86 Update TRENDS in Parasitology Vol.23 No.3

7 Peiper, O. (1910) Uber sauglingssterblichkeit und sauglingsernahrungim Bezirke Kilwa (Deutsch-Ostafrika). Arch. f. Schiffs- u. Tropen-Hyg.8, 233–259

8 Vittot, M. (1932) Bilharziose intestinale chez un tres jeune enfant.Arch. Mal. Appar. Dig. Mal. Nutr. 22, 47–48

9 Smith, F.M. and Gelfand, M. (1958) Bilharziasis in the African infantand child in theMtoko district, southern Rhodesia. Cent. Afr. J. Med. 4,287–288

10 Perel, Y. et al. (1985) Utilisation des collecteurs urinaires chez lesenfants de 0 a 4 ans en enquete de masse sur la schistosomose urinaireau Niger. Med. Trop. 45, 429–433

11 Traore,M. et al. (1998) Schistosomiasis haematobia inMali: prevalencerate in school-age children as index of endemicity in the community.Trop. Med. Int. Health 3, 214–221

12 Guyatt, H.L. et al. (1999) Can prevalence of infection in school-agedchildren be used as an index assessing community prevalence?Parasitology 118, 257–268

13 Woolhouse, M.E.J. et al. (2000) Exposure, infection and immuneresponses to Schistosoma haematobium in young children. Par-asitology 120, 37–44

14 Bosompem, K.M. et al. (2004) Infant schistosomiasis in Ghana: asurvey in an irrigation community. Trop. Med. Int. Health 9, 917–922

Corresponding author: Moreno, J. (javier.moreno@cib.csic.es).Available online 16 January 2007.

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15 Odogwu, S.E. et al. (2006) Schistosoma mansoni in infants (aged <3years) along the Ugandan shoreline of Lake Victoria. Ann. Trop. Med.Parasitol. 100, 315–326

16 Berhe, N. et al. (2004) Variations in helminth faecal egg counts inKato–Katz thick smears and their implications in assessinginfection status with Schistosoma mansoni. Acta Trop. 92, 205–212

17 Wilson, R.A. et al. (2006) The detection limits for estimates of infectionintensity in schistosomiasis mansoni established by a study in non-human primates. Int. J. Parasitol. 36, 1241–1244

18 King, C.H. et al. (2006) Transmission control for schistosomiasis – whyit matters now. Trends Parasitol. 22, 575–582

19 Balen, J. et al. (2006) Morbidity due to Schistosoma mansoni: anepidemiological assessment of distended abdominal syndrome inUgandan school children with observations before and 1-year afteranthelminthic chemotherapy. Trans. R. Soc. Trop. Med. Hyg. 100,1039–1048

20 Mehta, D.K. et al., eds (2004) WHO Model Formulary 2004. WHO( http://mednet3.who.int/EMLib/wmf.aspx)

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doi:10.1016/j.pt.2007.01.005

Changing views on Langerhans cell functions inleishmaniasis

Javier Moreno

Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientıficas, Ramiro de Maeztu 9, 28040-Madrid, Spain

The different functions of skin dendritic cell subsetsduring Leishmania infection were recently reviewed byRitter and Osterloh. In their article, they propose a newrole for epidermal Langerhans cells and dermal dendriticcells to explain the events that take place after inocu-lation by Leishmania.

The many functions of dendritic cellsDendritic cells (DCs) are a heterogeneous and widelydistributed group of migratory bone marrow-derived cellsthat specialize in the recognition, uptake, transport andprocessing of pathogen antigens. DCs have a key role in theadaptive immune response because they are the onlyantigen-presenting cell able to prime naıve T lymphocytes.DCs are also known to activate natural killer cells [1] andare involved in the induction of tolerance to self antigens inperipheral CD4+ and CD8+ T cells [2]. The expression ofmultiple cell-surface markers has also enabled the corre-lation between DC-specific subtypes and distinct effectorfunctions [3].

