Parasite Immunology, 2007, 29, 621–636
DOI: 10.1111/j.1365-3024.2007.00967.x
Review Article
Immune REVIEWresponse ARTICLE in neurocysticercosis Blackwell Publishing Ltd
The immune response in Taenia solium cysticercosis: protection and injury E. SCIUTTO,1 A. CHAVARRIA,2 G. FRAGOSO,1 A. FLEURY3 & C. LARRALDE1 1
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, UNAM, México D.F., México, 2Facultad de Medicina, Universidad Nacional Autónoma de México, UNAM, México D.F., México, 3Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, México D.F., México
SUMMARY
CYSTICERCOSIS: A PERSISTING THREAT
This article reviews current knowledge on the innate and acquired immune responses in human Taenia solium neurocysticercosis, highlighting the conditions that appear to be favourable for the survival or destruction of the parasite and for the benefit or injury to its host.
Taenia solium is an ancient parasite that still threatens public health and porcine husbandry in Latin America, Africa and Asia, and is re-emerging in developed countries on account of the massive human migrations of modern times (1–4). Humans are the only definitive hosts of the intestinal adult tapeworm, the stage in which the parasite is capable of sexual reproduction and of massive egg production. Pigs, humans and to a minor extent also dogs (5) are nowadays the preferred hosts for the T. solium’s larval stage (i.e. cysticercus), a necessary stage in the parasite’s life cycle before its eventual transformation into an adult tapeworm upon the ingestion of cysticerci by humans after eating uncooked pork meat (Figure 1). After ingestion, T. solium eggs hatch in the intestines of the intermediate hosts, liberating motile oncospheres that penetrate in the circulation and distribute in the organism. Oncospheres may be established in muscles, subcutaneous connective tissues, central nervous system (CNS), liver and other organs, where they develop into cysticerci (6). Upon anatomic inspection, cysticerci in humans and pigs are found in different morphological states, some are clearly cystic with intact structures (vesicular) while others seem coagulated and their structures somewhat disassembled (colloidal) or they may be necrotic and sometimes calcified, partially or totally (calcified) (2), all with the potential of causing functional disturbances due to space occupation and/or local inflammation. In experimental infections of pigs it seems that, once developed, some cysticerci may die leaving scar tissue or nodular calcifications while others remain vesicular for longer periods. Genetic diversity among the parasite and the host, as well as immunological factors related with the host immunological
Keywords cysticercosis, immunity, inflammation, neurocysticercosis, Taenia solium
Correspondence: Edda Sciutto, Departamento de Inmunología, Instituto de Investigaciones Biomédicas, UNAM, A.P. 70228, México D. F. 04510, México (e-mail:
[email protected]). Received: 28 February 2007 Accepted for publication: 7 July 2007
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; NC, neurocysticercosis; NSE, neurone-specific enolase © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd
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Figure 1 Taenia solium life cycle (CistiMex; http://www-lab.biomedicas.unam.mx/cistimex).
history, including concomitant immunity, could underlie in these developmental differences among cysticerci from a single or from repeated infections. The anatomic location of the cysticerci may also participate in the various outcomes in the development of cysticerci. Heterogeneity among established cysticerci is particularly notable between those located in the muscles and those in the brain of infected pigs, a compartment with some immunological privileges wherein the parasites remain vesicular for much longer periods than those established in muscles (6), also observed in others that live-on causing chronic, mild or severe organic malfunction because of space occupation and/or local inflammation, especially when located in the brain.
