Evaluation of Mucosal Humoral and Cellular Immune Responses to HIV in External Secretions and Mucosal Tissues

Author(s): Steffanie Sabbaj, Jiri Mestecky*.

Journal Name: Current Immunology Reviews

Volume 15 , Issue 1 , 2019

Submit Manuscript
Submit Proposal

Abstract:

The mucosal immune systems of the genital and intestinal tracts are considered as the most frequent sites of HIV-1 entry, displaying remarkable immunological differences in the systemic immune compartment which must be considered in the evaluation of humoral and cellular immune responses to HIV- 1. Marked differences in the fluids from the genital and intestinal tracts and in plasma with respect to the Ig isotypes, their levels, molecular forms and distinct effector functions must be taken into consideration in the evaluation and interpretation of humoral immune responses. Because of the low levels and highly pronounced variation in Ig content, HIV-1-specific antibody concentrations should always be related to the levels of total Ig of a given isotype. This practice will avoid inevitable differences due to the small volumes of collected fluids and sample dilution during the collection and processing of samples from external secretions. Furthermore, appropriate controls and immunochemical assays should be used to complement and confirm results generated by ELISA, which is prone to false positivity. In the evaluation of antibodymediated virus neutralization in external secretions, precautions and rigorous controls must be used to exclude the effect of innate humoral factors.

The evaluation of cell-mediated immune responses in mucosal tissues is difficult due to the low yields of cells obtained from tissue biopsies or cytobrush scrapings. Furthermore, tissue biopsies of, for example, rectal mucosa, provide information pertaining exclusively to this local site, which due to the differences in the distribution of cells of different phenotypes, does not provide generalized information to the entire intestinal tract. Importantly, studies concerning the kinetics of cellular responses are difficult to perform due to the limited availability of samples or the inability of obtaining frequently repeated tissue biopsies. For sampling the female genital tract, parallel collection of menstrual and peripheral blood yields high numbers of cells that permit their detailed phenotypic and functional analyses. In contrast to tissue biopsies, this non-traumatic collection procedure results in high cell yields and repeated monthly sampling permits extensive and parallel functional studies of kinetics and unique characteristics of HIV-1-specific cellular responses in the female genital tract and peripheral blood.

Keywords: Secretory IgA (S-IgA), Peyer's Patches, T cells, genital tract, gastrointestinal tract, immune responses.

