Инфекция и иммунитет. 2016; 6: 55-66
ИЗОТИПИЧЕСКАЯ СТРУКТУРА ВИРУССПЕЦИФИЧЕСКОГО СИСТЕМНОГО ГУМОРАЛЬНОГО ИММУННОГО ОТВЕТА У ВЗРОСЛЫХ ПАЦИЕНТОВ, ГОСПИТАЛИЗИРОВАННЫХ С ГРИППОМ А
https://doi.org/10.15789/2220-7619-2016-1-55-66Аннотация
Целью работы являлся сравнительный анализ изотипической структуры специфического противовирусного системного гуморального иммунного ответа у госпитализированных пациентов с гриппом, вызванным вирусами А(H3N2) или А(H1N1), включая А(H1N1)pdm09. Методом ИФА были проанализированы парные сыворотки крови, полученные в острый и реконвалесцентный периоды заболевания от 109 взрослых пациентов в возрасте от 18 до 67 лет, перенесших лабораторно установленный грипп А. В качестве антигенов для сенсибилизации твердой фазы в ИФА использовали очищенные фракции поверхностных гликопротеинов вирусов гриппа А различных субтипов, содержащие гемагглютинин и нейраминидазу. Отсутствие консервативных типоспецифичных внутренних белков в антигенном материале позволило проводить в ИФА субтиповую дифференцировку грипп-специфичных антител. Независимо от субтипа вируса гриппа А, вызвавшего заболевание, наиболее выраженный ответ наблюдали со стороны субтипоспецифичных IgG1 (70–90% сероконверсий). Впервые было показано, что характерной чертой иммунного ответа на вирус гриппа A(H1N1)pdm09 как при первичном, так и при повторном заболеваниях, является низкая активность вирусиндуцированных IgG2 (6–9% сероконверсий). В группах пациентов, неоднократно перенесших «сезонный» грипп в 2007–2008 гг. или грипп A(H3N2) в 2012–2014 гг., частота сероконверсий IgG2 составила 40–59% (р < 0,05). Реакция вирусспецифичных IgG3 также была выражена слабее у пациентов с гриппом A(H1N1)pdm09 (29–44% сероконверсий), чем у пациентов, перенесших грипп A(H1N1) или A(H3N2) (65 и 56% сероконверсий соответственно). При гриппе A(H1N1)pdm09 в реакции микронейтрализации были выявлены значимо более низкие показатели среднегеометрических титров вируснейтрализующих антител в фазе реконвалесценции (1/28 и 1/103 при первичном и повторном заболеваниях), чем у пациентов, переболевших гриппом A(H1N1) или гриппом A(H3N2) (СГТ составили 1/594 и 1/378 соответственно). Показано, что поверхностные гликопротеины вирусов гриппа А могут выступать в качестве аллергенов. Частоты сероконверсий вирусспецифических IgЕ была сопоставима во всех группах пациентов, достигая 25–45%. Выявлена высокая активность вирусспецифических сывороточных IgА в группах пациентов, перенесших грипп A(H3N2) или A(H1N1)pdm09 (60–79% сероконверсий). Таким образом, изучение активности вирусспецифичных иммуноглобулинов различных изотипов позволяет получить важную информацию о формировании адаптивного противовирусного иммунного ответа при гриппе А, оценить вклад его протективной и иммунопатогенной составляющих в патогенез заболевания.
Список литературы
1. Кривицкая В.З., Соминина А.А., Суховецкая В.Ф., Милькинт К.К., Сверлова М.В. Иммунопатологический аллергический Th2-тип противовирусного гуморального иммунного ответа у детей с респираторно-синцитиальной вирусной инфекцией // Цитокины и воспаление. 2004. Т. 3, № 3. С. 34–41. [Krivitskaya V.Z., Sominina A.A., Sukhovetskaya V.F., Milkint K.K., Sverlova M.V. Immunopathological allergic Th2-type anti-viral humoral immune response in infants with respiratory syncytial viral infection. Tsitokiny i vospalenie = Cytokines and inflammation, 2004, vol. 3, no. 3, pp. 34–41. (In Russ.)]
