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B1 B lymphocytes play a critical role in host protection against lymphatic filarial parasites.

Paciorkowski N, Porte P, Shultz LD, Rajan TV - J. Exp. Med. (2000)

Bottom Line: These results suggest that B1 B cells are necessary to mediate host resistance to Brugian infection.Sterile clearance of the remaining parasite burden appears to require cell-mediated immunity.These data raise the possibility that the identification of molecule(s) recognized by humoral immune mechanisms might help generate prophylactic vaccines.

View Article: PubMed Central - PubMed

Affiliation: University of Connecticut Health Center, Farmington, Connecticut 06030-3105, USA.

ABSTRACT
Host defense against multicellular, extracellular pathogens such as nematode parasites is believed to be mediated largely, if not exclusively, by T lymphocytes. During our investigations into the course of Brugia malayi and Brugia pahangi infections in immunodeficient mouse models, we found that mice lacking B lymphocytes were permissive for Brugian infections, whereas immunocompetent mice were uniformly resistant. Mice bearing the Btk(xid) mutation were as permissive as those lacking all B cells, suggesting that the B1 subset may be responsible for host protection. Reconstitution of immunodeficient recombination activating gene (Rag)-1(-/)- mice with B1 B cells conferred resistance, even in the absence of conventional B2 lymphocytes and most T cells. These results suggest that B1 B cells are necessary to mediate host resistance to Brugian infection. Our data are consistent with a model wherein early resistance to B. malayi is mediated by humoral immune response, with a significant attrition of the incoming infectious larval load. Sterile clearance of the remaining parasite burden appears to require cell-mediated immunity. These data raise the possibility that the identification of molecule(s) recognized by humoral immune mechanisms might help generate prophylactic vaccines.

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(A) Relative amounts of peritoneal T and B lymphocytes in CBA/N mice vs. PEC-reconstituted littermates 2 wk after B. pahangi infection. PECs were collected from both cohorts of mice by peritoneal lavage, stained with anti–mouse CD19-biotin (for B lymphocytes) and anti–mouse CD3-FITC (for T lymphocytes) antibodies, and analyzed by flow cytometry. Lymphocytes recovered from each individual mouse were analyzed separately. Bars represent the average percentages of T or B cells in total PEC populations ±SD. (B) Comparison of peritoneal B lymphocytes in PEC-reconstituted vs. nonmanipulated CBA/N mice. Peritoneal lymphocytes were collected from B. pahangi–infected mice at 2 wk after infection and stained with IgM-FITC, CD5-PE, and CD19-biotin. B lymphocytes were gated as CD19+ cells and further divided on the basis of surface IgM and CD5 expression. In both panels, CD19+ gated peritoneal lymphocytes are analyzed for expression of CD5 (y-axis) and IgM (x-axis). Left, representative CBA/N mice reconstituted with PECs from uninfected CBA/CaJ mouse; right, representative unmanipulated CBA/N mouse. Note that the unmanipulated mouse has no CD5+ cells; the mouse with PECs from CBA/CaJ has abundant CD5+ cells.
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Figure 4: (A) Relative amounts of peritoneal T and B lymphocytes in CBA/N mice vs. PEC-reconstituted littermates 2 wk after B. pahangi infection. PECs were collected from both cohorts of mice by peritoneal lavage, stained with anti–mouse CD19-biotin (for B lymphocytes) and anti–mouse CD3-FITC (for T lymphocytes) antibodies, and analyzed by flow cytometry. Lymphocytes recovered from each individual mouse were analyzed separately. Bars represent the average percentages of T or B cells in total PEC populations ±SD. (B) Comparison of peritoneal B lymphocytes in PEC-reconstituted vs. nonmanipulated CBA/N mice. Peritoneal lymphocytes were collected from B. pahangi–infected mice at 2 wk after infection and stained with IgM-FITC, CD5-PE, and CD19-biotin. B lymphocytes were gated as CD19+ cells and further divided on the basis of surface IgM and CD5 expression. In both panels, CD19+ gated peritoneal lymphocytes are analyzed for expression of CD5 (y-axis) and IgM (x-axis). Left, representative CBA/N mice reconstituted with PECs from uninfected CBA/CaJ mouse; right, representative unmanipulated CBA/N mouse. Note that the unmanipulated mouse has no CD5+ cells; the mouse with PECs from CBA/CaJ has abundant CD5+ cells.