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The traditional measures to control T. solium transmission (personal hygiene, proper sewage, meat inspection followed by destruction of infected carcasses) eventually rid Western Europe of cysticercosis in the late 18th century (7). Massive human treatment with niclosamide against the intestinal tapeworms, used in the Soviet Union in the first decades of the 1900s, is claimed to have been extremely effective (8). These control measures are not equally operative in underdeveloped countries of today. Poverty, ignorance, indolence, corruption, overpopulation and irregular distribution of civic privileges conspire with T. solium’s biological strategies to stabilize the endemia. Pursuit for profit has organized the clandestine trade of infected pork meat in rural endemic
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areas and is now menacing cities and nonendemic areas (9). The massive migration of rural people from endemic countries towards developed ones, carrying along with them the parasites, spread the infection and poses a threat of global proportions (4,10,11). Although much hope is now placed in developing technology to aid in diagnosis, prevention and treatment of neurocysticercosis (NC), the costs and logistics of applying the measures to obtain acceptable levels of control in endemic countries, where the parasite is firmly rooted, appear formidable (12). A fuller understanding of the immunological events and effectors may prove useful in dealing with the infection and its clinical outcome and costs.
ANTIGEN COMPOSITION OF CYSTICERCI The cysticercus of T. solium is an anatomically complex parasite (2) and so is its population’s genetic structure, quite diverse within and among continents (13–16) (Figure 2). It is therefore reasonable to expect that the parasite will express a complex and diverse set of antigens (17), which could contribute to the diversity of immune responses (Figure 3) and of the various clinical pictures of the disease. Few of its antigens are well documented to be specific of T. solium (18), a characteristic most valuable for diagnosis, but many others cross-react with those of the few other helminthes tested so far [i.e. T. saginata (19), T. crassiceps (20,21), Echinococcus granulosus (22), E. multilocularis (23) and Hymenolepis nana (24)]. Such extensive sharing of antigens may be viewed as a complex immunological network of different host and parasite species which, connecting through their common antigens, may potentially function as a collective unit embracing a number of host–parasite immunological relationships, thus modulating the course of the infections and the coevolution of the involved species (Figure 4). Table 1 (25–102) shows many of the T. solium antigens so far described, together with a mention of their relevance for the host–parasite relationship. Briefly, some of the most notorious prominent antigens in the literature are: (i) Antigen B (103), which is frequently recognized by patients with NC (93), is a paramyosin with properties similar to those of fibronectins in that it is capable of organizing the cells that surround the inflammatory reaction around the parasite through its association to human and porcine collagen (104). Antigen B can also bind factor C1q from the complement system, reducing the potential toxicity of antibody-mediated parasite damage (105); (ii) Other antigens extensively used in immunodiagnosis are some of the parasite’s glycoproteins that bind to lentil lectin (106) and are expressed in the parasite’s structures in contact with the host, as well as on the cells of the inflammatory response that surrounds the cysticercus, possibly modulating the associated immunologic
Figure 2 Genetic differences among pig Taenia solium cysticerci. Unweighted pair-group method with arithmetic means phenogram constructed using Nei and Li’s genetic distance among 90 T. solium cysticerci and a sample of T. crassiceps strain Ontario Research Foundation (Tc-ORF). Individuals with identical amplification profiles were grouped together and depicted with letters A–P. Central Mexico, Southeastern Mexico (SE Mexico) and Madagascar populations are structured in separate clusters, so is Tc-ORF, which acts as a positive control for random amplified polymorphic DNA capacity to distinguish between species of Taenia. The bold numbers at the nodes are the bootstrap confidence values obtained after 100 replicates (from 14).
response of the host (107); (iii) The cysticercus also secrets antigens to the environment with potential consequences in the regulation of the immune system (i.e. HP10, which was originally identified in T. saginata and is shared by T. solium (19,108), has been shown of value in the diagnosis of NC in the cerebrospinal fluid (CSF) (64) and in sera (109) of NC patients, and could have significant immunomodulatory consequences); (iv) TSOL 18, an oncospheral antigen of T. solium and T. saginata (110,111), confers high levels of protection to healthy pigs against a single controlled exposure to T. solium eggs in experimental optimal conditions (55,56); and (v) The peptide antigens GK1, KETc1 and KETc12, originally derived from T. crassiceps but also present in all
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Figure 3 Heterogeneous antibody composition in the cerebrospinal fluid of patients with neurocysticercosis against Taenia solium cysticercus antigens. Courtesy of Mario Perez.
developmental stages of T. solium (112,113), greatly reduce parasite loads and lowers prevalence of porcine cysticercosis by 50% –70% when used as a vaccine against natural infection in feral pigs living in highly endemic areas of Mexico (114).