2. Кривицкая В.З., Соминина А.А., Сорокин Е.В., Войцеховская Е.М., Милькинт К.К., Сироткин А.К. Разработка и изучение диагностических свойств ИФА-тест-систем для субтипоспецифической детекции антител к вирусам гриппа А (H1N1) и A (H3N2) // Вопросы вирусологии. 2002. Т. 47, № 3. С. 40–44. [Krivitskaya V.Z., Sominina A.A., Sorokin E.V., Voytsekhovskaia E.M., Milkint K.K., Sirotkin A.K. Development of immunoenzyme assay for subtype-specific detection of antibodies to influenza viruses A (H1N1) and A (H3N2). Voprosy virusologii = Problems of Virology, 2002, vol. 47, no. 3, рр. 40–44. (In Russ.)]
3. Соминина А.А., Кривицкая В.З., Войцеховская Е.М., Медведева Н.А., Липина Н.В., Потапенко Л.Б. Практические рекомендации по диагностике вирусных инфекций. СПб., 2005. 21 c. [Sominina A.A., Krivitskaya V.Z., Voytsekhovskaya E.M., Medvedeva N.A., Lipina N.V., Potapenko L.B. Prakticheskie rekomendacii po diagnostike virusnyh infekcij [Practical guidelines for the diagnosis of viral infections]. St. Petersburg, 2005, 21 p. (In Russ.)]
4. Akdis C.A., Blesken T., Akdis M., Alkan S.S., Heusser C.H., Blaser K. Glucocorticoids inhibit human antigen-specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro. Eur. J. Immunol., 1997, vol. 27, no. 9, pp. 2351–2357.
5. Al-Darmaki S., Knightshead K., Ishihara Y., Best A., Schenkein H., Tew J., Barbour S. Delineation of the role of platelet-activating factor in the immunoglobulin G2 antibody response. Clin. Diagnos. Labor. Immunol., 2004, vol. 11, no. 4, pp. 720–728.
6. Arankalle V.A., Lole K.S., Arya R.P., Tripathy A.S., Ramdasi A.Y., Chadha M.S., Sangle S.A., Kadam D.B. Role of host immune response and viral load in the differential outcome of pandemic H1N1 (2009) influenza virus infection in Indian patients. PLoS One, 2010, vol. 5, no. 10, e13099. doi: 10.1371/journal.pone.0013099
7. Braza F., Chesne J., Castagnet S., Magnan A., Brouard S. Regulatory functions of B cells in allergic diseases. Allergy, 2014, vol. 69, no. 11, pp. 1454–1463.
8. Burton O.T., Oettgen H.C. Beyond immediate hypersensitivity: evolving roles for IgE antibodies in immune homeostasis and allergic diseases. Immunol. Rev., 2011, vol. 242, no. 1, pp. 128–143. doi: 10.1111/j.1600-065X.2011.01024.x
9. El-Madhun A.S., Cox R.J., Haaheim L.R. The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination. J. Infect. Dis., 1999, vol. 180, no. 4, pp. 1356–1360.
10. Gordon C.L., Johnson P.D., Permezel M., Holmes N.E., Gutteridge G., McDonald C.F., Eisen D.P., Stewardson A.J., Edington J., Charles P.G., Crinis N., Black M.J., Torresi J., Grayson M.L. Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency. Clin. Infect. Dis., 2010, vol. 50, no. 5, pp. 672–678. doi: 10.1086/650462
11. Hocart M.J., Mackenzie J.S., Stewart G.A. Serum IgG subclass responses of humans to inactivated and live influenza A vaccines compared to natural infections with influenza A. J. Med. Virol., 1990, vol. 30, no. 2, pp. 92–96.
12. Hofmaier S., Comberiati P., Matricardi P.M. Immunoglobulin G in IgE-mediated allergy and allergen-specific immunotherapy. Eur. Ann. Allergy Clin. Immunol., 2014, vol. 46, no. 1, pp. 6–11.
13. Julkunen I., Hovi T., Seppälä I., Mäkelä O. Immunoglobulin G subclass antibody responses in influenza A and parainfluenza type 1 virus infections. Clin. Exp. Immunol., 1985, vol. 60, no. 1, pp. 130–138.
14. Kawano Y., Noma T., Yata J. Regulation of human IgG subclass production by cytokines. IFN-gamma and IL-6 act antagonistically in the induction of human IgG1 but additively in the induction of IgG2. J. Immunol., 1994, vol. 153, no. 11, pp. 4948–4958.