Mentions: Since Btkxid mice have deficits in B1 B lymphocytes, B2 B lymphocytes, and mast cells, we sought to further document that the lack of B1 lymphocytes is responsible for the permissiveness of Btkxid mice 14. Therefore, we reconstituted CBA/N mice with PECs from sex-matched uninfected CBA/CaJ mice. PECs are known to be enriched for B1 B cells, and the protocol for their isolation and transfer is well established 7. 6 d after reconstitution, reconstituted CBA/N mice (n = 10) and nonreconstituted controls (n = 9) received 50 B. pahangi L3 intraperitoneally. Both cohorts of mice were necropsied 2 wk after infection, and worm burdens were determined. The results, shown in Fig. 3, demonstrate a 50% reduction in worm burdens in PEC-reconstituted CBA/N mice compared with controls. At the time of necropsy, PECs from both reconstituted and nonmanipulated animals were recovered and stained for the presence of B1 or B2 lymphocytes, as well as T cells. FACS® analyses were performed on each mouse individually; however, since the animals within a cohort showed remarkable homogeneity, data are shown in Fig. 4 B from only one animal. Whereas there was little difference in the percentages of T cells between PEC-reconstituted and nonreconstituted CBA/N mice, the former show a significant increase in B lymphocyte percentage (Fig. 4 A). In addition, a population of CD5+ cells, missing in the control group, is seen in the CD19+IgM+ lymphocyte subset of PEC-reconstituted CBA/N mice. Thus, it would appear that host resistance to Brugia infection requires B1 B lymphocytes.


B1 B lymphocytes play a critical role in host protection against lymphatic filarial parasites.

Paciorkowski N, Porte P, Shultz LD, Rajan TV - J. Exp. Med. (2000)

