The Key to Mucosal Immunity: “M” Cells

Öz

Many of the lymphoid tissue in the body is found in the intestines. This is also where foreign antigens enter and exit the body. In our body, food pathogens, commensal intestinal flora and invasive pathogens can enter through the lumen of the digestive system, and there is a mucosal layer barrier created against these pathogens. This mucous layer is surrounded by mucous cells, microflora and immune cells. Mucosal barrier is the most important defense mechanism against factors with high immunological or pathogenic potential. M cells, which are immune system cells located within the mucosal epithelium, are one of the most important components of the mucosal barrier. T and B lymphocytes constantly interact with macrophages and other immune cells found in the intestinal. Intestinal-associated lymphoid tissue (GALT) is the largest lymphoid tissue in the human body and almost contains most of the immune system cells. Peyer plaques form the Galt structure. GALT, consisting of lymph follicles, produces antigen-specific IGA and secretes it onto the mucosal surface, producing an inductive and effector immune response. Peyer plaques are rich in carrying immune cells. The antigen taken by the M cell in Peyer plaques is delivered to antigen presenting cells such as dendritic or macrophage cells in the subepithelial dome region. M cells transport the particles, macro, micromolecules and microorganisms in the intestinal cavity through the intestinal epithelial barrier. It is known that M cells originate from Lgr5 positive stem cells in follicle-related epithelium and crypt epithelium. The most important feature of M cells is that it presents antigens to mucosal-associated lymphoid tissue located under the mucosa. Thus, they perform the first step of mucosal immunity by creating both a systemic and mucosal immune response. This review also provides information about the development, structural properties and functions of M cells.

Anahtar Kelimeler

• GALT
• M cells
• Mucosal Immunity

Mukozal Bağışıklığın Anahtarı ''M'' Hücreleri

Öz

Vücuttaki lenfoid dokunun büyük bir kısmı bağırsaklarda bulunur. Burası aynı zamanda yabancı antijenlerin vücuda giriş çıkış yaptığı yerdir. Gıdasal patojenler, komensal bağırsak florası ve istilacı patojenler sindirim sistemi lümeninden vücuda girebilir. Bu patojenlere karşı oluşturulan mukozal bir tabaka engeli vardır. Bu mukoza tabakası, mukoza hücreleri, mikroflora ve bağışıklık sistemine ait hücreler tarafından çevrilmiştir. Mukozal bariyer, immunolojik ya da patojenik potansiyeli yüksek olan faktörlere karşı en önemli savunma mekanizmasıdır. Mukozal epitel içerisine yerleşmiş bağışıklık sistemi hücreleri olan M hücreleri, mukozal bariyerin en önemli bileşenlerinden biridir. T ve B lenfositler, makrofajlar ve bağırsakta bulunan diğer bağışıklık hücreleri ile sürekli etkileşim içindedirler. Bağırsak ilişkili lenfoid doku (GALT) insan vücudunun en büyük lenfoid dokusudur ve neredeyse bağışıklık sistemi hücrelerinin çoğunu barındırır. GALT yapısını Peyer plakları oluşturur. Lenf foliküllerinden oluşan GALT, antijene spesifik IgA üretip, mukozal yüzeye salgılayarak indüktif ve efektör bir fonksiyonla bağışık yanıt oluşmasını gerçekleştirir. Peyer plaklarında M hücresi tarafından alınan antijen, subepitelyal dom bölgesindeki dendritik ya da makrofaj hücreleri gibi antijen sunan hücrelere verilir. M hücreleri, bağırsak epitel bariyeri boyunca bağırsak boşluğundaki partiküllerin, makro ve mikromoleküllerin, mikroorganizmaların aktarımını gerçekleştirir. M hücrelerinin folikül ilişkili epitel ve kript epitelinde bulunan Lgr5+ kök hücrelerden köken aldığı bilinmektedir. M hücrelerinin bilinen en önemli özelliği, mukoza altında yer alan mukoza ilişkili lenfoid dokuya antijen sunmalarıdır. Böylece hem sistemik hem de mukozal immun yanıt oluşturarak mukozal bağışıklığın ilk basamağını gerçekleştirirler. Bu derlemede M hücrelerinin gelişimi, yapısal özellikleri ve fonksiyonları hakkında bilgiler verilmiştir.