15. Li Z.N., Lin S.C., Carney P.J., Li J., Liu F., Lu X., Liu M., Stevens J., Levine M., Katz J.M., Hancock K. IgM, IgG, and IgA antibody responses to influenza A(H1N1)pdm09 hemagglutinin in infected persons during the first wave of the 2009 pandemic in the United States. Clin. Vaccine Immunol., 2014, vol. 21, no. 8, pp. 1054–1060. doi: 10.1128/CVI.00129-14
16. Lima M.T., Wilson D., Pitkin L., Roberts A., Nouri-Aria K., Jacobson M., Walker S., Durham S. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin. Exp. Allergy, 2002, vol. 32, no. 4, pp. 507–514.
17. Monteiro R.C. Role of IgA and IgA fc receptors in inflammation. J. Clin. Immunol., 2010, vol. 30, no. 1, pp. 1–9. doi: 10.1007/s10875-009-9338-0
18. Mewono L., Matondo Maya D.W., Matsiegui P.B., Agnandji S.T., Kendjo E., Barondi F., Issifou S., Kremsner P.G., Mavoungou E. Interleukin-21 is associated with IgG1 and IgG3 antibodies to erythrocyte-binding antigen-175 peptide 4 of Plasmodium falciparum in Gabonese children with acute falciparum malaria. Eur. Cytokine Netw., 2008, vol. 19, no. 1, pp. 30–36. doi: 10.1684/ ecn.2008.0114
19. Palladino G., Mozdzanowska K., Washko G., Gerhard W. Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice. J. Virol., 1995, vol. 69, no. 4, pp. 2075–2081.
20. Pedersen G.K., Höschler K., Øie Solbak S.M., Bredholt G., Pathirana R.D., Afsar A., Breakwell L., Nøstbakken J.K., Raae A.J., Brokstad K.A., Sjursen H., Zambon M., Cox R.J. Serum IgG titres, but not avidity, correlates with neutralizing antibody response after H5N1 vaccination. Vaccine, 2014, vol. 32, no. 35, pp. 4550–4557. doi: 10.1016/j.vaccine.2014.06.009
21. Schild G.C., Newman R.W., McGregor I.A., Williams K. The use of transportable single-radial-diffusion immunoplates in seroepidemiological studies of influenza in the Gambia. The occurrence and persistence of antibody to influenza A/Hong Kong/68
22. (H3N2) virus in selected inhabitants of two rural villages. Bull. World Health Organ., 1977, vol. 55, no. 1, pp. 3–13.
23. Smith-Norowitz T.A., Kusonruksa M., Wong D., Norowitz M.M., Joks R., Durkin H.G., Bluth M.H. Long-term persistence of IgE anti-influenza A HIN1 virus antibodies in serum of children and adults following influenza A vaccination with subsequent H1N1 infection: a case study. J. Inflamm. Res., 2012, vol. 5, pp. 111–116. doi: 10.2147/JIR.S34152
24. Stavnezer J., Kang J. The surprising discovery that TGF beta specifically induces the IgA class switch. J. Immunol., 2009, vol. 182, no. 1, pp. 5–7.
25. Sun Y., Bian C., Xu K., Hu W., Wang T., Cui J., Wu H., Ling Z., Ji Y., Lin G., Tian L., Zhou Y., Li B., Hu G., Yu N., An W., Pan R., Zhou P., Leng Q., Huang Z., Ma X., Sun B. Immune protection induced on day 10 following administration of the 2009 A/H1N1pandemic influenza vaccine. PLoS One, 2010, vol. 5, no. 12, e14270. doi: 10.1371/journal.pone.0014270
26. Torres M., Casadevall A. The immunoglobulin constant region contributes to affinity and specificity. Trends Immunol., 2008, vol. 29, no. 2, pp. 91–97. doi: 10.1016/j.it.2007.11.004
27. Vidarsson G., Dekkers G., Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol., 2014, vol. 5:520. doi: 10.3389/fimmu.2014.00520
28. Widhe M., Ekerfelt C., Forsberg P., Bergström S., Ernerudh J. IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-gamma-predominated disease. Scand. J. Immunol., 1998, vol. 47, no. 6, pp. 575–581.