[1]
Jackson S, Moldoveanu Z, Mestecky J. Appendix I: Collection and processing of human mucosal secretions. In: Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroute H, Lambrecht BN, Eds. Mucosal Immunology. 4th ed. Elsevier/Academic Press, Amsterdam 2015; 2345-2344.
[2]
Mestecky J, Moldoveanu Z, Smith PD, Hel Z, Alexander RC. Mucosal immunology of the genital and gastrointestinal tracts and HIV-1 infection. J Reprod Immunol 2009; 83: 196-200.
[3]
Wahl SM, Redford M, Christensen BS, et al. Systemic and mucosal differences in HIV burden, immune and therapeutic responses. AIDS 2011; 56: 401-11.
[4]
Mestecky J, Jackson S, Moldoveanu Z, et al. Paucity of antigen-specific IgA responses in sera and external secretions of HIV-1-infected individuals. AIDS Res Hum Retroviruses 2004; 20: 972-88.
[5]
Conley ME, Delacroix DL. Intravascular and mucosal immunoglobulin A: Two separate but related systems of immune defense? Ann Intern Med 1987; 106: 892-9.
[6]
Mestecky J, Raska M, Novak J, Alexander RC, Moldoveanu Z. Antibody-mediated protection and the mucosal immune system of the genital tract: Relevance to vaccine design. J Reprod Immunol 2010; 85: 81-5.
[7]
Mestecky J. Humoral immune responses to the Human Immunodeficiency Virus type-1 (HIV-1) in the genital tract as compared to other mucosal sites. J Reprod Immunol 2007; 73: 86-97.
[8]
Mestecky J, Moldoveanu Z, Russell MW. The immunological uniqueness of the genital tract: Challenge for vaccine development. Am J Reprod Immunol 2005; 53: 208-14.
[9]
Mestecky J, Alexander RC, Wei Q, Moldoveanu Z. Methods of evaluation of humoral immune responses in human genital tract secretions. Am J Reprod Immunol 2011; 65: 361-7.
[10]
Raux M, Finkielsztejn L, Salmon-Ceron D, et al. Development and standardization of methods to evaluate the antibody response to an HIV-1 candidate vaccine in secretions and sera of seronegative vaccine recipients. J Immunol Methods 1999; 222: 111-24.
[11]
Mestecky J, Jackson S, Moldoveanu Z. Manual for Collection and Processing of mucosal specimens Germantown. MD: NIH AIDS Research and Reference Reagent Program 1999 Available from:.https://www.aidsreagent.org/support_docs/manual.pdf
[12]
Woof JM, Mestecky J. Mucosal Immunoglobulins. In: Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroute H, Lambrecht BNMucosal Immunology4th Edition Elsevier/Academic Press, Amsterdam 2015; Chapter 17, pp 287-324.
[13]
Pakkanen SH, Kantele JM, Moldoveanu Z, et al. Expression of homing receptors on IgA1 and IgA2 plasmablasts in blood reflects the differential distribution of IgA1 and IgA2 in various body fluids. Clin Vaccine Immunol 2010; 17: 393-401.
[14]
Crowley-Nowick PA, Bell M, Edwards RP, et al. Normal uterine cervix: Characterization of isolated lymphocyte phenotypes and immunoglobulin secretion. Am J Reprod Immunol 1995; 34: 241-7.
[15]
Kutteh W, Hammond K, Prince S, Wester R, Mestecky J. Production of immunoglobulin A by the cervix of the human female genital tract. In: Dondero F, Johnson PM, Eds. Reproductive Immunology. Raven Press: New York, 1993; 97: 151-8.
[16]
Kutteh WH, Hatch KD, Blackwell RE, Mestecky J. Secretory immune system of the female reproductive tract: I. Immunoglobulin and secretory component-containing cells. Obstet Gynecol 1988; 71: 56-60.
[17]
Jalanti R, Isliker H. Immunoglobulins in human cervicovaginal secretions. Int Arch Allergy Appl Immunol 1977; 53: 402-8.
[18]
Kutteh WH, Prince SJ, Hammonds KR, Kutteh CC, Mestecky J. Variations in immunoglobulins and IgA subclasses of human uterine cervical secretions around the time of ovulation. Clin Exp Immunol 1996; 104: 538-42.
[19]
Crowley-Nowick PA, Edwards RP, Moldoveanu Z, Kutteh W, Mestecky J. Menstrual cycle: Effects on vaccine-induced antibodies in genital tract secretions. In: Husband AJ, Beagley mucosal immunology. The University of Sydney, Australia 1997; 1: 393-401
[20]
Moldoveanu Z, Huang WQ, Kulhavy R, Pate MS, Mestecky J. Human male genital tract secretions: Both mucosal and systemic immune compartments contribute to the humoral immunity. J Immunol 2005; 175: 4127-36.
[21]
Anderson DJ, Pudney J. Human male genital tract immunity.In: Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroute H, Lambrecht BN. Mucosal Immunology4th Edition Elsevier/Academic Press, Amsterdam 2015; Chapter 109, pp 287- 324.