THE IMMUNE RESPONSE IN HUMAN NEUROCYSTICERCOSIS The main clinical features of human NC In humans, cysticerci have been found in the CNS, the subcutaneous connective tissue, eyes, and skeletal and cardiac muscles (2). Cysticerci located in the CNS causes NC, the most severe form of the human infection. Human NC is clinically heterogeneous; it may course asymptomatic indefinitely or may lead to convulsions, cranial hypertension and cognitive disorders that require expert and expensive medical attention, sometimes surgery, chronically incapacitating the patient and disrupting the families’ occupations and economies (115). Human NC may also be fatal. In most infectious diseases, there is increasing evidence that the host’s immune inflammatory response to a pathogen implies benefits and costs to the host. The response may be seen as a two-edged physiological mechanism in which damage to the parasite (i.e. antibody-dependent, complementmediated parasite toxicity) implies the costs of injuring the host’s tissues (i.e. inflammation, necrosis and fibrosis). The balance of such a match possibly underlies in the very heterogeneous course and outcomes of infections (116): some infections being asymptomatic and others symptomatic, and even fatal. This could also be the case for NC, in which the immune response may lead to the destruction of the invading oncospheres and of the cysticercus, but it can also
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promote an inflammatory injury of surrounding tissues when the immune effectors engage with the parasite antigens. Thus, an energetic immune response by the human hosts may protect many from severe infection but may also cause in some an inflammatory reaction in the brain with significant clinical consequences (115). In fact, in severe NC cases, anti-inflammatory and/or immunosuppressive treatments to the host are frequently indicated, especially before and during cysticidal therapy (117,118), to counter the inflammatory reaction. On the other hand, some authors argue that antiinflammatory treatment could also be retarding the destruction of the parasite (119). The identification of the main organic scenarios where actors and mechanisms of the immunological response interact with the parasite to induce protection and/or injury could serve to develop stronger and safer strategies for the prevention and treatment of NC. More thorough research on the immunology of cysticercosis is also of interest for the design of better methods of immunodiagnosis and prognosis.
The plot and scenarios of immunity in NC When a pathogen enters an immunologically competent organism, an innate (nonspecific) and adaptive (specific) immunological response by the host may culminate with the destruction of the pathogen and/or of the host. The protective or pathogenic effectiveness of the innate response greatly depends on the generation of a nonspecific inflammatory phenomena locally in the surroundings of the pathogen, while that of the adaptive immune response rests on a systemic selective clonal proliferation of lymphoid cells and their posterior differentiation to effector cells type TH1 or TH2, with the subsequent production of various cytokines, or to plasma cells with the consequent production of specific antibodies. In humans, the great diversity of clinical forms associated with NC suggests its origins involve a complex participation of the immune system. The location of the parasite in the CNS, a compartment still under extense immunological study, difficults reaching reliable conclusions.
The local immunological actors in the brain Table 2 (120–135) shows the immunologic actors associated with the different clinical or radiological phenotypes of NC. From necropsies come the harder data on the immunological actors involved in the inflammatory process in NC. The cellular types associated with inflammation in the CNS are B and T lymphocytes, plasma cells, macrophages and mast cells (136). As for cytokines, it stands-out the presence of pro-inflammatory cytokines (IFNγ, IL6 and IL18), the TH2 cytokines (IL4, IL13), the anti-inflammatory cytokines
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Figure 4 Illustrative Western blots of sera from patients with neurocysticercosis and hydatid disease and normal donors with the antigens in the vesicular fluid of Taenia solium, Echinococcus granulosus and T. crassiceps metacestodes. The Western blot master pattern of each antigen preparation is shown on the left margin of each panel of blots (from 21). © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd, Parasite Immunology, 29, 621–636
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Figure 5 (a) Human cranial CT scan image of a single cysticercus without apparent anatomical alteration. (b) Multiple cysticerci displace and compress the cerebral brainstem.
