Das mucosale Immunsystem

Appendices

Aufgaben

1 12.1 Multiple Choice

Welche Aussage trifft nicht zu?

• A. Mikrofaltenzellen besitzen eine gefaltete luminale Oberfläche und eine dicke Schleimschicht, durch die Mikroorganismen in die Peyer-Plaques gelangen können.

• B. Mikrofaltenzellen erkennen verschiedene bakterielle Proteine durch GP2 und setzen mithilfe der Transcytose Material in den Extrazellularraum frei.

• C. Mit dem Darm assoziierte lymphatische Gewebe locken mithilfe von Chemokinen wie CCL20 und CCL9 dendritische Zellen an.

• D. Pathogene wie Yersinia pestis und Shigella steuern Mikrofaltenzellen an und können dadurch in den Subepithelialraum gelangen.

1 12.2 Richtig oder falsch

Die intraepithelialen Lymphocyten umfassen vor allem CD4-T-Zellen, während in der Lamina propria CD8-T-Zellen vorherrschend sind.

1 12.3 Bitte zuordnen

Welches Chemokin beziehungsweise welcher Chemokinrezeptor gehört zu welcher gewebespezifischen Homing-Funktion?

A.	CXCL13 _____	i.	Rekrutierung von Lymphocyten in den Dickdarm, in die Milchdrüse der Brust und in die Speicheldrüsen
B.	CCL25 _____	ii.	Rekrutierung von B- und T-Zellen in den Dünndarm
C.	CCL28 _____	iii.	Lenkung der Lymphocyten in die Haut
D.	CCR4 _____	iv.	Rekrutierung naiver B-Zellen in die Peyer-Plaques

1 12.4 Multiple Choice

Welche Aussage trifft zu?

• A. Dendritische CD11b⁺-Zellen stimulieren ILC3-Zellen und sind in den Peyer-Plaques die wichtigste Quelle für IL-12.

• B. Dendritische CD11b⁻-Zellen benötigen BATF3 für ihre Entwicklung.

• C. Die Produktion von Retinsäure durch naive T-Zellen ist notwendig für dendritische Zellen, damit T_reg-Zellen gebildet werden können.

• D. CCL20 verhindert, dass dendritische Zellen in die Epithelschicht der Peyer-Plaques gelangen.

1 12.5 Kurze Antwort: IgA:Antigen-Komplexe können zurück in das Darmlumen transportiert werden, wodurch dort die Ausscheidung von Pathogenen aus dem Körper verstärkt wird. Andererseits kann die Bildung von IgA

Antigen-Komplexen auch die Aufnahme von Antigenen aus dem Lumen erhöhen. Inwieweit ist die Aufnahme von Antigenen für den Körper vorteilhaft?

1 12.6 Kurze Antwort

B-Zellen und Plasmazellen im Darm produzieren große Mengen an IgA. Diese werden in das Lumen freigesetzt, sodass die Mikroflora in Schach gehalten und ein Eindringen von Pathogenen verhindert wird. Allerdings sind die meisten Personen mit einem IgA-Mangel gegenüber Infektionen nicht übermäßig anfällig. Warum ist das so?

1 12.7 Multiple Choice

Welche Aussage beschreibt intraepitheliale Lymphocyten (iELs) am besten?

• A. Expression von CCR9 und α₄:β₇-Integrin

• B. Expression von CCR9 und α_E:β₇-Integrin (CD103)

• C. Das Verhältnis CD4- zu CD8-T-Zellen beträgt 3:1.

• D. Dazu gehören auch CD4⁺-T-Zellen, die IFN-γ, IL-17 und IL-22 produzieren.

• E. bestehen zu 90 % aus T-Zellen, von denen 80 % CD8 als α:α-Homodimer oder α:β-Heterodimer exprimieren

• F. Antwort A und C

• G. Antwort B und E

• H. Antwort A, C und D

1 12.8 Multiple Choice

Bei welchem der folgenden Zelltypen hängt die korrekte Entwicklung von der Expression des Arylkohlenwasserstoffrezeptors ab?

• A. intraepitheliale Lymphocyten vom Typ b

• B. ILC1

• C. B-Zellen

• D. Makrophagen

• E. ILC2

• F. neutrophile Zellen

1 12.9 Bitte zuordnen

Welche Krankheit des Menschen geht mit welcher pathologischen Symptomatik einher?