[22]
Tjokronegoro A, Sirisinha S. Degradation of immunoglobulins by secretions of the human reproductive tract. J Reprod Fertil 1974; 38: 221-5.
[23]
Bouvet JP, Belec L, Pires R, Pillot J. Immunoglobulin G antibodies in human vaginal secretions after parenteral vaccination. Infect Immun 1994; 62: 3957-67.
[24]
Underdown B. Parenteral Immunization induces mucosal protection: A Challenge to mucosal immunity paradigm. In: Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayer L, EdsMucosal Immunology3rd ed Amsterdam, The Netherlands, Elsevier Academic Press; 2005, Chapter 45, p 831- 40.
[25]
Li Z, Palaniyandi S, Zeng R, Tuo W, Roopenian DC, Zhu X. Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection. Proc Natl Acad Sci USA 2011; 108: 4388-93.
[26]
Russell MW, Lue C, van den Wall Bake AWL, Moldoveanu Z, Mestecky J. Molecular heterogeneity of human IgA antibodies during an immune response. Clin Exp Immunol 1992; 87: 1-6.
[27]
Russell MW, Kilian M. Biological activities of IgA.. In: Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayer L, EdsMucosal Immunology. 3rd ed. Amsterdam, The Netherlands: Elsevier Academic Press 2005; pp. 267-89.
[28]
van Egmond M, Bakema JE, Woof JM. Fc receptors in mucosal immunology. In: Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroute H, Lambrecht BN.Mucosal Immunology, 4th Edition Elsevier/Academic Press, Amsterdam 2015; Chapter 20, pp 409- 428.
[29]
Baker K, Blumberg RS, Kaetzel CS. Immunoglobulin transport and immunoglobulin receptors.In: Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroute H, Lambrecht BN. Mucosal Immunology, 4th Edition. Elsevier/Academic Press, Amsterdam 2015; Chapter 19, pp. 349-407
[30]
Huang YT, Wright A, Gao X, Kulick L, Yan H, Lamm M. Intraepithelial cell neutralization of HIV-1 replication. J Immunol 2005; 174: 4828-35.
[31]
Mestecky J, McGhee JR, Immunoglobulin A. IgA): Molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv Immunol 1987; 40: 153-245.
[32]
Mestecky J, Qing W, Alexander R, Raska M, Novak J, Moldoveanu Z. Humoral immune responses to HIV in the mucosal secretions and sera of HIV-infected women. Am J Reprod Immunol 2004; 71: 600-7.
[33]
Wei Q, Moldoveanu Z, Huang WQ, Alexander RC, Goepfert PA, Mestecky J. Comparative evaluation of HIV-1 neutralization in external secretions and sera of HIV-1-infected women. Open AIDS J 2012; 6: 293-302.
[34]
Mestecky J, Wright PF, Lopalco L, et al. Sparcity or absence of humoral immune responses in the plasma and cervicovaginal lavage fluids of heavily HIV-1-exposed but persistently seronegative women. AIDS Res Hum Retroviruses 2011; 27: 469-86.
[35]
Moldoveanu Z, Mestecky J. Mucosal antibody responses to HIV.In: Prasad, VR, Kalpana, GV, Eds. HIV Protocols, 2nd Ed. Humana Press/Springer Science, New York, 2009, Chapter 22; 485: 333-45
[36]
Nag P, Kim J, Sapiega V, et al. Women with cervicovaginal antibody- dependent cell-mediated cytotoxicity have lower genital HIV-1 RNA loads. J Infect Dis 2004; 190: 1970-80.
[37]
Wright PF, Mestecky J, McElrath MJ, et al. Comparison of systemic and mucosal delivery of 2 Canarypox virus vaccines expressing either HIV-1 genes or the gene for rabies virus G protein. J Infect Dis 2004; 189: 1221-31.
[38]
Wright PF, Kozlowski PA, Rybczyk GK, et al. Detection of mucosal antibodies in HIV-1 type 1-infected individuals. AIDS Res Hum Retroviruses 2002; 18: 1291-300.
[39]
Mohamed OA, Ashley R, Goldstein A, McElrath J, Dalessio J, Corey L. Detection of rectal antibodies to HIV-1 by a sensitive chemiluminescence western blot immunodetection method. J Acquir Immune Defic Syndr 1994; 7: 375-80.
[40]
Tamaras GD, Haynes BF. HIV-1-specific antibody responses during acute and chronic HIV-1 infection. Curr Opin HIV AIDS 2009; 4: 373-9.
[41]
Overbaugh J, Morris L. The antibody response against HIV-1. In: Bushman FD, Nabel GJ, Swanstrom R. EdsCold Springs Harbor Perspectives in MedicineCold Spring Harbor Laboratory Press, Cold Spring Harbor, NY 2012; 1-9.
[42]
Kozlowski PA, Jackson S. Serum IgA subclass and molecular forms in HIV infection: Selective increase in monomer and apparent restriction of the antibody response to IgA1 antibodies mainly directed at env glycoprotein. AIDS Res Hum Retroviruses 1992; 8: 1773-80.
