The adjuvant effect of benzo(a)pyrene on specific IgE production is linked with the accumulation of germinal center B cells within the spleen and extrafollicular b-cells ativation within the lungs

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Abstract

Despite a large number of works focused on the search for the mechanisms of formation of IgE-producing B cells, the question of the relative contribution of germinal centers and extrafollicular foci B cells in this process still remains controversial. Of particular interest is the study of the mechanisms of stimulation of the allergic immune response under the influence of air pollutants. The aim of the work was to study the connection between the adjuvant effect of benzo(a)pyrene (BaP) on the production of specific IgE in a novel low-dose allergy model with changes in the subpopulation composition of B-cells in the tissue of the immunization site and secondary lymphoid organs. Antigen without any stimuli was administrated to one group of BALB/c mice for 9 weeks in a low (0.3 μg) dose. BaP was administrated to another group of mice along with antigens at a dose of 4 ng. B-cell subpopulations were analyzed by flow cytometry. BaP significantly stimulated the production of allergen-specific IgG1 at early (3 weeks) time point, and allergen-specific IgE at late (9 weeks) time point. The aeropollutant increased the content of CD19+CD38–CD95+B220+ germinal center B-cells with the phenotype and their precursors (CD19+CD38+CD95+B220+) with the phenotype in the spleen at early and late time points, but not in the lungs or regional lymph nodes. Under its influence, the content of CD19+CD38–CD95+B220– and CD19+CD38+CD95+B220+ extrafollicular plasmablasts in the spleen at an early time point and in lung tissue at a later time point also increases. In the spleen, BaP increased the content of CD138+CD19–B220+ and CD138+CD19–B220– mature plasma cells, and in regional lymph nodes the content of CD138+CD19+B220– immature plasma cells at a later time point. The adjuvant effect of BaP on the production of specific IgE was largely associated with stimulation of the formation of germinal centers in the spleen and with extrafollicular activation of B cells in lung tissue.

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About the authors

D. B. Chudakov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Author for correspondence.
Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

O. A. Shustova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

M. A. Streltsova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

A. A. Generalov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

R. A. Velichinskii

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

O. D. Kotsareva

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

G. V. Fattakhova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, RAS

Email: boris-chudakov@yandex.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

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2. Fig. 1. Humoral response in BALB/c mice at early and late stages. Titers of specific IgE (a) and IgG1 (b) antibodies in BALB/c mice – intact (Int) or immunized intranasally with ovalbumin antigen (OVA) without benzo(a)pyrene or ovalbumin with benzo(a)pyrene (OVA + BaP) at the indicated times. * p < 0.05, ** p < 0.01 – reliability of differences between the indicated group and the intact group; # p < 0.05, ## p < 0.01 – reliability of differences between the groups immunized with and without BaP.

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3. Fig. 2. Strategy for analysis of B-lymphocyte and plasma cell subpopulations. The following subpopulations mentioned in the article are designated by numbers: I – total lymphoid cells; II – single cells; III – living cells; IV – CD138+CD19–B220+ mature plasma cells; V – CD138+CD19–B220– mature plasma cells; VI – CD138+CD19+B220+ plasmablasts; VII – CD138+CD19+B220–CD19+ immature plasma cells; VIII – CD38–CD95+B220–CD19+ activated plasmablasts of extrafollicular response; IX – CD38+CD95+B220–CD19+ activated plasmablasts of extrafollicular response; X – CD38–CD95+B220+CD19+ B-lymphocytes of germinal centers; XI – CD38+CD95+B220+CD19+ precursors of B-lymphocytes of germinal centers.

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4. Fig. 3. Content of subpopulations of follicularly activated B-lymphocytes in mice at different time points. The proportion of B-lymphocytes – precursors of germinal center cells CD38+CD95+B220+CD19+ (a–c) and actual germinal center B-lymphocytes CD38–CD95+B220+CD19+ (d–e) in CD19+ B-lymphocytes of lung tissue (a, g), regional lymph nodes (b, d) and spleen (c, f) in immunized mice at the indicated time points. * p < 0.05, ** p < 0.01 – reliability of differences between the indicated group and the intact group; # p < 0.05, ## p < 0.01 – reliability of differences between the groups immunized with and without BaR.

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5. Fig. 4. Content of subpopulations of extrafollicularly activated B lymphocytes in mice at different times. The proportion of different subpopulations of extrafollicularly activated B lymphocytes – CD38+CD95+B220–CD19+ (a–c) and CD38–CD95+B220–CD19+ (d–e) in CD19+ B lymphocytes of the lung tissue (a, g), regional lymph nodes (b, d) and spleen (c, f) in immunized mice at the indicated times. * p < 0.05, ** p < 0.01 – reliability of differences between the indicated group and the intact group; # p < 0.05, ## p < 0.01 – reliability of differences between the groups immunized with and without BaR.

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6. Fig. 5. Content of mature plasma cell subpopulations in mice at different time points. The proportion of subpopulations of mature CD138+CD19– plasma cells with high (a–c) and low (d–e) levels of B220 expression in living lymphoid cells of the lung tissue (a, g), regional lymph nodes (b, d) and spleen (c, f) in immunized mice at the indicated time points. * p < 0.05, ** p < 0.01 – reliability of differences between the indicated group and the intact group; # p < 0.05, ## p < 0.01 – reliability of differences between the groups immunized with and without BaR.

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7. Fig. 6. Content of immature plasma cell subpopulations in mice at different time points. The proportion of immature CD138+CD19+ plasma cell subpopulations with high (a–c) and low (d–e) B220 expression levels in living lymphoid cells of the lung tissue (a, g), regional lymph nodes (b, d) and spleen (c, f) in immunized mice at the indicated time points. * p < 0.05, ** p < 0.01 – significance of differences between the indicated group and the intact group; # p < 0.05, ## p < 0.01 – significance of differences between the groups immunized with and without BaR.

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