A.	anormale Reaktion auf das Weizenprotein Gluten, was zu einem vermehrten Auftreten von IEL-Zellen mit einer MIC-A-abhängigen cytotoxischen Aktivität gegen Darmepithelzellen führt	i.	Infektion mit Clostridium difficile
B.	Unterbrechung des normalen Flusses der Fäzes im Dickdarm, sodass die Enterocyten Entzündungen und Nekrosen entwickeln, da kurzkettige Fettsäuren (SCFAs) fehlen, die von kommensalen Bakterien produziert werden	ii.	Zöliakie
C.	Eine Behandlung mit Antibiotika beseitigt einen großen Teil der kommensalen Mikroflora, sodass sich eine bestimmte Spezies übermäßig vermehrt und Toxine produziert, die schweren Durchfall verursachen und die Schleimhaut schädigen.	iii.	entzündliche Darmerkrankung (Morbus Crohn und Colitis ulcerosa)
D.	übermäßig aktive Immunantworten gegen kommensale Bakterien aufgrund eines Defekts in Genen der angeborenen Immunität	iv.	Diversionscolitis

1 12.10 Richtig oder falsch

Die CD4⁺-T-Zellen in der Lamina propria sezernieren große Mengen an Cytokinen wie IFN-γ, IL-17 und IL-22 nur als Reaktion auf Krankheitserreger und Schädigungen durch eine Entzündung.

1 12.11 Richtig oder falsch

Die meisten T_reg-Zellen im Dünndarm exprimieren kein FoxP3.

Literatur

1.1 Allgemeine Literatur

• ■ Hooper, L.V., Littman, D.R., and Macpherson, A.J.: Interactions between the microbiota and the immune system. Science 2012, 336:1268–1273.

• ■ MacDonald, T.T., Monteleone, I., Fantini, M.C., and Monteleone, G.: Regulation of homeostasis and inflammation in the intestine. Gastroenterology 2011, 140: 1768–1775.

• ■ Mowat, A.M.: Anatomical basis of tolerance and immunity to intestinal anti-gens. Nat. Rev. Immunol. 2003, 3:331–341.

• ■ Society for Mucosal Immunology: Principles of Mucosal Immunology, 1st edu. New York, Garland Science, 2013.

1.2 Literatur zu den einzelnen Abschnitten

1.2.1 Abschnitt 12.1.1

• ■ Brandtzaeg, P.: Function of mucosa-associated lymphoid tissue in antibody formation. Immunol. Invest. 2010, 39:303–355.

• ■ Cerutti, A., Chen, K., and Chorny, A.: Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011, 29:273–293.

• ■ Corthesy, B.: Role of secretory IgA in infection and maintenance of homeotasis. Autoimmun. Rev. 2013, 12:661–665.

• ■ Fagarasan, S., Kawamoto, S., Kanagawa, O., and Suzuki, K.: Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 2010, 28:243–273.

• ■ Matsunaga, T. and Rahman, A.: In search of the origin of the thymus: the thymus and GALT may be evolutionarily related. Scand. J. Immunol. 2001, 53:1–6.

• ■ Naz, R.K.: Female genital tract immunity: distinct immunological challenges for vaccine development. J .Reprod. Immunol. 2012, 93:1–8.

• ■ Randall, T.D.: Bronchus-associated lymphoid tissue (BALT) structure and function. Adv. Immunol. 2010, 107:187–241.

• ■ Sato, S. and Kiyono, H. The mucosal immune system of the respiratory tract. Curr. Opin. Virol. 2012, 2:225–232.

1.2.2 Abschnitt 12.1.2

• ■ Baptista, A.P., Olivier, B.J., Goverse, G., Greuter, M., Knippenberg, M., Kusser, K., Domingues, R.G., Veiga-Fernandes, H., Luster, A.D., Lugering, A., et al.: Colonic patch and colonic SILT development are independent and differentially regulated events. Mucosal Immunol. 2013, 6:511–521.

• ■ Brandtzaeg, P., Kiyono, H., Pabst, R., and Russell, M.W.: Terminology: nomenclature of mucosa-associated lymphoid tissue. Mucosal. Immunol. 2008, 1:31–37.

• ■ Eberl, G. and Sawa, S.: Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 2010, 31:50–55.

• ■ Lee, J.S., Cella, M., McDonald, K.G., Garlanda, C., Kennedy, G.D., Nukaya, M., Mantovani, A., Kopan, R., Bradfield, C.A., Newberry, R.D., et al.: AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 2012, 13:144–151.

• ■ Macpherson, A.J., McCoy, K.D., Johansen, F.E., and Brandtzaeg, P.: The immune geography of IgA induction and function. Mucosal. Immunol. 2008, 1:11–22.

• ■ Pabst, O., Herbrand, H., Worbs, T., Friedrichsen, M., Yan, S., Hoffmann, M.W., Korner, H., Bernhardt, G., Pabst, R., and Forster, R.: Cryptopatches and isolated lymphoid follicles: dynamic lymphoid tissues dispensable for the generation of intraepithelial lymphocytes. Eur. J. Immunol. 2005, 35:98–107.

• ■ Randall, T.D.: Bronchus-associated lymphoid tissue (BALT) structure and function. Adv. Immunol. 2010, 107:187–241.

• ■ Randall, T.D. and Mebius, R.E.: The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms. Mucosal Immunol. 2014, 7:455–466.

• ■ Suzuki, K., Kawamoto, S., Maruya, M., and Fagarasan, S.: GALT: organization and dynamics leading to IgA synthesis. Adv. Immunol. 2010, 107:153–185.