Anahtar Kelimeler

• GALT
• M hücreleri
• Mukozal Bağışıklık

Kaynakça

1. 1. Keshav S, Allan P. Anatomy and Physiology of the Gastrointestinal Tract. Metabolism of Human Disease. 2014;123.
2. 2. Göçer E, Ergin F, Küçükçetin A. Sindirim Sistemi Modellerinde Probiyotik Mikroorganizmaların Canlılığı. Akademik Gıda. 2016;14(2):158-165.
3. 3. Özden A. Gastro-intestinal Sistem ve Probiyotik-prebiyotik Synbiyotik. Güncel Gastroenteroloji 2005;9(3):124-133.
4. 4. Shanahan F. Probiotics in Perspective. Gastroenterol 2010;139:1808-1812.
5. 5. Karakan M, Elmacioğlu MA, Nazlikul H. Probiyotikler-Prebiyotikler ve Bağışıklık Sistemi. Bilimsel Tamamlayıcı Tıp, Nöralterapi Dergisi 2016;10(1): 22-25.
6. 6. Ahluwalia B, Magnusson M, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand. J Gastroenterol 2017;52(11):1185-1193.
7. 7. Tahoun A, Mahajan S, Paxton E, et al. Salmonella transforms follicle-associated epithelial cells into M cells to promote intestinal invasion. Cell Host Microbe 2012;12(5):645-656.
8. 8. Mabbott NA, David DS, Ohno H, Williams IR, Mahajan A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 2013;6:666-77.