Langerhans cells (LCs) are a specific subset of skin DCsthat form a dense network in the supra-basal layer of theepidermis. LCs are thought to serve as sentinel cells thatsurvey the epidermis and are also speculated to haveprotective functions. It was widely accepted that upon

microbial infection, LCs take up antigens from thepathogen and then migrate to a T-cell-dependent area ofthe skin-draining lymph nodes in order to prime naıveT cells, a life cycle that established a paradigm for theother DCs [4] (Box 1). However, recent studies of themultiple DC types found in the lymphoid organs of miceand humans have shown that most DC subsets fail tofollow the life cycle typified by LCs. This has given rise toa scientificdebateon the functions ofLCs in vivo [5].A recentarticle by Ritter and Osterloh that revises the role of DCsubsets in the experimental model of leishmaniasis hasadded to the discussion [6]. The authors propose that theT-cell immune response against Leishmania major is,in fact, generated by dermal DCs and that LCs have aregulatory function instead and might be responsible forthe suppression of the inflammatory response againstL. major infection.

Visualizing skin dendritic cellsRitter and Osterloh [6] reconsider the new findings on thebiological role of both LCs and dermal DCs during L. majorinfection. These data enable a more accurate view of theevents that currently take place during parasite infection.Previous studies on the experimental mouse model ofleishmaniasis led to the ‘LC paradigm’ for this parasiticinfection. The cutaneous localization of LCs, the ability ofthese cells to phagocytose Leishmania parasites andto stimulate L. major-specific T-cell proliferation andlymphokine production in vitro, led Moll to propose that

Box 1. The Langerhans cell paradigm

The term ‘Langerhans cell paradigm’ makes reference to the process

of maturation and phenotypic differentiation that enables dendritic

cells to acquire immunogenic effector functions. LCs are usually

located in the skin where they are said to be immature. Upon

infection, LCs takeup microbial antigens and migrate to the draining

lymph node where they undergo maturation (accompanied by

phenotypic changes) and are then able to present peptides by MHC

receptors to prime T cells. It was frequently believed that this

differentiation process was common for all DCs and, therefore, the

LC situation became a paradigm.

Although the concept is not new, the term Langerhans cell

paradigm was recently coined by Wilson and Villadangos in an

article in which they proposed that this concept was not correct [4].

Update TRENDS in Parasitology Vol.23 No.3 87

LCs have a central role in the immune response againstLeishmania. It is thought that LCs take up parasites andtransport them to the draining lymph node to be presentedto specific T cells [7]. The development of geneticallyengineered mice that express enhanced green fluorescentprotein under the control of the Langerin gene (CD207), aC-type lectin that is a characteristic marker of epidermalLCs, has facilitated finding and distinguishing LCs fromdermal DCs in vivo. These two DC subsets are now knownto migrate to distinct areas of the T-cell-rich paracortex ofthe draining lymph nodes. LCs were located in the innerparacortex, whereas dermal DCs occupied the outer para-cortex, just beneath the B-cell follicles [8]. It has also beendemonstrated that contact hypersensitivity was exacer-bated rather than abrogated in the absence of LCs [9]and that dermal CD8a+ DCs are the main DC subsetinvolved in the triggering of cytotoxic T-lymphocyte immu-nity to subcutaneous infection by the influenza, herpessimplex and vaccinia viruses [10].

In the case ofL.major experimental infection, it has alsobeen shown that dermal DCs, rather than LCs, are crucialfor the initiation of specific T-cell responses. Differentassays demonstrated that in the draining lymph node ofL. major-infected mice, CD11b+ and CD8a+ DCs weresufficient to initiate a CD4+ T helper type 1 cell responseto control the parasite. Finally, Ritter et al. [11] demon-strated that after subcutaneous inoculation of L. major,parasite uptake was carried out in the dermis and the DCscapable of stimulating antigen-specific T-cell proliferationwere Langerin negative.

A new role for Langerhans cells in leishmaniasisThis new information enabled Ritter and Osterloh topropose that dermal DCs are responsible for the protectiveimmune response to intracellular L. major infectionin vivo. They also suggested a suppressor role for LCs thatwas based on their capacity to process and present parasiteantigens through theMHC class II receptor to CD4+ T cells,which might then differentiate into regulatory T cells.The authors speculate that LC-primed T cells would bein charge of suppressing the ongoing immune responseagainst the parasite, as previously postulated for contacthypersensitivity [9].

