed that the vessels bearing ß-protein- or cystatin C-related amyloid without apparent inflammation were commonly associated with an increase or activation of monocyte/macrophage lineage cells. A prominent reaction of monocyte/macrophage lineage cells admixed with T cell infiltration was found with ß-protein angiopathy in the cases of CAA with granulomatous angiitis. Furthermore, in one of these cases we demonstrated the absence of AP, which was reported to be a common component of amyloid and to prevent phagocytic proteolysis of amyloid fibrils of ß-protein.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Eleven elderly patients with sporadic severe CAA (age, 78 to 90 years), 2 patients with Icelandic familial CAA (HCHWA-I), 2 patients with CAA and (isolated) granulomatous angiitis of the brain,^{5 13} and 4 normal control subjects with no CAA or neurological disease (age, 69 to 90 years) were included in this study. In all the patients with sporadic CAA or HCHWA-I, most of the leptomeningeal and cortical vessels were heavily infiltrated with amyloid. The media and adventitia of the vessel walls were frequently replaced by amyloid deposits, associated with vascular changes such as double barreling, aneurysmal dilatation, hyalinous thickening, and fibrinoid necrosis of the vessel walls. The 11 patients with sporadic CAA presented with lobar cerebral hemorrhages or multiple cortical infarction/microhemorrhages. The 2 patients with HCHWA-I suffered from multiple lobar cerebral hemorrhages. Clinicopathologic profiles of the 2 patients with CAA and granulomatous angiitis are shown in Table 1.^{5 13}

View this table: [in this window] [in a new window]   Table 1. Profiles of the Two Patients With CAA and Granulomatous Angiitis

Formalin-fixed, paraffin-embedded, 8-µm-thick sections of the brain obtained at autopsies were immunostained with the avidin-biotin-peroxidase complex method²⁰ with the following antibodies to amyloid proteins and to markers of the infiltrating leukocytes: antibodies to amyloid ß-protein (synthetic ß-peptide 1-42) (mouse monoclonal)²¹ ; cystatin C (rabbit polyclonal)²² ; AP (rabbit polyclonal) (DAKO); human tau (rabbit polyclonal)²³ ; ubiquitin (rat monoclonal)²⁴ ; human macrophage CD11c (Ki-M1P) (mouse monoclonal) (Seikagaku Corp); human leukocyte common antigen CD45RB (LCA), which intensely labels lymphoid cells (mouse monoclonal) (DAKO); human B cell CD20 (L26) (mouse monoclonal) (DAKO); human T cell CD45RO (UCHL1) (mouse monoclonal) (DAKO); human T cell subset (OPD4), which reacts with an antigen expressed on a helper/inducer (CD4⁺) subset of T cells (mouse monoclonal) (DAKO); and human T cell subset (CD8), which reacts with a CD8 molecule expressed on a cytotoxic/suppressor subset of T cells (mouse monoclonal) (DAKO). The specificity of the antibody to AP was ascertained by crossed immunoelectrophoresis according to the vendor's information. Ki-M1P reacts with a formalin-resistant antigen (CD11c) of monocyte/macrophage lineage cells²⁵ and is a marker of the microglial and perivascular cells in the human brain.^{18 26} The antibody to CD8 can react with CD8⁺ (cytotoxic/suppressor) T cells in formalin-fixed, paraffin-embedded sections after the microwave pretreatment.²⁷ Details of the avidin-biotin-peroxidase complex method were described previously.^{28 29} Sections incubated with no antibody, with nonimmunized animal sera, and with irrelevant antibodies served as negative controls. Sections of a lymph node served as positive controls for immunostaining of the leukocyte markers. The specific staining pattern of the lymph node was confirmed for each marker.

To evaluate the vessel-associated monocyte/macrophage lineage cells quantitatively, Ki-M1P-positive cells were counted for 100 leptomeningeal or cortical small arteries (diameters, 100 µm on average) in each case; the average number of the Ki-M1P-positive cells per vessel was calculated.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In normal control brains, leptomeningeal and cortical vessels showed a few perivascular cells that were immunostained with Ki-M1P (Fig 1). In the subarachnoid space of the normal control brains, a few mononuclear cells positive for LCA and UCHL1 (T cells) were occasionally scattered.