(IL10 and TGF-β) and an increased expression of molecules associated with antigen presentation (137). It is debated whether the cytokines of the inflammatory phenomenon participate in the local damage of the CNS tissues as its cause or consequence (Figure 5). However, recent studies on the CSF of NC patients have failed to find enolase, a molecule associated with neuronal damage (138), suggesting that the anti-inflammatory cytokines may effectively control the potential damage of the inflammatory cytokines or that enolase is not an all-around effective indicator of brain damage. Attempts to characterize the phenotype of the inflammatory cells present in the CSF of NC cases have reported an increased number of B and CD8+ cells, many in an activated state (135), as well as an increment in the expression of adhesion molecules, especially in cases with highly inflammatory NC (28). In the same way, several studies have determined the types of cytokines present in the CSF. In patients with symptomatic NC, increased levels of inflammatory IL5 and IL6 were detected (122,123,127,134) together with the pro-inflammatory cytokines IL1β and TNFα in the CSF of NC cases with cysticerci located at the subarachnoidal space (120,123). In accordance with the histological observations of necropsies, high levels of IL10 in CSF were also detected, an immunosuppresor cytokine possibly participating in regulating the inflammation in NC (122,127).
The systemic immunological actors The CNS injuries, such as mechanical lesions or stroke, induce a systemic immunosuppression, which is characterized by a systemic shift towards a Th2 cytokine pattern which results in increased neuroprotection and regeneration (139) but may imply significant costs to the host’s health in other scenarios where antibodies are protective. A similar course may be followed by NC. However, the systemic immunological
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response in NC has been seldom explored in relation to the various clinical forms of the infection. The scarce reported information does not coincide totally among studies. Lack of coincidence may be pointing to NC heterogeneity or to significant differences in the studies’ inclusion criteria of NC cases. A first early study reported a systemic depression of the immunological response in patients with NC who were also receiving anti-inflammatory steroid therapy, a confounding variable because of the steroids’ intrinsic immunodepressive effects (138). However, later studies confirmed depressed, specific, systemic immunological responses in NC cases before treatment was established (28,130,133). Two of these latter studies reported that the NC cases had lower levels of antigen-specific cell proliferation than the controls, and that the cases with calcified NC were more deeply depressed than the cases with active NC (28,130). Moreover, the mononuclear cells in the peripheral blood of NC cases with inflammatory or active NC mainly produced IL4, IL12 and TNFα, while the cases with noninflammatory and inactive NC produced IL6, IL10, IL12 and TNFα (130). An additional study showed that symptomatic NC cases, affected predominantly by multiple vesicular parasites, exhibited low levels of antigen-specific lymphocyte proliferation without production of cytokines and high levels of the four subclasses of specific IgG in serum in comparison to the asymptomatic NC cases (127). It is possible that the high levels of specific antibodies detected could be a result of the presence of live parasites in the symptomatic NC cases, which actively stimulate the immunologic system by secreted antigens (71,72,127). On the other hand, the asymptomatic NC patients, with calcified lesions, could reflect infections resolved months or years before the studies were made and, for this reason, it associates to levels of antibodies that progressively decrease in tune with the progressive absence of antigenic stimuli (132). It is possible that antigen-specific immunodepression participates in the pathogenesis of NC by controlling the extension of the inflammatory phenomenon in the CNS, thus preventing major damage mediated by the entrance to the CNS of peripheral activated lymphocytes. Contrasting with the reported depression of antigenspecific cellular response, there are other reports of an increased proliferative response in NC, together with incremented production of IFNγ and IL2 when compared to the controls (121,129). People with asymptomatic NC from a rural community highly exposed to the parasite did not show increased rates of antigen-specific cellular proliferation in comparison with the controls of the same community, with the additional feature that the asymptomatic NC cases showed a cytokine profile predominantly of type TH2 (IL4, IL5 and IL13) (132). These immunological profiles were confirmed in a larger group of asymptomatic NC patients when compared to symptomatic patients (133).
