Abstract
The mechanisms involved in the development of resistance to infection/reinfection by Schistosoma mansoni still arouse great interest and controversy. Some authors demonstrate that resistance to infection is attributed to a mixed Th1 and Th2 response and resistance to reinfection after repeated treatments through mechanisms associated with the Th2 response. Through flow cytometry, the phenotypic characterization of B and T lymphocytes in individuals residing in endemic areas with low parasite loads over 10 years was evaluated for the first time in humans. In this study, individuals with low parasite loads for Schistosoma mansoni had a higher proportion of Th1 and Th2 cells. In addition, lymphocytes from these individuals showed a higher degree of expression of costimulatory molecules CD28 and CTLA-4 and regulatory molecules FoxP3 and IL-10, when compared to individuals with high parasite loads. Our data indicate that the control of the parasite load of S. mansoni must be associated with a Th1, Th2, and regulatory response, and that further studies are needed to elucidate the possibility of mechanisms associated with the hyporesponsiveness of lymphocytes from individuals with high parasite loads.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
References
Andrade ZA (2009) Schistosomiasis and liver fibrosis: schistosomiasis and liver fibrosis. Parasite Immunol 31:656–663. https://doi.org/10.1111/j.1365-3024.2009.01157.x
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4 + CD25 high regulatory cells in human peripheral blood. J Immunol 167:1245–1253. https://doi.org/10.4049/jimmunol.167.3.1245
Bahia-Oliveira LMG, Gazzinelli G, Eloi-Santos SM et al (1992) Differential cellular reactivity to adult worm antigens of patients with different clinical forms of schistosomiasiS. mansoni. Trans R Soc Trop Med Hyg 86:57–61. https://doi.org/10.1016/0035-9203(92)90441-E
Bensinger SJ, Walsh PT, Zhang J et al (2004) Distinct IL-2 receptor signaling pattern in CD4 + CD25 + regulatory T cells. J Immunol 172:5287–5296. https://doi.org/10.4049/jimmunol.172.9.5287
Boesteanu AC, Katsikis PD (2009) Memory T cells need CD28 costimulation to remember. Semin Immunol 21:69–77. https://doi.org/10.1016/j.smim.2009.02.005
Brasil - Ministério da Saúde (2018) Situação epidemiológica e estratégias de prevenção, controle e eliminação das doenças tropicais negligenciadas no Brasil, 1995 a 2016
Brito CF, Caldas IR, Coura Filho P et al (2000) CD4+ T cells of schistosomiasis naturally resistant individuals living in an endemic area produce interferon-gamma and tumour necrosis factor-alpha in response to the recombinant 14KDA Schistosoma mansoni fatty acid-binding protein. Scand J Immunol 51:595–601. https://doi.org/10.1046/j.1365-3083.2000.00710.x
Burke ML, Jones MK, Gobert GN et al (2009) Immunopathogenesis of human schistosomiasis. Parasite Immunol 31:163–176. https://doi.org/10.1111/j.1365-3024.2009.01098.x
Caldas IR, Campi-Azevedo AC, Oliveira LFA et al (2008) Human schistosomiasiS. mansoni: immune responses during acute and chronic phases of the infection. Acta Trop 108:109–117. https://doi.org/10.1016/j.actatropica.2008.05.027
Caldas IR, Correa-Oliveira R, Colosimo E et al (2000) Susceptibility and resistance to Schistosoma mansoni reinfection: parallel cellular and isotypic immunologic assessment. Am J Trop Med Hyg 62:57–64. https://doi.org/10.4269/ajtmh.2000.62.57
Chensue SW, Wellhausen SR, Boros DL (1981) Modulation of granulomatous hypersensitivity. II. Participation of Ly 1+ and Ly 2+ T lymphocytes in the suppression of granuloma formation and lymphokine production in Schistosoma mansoni-infected mice. J Immunol 127:363–367
Churlaud G, Pitoiset F, Jebbawi F, et al (2015) Human and mouse CD8+CD25+FOXP3+ regulatory T cells at steady state and during interleukin-2 therapy. Front Immunol 6:. https://doi.org/10.3389/fimmu.2015.00171
Correa-Oliveira R, Malaquias LC, Falcão P, et al (1998) Cytokines as determinants of resistance and pathology in human Schistosoma mansoni infection. Brazilian journal of medical and biological research = Revista brasileira de pesquisas médicas e biológicas / Sociedade Brasileira de Biofísica . [et al] 31:171–7. https://doi.org/10.1590/S0100-879X1998000100024
Correa-Oliveira R, Pearce EJ, Oliveira GC et al (1989) The human immune response to defined immunogens of Schistosoma mansoni: elevated antibody levels to paramyosin in stool-negative individuals from two endemic areas in Brazil. Trans R Soc Trop Med Hyg 83:798–804. https://doi.org/10.1016/0035-9203(89)90334-9