29. Yamamoto T., Mizoguchi Y., Kaneno H., Yamamoto K., Inoue Y., Kawashima H., Kase T., Shimotsuji T. Serum immunoglobulin G subclass levels and estimated clinical severity caused by possible influenza A (H1N1) pdm 2009 infection. J. Infect. Chemother., 2013, vol. 19, no. 5, pp. 833–842. doi: 10.1007/s10156-013-0570-4
Russian Journal of Infection and Immunity. 2016; 6: 55-66
VIRUS-SPECIFIC HUMORAL IMMUNE RESPONSE ISOTYPIC STRUCTURE IN ADULT PATIENTS HOSPITALIZED WITH INFLUENZA A
https://doi.org/10.15789/2220-7619-2016-1-55-66Abstract
The aim of this investigation was a comparative analysis of isotypic structure of specific antiviral systemic humoral immune response in hospitalized patients with influenza caused by virus A(H3N2) or A(H1N1), including the A(H1N1)pdm09. Paired acute and convalescent phase sera from 109 adult patients aged 18 to 67 years with laboratoryconfirmed influenza A were analyzed by ELISA. Purified surface glycoproteins of influenza A viruses of different subtypes containing the hemagglutinin and neuraminidase were used as antigen for sensitization of plates in ELISA.The absence of type-specific conserved internal proteins in antigenic material allowed to carry out a subtype-specific differentiation of antibodies against influenza viruses in ELISA. Regardless of the subtype of influenza A viruses caused the disease, the most pronounced response was observed by subtype-specific IgG1 (70–90% of seroconversions). It has been shown for the first time that low activity of virus-induced IgG2 (6–9% of seroconversions) is a peculiarity of the immune response both to primary or recurrent infections with A(H1N1)pdm09. In patients repeatedly suffered by «seasonal» influenza A(H1N1) in 2007/2008 or influenza A(H3N2) in 2012–2014 IgG2 seroconversion’s rates were 40–59% (р < 0,05). Reaction virusspecific IgG3 was also weaker in patients with influenza A(H1N1)pdm09 (29–44% of seroconversions) than in subjects with influenza A(H1N1) or A(H3N2) (65% and 56% of seroconversions, respectively). Geometric mean titers of virus neutralizing antibodies identified during recovery phase in patients with primary and secondary influenza A(H1N1)pdm09 (1/28 and 1/103, respectively) were significantly lower than in patients recovered from influenza A(H1N1) or A(H3N2) (GMT were 1/594 and 1/378, respectively). It was shown that the surface glycoproteins of influenza A viruses may be an allergens. Virus-specific IgE seroconversion rates were comparable in all groups reaching 25–45%. The high activity of virus-induced serum IgA was detected in patients with influenza A(H3N2) or A(H1N1)pdm09 (60–79% of seroconversions). Thus, study of virus-specific activity of various immunoglobulin isotypes provides important information about the formation of adaptive antiviral immune response to influenza A viruses, and also estimate the contribution of its protective and immunopathogenic components to pathogenesis of the disease.
References
1. Krivitskaya V.Z., Sominina A.A., Sukhovetskaya V.F., Mil'kint K.K., Sverlova M.V. Immunopatologicheskii allergicheskii Th2-tip protivovirusnogo gumoral'nogo immunnogo otveta u detei s respiratorno-sintsitial'noi virusnoi infektsiei // Tsitokiny i vospalenie. 2004. T. 3, № 3. S. 34–41. [Krivitskaya V.Z., Sominina A.A., Sukhovetskaya V.F., Milkint K.K., Sverlova M.V. Immunopathological allergic Th2-type anti-viral humoral immune response in infants with respiratory syncytial viral infection. Tsitokiny i vospalenie = Cytokines and inflammation, 2004, vol. 3, no. 3, pp. 34–41. (In Russ.)]
2. Krivitskaya V.Z., Sominina A.A., Sorokin E.V., Voitsekhovskaya E.M., Mil'kint K.K., Sirotkin A.K. Razrabotka i izuchenie diagnosticheskikh svoistv IFA-test-sistem dlya subtipospetsificheskoi detektsii antitel k virusam grippa A (H1N1) i A (H3N2) // Voprosy virusologii. 2002. T. 47, № 3. S. 40–44. [Krivitskaya V.Z., Sominina A.A., Sorokin E.V., Voytsekhovskaia E.M., Milkint K.K., Sirotkin A.K. Development of immunoenzyme assay for subtype-specific detection of antibodies to influenza viruses A (H1N1) and A (H3N2). Voprosy virusologii = Problems of Virology, 2002, vol. 47, no. 3, rr. 40–44. (In Russ.)]
