Taenia solium neurocysticercosis - Wiley Online Library

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Dec 8, 2015 - Neurocysticercosis is a clinically and radiologically heteroge- neous disease, ranging from asymptomatic infection to a sev- ere, potentially fatal ...
Parasite Immunology, 2016, 38, 147–157

DOI: 10.1111/pim.12299

Review Article

Immunopathology in Taenia solium neurocysticercosis A. FLEURY,1 G. CARDENAS,1 L. ADALID-PERALTA,1 G. FRAGOSO2 & E. SCIUTTO2 1 Unidad Periférica de Neuroinflamación Instituto de Investigaciones Biomédicas/Instituto Nacional de Neurología y Neurocirugía, México City, México, 2Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México

SUMMARY Neurocysticercosis is a clinically and radiologically heterogeneous disease, ranging from asymptomatic infection to a severe, potentially fatal clinical picture. The intensity and extension of the parasite-elicited inflammatory reaction is a key factor for such variability. The main features of the inflammatory process found in the brain and in the peripheral blood of neurocysticercosis patients will be discussed in this review, and the factors involved in its modulation will be herein presented. Keywords immunity, inflammation, Neurocysticercosis, susceptibility, Taenia solium

disease and its response to treatment. It became apparent that this variability results from factors related to exposure (6), the parasite location, size, number, degenerative status, and to the age and gender of the host (7, 8). All these factors affect the magnitude of the inflammatory response, which critically correlates with the severity of the disease. The most prominent findings on the central and peripheral immune–inflammatory response, its regulation and its relation with the observed heterogeneity in neurocysticercosis are summarized in this article.

CENTRAL INFLAMMATION Brain tissue

INTRODUCTION Neurocysticercosis (NC) is a parasitic disease caused by the establishment of Taenia solium larvae in the central nervous system, which frequently and severely affects human health in developing countries (1). While most NC cases occur in developing countries (2), it is increasingly regarded an emerging disease and a growing public health concern in developed nations due to immigration (3, 4). An outstanding feature of NC is a heterogeneous clinical picture: it can be asymptomatic or range from clinically mild forms (headache, dizziness or occasional seizures) to a very severe neurological syndrome with intracranial hypertension (5). A number of biological factors both from the host and the parasite have been found involved in the susceptibility to NC infection, the severity of the

Correspondence: Agnès Fleury, Instituto de Investigaciones Biomédicas, UNAM, México/Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, Col. La Fama, México City, DF 14269, México. (e-mail: [email protected]) Disclosures: None. Received: 3 June 2015 Accepted for publication: 8 December 2015 © 2015 John Wiley & Sons Ltd

Few studies have analysed the local immune–inflammation surrounding human cysticerci when located in the brain. The characteristics of the findings are strongly influenced by the degenerative stages of the parasites. When the parasite is viable (vesicular stage), it presents a translucent wall, the fluid of the vesicle is transparent, and the scolex is viable and invaginated. In these cases, the inflammatory reaction around the parasite is scant, mainly composed by lymphocytes, plasma cells and eosinophils (9) (Table 1). In the colloidal stage, the parasite is degenerating, the wall of the vesicle is thick, and the vesicular fluid turbid and the scolex shows signs of hyaline degeneration. The inflammatory infiltrate is intense with a predominant NK response and abundance of macrophages and T cells, as with an antibody response (IgM+ plasmatic cells) (10). The main cytokines found are IL-2, IL-6, IL-12, TGF-b and IFN-c, while IL-4 is absent, showing the predominance of a Th1 inflammatory response (10). In the next degeneration stage (granular) in which scolex is completely degenerated, the most abundant cell types in the infiltrate around parasites are plasma cells, B and T lymphocytes, macrophages and mast cells. Th1 cytokines are prevalent and included IFNc, IL-18 and TGF-b. The Th2 cytokines IL-4, IL-13 and

147

148 Macrophages+++ (V, D) Plasma cell +++ (V, D) Lymphocytes ++ (V, D) Eosinophils ++ (V, D) (Brain tissue)

IL-10+++, IL-4++, TNF-a ++, IL-17+, IL-6+ (V, D) (Brain tissue) IL-4, IL-10, IL-1b, IL-2, IL-6, IL-8, IFN-c (D) (Brain tissue) Macrophages+++ (V) Plasmocytes ++ (V) Lymphocytes+ (V) Eosinophils+ (V) Neutrophils+ (V) (Brain tissue)