© 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd, Parasite Immunology, 29, 621–636
Type of antigens
Denomination
Total antigens Vesicular fluid
Oncosphere
Scolex
10 kDa 26 kDa 35 kDa 70 kDa TSOL18 TSOL45 22, 22·5 kDa 31·3 kDa 64 kDa 70 kDa 13 kDa 17 kDa 26 kDa
Cystic wall Membrane antigens Secretion antigens
E/S
Use
Functional characterization
Reference
Diagnostic clinical follow Diagnostic characterization
Detection of antibodies in saliva, serum and CSF of NC patients. Specific PBMC proliferation of NC patients Antibody detection in serum and CSF of NC patients
(18,25– 36)
Antigenic differences between cysticerci from different continents
Diagnostic
Almost complete protection in experimental porcine cysticercosis Antibody detection in serum from pigs with porcine cysticercosis Detection of teniosis
(55– 58)
Diagnostic
Antibody detection in serum of active NC patients Specific PBMC proliferation of NC patients
(37,59,60)
Diagnostic Diagnostic
Antibody detection in serum of active NC patients Antibody detection in CSF of NC patients. Specific PBMC proliferation of NC patients Detection of circulating parasite antigens in serum and CSF of NC patients Detection of circulating parasite antigens in serum of epileptic patients and persons with teniosis Antibody detection in CSF of NC patients Correlation with parasite stage Detection of antibodies in saliva, serum and CSF of NC patients
(37) (35,51,59)
Diagnostic
HP10
Glycoproteins
66 kDa 190, 230 kDa Ts18var1
LLPG GP10, 13 GP24
Ag2 12, 16, 18, 32 kDa 30, 53, 64 100 kDa 200 kDa
Diagnostic physiopathology characterization
Detection of teniosis Detection of parasite-exposed persons Localization of antigenic glycoproteins during different parasite stages and during inflammation Specific PBMC proliferation of NC patients Evaluation of carbohydrates contribution to antigenicity Description of biochemical components from different glycoproteic fractions
(19,41,61– 75)
(25,30,32,41,42, 50,52,53,76– 92)
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GP39-42 GP50 Ag1V1
(20,21,31,35 – 54)
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Table 1 Taenia solium antigens recognized by NC patients
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Denomination
Antigen B
N-octil-βδ-glucopiranoside extract Recombinant antigens obtained from cDNA libraries
Tsol-sHSP35·6
GSL-I Calcium-binding protein Antibody detection in serum of NC patients
Functional characterization
Reference
Diagnostic
Antibody detection in CSF of NC patients Specific PBMC proliferation of NC patients Antibody detection in serum of NC patients Localization of glucose cotransporter sodium-dependent in different parasite stages Antibody detection in serum of NC patients Antibody detection in CSF of NC patients Calcareous corpuscles formation
(93,94)
Diagnostic Parasite physiology Diagnostic Diagnostic Physiopathology diagnostic
Diagnostic NC-3 NC-9 F18 Rec-Ag1V1/Ag2
(95) (96) (97) (98) (99)
Antibody detection in serum of NC patients
(41)
Antibody detection in serum of NC patients
(100 – 102)
Diagnostic
CSF, cerebrospinal fluid; LLPG, lentil lectin-purified glycoprotein; NC, neurocysticercosis; PBMC, peripheral blood mononuclear cells.