9. 9. Şimşek Y, Yılmaz Ö, Yüksel H. Mukozal Bağışıklığın Anahtar Hücresi: M Hücresi. Turk J Immunol 2014;2(3):52-56.
10. 10. Reboldi A, Cyster JG. Peyer's patches: organizing B-cell responses at the intestinal frontier. Immunol Rev 2016;271(1):230–245.
11. 11. Kobayashi N, Takashi D, Takano S, Kimura S, Hase K. The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases. Front Immunol 2019;(10):23-45.
12. 12. Eberl G, Marmon S, Sunshine MJ, et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat Immunol 2004;5(1):64-73.
13. 13. Gebert A, Rothkötter HJ, Pabst R. M cells in Peyer's patches of the intestine. Int Rev cytol 1996;167:91-159.
14. 14. Beyaz F, Aşti RN. Development of ileal Peyer's patches and follicle associated epithelium in bovine foetuses. Anat Histol Embryol 2004;33(3):172-179.
15. 15. Mestecky J, Bienenstock J, McGhee JR, et al. Historical aspects of mucosal immunology. Mucosal Immunol 2005;23-43.
16. 16. Williams AE. Immunology: mucosal and body surface defences; 2011.
17. 17. Neutra MR. M cells in antigen sampling in mucosal tissues. Curr Top Microbiol Immunol 1999;236:17-32.
18. 18. Clark MA, Jepson MA. İntestinal M cells and their role in bacterial infection. Int J Med Microbiol 2003;293:17-39.
19. 19. Hathaway LJ, Kraehenbuhl JP. The role of M cells in mucosal immunity. Cell Mol Life Sci 2000;57:323-332.
20. 20. Mach J, Hshieh T, Hshieh D, Grubbs N, Chervonsky A. Development of intestinal M cells. Immunol Rev 2005;206(1):177-189.
21. 21. Yan Z, Wang JB, Gong SS, Huang X. Cell proliferation in the endolymphatic sac in situ after the rat Waldeyer ring equivalent immunostimulation. The Laryngoscope 2003;113(9):1609-1614.
22. 22. Kiyono H, Fukuyama S. NALT-versus Peyer's-patch-mediated mucosal immunity. Nat Rev Immunol 2004;4(9):699-710.
23. 23. Kunisawa J, Kurashima Y, Kiyono H. Gut-associated lymphoid tissues for the development of oral vaccines. Adv Drug Deliv Rev 2012;64(6):523-530.
24. 24. Owen RL. Uptake and transport of intestinal macromolecules and microorganisms by M cells in Peyer's patches-a personal and historical perspective. Sem Immunol 1999;11(3):157-163.
25. 25. Kurtdede N, Aştı RN, Ergün L, Ergün E. Ankara keçilerinin alt solunum yolları mast hücreleri üzerine histolojik çalışmalar. AÜ Vet Fak Derg 2000;47:339-349.
26. 26. Kato T. Structure and function of intestinal mucosal epithelium. Hand Mucosal Immunol 1999;11-26.
27. 27. Fujimura Y, Lida M. A new marker for cup cells in the rabbit small intestine: expression of vimentin intermediate filament protein. Med Electron Microsc 2001;34(4):223-229.
28. 28. Iwatsuki H, Ogawa C, Suda M. Vimentin-positive cells in the villus epithelium of the rabbit small intestine. Histochem Cell Biol 2002;117(4):363-370.
29. 29. Jang MH, Kweon MN, Iwatani K, et al. Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc Natl Acad Sci USA 2004;101(6):6110-6115.
30. 30. Hsieh EH, Fernandez X, Wang J, et al. CD137 is required for M cell functional maturation but not lineage commitment. Am J Pathol 2010;177(2):666–676.
31. 31. Lo DD, Dillon A. M cells: Intelligent engineering of mucosal immune surveillance. Front Immunol 2019;10:1499.
32. 32. Cesta MF. Normal structure, function, and histology of mucosa-associated lymphoid tissue. Toxicol Pathol 2006;34(5):599-608.
33. 33. Neutra MR, Mantis NJ, Kraehenbuhl JP. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat Immunol 2001;2(11):1004-1009.
34. 34. Lopez-Garcia C, Klein AM, Simmons BD, Winton DJ. Intestinal stem cell replacement follows a pattern of neutral drift. Science 2010;330(6005):822-825.
35. 35. Snippert HJ, Van Der Flıer LG, Sato T, et al. Intestinal Crypt Homeostasis Results From Neutral Competition Between Symmetrically Dividing Lgr5 Stem Cells. Cell 2010;143(1):134-144.
36. 36. Lau W, Kujala P, Schneeberger K, et al. Peyer’s Patch M Cells Derive From Lgr5 Stem Cells, Require SpiB and are İnduced by Rankl İn Cultured ‘miniguts’. Mol Cell Biol 2012;32(18):3639-3647.
37. 37. Heath JP. Epithelial cell migration in the intestine. Cell Biol Int 1996;20(2):139-146.
38. 38. Sierro F, Pringault E, Assman PS, Kraehenbuhl JP, Debard N. Transient expression of M-cell phenotype by enterocyte-like cells of the follicle-associated epithelium of mouse Peyer’s patches. Gastroenterol 2000;119(3):734-743.
39. 39. Kerneis S, Bogdonova A, Kraehenbuhl JP, Pringault E. Conversion by Peyer’s patch lymphocytes of human enterocytes into M-cells that transport bacteria. Science 1997;277(5328):949-952.
40. 40. Gebert A, Fassbender S, Werner K, Wiessferdt A. The development of M cells in Peyer’s patches is restricted to specialized dome-associated crypts. Am J Physiol 1999;154(5):1573-1582.
41. 41. Kerneis S, Pringault E. Plasticity of the gastrointestinal epithelium: the M cell paradigm and opportunism of pathogenic microorganisms. Semin Immunol 1999;11(3):205-215: Academic Press.
42. 42. Kanaya T, Aso H, Kido T, et al. Staining patterns for actin and villin distinguish M-cells in bovine follicle- associated epithelium. Res Vet Sci 2007;82(2):141-149.
43. 43. Corr SC, Gahan CC, Hill C. M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis. FEMSImmunol Med Microbiol 2008;52(1):2-12.