(A) Relative amounts of peritoneal T and B lymphocytes in CBA/N mice vs. PEC-reconstituted littermates 2 wk after B. pahangi infection. PECs were collected from both cohorts of mice by peritoneal lavage, stained with anti–mouse CD19-biotin (for B lymphocytes) and anti–mouse CD3-FITC (for T lymphocytes) antibodies, and analyzed by flow cytometry. Lymphocytes recovered from each individual mouse were analyzed separately. Bars represent the average percentages of T or B cells in total PEC populations ±SD. (B) Comparison of peritoneal B lymphocytes in PEC-reconstituted vs. nonmanipulated CBA/N mice. Peritoneal lymphocytes were collected from B. pahangi–infected mice at 2 wk after infection and stained with IgM-FITC, CD5-PE, and CD19-biotin. B lymphocytes were gated as CD19+ cells and further divided on the basis of surface IgM and CD5 expression. In both panels, CD19+ gated peritoneal lymphocytes are analyzed for expression of CD5 (y-axis) and IgM (x-axis). Left, representative CBA/N mice reconstituted with PECs from uninfected CBA/CaJ mouse; right, representative unmanipulated CBA/N mouse. Note that the unmanipulated mouse has no CD5+ cells; the mouse with PECs from CBA/CaJ has abundant CD5+ cells.
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Figure 4: (A) Relative amounts of peritoneal T and B lymphocytes in CBA/N mice vs. PEC-reconstituted littermates 2 wk after B. pahangi infection. PECs were collected from both cohorts of mice by peritoneal lavage, stained with anti–mouse CD19-biotin (for B lymphocytes) and anti–mouse CD3-FITC (for T lymphocytes) antibodies, and analyzed by flow cytometry. Lymphocytes recovered from each individual mouse were analyzed separately. Bars represent the average percentages of T or B cells in total PEC populations ±SD. (B) Comparison of peritoneal B lymphocytes in PEC-reconstituted vs. nonmanipulated CBA/N mice. Peritoneal lymphocytes were collected from B. pahangi–infected mice at 2 wk after infection and stained with IgM-FITC, CD5-PE, and CD19-biotin. B lymphocytes were gated as CD19+ cells and further divided on the basis of surface IgM and CD5 expression. In both panels, CD19+ gated peritoneal lymphocytes are analyzed for expression of CD5 (y-axis) and IgM (x-axis). Left, representative CBA/N mice reconstituted with PECs from uninfected CBA/CaJ mouse; right, representative unmanipulated CBA/N mouse. Note that the unmanipulated mouse has no CD5+ cells; the mouse with PECs from CBA/CaJ has abundant CD5+ cells.
Mentions: Since Btkxid mice have deficits in B1 B lymphocytes, B2 B lymphocytes, and mast cells, we sought to further document that the lack of B1 lymphocytes is responsible for the permissiveness of Btkxid mice 14. Therefore, we reconstituted CBA/N mice with PECs from sex-matched uninfected CBA/CaJ mice. PECs are known to be enriched for B1 B cells, and the protocol for their isolation and transfer is well established 7. 6 d after reconstitution, reconstituted CBA/N mice (n = 10) and nonreconstituted controls (n = 9) received 50 B. pahangi L3 intraperitoneally. Both cohorts of mice were necropsied 2 wk after infection, and worm burdens were determined. The results, shown in Fig. 3, demonstrate a 50% reduction in worm burdens in PEC-reconstituted CBA/N mice compared with controls. At the time of necropsy, PECs from both reconstituted and nonmanipulated animals were recovered and stained for the presence of B1 or B2 lymphocytes, as well as T cells. FACS® analyses were performed on each mouse individually; however, since the animals within a cohort showed remarkable homogeneity, data are shown in Fig. 4 B from only one animal. Whereas there was little difference in the percentages of T cells between PEC-reconstituted and nonreconstituted CBA/N mice, the former show a significant increase in B lymphocyte percentage (Fig. 4 A). In addition, a population of CD5+ cells, missing in the control group, is seen in the CD19+IgM+ lymphocyte subset of PEC-reconstituted CBA/N mice. Thus, it would appear that host resistance to Brugia infection requires B1 B lymphocytes.

Bottom Line: These results suggest that B1 B cells are necessary to mediate host resistance to Brugian infection.Sterile clearance of the remaining parasite burden appears to require cell-mediated immunity.These data raise the possibility that the identification of molecule(s) recognized by humoral immune mechanisms might help generate prophylactic vaccines.

View Article: PubMed Central - PubMed

Affiliation: University of Connecticut Health Center, Farmington, Connecticut 06030-3105, USA.

ABSTRACT
Host defense against multicellular, extracellular pathogens such as nematode parasites is believed to be mediated largely, if not exclusively, by T lymphocytes. During our investigations into the course of Brugia malayi and Brugia pahangi infections in immunodeficient mouse models, we found that mice lacking B lymphocytes were permissive for Brugian infections, whereas immunocompetent mice were uniformly resistant. Mice bearing the Btk(xid) mutation were as permissive as those lacking all B cells, suggesting that the B1 subset may be responsible for host protection. Reconstitution of immunodeficient recombination activating gene (Rag)-1(-/)- mice with B1 B cells conferred resistance, even in the absence of conventional B2 lymphocytes and most T cells. These results suggest that B1 B cells are necessary to mediate host resistance to Brugian infection. Our data are consistent with a model wherein early resistance to B. malayi is mediated by humoral immune response, with a significant attrition of the incoming infectious larval load. Sterile clearance of the remaining parasite burden appears to require cell-mediated immunity. These data raise the possibility that the identification of molecule(s) recognized by humoral immune mechanisms might help generate prophylactic vaccines.

Show MeSH
Related in: MedlinePlus