View larger version (101K): [in this window] [in a new window]   Figure 1. Leptomeningeal (a) and cortical (b) blood vessels of the normal control brain immunostained with Ki-M1P. Some perivascular cells are positive for Ki-M1P, indicating that these cells are of monocyte/macrophage lineage. a, Ki-M1P, counterstained with methyl green, magnification x228, bar=100 µm; b, Ki-M1P, counterstained with methyl green, magnification x345, bar=100 µm.

In the elderly patients with sporadic CAA, the vascular amyloid was positive for ß-protein (Fig 2a) and AP (Fig 2b). Some vessels showed coexistence of cystatin C-like immunoreactivity with the ß-protein immunostaining. However, the CAA was judged to be essentially of the ß-protein type, because only a part of ß-protein-positive vessels had cystatin C-like immunoreactivities, and it was reported that cystatin C was not a component of the amyloid fibrils in cases showing immunohistochemical coexistence of ß-protein and cystatin C.³⁰ In all of the cases, leptomeningeal and cortical vessels heavily deposited with the amyloid frequently showed an increase of Ki-M1P-positive monocyte/macrophage lineage cells (Fig 2c) compared with normal control subjects (Fig 1) (Table 2). When vasculopathies such as hyalinous changes, aneurysmal formations, and fibrinoid degeneration were present in association with severe CAA, there was apparent infiltration of mononuclear cells consisting of a larger number of Ki-M1P-positive cells and some UCHL1-positive T cells. When vascular amyloid formed perivascular plaques, brain parenchyma around the amyloid-laden vessels showed Ki-M1P-positive microglial cells with tau- and ubiquitin-positive dystrophic neurites. In an 87-year-old woman showing severe CAA and multiple cortical infarction and hemorrhage, Ki-M1P-positive multinucleated giant cells were occasionally observed around ß-protein amyloid-laden cortical vessels without infiltration of lymphocytes (Fig 3).

View larger version (73K): [in this window] [in a new window]   Figure 2. Immunostaining of a cortical artery with anti-ß-protein (a), anti-AP (b), and Ki-M1P (c) in elderly patients with sporadic CAA. The vascular amyloid is positive for ß-protein (a) and AP (b). The amyloid-laden vessel shows an increase of Ki-M1P-positive monocyte/macrophage lineage cells (c) compared with the normal control brain (see Fig 1). a, Anti-ß-protein, counterstained with hematoxylin; b, anti-AP, counterstained with hematoxylin; c, Ki-M1P, counterstained with methyl green; a, b, c, magnification x228, bar=100 µm.

View this table: [in this window] [in a new window]   Table 2. Average Number of Ki-M1P-Positive Monocyte/Macrophage Lineage Cells per Vessel

View larger version (92K): [in this window] [in a new window]   Figure 3. A perivascular multinucleated giant cell (a) in an 87-year-old woman with severe CAA. A ß-protein amyloid-laden cortical vessel (b) is associated with a Ki-M1P-positive multinucleated giant cell of monocyte/macrophage lineage (arrows) (c). a, Hematoxylin-eosin; b, anti-ß-protein, counterstained with hematoxylin; c, Ki-M1P, counterstained with methyl green; a, b, c, magnification x320, bar=100 µm.

In the patients with HCHWA-I, the vascular amyloid was immunostained with the antibodies to cystatin C (Fig 4a) and AP (Fig 4b) but not with the antibody to ß-protein. The cystatin C amyloid-laden vessels also presented with an increase of Ki-M1P-positive monocyte/macrophage lineage cells (Fig 4c) compared with normal control subjects (Fig 1) (Table 2).