This new viewpoint on the role of LCs and dermal DCsin Leishmania infection represents an important challengeto the understanding of the immunopathogenesis of

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the disease. The function now assigned to LCs could haveimportant implications in the establishment and pro-gression of leishmaniasis and should be taken into accountin present and future research in this field. One aspect toevaluate is the role that LCs have in host susceptibility toinfection. According to the new model, the infection of LCsby L. major promastigotes could represent an evasionmechanism to avoid the host immune response and toinduce Leishmania-specific immunosupression, insteadof parasite control. Another aspect to analyse is the import-ance of LCs in the different clinical forms of cutaneousleishmaniasis and their interactions with different speciesof Leishmania.

LCs are also involved in the maintenance of peripheraltolerance to self antigens and, although the exact mech-anisms of tolerance induction are not well known, there aresome studies which confirm that LCs induce tolerance invivo when they present antigen in the steady state [12].In the absence of microbial threat, LCs might induceT-cell unresponsiveness against self antigens or harmlessenvironmental proteins. Leishmania parasites couldtake advantage of this tolerant state of LCs by infectingthem and inducing suppression. This situation mightexplain why LCs pulsed with L. major antigens fail toconfer complete protection to susceptible mice [13]and, although there is evidence for an immunogenicrole of LCs, it might restrict the use of antigen-pulsedLCs as a strategy for vaccination and therapy againstleishmaniasis.

Concluding remarksNew experimental models now enable the distinctionbetween DC subtypes that exist in the skin (i.e. epidermalLCs and dermal DCs). This enabled Ritter and Osterloh topropose that dermal DCs are responsible for the protectiveimmune response to intracellular L. major infection in vivoand that LCs could have a regulatory function and mightbe responsible for the suppression of the inflammatoryresponse against L. major infection. Further studies thatuse these experimental models will provide new insightsinto the immunopathogenesis of the disease.

Finally, future studies on DCs and their role inleishmaniasis will also have to consider those lymphoid-resident DCs populations, like plasmacytoid DCs andCD8+ DCs, which are dedicated to the presentation ofantigens that are donated by migratory skin-derivedDCs and that might have a key role in tolerance andimmunity to Leishmania parasites [14,15].

AcknowledgementsI thank Felix Tapia for critical reading and comments on the article. I amsupported by a ‘Ramon y Cajal’ contract from the Ministerio de Educaciony Ciencia and granted by Red de Investigacion Colaborativa enEnfermedades Tropicales from Fondo de Investigacion Sanitaria.

References1 Granucci, F. et al. (2004) A contribution of mouse dendritic cell-derived

IL-2 for NK cell activation. J. Exp. Med. 200, 287–2952 Steinman, R.M. et al. (2003) Tolerogenic dendritic cells. Annu. Rev.

Immunol. 21, 685–7113 Shortman, K. and Liu, Y.J. (2002) Mouse and human dendritic cell

subtypes. Nat. Rev. Immunol. 2, 151–161

88 Update TRENDS in Parasitology Vol.23 No.3

4 Wilson, N.S. and Villadangos, J.A. (2004) Lymphoid organ dendriticcells: beyond the Langerhans cells paradigm. Immunol. Cell Biol. 82,91–98

5 Romani, N. et al. (2006) Epidermal Langerhans cells – changing viewson their function in vivo. Immunol. Lett. 106, 119–125

6 Ritter, U. and Osterloh, A. (2006) A new view on cutaneous dendriticcell subsets in experimental leishmaniasis. Med Microbiol Immunol(Berl) (in press)

7 Moll, H. (1993) Epidermal Langerhans cells are critical forimmunoregulation of cutaneous leishmaniasis. Immunol. Today 14,383–387

8 Kissenpfennig, A. et al. (2005) Dynamics and function of Langerhanscells in vivo: dermal dendritic cells colonize lymph node areas distinctfrom slower migrating Langerhans cells. Immunity 22, 643–654

9 Kaplan, D.H. et al. (2005) Epidermal langerhans cell-deficient micedevelop enhanced contact hypersensitivity. Immunity 23, 611–620

10 Belz, G.T. et al. (2004) Cutting edge: conventional CD8a+ dendriticcells are generally involved in priming CTL immunity to viruses.J. Immunol. 172, 1996–2000

Corresponding author: Helmby, H. (helena.helmby@lshtm.ac.uk).Available online 16 January 2007.