3. Sominina A.A., Krivitskaya V.Z., Voitsekhovskaya E.M., Medvedeva N.A., Lipina N.V., Potapenko L.B. Prakticheskie rekomendatsii po diagnostike virusnykh infektsii. SPb., 2005. 21 c. [Sominina A.A., Krivitskaya V.Z., Voytsekhovskaya E.M., Medvedeva N.A., Lipina N.V., Potapenko L.B. Prakticheskie rekomendacii po diagnostike virusnyh infekcij [Practical guidelines for the diagnosis of viral infections]. St. Petersburg, 2005, 21 p. (In Russ.)]
4. Akdis C.A., Blesken T., Akdis M., Alkan S.S., Heusser C.H., Blaser K. Glucocorticoids inhibit human antigen-specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro. Eur. J. Immunol., 1997, vol. 27, no. 9, pp. 2351–2357.
5. Al-Darmaki S., Knightshead K., Ishihara Y., Best A., Schenkein H., Tew J., Barbour S. Delineation of the role of platelet-activating factor in the immunoglobulin G2 antibody response. Clin. Diagnos. Labor. Immunol., 2004, vol. 11, no. 4, pp. 720–728.
6. Arankalle V.A., Lole K.S., Arya R.P., Tripathy A.S., Ramdasi A.Y., Chadha M.S., Sangle S.A., Kadam D.B. Role of host immune response and viral load in the differential outcome of pandemic H1N1 (2009) influenza virus infection in Indian patients. PLoS One, 2010, vol. 5, no. 10, e13099. doi: 10.1371/journal.pone.0013099
7. Braza F., Chesne J., Castagnet S., Magnan A., Brouard S. Regulatory functions of B cells in allergic diseases. Allergy, 2014, vol. 69, no. 11, pp. 1454–1463.
8. Burton O.T., Oettgen H.C. Beyond immediate hypersensitivity: evolving roles for IgE antibodies in immune homeostasis and allergic diseases. Immunol. Rev., 2011, vol. 242, no. 1, pp. 128–143. doi: 10.1111/j.1600-065X.2011.01024.x
9. El-Madhun A.S., Cox R.J., Haaheim L.R. The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination. J. Infect. Dis., 1999, vol. 180, no. 4, pp. 1356–1360.
10. Gordon C.L., Johnson P.D., Permezel M., Holmes N.E., Gutteridge G., McDonald C.F., Eisen D.P., Stewardson A.J., Edington J., Charles P.G., Crinis N., Black M.J., Torresi J., Grayson M.L. Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency. Clin. Infect. Dis., 2010, vol. 50, no. 5, pp. 672–678. doi: 10.1086/650462
11. Hocart M.J., Mackenzie J.S., Stewart G.A. Serum IgG subclass responses of humans to inactivated and live influenza A vaccines compared to natural infections with influenza A. J. Med. Virol., 1990, vol. 30, no. 2, pp. 92–96.
12. Hofmaier S., Comberiati P., Matricardi P.M. Immunoglobulin G in IgE-mediated allergy and allergen-specific immunotherapy. Eur. Ann. Allergy Clin. Immunol., 2014, vol. 46, no. 1, pp. 6–11.
13. Julkunen I., Hovi T., Seppälä I., Mäkelä O. Immunoglobulin G subclass antibody responses in influenza A and parainfluenza type 1 virus infections. Clin. Exp. Immunol., 1985, vol. 60, no. 1, pp. 130–138.
14. Kawano Y., Noma T., Yata J. Regulation of human IgG subclass production by cytokines. IFN-gamma and IL-6 act antagonistically in the induction of human IgG1 but additively in the induction of IgG2. J. Immunol., 1994, vol. 153, no. 11, pp. 4948–4958.