View larger version (74K): [in this window] [in a new window]   Figure 4. Immunostaining of a cortical artery with anti-cystatin C (a), anti-AP (b), and Ki-M1P (c) in HCHWA-I. The amyloid is positive for cystatin C (a) and AP (b). The Ki-M1P-positive perivascular cells are increased (c) in comparison with the normal control brain (see Fig 1). a, Anti-cystatin C, counterstained with hematoxylin; b, anti-AP, counterstained with hematoxylin; c, Ki-M1P, counterstained with methyl green; a, b, c, magnification x276, bar=100 µm.

In the two patients with granulomatous angiitis and CAA, the vascular amyloid was positive for ß-protein (Figs 5a and 6a). The vascular amyloid was positive for AP in patient 2 but negative for AP in patient 1 (Fig 5b). There was no difference in the immunohistochemical features of granulomatous inflammation between the two patients. In the vascular walls, perivascular areas, and subarachnoid space, there were many Ki-M1P-positive monocyte/macrophage lineage cells, including multinucleated giant cells (Figs 5c and 6b) (Table 2). The multinucleated giant cells (Figs 5c and 6b) frequently contained ß-protein immunoreactivity in their cytoplasm (Figs 5a and 6a). In addition to the Ki-M1P-positive monocyte/macrophage lineage cells, there was infiltration of LCA-positive mononuclear cells. Most of them were UCHL1-positive (CD45RO⁺) T cells (Fig 6c) lacking a B cell marker (Fig 6d). As for T cell subsets, both CD4⁺ (helper/inducer) (Fig 6e) and CD8⁺ (cytotoxic/suppressor) (Fig 6f) subsets were observed. CD8⁺ cells frequently predominated over CD4⁺ cells. Some of the leptomeningeal and cortical vessels bearing ß-protein deposits presented with no granulomatous inflammation or overt cellular infiltration.

View larger version (77K): [in this window] [in a new window]   Figure 5. Immunostaining of a leptomeningeal artery with anti-ß-protein (a), anti-AP (b), and Ki-M1P (c) in a patient with CAA and granulomatous angiitis (patient 1 in Table 1). The vascular amyloid is positive for ß-protein (a) but negative for AP (b). There are a large number of Ki-M1P-positive monocyte/macrophage lineage cells in and around the vessels, including multinucleated giant cells (arrows) (c). The cytoplasm of the giant cells is positive for ß-protein, suggesting the phagocytosis of the amyloid (a). a, Anti-ß-protein, counterstained with hematoxylin; b, anti-AP, counterstained with hematoxylin; c, Ki-M1P, counterstained with methyl green; a, b, c, magnification x173, bar=100 µm.

View larger version (173K): [in this window] [in a new window]   Figure 6. Immunostaining of infiltrating inflammatory cells in and around the leptomeningeal vessels with anti-ß-protein (a), Ki-M1P (b), UCHL1 (T cell CD45RO) (c), L26 (B cell CD20) (d), OPD4 (CD4+ subset of T cells) (e), and CD8 (CD8+ subset of T cells) (f) in a patient with CAA and granulomatous angiitis (patient 1 in Table 1). Immunoreactivity of ß-protein is found in the cytoplasm of Ki-M1P-positive multinucleated giant cells (arrows) (a, b). Beside many Ki-M1P-positive monocyte/macrophage lineage cells (b), most of the mononuclear cells are UCHL1-positive T cells (c); B cells are almost absent (d). As for T cell subsets, both the CD4+ (e) and CD8+ cell subsets (f) are observed. The number of CD8+ cells appears larger than that of CD4+ cells. a, Anti-ß-protein, counterstained with hematoxylin; b, Ki-M1P, counterstained with methyl green; c, UCHL1, counterstained with methyl green; d, L26, counterstained with methyl green; e, OPD4, counterstained with methyl green; f, CD8, counterstained with methyl green; a through e, magnification x265, bar=100 µm.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In hereditary cerebral hemorrhage with amyloidosis, Dutch type (familial CAA characterized by deposition of a variant of ß-protein associated with a mutation in the amyloid ß-protein precursor gene),³¹ an increase of immunoreactivities of perivascular cell markers was previously described.³² Our results revealed that vascular amyloid deposition, in both elderly sporadic CAA (ß-protein amyloid angiopathy without mutation in the amyloid ß-protein precursor gene)³³ and HCHWA-I (cystatin C amyloid angiopathy with a mutation in the cystatin C gene),^{34 35 36 37} is commonly associated with an increase of vessel-associated monocyte/macrophage lineage cells. In a case of sporadic ß-protein amyloid angiopathy, multinucleated giant cells of monocyte/macrophage lineage were also observed in a few vessels heavily infiltrated with amyloid, suggesting more activation of the phagocytic cells. Since the increase or activation of monocyte/macrophage lineage cells was found in some but not all of the amyloid-laden vessels, it appeared unlikely that the increase or activation of vessel-associated monocyte/macrophage lineage cells was an event that is essentially required to induce or initiate vascular amyloid deposition, which would represent an immune reaction against the massive vascular deposition of amyloid proteins. This is consistent with the observation that strong monocyte/macrophage marker immunoreactivity was absent in the less advanced degree of vascular amyloid deposition of patients with Alzheimer's disease or Down's syndrome.³² The fact that the increase of perivascular and vascular monocyte/macrophage lineage cells was so mild that it could be recognized only by immunohistochemical analysis in most of the CAA cases may suggest that the amyloid deposits are immunologically rather inactive materials. Alternatively, there is the possibility that perivascular cells contribute to vascular deposition of vascular amyloid, as discussed by Wisniewski et al.¹⁹