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Heat shock proteins Glucose cotransporter sodium-dependent Ether-delipidized antigens Major glycolipid Fraction of calcareous corpuscle
Use
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Table 2 Principal findings reported in the study of the immune response associated with NC Type of NC (number of cases)
Type of sample
Immune response
Reference
Immune response in the CNS Subarachnoid (55) Parenchyma (2), leptomeninges (2)
CSF Cerebral tissue
(120) (121)
Active (22), inactive (13)
CSF
Active (6), inactive (6)
CSF
Multiple (8), single (2)
Cerebral tissue
Colloidal (5), granulonodular (3)
Cerebral tissue
Colloidal (4), granulonodular (1)
Cerebral tissue
Inflammatory CSF (30), noninflammatory CSF (15)
CSF
Increased levels of IgG, IgM, IgE, IL1β and IL6 in NC patients Most frequent cell types found were plasma cells, NK cells, macrophages, granulocytes and T cells. IL12 and TGF-β were the predominant cytokines; INFγ, IL6 and IL10 were also detected. IL4 was not found Active NC patients presented higher levels of IL5 than controls. Patients with inflammatory CSF showed high levels of IL5 and IL10 Children with active NC had higher levels of TNFα when compared to those with inactive NC. Patients with NC of the subarachnoid space had increased levels of IL6 Numerous mast cells were found in the cerebral tissue of NC cases. Mast cells triptase positive infiltrate principally meninges and cerebral parenchyma around viable or necrotic parasites. Mast cells triptase-chymase positive are found principally in the perivascular space of deep cerebral blood vessels Damaged parasites are associated with fibrosis, angiogenesis and with an inflammatory infiltrate. The cell types more frequently found were plasma cells, B and T lymphocytes, macrophages and mast cells. TH1 (IFNγ and IL18), TH2 (IL4, IL10 and IL13) cytokines and TGF-β were also found Pro-inflammatory (IFNγ and IL18) and anti-inflammatory cytokines (TGF-β and IL10), and MHCII expression were increased in the nervous tissue associated with chronic lesions. Angiogenesis, collagen deposit and glial scar formation were also found Inflammatory CSF was associated with high levels of the four specific IgG subclasses, IL5, IL6 and IL10, proteins, and the presence of eosinophils. Clinical severity was associated with increased CSF cellularity. Multiple NC cases presented higher levels of IL5, IL6 and IL10 than patients with single lesions. Women showed higher levels of IL5, IL6 and IL10 than men. Patients with parasites in the subarachnoid space of the base or in ventricles presented higher levels of the four specific IgG subclasses, IL5, IL6 and IL10 NC cases with multiples lesions showed lower levels of chemotaxis than controls. NC cases with single lesions behaved the same as controls in the chemotactic response. Cellular proliferation, levels of CD4 and proportion of CD4/CD8 was normal in both groups when compared to controls NC cases showed increased specific cellular proliferation, less CD8+ cells, higher levels of IFNγ and IL2 when compared to controls NC patients showed specific cellular suppression when compared to controls. Patients with calcified NC showed more cellular suppression than patients with active NC NC patients showed similar levels of CD3, CD4 and CD8 cells, specific cellular proliferation and messenger RNA of IL2, IFNγ, IL10 and IL4 when compared to controls
(128)
Peripheral immune response Multiples (14), single (14)
PBMC
Multiples (15)
PBMC
Calcified (4), mixed (3), colloidal (4)
PBMC
Active (37)
PBMC
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(122)
(123)
(124)
(125)
(126)
(127)
(129)
(130)
(131)
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Table 2 Continued Type of NC (number of cases)
Type of sample
Immune response
Reference
Calcified (4), mixed (6)
PBMC/serum
(125)
Active (30), calcified (20)
PBMC/serum
Asymptomatic (10)
PBMC/serum
Asymptomatic (26), symptomatic (26)
PBMC/serum