15. Li Z.N., Lin S.C., Carney P.J., Li J., Liu F., Lu X., Liu M., Stevens J., Levine M., Katz J.M., Hancock K. IgM, IgG, and IgA antibody responses to influenza A(H1N1)pdm09 hemagglutinin in infected persons during the first wave of the 2009 pandemic in the United States. Clin. Vaccine Immunol., 2014, vol. 21, no. 8, pp. 1054–1060. doi: 10.1128/CVI.00129-14
16. Lima M.T., Wilson D., Pitkin L., Roberts A., Nouri-Aria K., Jacobson M., Walker S., Durham S. Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clin. Exp. Allergy, 2002, vol. 32, no. 4, pp. 507–514.
17. Monteiro R.C. Role of IgA and IgA fc receptors in inflammation. J. Clin. Immunol., 2010, vol. 30, no. 1, pp. 1–9. doi: 10.1007/s10875-009-9338-0
18. Mewono L., Matondo Maya D.W., Matsiegui P.B., Agnandji S.T., Kendjo E., Barondi F., Issifou S., Kremsner P.G., Mavoungou E. Interleukin-21 is associated with IgG1 and IgG3 antibodies to erythrocyte-binding antigen-175 peptide 4 of Plasmodium falciparum in Gabonese children with acute falciparum malaria. Eur. Cytokine Netw., 2008, vol. 19, no. 1, pp. 30–36. doi: 10.1684/ ecn.2008.0114
19. Palladino G., Mozdzanowska K., Washko G., Gerhard W. Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice. J. Virol., 1995, vol. 69, no. 4, pp. 2075–2081.
20. Pedersen G.K., Höschler K., Øie Solbak S.M., Bredholt G., Pathirana R.D., Afsar A., Breakwell L., Nøstbakken J.K., Raae A.J., Brokstad K.A., Sjursen H., Zambon M., Cox R.J. Serum IgG titres, but not avidity, correlates with neutralizing antibody response after H5N1 vaccination. Vaccine, 2014, vol. 32, no. 35, pp. 4550–4557. doi: 10.1016/j.vaccine.2014.06.009
21. Schild G.C., Newman R.W., McGregor I.A., Williams K. The use of transportable single-radial-diffusion immunoplates in seroepidemiological studies of influenza in the Gambia. The occurrence and persistence of antibody to influenza A/Hong Kong/68
22. (H3N2) virus in selected inhabitants of two rural villages. Bull. World Health Organ., 1977, vol. 55, no. 1, pp. 3–13.
23. Smith-Norowitz T.A., Kusonruksa M., Wong D., Norowitz M.M., Joks R., Durkin H.G., Bluth M.H. Long-term persistence of IgE anti-influenza A HIN1 virus antibodies in serum of children and adults following influenza A vaccination with subsequent H1N1 infection: a case study. J. Inflamm. Res., 2012, vol. 5, pp. 111–116. doi: 10.2147/JIR.S34152
24. Stavnezer J., Kang J. The surprising discovery that TGF beta specifically induces the IgA class switch. J. Immunol., 2009, vol. 182, no. 1, pp. 5–7.
25. Sun Y., Bian C., Xu K., Hu W., Wang T., Cui J., Wu H., Ling Z., Ji Y., Lin G., Tian L., Zhou Y., Li B., Hu G., Yu N., An W., Pan R., Zhou P., Leng Q., Huang Z., Ma X., Sun B. Immune protection induced on day 10 following administration of the 2009 A/H1N1pandemic influenza vaccine. PLoS One, 2010, vol. 5, no. 12, e14270. doi: 10.1371/journal.pone.0014270
26. Torres M., Casadevall A. The immunoglobulin constant region contributes to affinity and specificity. Trends Immunol., 2008, vol. 29, no. 2, pp. 91–97. doi: 10.1016/j.it.2007.11.004
27. Vidarsson G., Dekkers G., Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol., 2014, vol. 5:520. doi: 10.3389/fimmu.2014.00520
28. Widhe M., Ekerfelt C., Forsberg P., Bergström S., Ernerudh J. IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-gamma-predominated disease. Scand. J. Immunol., 1998, vol. 47, no. 6, pp. 575–581.
29. Yamamoto T., Mizoguchi Y., Kaneno H., Yamamoto K., Inoue Y., Kawashima H., Kase T., Shimotsuji T. Serum immunoglobulin G subclass levels and estimated clinical severity caused by possible influenza A (H1N1) pdm 2009 infection. J. Infect. Chemother., 2013, vol. 19, no. 5, pp. 833–842. doi: 10.1007/s10156-013-0570-4