44. 44. Golovkina TV, Shlomchik M, Hannum L, Chervonsky A. Organogenic role of B lymphocytes in mucosal immunity. Science 1999;286(5446):1965–1968.
45. 45. Kanaya T, Ohno H. The Mechanisms of M-cell Differentation. Biosci Microb Food H 2014;33(3):91-97.
46. 46. Inagaki-Ohara K, Chinen T, Matsuzaki G, et al. Mucosal T cells bearing TCRγδ play a protective role in intestinal inflammation. J Immunol 2004;173(2):1390-1398.
47. 47. Mowat AM. Dendritic cells and immune responses to orally administered antigens. Vaccine 2005;23(15):1797-1799.
48. 48. Wu Y, Wang X, Csencsits KL, et al. M cell-targeted DNA vaccination. Proc Natl Acad Sci USA 2001;98(16):9318–9323.
49. 49. Garinot M, Fiévez V, Pourcelle V, et al. Pegylated PLGA-based nanoparticles targeting M cells for oral vaccination. J Control Release 2007;120(3):195–204. 50. Baptista AP, Olivier BJ, Goverse G, et al. Colonic patch and colonic SILT development are independent and differentially regulated events. Mucosal Immunol 2013;6(3):511–521.
50. 51. Wershil BK, Furuta GT. Gastrointestinal mucosal immunity. J Allergy Clin Immunol 2008;121(2):380-383.
51. 52. Neutra MR, Giannasca PJ, Giannasca KT, Kraehenbuhl JP. M cells and microbial pathogens. Infections of the GI tract 1995;163-78: Raven Press.
52. 53. Kraehenbuhl JP, Neutra MR. Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 2000;16(1):301-332.
53. 54. Clark MA, Jepson MA, Simmons NL, Booth TA, Hirst BH. Differential expression of lectin binding sites defines mouse intestinal M cells. J Histochem Cytochem 1993;41(11):1679-87. 55. Lorenz RG, Newberry RD. Isolated lymphoid follicles can function as sites for induction of mucosal immune responses. Ann New York Acad Sci 2004;1029(1):44-57.
54. 56. Miller H, Zhang J, KuoLee R, Patel GB, Chen W. Intestinal M cells: the fallible sentinels. World J Gastroenterol 2007;13(10):1477.
55. 57. Maib H, Smythe E, Ayscough K. Forty years on: clathrin-coated pits continue to fascinate. Mol Biol Cell 2017;28(7):843–847.
56. 58. Liang E, Kabcenell AK, Coleman JR, et al. Permeability measurement of macromolecules and assessment of mucosal antigen sampling using in vitro converted M cells. J Pharmacol Toxicol Methods 2001;46(2):93-101.
57. 59. Pappo J, Mahlman RT. Follicle epithelial M cells are a source of interleukin-1 in Peyer's patches. Immunol 1993;78(3):505.
58. 60. Nagashima K, Sawa S, Nitta T, et al. Identification of subepithelial mesenchymal cells that induce IgA and diversity gut microbiota. Nat Immunol 2017;18(6):675.
59. 61. Taylor RT, Patel SR, Lin E, et al. Lymphotoxin-Independent Expression Of TNF-Related Activation-Induced Cytokine by Stromal Cells In cryptopatches, isolated lymphoid Follicles, and Peyer’s Patches. J Immunol 2007;178(9):5659-5667.
60. 62. Katakai T, Suto H, Sugai M, et al. Organizer-Like Reticular Stromal Cell Layer Common To Adult Secondary Lymphoid Organs. J Immunol 2008;181(9):6189-6200.
61. 63. Kanaya T, Hase K, Takahashi D, et al. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat Immunol 2012;13(8):729.
62. 64. Sato S, Kaneto S, Shibata N, et al. Transcription Factor Spi-B-Dependent and -Independent Pathways For The Development Of Peyer's Patch M Cells. Mucosal immunol 2013;6(4):838-846.
63. 65. Knoop KA, Kumar N, Butler BR, et al. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J Immunol 2009;183(9):5738-5747.
64. 66. Nakamura Y, Kimura S, Hase K. M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance. Inflammation and Regeneration 2018;38(1):15.
65. 67. Wang J, Gusti V, Saraswati A, Lo DD. Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J Immunol 2011;187(10):5277-5285.
66. 68. Lelouardi H, Fallet M, De Bovis B, Meresse S, Gorvel JP. Peyer’s patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterol 2012;142(3):592-601.
67. 69. Hase K, Kawano K, Nochi T, et al. Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune responses. Nature 2009;462(7270):226-230.
68. 70. Granucci F, Ricciardi-Castagnoli P. Interactions of bacterial pathogens with dentritic cells during invasion of mucosal surfaces. Curr Options Microbiol 2003;6(1):72-76.
69. 71. Jones BD, Ghori N, Falkow S. Salmonella typhimurium initiates murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer’s patches. J Exp Med 1994;180(1):15-23.
70. 72. Meynell HM, Thomas NW, James PS. Up-regulation of microsphere transport across the follicle-associated epithelium of Peyer’s patch by exposure to Streptococcus pneumoniae R36a. The FASEB J 1999;13(6):611-619.
71. 73. Bennett KM, Parnell EA, Sanscartier C, et al. Induction of Colonic M Cells during Intestinal Inflammation. Am J Pathol 2016;186(5):1166–1179.
72. 74. Parnell EA, Walch EM, Lo DD. Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltβr, identifying distinct signalling requirements for constitutive versus inducible M cells. J Crohns Colitis 2017;11(6):751–760.
73. 75. Clark MA, Blair H, Liang L, et al. Targeting polymerised liposomoe vaccine carriers to intestinal M cells. Vaccine 2001;20(1-2):208-217.
74. 76. Jepson MA, Clark MA, Hirst BH. M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery. Adv Drug Del Rev 2004;56(4):511-525.
75. 77. Shima H, Watanabe T, Fukuda S, et al. A novel mucosal vaccine targeting Peyer’s patch M cells induces protective antigen-specific IgA responses. Int Immunol 2014;26(11):619-625.