NC cases had higher specific cellular proliferation indexes than controls. About 80% of the patients presented antibodies against the cestode glycoprotein Serum of NC cases recognizes preferentially carboxyl terminal region of the parasite’s paramyosin; in contrast, cellular response showed no preferential recognition Asymptomatic NC was associated with a TH2 immunological profile (IL4, IL5, IL13 and specific IgG4) Asymptomatic NC showed a TH2 profile (IL4, IL5 and IL13) with IL12 production and low levels of the four specific IgG subclasses. Symptomatic NC showed a specific T depression with high levels of the four specific IgG subclasses Specific IgG, soluble IL2R and neopterin in CSF diminished after praziquantel treatment. IL1β in serum and in CSF was in normal parameters. Neopterin in serum was in normal limits. Soluble IL2R in serum was increased during the follow-up year Increased levels of eotaxin and IL5 in serum and increased levels of IL5 and IL6 in CSF were found in NC patients when compared to controls NC patients presented normal percentages of CD3+ cells in peripheral blood and in CSF. CD69+ cells were only increased in CSF. Three inflammatory NC cases showed higher levels of CD8+ cells. Only patients with specific antibodies in CSF showed higher levels of CD45+ CD19+ cells Increased levels of CD19+ and CD56+ cells in CSF of NC patients. Inflammatory NC cases showed higher levels of adhesion molecules HCAM and ICAM and higher levels of CD8+ cells in peripheral blood and CSF compared with noninflammatory cases. All CSF cells of NC patients were CD69+, while in peripheral blood, only inflammatory patients presented higher levels of CD69+ cells. Lower levels of specific cell proliferation in NC cases than in controls. Inflammatory NC patients showed higher proliferation indexes than noninflammatory cases. Inflammatory cases showed principally IL4, IL12, TNFα, ICAM and VCAM, while noninflammatory cases showed IL6, IL10, IL12, TNFα, ICAM and VCAM
(34)
Peripheral and CNS immune response Parenchyma (17) CSF/serum
Multiple (12), single (2)
CSF/serum
Parenchyma (6), ventricular (1)
PBMC/CSF
Active/inflammatory (11), inactive/noninflammatory (11)
PBMC/CSF
(94)
(132) (133)
(134)
(135)
(28)
CNS, central nervous system; CSF, cerebrospinal fluid; NC, neurocysticercosis; PBMC, peripheral blood mononuclear cells; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; HCAM, human cell adhesion molecule.
The study of the immunologic response in human NC has allowed the sketching of profiles related to contact with T. solium but without apparent establishment of cysticerci. Such is inferred from the significant differences in the immune profiles of people living in nonendemic zones with those of highly endemic rural communities, which have higher levels of antigen-specific lymphocyte proliferation and IgG antibody levels, and a mixed TH1/TH2 cytokine profile characterized by the production of IL10 and TNFα after antigen-specific stimulation of peripheral mononuclear lymphoid cells (132).
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The benefits of immunity in NC While the mentioned observations point to some actors of the hosts’ immunological response associated with NC, their antiparasite activity remains somewhat unexplored and dubious overall. One of the better and early recognized protective mechanisms is that immune serum, presumably antibodies, destroy in vitro T. solium oncospheres, but not cysticerci, by fixing complement (57), pointing to the vulnerability of the early larval phases of parasite development and wide spreading the notion that cysticerci are impregnable
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to antibody attack. Later on, it was observed that vaccination of mice and pigs with a parasite epitope (GK1) induces the synthesis of antibodies that are capable of interfering with the cysticerci transformation into tapeworms in the intestines of hamsters (78,140). Likewise, intestinal tapeworms in hamsters and gerbils induce the apparition of masses of mast cells fully loaded with histamine near the tapeworms’ attachment sites in the intestinal mucosa and also promote the synthesis of specific antibodies circulating along with parasite-derived antigen, a fact taken to indicate that damage at the mucosal attachment sites allows for the triggering of a systemic immune response that injures the tapeworm letting out its antigens (141). The presence of great amounts of immunoglobulin on the surface of the cysticercus is consistent with a possible antigen-masking effect of antibodies protecting the parasite from a more efficient immunotoxic attack (93). In short, there is ample evidence of strong, varied and diverse immunological responses against T. solium by the infected human host, but the net beneficial effects of the multiple immune effectors may have upon the course of infection is incomplete.