Corrêa-Oliveira R, Rodrigues Caldas I, Gazzinelli G (2000) Natural versus drug-induced resistance in Schistosoma mansoni infection. Parasitol Today 16:397–399. https://doi.org/10.1016/S0169-4758(00)01740-3
Couissinier-Paris P, Dessein AJ (1995) Schistosoma-specific helper T cell clones from subjects resistant to infection by Schistosoma mansoni are Th0/2. Eur J Immunol 25:2295–2302. https://doi.org/10.1002/eji.1830250827
de Jesus AR, Silva A, Santana LB et al (2002) Clinical and immunologic evaluation of 31 patients with acute schistosomiasiS. mansoni. J Infect Dis 185:98–105. https://doi.org/10.1086/324668
Dunne DW, Butterworth AE, Fulford AJ et al (1992) Immunity after treatment of human schistosomiasis: association between IgE antibodies to adult worm antigens and resistance to reinfection. Eur J Immunol 22:1483–1494. https://doi.org/10.1002/eji.1830220622
Elsheikh M, Doehring-Schwerdtfeger E, Kaiser C et al (1989) Renal function in Sudanese school children with Schistosoma mansoni infection. Pediatr Nephrol 3:259–264. https://doi.org/10.1007/BF00858526
Gazzinelli G, Colley DG (1992) Human immune responses during schistosomiasiS. mansoni. Rev Soc Bras Med Trop 25:125–134. https://doi.org/10.1590/S0037-86821992000200006
Gryschek RCB, Chieffi PP (2008) Esquistossomose. In: Parasitologia: uma abordagem clínica, 1st edn. Elsevier, p 456
Grzych JM, Pearce E, Cheever A et al (1991) Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasiS. mansoni. J Immunol 146:1322–1327
Hagan P, Wilkins HA, Blumenthal UJ et al (1985) Eosinophilia and resistance to Schistosoma haematobium in man. Parasite Immunol 7:625–632. https://doi.org/10.1111/j.1365-3024.1985.tb00106.x
Harris DP, Haynes L, Sayles PC et al (2000) Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 1:475–482. https://doi.org/10.1038/82717
Hirsch C, Goes AM (1996) Characterization of fractionated Schistosoma mansoni soluble adult worm antigens that elicit human cell proliferation and granuloma formation in vitro. Parasitology 112(Pt 6):529–535. https://doi.org/10.1017/s0031182000066105
Katz N, Coelho PM, Pellegrino J (1970) Evaluation of Kato’s quantitative method through the recovery of Schistosoma mansoni eggs added to human feces. J Parasitol 56:1032–1033
Lambertucci JR, Rayes AA, Barata CH et al (1997) Acute schistosomiasis: report on five singular cases. Mem Inst Oswaldo Cruz 92:631–635. https://doi.org/10.1590/s0074-02761997000500013
Lu L, Hu J, Chao T et al (2020) Loss of natural resistance to schistosome in T cell deficient rat. PLoS Negl Trop Dis 14:e0008909. https://doi.org/10.1371/journal.pntd.0008909
Lund FE, Randall TD (2010) Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 10:236–247. https://doi.org/10.1038/nri2729
McCormick PA, Murphy KM (2000) Splenomegaly, hypersplenism and coagulation abnormalities in liver disease. Baillieres Best Pract Res Clin Gastroenterol 14:1009–1031. https://doi.org/10.1053/bega.2000.0144
Ministério da Saúde (2021) Boletins epidemiológicos. https://antigo.saude.gov.br/images/pdf/2018/novembro/19/2018-032.pdf. Accessed 24 Jul 2021
Oliveira RR, Figueiredo JP, Cardoso LS et al (2012) Factors associated with resistance to Schistosoma mansoni infection in an endemic area of Bahia, Brazil. Am J Trop Med Hyg 86:296–305. https://doi.org/10.4269/ajtmh.2012.11-0204
Oliveira-Prado R, Caldas IR, Teixeira-Carvalho A et al (2009) CD4 and CD8 distribution profile in individuals infected by Schistosoma mansoni. Scand J Immunol 69:521–528. https://doi.org/10.1111/j.1365-3083.2009.02247.x
Pearce EJ, Caspar P, Grzych JM et al (1991) Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med 173:159–166. https://doi.org/10.1084/jem.173.1.159
Ridefelt P, Gustafsson J, Aldrimer M, Hellberg D (2014) Alkaline phosphatase in healthy children: reference intervals and prevalence of elevated levels. Horm Res Paediatr 82:399–404. https://doi.org/10.1159/000369205
Rodríguez-Pinto D, Moreno J (2005) B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154-CD40-dependent manner. Eur J Immunol 35:1097–1105. https://doi.org/10.1002/eji.200425732
Rumbley CA, Sugaya H, Zekavat SA et al (1999) Activated eosinophils are the major source of Th2-associated cytokines in the schistosome granuloma. J Immunol 162:1003–1009
Saito S, Sasaki Y, Sakai M (2005) CD4(+)CD25high regulatory T cells in human pregnancy. J Reprod Immunol 65:111–120. https://doi.org/10.1016/j.jri.2005.01.004
Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352. https://doi.org/10.1038/ni1178