[43]
Raux M, Finkielsztejn L, Salmon-Ceron D, et al. Comparison of antibodies in serum and various mucosal fluids of HIV type 1-infected subjects. AIDS Res Hum Retroviruses 1999; 15: 1365-76.
[44]
Alexander R, Mestecky J. Neutralizing antibodies in mucosal secretions: IgG or IgA? Curr HIV Res 2007; 5: 588-93.
[45]
Jackson S, Prince S, Kulhavy R, Mestecky J. False positivity of enzyme-linked immunosorbent assay for measurement of secretory IgA antibodies directed at HIV-1 antigens. AIDS Res Hum Retroviruses 2000; 16: 595-602.
[46]
Chaoul N, Burelout C, Peruchon S, et al. Default in plasma and intestinal IgA responses during acute infection by simian immunodeficiency virus. Retrovirology 2012; 9: 43.
[47]
Xu W, Santini PA, Sullivan JS, et al. HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits. Nat Immunol 2009; 10: 1008-17.
[48]
McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM. Secretory leukocyte protease inhibitor: A human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest 1995; 96: 456-64.
[49]
Wahl SM, McNeely TB, Janoff EN, et al. Secretory Leukocyte Protease Inhibitor (SLPI) in mucosal fluids inhibits HIV-1. Oral Dis 1997; 3: 64-9.
[50]
Kazmi SH, Naglik JR, Sweet SP, et al. Comparison of human immunodeficiency virus type 1-specific inhibitory activities in saliva and other human mucosal fluids. Clin Vaccine Immunol 2006; 13: 1111-8.
[51]
Orsi N. The antimicrobial activity of lactoferrin: Current status and perspectives. Biometals 2004; 17: 189-96.
[52]
Iwasaki A. Antiviral immune responses in the genital tract: Clues for vaccines. Nat Rev Immunol 2010; 10(10): 699-711.
[53]
Mestecky J, Kutteh WH, Jackson S. Mucosal immunity in the female genital tract: Relevance to vaccination efforts against the human immunodeficiency virus. AIDS Res Hum Retroviruses 1994; 10(Suppl. 2): S11-20.
[54]
Givan AL, White HD, Stern JE, et al. Flow cytometric analysis of leukocytes in the human female reproductive tract: Comparison of fallopian tube, uterus, cervix, and vagina. Am J Reprod Immunol 1997; 38(5): 350-9.
[55]
Kamat BR, Isaacson PG. The immunocytochemical distribution of leukocytic subpopulations in human endometrium. Am J Pathol 1987; 127(1): 66-73.
[56]
Morris H, Edwards J, Tiltman A, Emms M. Endometrial lymphoid tissue: an immunohistological study. J Clin Pathol 1985; 38(6): 644-52.
[57]
Yeaman GR, Guyre PM, Fanger MW, et al. Unique CD8+ T cell-rich lymphoid aggregates in the human uterine endometrium. J Leukoc Biol 1997; 61(4): 427-35.
[58]
McKinnon LR, Hughes SM, De Rosa SC, et al. Optimizing viable leukocyte sampling from the female genital tract for clinical trials: an international multi-site study. PLoS One 2014; 9(1): e85675.
[59]
Shacklett BL, Cu-Uvin S, Beadle TJ, et al. Quantification of HIV-1-specific T-cell responses at the mucosal cervicovaginal surface. AIDS 2000; 14(13): 1911-5.
[60]
Kaul R, Thottingal P, Kimani J, et al. Quantitative ex vivo analysis of functional virus-specific CD8 T lymphocytes in the blood and genital tract of HIV-infected women. AIDS 2003; 17(8): 1139-44.
[61]
Jaspan HB, Liebenberg L, Hanekom W, et al. Immune activation in the female genital tract during HIV infection predicts mucosal CD4 depletion and HIV shedding. J Infect Dis 2011; 204(10): 1550-6.
[62]
Prakash M, Kapembwa MS, Gotch F, Patterson S. Oral contraceptive use induces upregulation of the CCR5 chemokine receptor on CD4(+) T cells in the cervical epithelium of healthy women. J Reprod Immunol 2002; 54(1-2): 117-31.
[63]
Shannon B, Yi TJ, Thomas-Pavanel J, et al. Impact of asymptomatic herpes simplex virus type 2 infection on mucosal homing and immune cell subsets in the blood and female genital tract. J Immunol 2014; 192(11): 5074-82.
[64]
McKinnon LR, Nyanga B, Chege D, et al. Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility. J Immunol 2011; 187(11): 6032-42.
[65]
Shanmugasundaram U, Critchfield JW, Pannell J, et al. Phenotype and functionality of CD4+ and CD8+ T cells in the upper reproductive tract of healthy premenopausal women. Am J Reprod Immunol 2014; 71(2): 95-108.
[66]