The costs of immunity in NC Regarding the pathogenic effect upon the human host, brought about the host’s own immune response against T. solium, here follows a brief account of existing evidence and speculations that have led to the notion that immunoinflammation is involved in human NC brain pathology. The inflammatory response triggered by the cysticerci in the CNS can lead to the local increase of cytokines, polypeptides that regulate multiple functions and often trigger unpredictable interactions, such as the pro-inflammatory cytokines IL6 and IL5 (127). IL6 is one of the major inflammation-associated cytokines and is central to the global regulation of neurones, astrocytes and microglia, and to their activation in an injured nervous system (137). Elevated levels of these cytokines have been reported in different infectious diseases, including infections of the CNS (142). IL5 may induce infiltration and activation of eosinophils in the CNS, cells that can release inflammatory mediators which in turn will promote the inflammatory response (137). IL5 plus eotaxin, another eosinophil-selective mediator, could contribute to the recruitment of eosinophils (134). The production of these cytokines in the CNS could be critical for induction of Th1 activation, even if directed towards the destruction of the parasite, because neuroinflammatory processes can cause significant damage to the brain, triggering synaptic dysfunction and neuronal death (142). Recent efforts revealed that the levels in CSF of a glycolytic enzyme, almost exclusively present in neurones and neuroendocrine
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cells [neurone-specific enolase (NSE)], and the levels of a calcium-binding protein (S100B), produced and released predominantly by astrocytes (143), may be taken to estimate neuronal injury in different neurological disorders. However, the inflammatory response associated with cases of NC bearing a small number of degenerating cysts seems not to provoke significant neuronal damage as assessed by NSE and S100B levels in sera and CSF (144–146). The ability of IL10 to regulate microglial cell production of immune mediators and thereby diminish the pro-inflammatory response induced by the parasite could orchestrate the inflammatory response without clear damage to the CNS (147,148). The effect of IL10 over the resident glial cells can limit potentially damaging inflammation within the CNS in response to cysticerci and may underlie the reduced inflammation seen within most of the cysticerci located in brain parenchyma in most of the human NC cases. The possible neuroprotective role of IL6 could also contribute to prevent nondesirable effects upon the CNS. Indeed, neuroprotection is likely mediated by the IL6-induced protective factors, metallothioneinsI and -II (MT-I + II), both antioxidants and neuroregenerative factors in the CNS (149,150). The role of IL6 in the up-regulation of the hypothalamic–pituitary–adrenal axis could also contribute to produce additional factors that can modulate the inflammatory response related to NC (151). Nonetheless, the increased cell proliferation occurring in neuroinflammation (152) could enhance the probability of chromosome aberrations in the harbour regions constantly rearranged during T and B lymphocyte maturation (153), leading to malignant and neurodegenerative disorders (154 – 157). Although, however, in a retrospective cohort study including 10 350 neurological patients, it was concluded that the coexistence of NC and other lesions may be an incidental observation in the few patients referred from areas of high NC prevalence (158). Nevertheless, considering the increasing evidence of the relevance of neuroinflammation in neurodegenerative diseases and the clear histological evidence of damage in the nervous tissue adjacent to chronic cysticerci in NC (126), additional research should be encouraged to consider evaluating the impact of NC effects upon memory and cognitive abilities.
CONCLUSIONS In short then, as with the protective role of the immune response against T. solium, there is increasing evidence that many of the actors and mechanisms of the innate and acquired immune responses are deployed in the brain of human NC cases. However, the immune actors are so many in nature and function – and are connected in so complex a fashion – that no clear general statement may be confidently
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uttered other than that the immune system is surely capable of both destroying the parasite and of causing injury to the host. The net outcome depends on which of the many possible combinations involving the immune and the inflammatory response is in operation in the CNS surrounding the cysticerci of each patient at a given time and place. For practical therapeutic matters, it seems wise not to interfere with the inflammatory response of an NC patient as a general rule. Anti-inflammatory drugs could be reserved for the specific NC case of persisting severity coursing with diffuse encephalitis and/or basal meningitis, and intracranial hypertension (119).
ACKNOWLEDGEMENTS We thank Mercedes Baca and Marisela Hernandez for technical assistance. This work was supported by Dirección General de Asuntos del Personal Académico (IN-221905) and the CONACyT (46953-m and 2004-01-040).
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