Macrophages+++ (V, D) Neutrophils++ (V, D) Eosinophils+ (V, D) T and B Lymphocytes+ (V, D) Mast cells ++ (D) NK cells +++ (V, D) Plasma cells+++ (V, D) Astrocytic gliosis +++ (D) Microglial proliferation (Brain tissue) Macrophages ++ (D) Mast cells ++ (D) Neutrophils + (D) CD4+ CD25 high (CSF) (V) CD4+ CD25 high FOXP3 (CSF) (V)

IL-2, IL-12, TGF-b (V) TGF-b, IL-10, IFN-c, IL-18, IL-4, IL-13 (D) IL-6, IL-10, IL-12, TGF-b, IFN-c, TNF-a, IL-18, IL-4 (VD) (Brain tissue) IL-1, IL-6, IL-5, IL10 (V, D) (CSF) IL-6, IL-5, IL-10, TGF-b (V, D) (CSF) Untreated inflammatory vs. noninflammatory IL-10, IL-17AF (V) (CSF) Treatment responder vs. nonresponder IFN-c, TNF-a, IL-4, IL-10, IL-23, IL-17, TGF-b (sera) IL-1, IL-10, IL-6 (V) (PBMC-SN)

IL-4, IL-5, IL-13, IgG4 (V, D) (PBMC-SN)

CD4+ CD25 high (V) CD4+ CD25 high FOXP3 (V) CD4+ CD25 high CTLA4 (V) CD4+ CD25 high IL-10 (V) CD4+ CD25 high FOXP3+ CD127- (V, D) CD4/8+ CD69+ (V) CD4+ CD38+ (V) SLAM+CD11C+ (V, D) CD205+ CD11C+ (Dendritic cell) (V, D)

Cells

CSF, cerebrospinal fluid; PBMC, peripheral blood mononuclear cells; SN, supernatant culture; +++, abundant; ++, moderate; +, few; V, vesicular; D, degenerative (colloidal, calcified or mixed).

Rat (73)

Pigs (13–15, 35, 71, 72)

Extraparenchymal (18, 19, 22, 27, 29)

Human Parenchyma/ subarachnoid sulci (10–12, 16, 18, 26, 62, 70)

Inflammatory mediators

Inflammatory mediators

Cells

Peripheral

Central nervous system

Table 1 Summary of immunopathological findings in T. solium neurocysticercosis

F. Agnes et al. Parasite Immunology

© 2015 John Wiley & Sons Ltd, Parasite Immunology, 38, 147–157

Volume 38, Number 3, March 2016

Immunopathology of Neurocysticercosis

Anomalies in cellularity and protein content in cerebrospinal fluid (CSF), as well as glycorrhachia, were found chiefly in cases of extraparenchymal parasite location. An increase in cell numbers (generally >300/mm3, mainly lymphocytes) and protein concentration (generally >300 mg/ mm3) along with a decrease in glucose concentration are frequent findings in these cases. Some in-depth descriptions of the cellular and immune– inflammatory status in NC patients have been undertaken. Chavarria et al. conducted studies where patients were stratified according to the clinical and radiological description of NC and were classified as mild, moderate or severe. The authors assessed the inflammation level according to the number of infiltrating lymphocytes in CSF. They found a relation between clinical severity and high CSF inflammation in NC patients. In addition, severe NC patients presented higher protein content values, higher eosinophil levels and higher IL-5, IL-10, IgG1, IgG2, IgG3 and IgE levels when compared to the mild and moderate NC patient groups (16). With respect to parasite location, a clear immune–inflammatory CSF profile was displayed in patients with

cysticerci located in the subarachnoid space (SA) of the base or intraventricularly, and most of them showed severe symptomatology, vesicular parasites and exhibited increased IL-5, IL-6 and IL-10 levels. In contrast, patients with cysticerci located in the SA of the sulci or parenchyma showed lower cytokine levels (16). Most inflammatory NC cases occurred when the parasite was vesicular and established in the SA of the base or in the ventricles. Interestingly, the parasite failed to show any radiological evidence of damage, a finding compatible with the infectiveness of the inflammatory response in these locations. Conversely, those parasites found in the SA of the sulci or in the parenchyma appeared frequently damaged, with low CSF inflammation and only mild or moderate symptomatology (16). Besides parasite location, another factor that seems to influence CSF inflammation is gender, as women display increased CSF cellularity (17). To evaluate the relevance of CSF cellularity, Saenz et al., analysed NC patients with inflammatory (≥10 infiltrating cells per mm3) and noninflammatory (