Bere A, Denny L, Burgers WA, Passmore JA. Polyclonal expansion of cervical cytobrush-derived T cells to investigate HIV-specific responses in the female genital tract. Immunology 2010; 130(1): 23-33.
[67]
Bere A, Denny L, Naicker P, Burgers WA, Passmore JA. HIV-specific T cell responses detected in the genital tract of chronically HIV-infected women are largely monofunctional. Immunology 2013; 139(3): 342-51.
[68]
Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ. HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women. J Exp Med 1997; 185(2): 293-303.
[69]
Bull ME, Legard J, Tapia K, et al. HIV-1 shedding from the female genital tract is associated with increased Th1 cytokines/chemokines that maintain tissue homeostasis and proportions of CD8+FOXP3+ T cells. J Acquir Immune Defic Syndr 2014; 67(4): 357-64.
[70]
Chandra N, Thurman AR, Anderson S, et al. Depot medroxyprogesterone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues. AIDS Res Hum Retroviruses 2013; 29(3): 592-601.
[71]
Kutteh WH, Blackwell RE, Gore H, Kutteh CC, Carr BR, Mestecky J. Secretory immune system of the female reproductive tract. II. Local immune system in normal and infected fallopian tube. Fertil Steril 1990; 54(1): 51-5.
[72]
Chen CK, Huang SC, Chen CL, Yen MR, Hsu HC, Ho HN. Increased expressions of CD69 and HLA-DR but not of CD25 or CD71 on endometrial T lymphocytes of nonpregnant women. Hum Immunol 1995; 42(3): 227-32.
[73]
Ho HN, Chao KH, Chen CK, Yang YS, Huang SC. Activation status of T and NK cells in the endometrium throughout menstrual cycle and normal and abnormal early pregnancy. Hum Immunol 1996; 49(2): 130-6.
[74]
Johansson EL, Rudin A, Wassen L, Holmgren J. Distribution of lymphocytes and adhesion molecules in human cervix and vagina. Immunology 1999; 96(2): 272-7.
[75]
Hladik F, Lentz G, Delpit E, McElroy A, McElrath MJ. Coexpression of CCR5 and IL-2 in human genital but not blood T cells: Implications for the ontogeny of the CCR5+ Th1 phenotype. J Immunol 1999; 163(4): 2306-13.
[76]
Jones RK, Bulmer JN, Searle RF. Phenotypic and functional studies of leukocytes in human endometrium and endometriosis. Hum Reprod Update 1998; 4(5): 702-9.
[77]
Yeaman GR, Asin S, Weldon S, et al. Chemokine receptor expression in the human ectocervix: Implications for infection by the human immunodeficiency virus-type I. Immunology 2004; 113(4): 524-33.
[78]
White HD, Musey LK, Andrews MM, et al. Human immunodeficiency virus-specific and CD3-redirected cytotoxic T lymphocyte activity in the human female reproductive tract: Lack of correlation between mucosa and peripheral blood. J Infect Dis 2001; 183(6): 977-83.
[79]
Saba E, Grivel JC, Vanpouille C, et al. HIV-1 sexual transmission: early events of HIV-1 infection of human cervico-vaginal tissue in an optimized ex vivo model. Mucosal Immunol 2010; 3(3): 280-90.
[80]
McElrath MJ, Ballweber L, Terker A, et al. Ex vivo comparison of microbicide efficacies for preventing HIV-1 genomic integration in intraepithelial vaginal cells. Antimicrob Agents Chemother 2010; 54(2): 763-72.
[81]
Sabbaj S, Hel Z, Richter HE, Mestecky J, Goepfert PA. Menstrual blood as a potential source of endometrial derived CD3+ T cells. PLoS One 2011; 6(12): e28894.
[82]
Hosseini S, Shokri F, Tokhmechy R, et al. Menstrual blood contains immune cells with inflammatory and anti-inflammatory properties. J Obstet Gynaecol Res 2015; 41(11): 1803-12.
[83]
Hosseini S, Zarnani AH, Asgarian-Omran H, et al. Comparative analysis of NK cell subsets in menstrual and peripheral blood of patients with unexplained recurrent spontaneous abortion and fertile subjects. J Reprod Immunol 2014; 103: 9-17.
[84]
van der Molen RG, Schutten JH, van Cranenbroek B, et al. Menstrual blood closely resembles the uterine immune micro-environment and is clearly distinct from peripheral blood. Hum Reprod 2014; 29(2): 303-14.
[85]
Moylan DC, Goepfert PA, Colette-Kempf M, et al. Diminished CD103 (αEβ7) Expression on Resident T cells from the Female Genital Tract of HIV-positive Women. Pathog Immun 2016; 1(2): 371-87.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 15
ISSUE: 1
Year: 2019
Page: [41 - 48]
Pages: 8
DOI: 10.2174/1573395514666180621152303
Price: $58

Article Metrics

PDF: 43
HTML: 4