Silveira AMS, Gazzinelli G, Alves-Oliveira LF et al (2004) Human schistosomiasiS. mansoni: intensity of infection differentially affects the production of interleukin-10, interferon-gamma and interleukin-13 by soluble egg antigen or adult worm antigen stimulated cultures. Trans R Soc Trop Med Hyg 98:514–519. https://doi.org/10.1016/j.trstmh.2003.11.009
Smythies LE, Coulson PS, Wilson RA (1992) Monoclonal antibody to IFN-gamma modifies pulmonary inflammatory responses and abrogates immunity to Schistosoma mansoni in mice vaccinated with attenuated cercariae. J Immunol 149:3654–3658
Sornasse T, Larenas PV, Davis KA et al (1996) Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level. J Exp Med 184:473–483. https://doi.org/10.1084/jem.184.2.473
Souza RP, Araújo MI, Lopes DM et al (2019) Characterization of memory T cells in individuals resistant to Schistosoma mansoni infection. Parasite Immunol 41:e12671. https://doi.org/10.1111/pim.12671
Souza RP, Cardoso LS, Lopes GTV et al (2012) Cytokine and chemokine profile in individuals with different degrees of periportal fibrosis due to Schistosoma mansoni infection. J Parasitol Res 2012:394981. https://doi.org/10.1155/2012/394981
Swartz JM, Dyer KD, Cheever AW et al (2006) Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood 108:2420–2427. https://doi.org/10.1182/blood-2006-04-015933
Takanaski S, Nonaka R, Xing Z et al (1994) Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils. J Exp Med 180:711–715. https://doi.org/10.1084/jem.180.2.711
Tung JW, Mrazek MD, Yang Y et al (2006) Phenotypically distinct B cell development pathways map to the three B cell lineages in the mouse. Proc Natl Acad Sci U S A 103:6293–6298. https://doi.org/10.1073/pnas.0511305103
Viana IR, Correa-Oliveira R, dos Carvalho O, S, et al (1995) Comparison of antibody isotype responses to Schistosoma mansoni antigens by infected and putative resistant individuals living in an endemic area. Parasite Immunol 17:297–304. https://doi.org/10.1111/j.1365-3024.1995.tb00895.x
Viana IR, Sher A, Carvalho OS et al (1994) Interferon-gamma production by peripheral blood mononuclear cells from residents of an area endemic for Schistosoma mansoni. Trans R Soc Trop Med Hyg 88:466–470. https://doi.org/10.1016/0035-9203(94)90436-7
Walsh CM, Smith P, Fallon PG (2007) Role for CTLA-4 but not CD25+ T cells during Schistosoma mansoni infection of mice. Parasite Immunol 29:293–308. https://doi.org/10.1111/j.1365-3024.2007.00947.x
Wang Y, Su MA, Wan YY (2011) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35:337–348. https://doi.org/10.1016/j.immuni.2011.08.012
WHO - World Health Organization (2021) Schistosomiasis (Bilharzia). https://www.who.int/health-topics/schistosomiasis. Accessed 24 Jul 2021
Williams ME, Montenegro S, Domingues AL et al (1994) Leukocytes of patients with Schistosoma mansoni respond with a Th2 pattern of cytokine production to mitogen or egg antigens but with a Th0 pattern to worm antigens. J Infect Dis 170:946–954. https://doi.org/10.1093/infdis/170.4.946
Wohlfert EA, Grainger JR, Bouladoux N et al (2011) GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J Clin Invest 121:4503–4515. https://doi.org/10.1172/JCI57456
Wynn TA, Oswald IP, Eltoum IA et al (1994) Elevated expression of Th1 cytokines and nitric oxide synthase in the lungs of vaccinated mice after challenge infection with Schistosoma mansoni. J Immunol 153:5200–5209
Yan J, Harvey BP, Gee RJ et al (2006) B cells drive early T cell autoimmunity in vivo prior to dendritic cell-mediated autoantigen presentation. J Immunol 177:4481–4487. https://doi.org/10.4049/jimmunol.177.7.4481
Funding
This work was supported by the Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), EDITAL 014/2013 – Apoio a Projetos de Pesquisa em Doenças Negligenciadas e do Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq/MST/INCT-DT, grant number 465229/2014-0.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by Robson da Paixão de Souza and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Gonçalo Moniz Research Center – CPqGM/Fiocruz/Ba (Opinion/Resolution n° 385.806 – 05/09/2013).
Consent
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare no competing interests.
Additional information
Section Editor: Robin Flynn
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
da Paixão de Souza, R., Araújo, M.I., Lopes, D.M. et al. Profile of T and B lymphocytes in individuals resistant to Schistosoma mansoni infection. Parasitol Res 121, 951–963 (2022). https://doi.org/10.1007/s00436-022-07435-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-022-07435-5