We further analyzed the cases of CAA with granulomatous angiitis. Coexistence of CAA and granulomatous angiitis has been reported in several cases.^{1 3 4 5 7 8 9 10 11 12 13} Among such cases, the nature of amyloid protein was reported to be ß-protein in four patients^{9 10 11 12} and AL (amyloid protein derived from immunoglobulin light chains) in one patient³ ; clinical and laboratory evidence of cerebral angiitis was present in some patients^{4 5 8} but not in others, and some patients presented with radiological evidence of mass lesions.^{3 7 11 12} Granulomatous angiitis of the CNS is defined histologically by granulomatous inflammation of cerebral blood vessels.^{38 39 40 41} Different conditions such as infection and altered immunity may induce granulomatous angiitis, suggesting that granulomatous angiitis is not a unique disease but a nonspecific immune reaction in the blood vessels of the CNS.³⁸

In this study we characterized the deposited amyloid proteins and phenotypical composition of the infiltrating inflammatory cells in the two patients with coexisting CAA and granulomatous angiitis. Both of these cases showed vascular deposition of ß-protein. Marked vascular and perivascular infiltration of monocyte/macrophage lineage cells, including multinucleated giant cells, was observed. The cytoplasm of the giant cells frequently contained ß-protein. In addition to monocyte/macrophage lineage cells, infiltration of T cells also occurred. B cells were not observed. The infiltrating T cells included CD4⁺ (helper/inducer) and CD8⁺ (cytotoxic/suppressor) subsets; the CD8⁺ cells frequently predominated over the CD4⁺ cells in both cases. There have been no immunophenotypical studies of the infiltrating inflammatory cells in cases of CAA with granulomatous angiitis. In granulomatous angiitis of the CNS without CAA, absence of antibodies or immune complexes in the vascular wall was reported, suggesting a disorder of cell-mediated immunity.⁴² In a patient with isolated granulomatous angiitis of the spinal cord, the inflammatory infiltrate was reported to be predominantly composed of CD4⁺ T cells with sparse B and CD8⁺ T cells.⁴³