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11 Ritter, U. et al. (2004) CD8a- and Langerin-negative dendritic cells, butnot Langerhans cells, act as principal antigen-presenting cells inleishmaniasis. Eur. J. Immunol. 34, 1542–1550

12 Shibaki, A. et al. (2004) Induction ofGVHD-like skindisease bypassivelytransferred CD8+ T-cell receptor transgenic T cells into keratin 14-ovalbumin transgenic mice. J. Invest. Dermatol. 123, 109–115

13 Berberich, C. et al. (2003) Dendritic cell (DC)-based protection againstan intracellular pathogen is dependent upon DC-derived IL-12 andcan be induced by molecularly defined antigens. J. Immunol. 170,3171–3179

14 Baldwin, T. et al. (2004) Dendritic cell populations in Leishmaniamajor-infected skin and draining lymph nodes. Infect. Immun. 72,1991–2001

15 Carbone, F.R. et al. (2004) Transfer of antigen between migrating andlymph node-resident DCs in peripheral T-cell tolerance and immunity.Trends Immunol. 25, 655–658

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doi:10.1016/j.pt.2007.01.002

Schistosomiasis and malaria: another piece of thecrossreactivity puzzle

Helena Helmby

Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel

Street, London WC1E 7HT, UK

The recent discovery that individuals living in endemicareas have antibodies in their sera that are crossreactivefor both helminth and malaria parasites raises importantquestions both of the interpretation of existing immu-noepidemiological data and of the basic biology of thehost and the parasites. One such shared antigen(SmLRR) has now been cloned and has, therefore,opened up an intriguing and exciting field of researchfor immunologists and parasitologists.

Do worm and Plasmodium co-infections really makeany difference?Two of the most important parasitic diseases in humansare malaria and schistosomiasis. Around 200 millionpeople are chronically infected with schistosomiasis and�300 million people contract malaria each year. In manyareas of the world, the two diseases are coendemic and,therefore, co-infections are common. For many parasiticinfections, protection is associated with either a T helper(Th)1 or a Th2 cytokine response and associated immuneeffector mechanisms. Animal models have clearly demon-strated that in the case of malaria a pro-inflammatory Th1response is often seen, whereas schistosomiasis is domi-nated by a robust Th2 response during chronic infection.Because these two types of responses are considered tobe mutually regulating, it has been suggested that oneresponse might dominate, perhaps leading to more severedisease.

It has already been established using animal models ofSchistosoma–Plasmodium co-infection that an inter-action between the two diseases can be detected [1,2]and the possible impact of helminth infections on malariamorbidity in humans is now under intense investigation[3,4]. Interestingly, several studies have reported conflict-ing results, ranging from increased severity of malaria toreduced incidence of malaria in co-infected individuals.The underlying reason for such different outcomes islikely to involve numerous factors, including differencesin study design and case definition in addition to meth-odology. Unsurprisingly, the immunoepidemiology of co-infections is a challenging field in which unexpectedresults often occur and great care is needed with dataanalysis and interpretation. The demonstration of anti-gen crossreactivity between co-infecting organisms adds afurther complication. A study by Naus et al. describedthe occurrence of Plasmodium falciparum–Schistosomamansoni crossreactive antibodies in sera from individualsliving in endemic areas [5]. This raised important ques-tions regarding the specificity of antibody responsesand the interpretation of data from the field obtainedusing crude antigen preparations. Recently, a study byPierrot et al. has characterized one such crossreactiveantigen (SmLRR) that is shared between Schistosomamansoni and Plasmodium falciparum [6]. This shedsnew light on the complexities of human immunoepide-miology and, perhaps, will encourage further evaluationof the importance of crossreacting antigens in P. falci-parum–S. mansoni infection in general and SmLRR inparticular.