In one case of CAA with granulomatous angiitis (patient 1 in Table 1), the vascular amyloid was not labeled with the antibody to AP, suggesting the absence or scarcity of AP in the amyloid deposits. In the other case (patient 2) of CAA with granulomatous angiitis, sporadic ß-protein angiopathy of the elderly, and Icelandic hereditary cystatin C angiopathy, the vascular amyloid deposits were positive for AP. AP was a universal, nonfibrillar component of amyloid deposits produced by hepatocytes, although the physiological role of AP is not known.^{44 45} Pepys and colleagues⁴⁵ reported that AP prevents proteolysis of the amyloid fibrils of ß-protein and other systemic amyloidosis. They suggest that AP might protect amyloid from degradation by masking the abnormal fibrillar conformation that would otherwise be expected to trigger phagocytic clearance mechanisms^{44 45} and that phagocytes (monocyte/macrophage lineage cells) may lack receptor for AP because the only significant site of in vivo catabolism of AP is the hepatocyte.⁴⁶ These findings suggest that the absence or scarcity of AP in the vascular amyloid of patient 1 in our study might lead to exceptionally prominent reactions of monocyte/macrophage lineage cells (granulomatous angiitis) against the ß-protein. However, the observations that AP was detected in patient 2 in our study and two other reported cases of CAA with granulomatous angiitis^{3 11} indicate that granulomatous inflammation is not always associated with the absence of AP in amyloid deposits.

Prominent phagocytic reactions in CAA with granulomatous angiitis may be related to an abnormal immunologic condition of the host. Phagocytic reactions against amyloid deposits were observed in some patients with types of amyloidosis other than CAA.^{47 48 49} In ß₂-micro-globulin amyloidosis associated with hemodialysis, infiltration of macrophages was commonly found; it may be related to hemodialysis membrane-induced activation of phagocyte oxidative responses.^{49 50}

We considered that granulomatous angiitis represents a prominent granulomatous reaction against vascular amyloid, possibly through the aforementioned mechanisms. This is supported by the following observations: (1) an increase or activation of monocyte/macrophage lineage cells, including the occasional appearance of multinucleated giant cells, was found in CAA cases without granulomatous angiitis; and (2) even in the cases with coexisting CAA and granulomatous angiitis, some of the vessels bearing amyloid did not exhibit granulomatous inflammation.

The alternative possibility concerning the relationship between CAA and granulomatous angiitis is that chronic granulomatous inflammation of vessels (caused by an unidentified agent) disrupts homeostasis of ß-protein in the vessels and results in vascular deposition of ß-protein amyloid. This possibility suggests that existing vascular abnormalities, such as angiitis and vascular malformation,⁵¹ may be predisposing factors for deposition of ß-protein.

Although local secretion of cytokines has not been documented in granulomatous angiitis of the CNS, extracranial giant cell arteritis has shown in situ production of macrophage- and T cell-derived cytokines that would be involved in the progression of arteritis.⁵² Irrespective of the causal relationship between CAA and granulomatous inflammation, the infiltrating monocyte/macrophage lineage cells and T cells, as demonstrated in this study, would release cytokines and superoxide,^{52 53} resulting in further inflammation and tissue destruction in the vessel walls. Therefore, treatment of CAA-related granulomatous angiitis with corticosteroids or other immunosuppressive drugs may improve the clinical manifestations, as reported previously.^{8 12} An understanding of the etiology will aid in the determination of specific treatments.

In conclusion, in both the ß-protein and cystatin C amyloid angiopathies, cerebrovascular amyloid deposition was associated with an increase or activation of monocyte/macrophage lineage cells. Prominent reactions of monocyte/macrophage lineage cells admixed with CD4⁺ and CD8⁺ T cells (granulomatous angiitis) were occasionally associated with CAA. In some cases, the granulomatous reaction might be related to the absence or scarcity of AP, which has been reported to prevent phagocytic proteolysis of amyloid fibrils of ß-protein.

	Selected Abbreviations and Acronyms

 

AP = amyloid P component CAA = cerebral amyloid angiopathy CNS = central nervous system HCHWA-I = hereditary cerebral hemorrhage with amyloidosis, Icelandic type

	Acknowledgments

 
This study was supported in part by Health Science Research Grants (Mechanism of Abnormal Deposition in Brain Dementia) from the Ministry of Health and Welfare of Japan. The authors are grateful to Dr H. Mori for kindly providing the antibodies to amyloid ß-protein, human tau, and ubiquitin and to Dr A.O. Grubb for kindly providing the antibody to cystatin C.

Received January 26, 1996; revision received March 21, 1996; accepted April 3, 1996.

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