1.2.3 Abschnitt 12.1.3

• ■ Anosova, N.G., Chabot, S., Shreedhar, V., Borawski, J.A., Dickinson, B.L., and Neutra, M.R.: Cholera toxin, E. coli heat-labile toxin, and non-toxic derivatives induce dendritic cell migration into the follicle-associated epithelium of Peyer’s patches. Mucosal Immunol. 2008, 1:59–67.

• ■ Hase, K., Kawano, K., Nochi, T., Pontes, G.S., Fukuda, S., Ebisawa, M., Kadokura, K., Tobe, T., Fujimura, Y., Kawano, S., et al.: Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response. Nature 2009, 462:226–230.

• ■ Jang, M.H., Kweon, M.N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P.D., et al.: Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 2004, 101:6110–6115.

• ■ Lelouard, H., Fallet, M., de Bovis, B., Meresse, S., and Gorvel, J.P.: Peyer’s patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterology 2012, 142:592–601.

• ■ Mabbott, N.A., Donaldson, D.S., Ohno, H., Williams, I.R., and Mahajan, A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013, 6:666–677.

• ■ Sato, S., Kaneto, S., Shibata, N., Takahashi, Y., Okura, H., Yuki, Y., Kunisawa, J., and Kiyono, H.: Transcription factor Spi-B-dependent and -independent pathways for the development of Peyer’s patch M cells. Mucosal Immunol. 2013, 6:838–846.

• ■ Salazar-Gonzalez, R.M., Niess, J.H., Zammit, D.J., Ravindran, R., Srinivasan, A., Maxwell, J.R., Stoklasek, T., Yadav, R., Williams, I.R., Gu, X., et al.: CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches. Immunity 2006, 24:623–632.

• ■ Zhao, X., Sato, A., Dela Cruz, C.S., Linehan, M., Luegering, A., Kucharzik, T., Shirakawa, A.K., Marquez, G., Farber, J.M., Williams, I., et al.: CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer’s patch CD11b+ dendritic cells. J. Immunol. 2003, 171:2797–2803.

1.2.4 Abschnitt 12.1.4

• ■ Belkaid, Y., Bouladoux, N., and Hand, T.W.: Effector and memory T cell responses to commensal bacteria. Trends Immunol. 2013, 34:299–306.

• ■ Brandtzaeg, P.: Mucosal immunity: induction, dissemination, and effector functions. Scand. J. Immunol. 2009, 70:505–515.

• ■ Cao A.T., Yao S., Gong B., Elson C.O., and Cong Y.: Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J. Immunol. 2012, 189:4666–4673.

• ■ Cheroutre, H. and Lambolez, F.: Doubting the TCR coreceptor function of CD8αα. Immunity 2008, 28:149–159.

• ■ Cauley, L.S. and Lefrancois, L.: Guarding the perimeter: protection of the mucosa by tissue-resident memory T cells. Mucosal Immunol. 2013, 6:14–23.

• ■ Maynard, C.L. and Weaver, C.T.: Intestinal effector T cells in health and disease. Immunity 2009, 31:389–400.

• ■ Sathaliyawala, T., Kubota, M., Yudanin, N., Turner, D., Camp, P., Thome, J.J., Bickham, K.L., Lerner, H., Goldstein, M., Sykes, et al.: Distribution and compart-mentalization of human circulating and tissue-resident memory T cell subsets. Immunity 2013, 38:187–197.

1.2.5 Abschnitt 12.1.5

• ■ Agace, W.: Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol. Lett. 2010, 128:21–23.

• ■ Hu, S., Yang, K., Yang, J., Li, M., and Xiong, N.: Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines. Proc. Natl Acad. Sci. USA 2011, 108:E1035–1044.

• ■ Kim, S.V., Xiang, W.V., Kwak, C., Yang, Y., Lin, X.W., Ota, M., Sarpel, U., Rifkin, D.B., Xu, R. and Littman, D.R.: GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 2013, 340:1456–1459.

• ■ Macpherson, A.J., Geuking, M.B., Slack, E., Hapfelmeier, S., and McCoy, K.D.: The habitat, double life, citizenship, and forgetfulness of IgA. Immunol. Rev. 2012, 245:132–146.

• ■ Mikhak, Z., Strassner, J.P., and Luster, A.D.: Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J. Exp. Med. 2013, 210:1855–1869.

• ■ Mora, J.R. and von Andrian, U.H.: Differentiation and homing of IgA-secreting cells. Mucosal Immunol. 2008, 1:96–109.

• ■ Pabst, O. and Bernhardt, G.: On the road to tolerance-generation and migration of gut regulatory T cells. Eur. J. Immunol. 2013, 43:1422–1425.

1.2.6 Abschnitt 12.1.6

• ■ Agnello, D., Denimal, D., Lavaux, A., Blondeau-Germe, L., Lu, B., Gerard, N.P., Gerard, C., and Pothier, P.: Intrarectal immunization and IgA antibody-secreting cell homing to the small intestine. J. Immunol. 2013, 190:4836–4847.

• ■ Brandtzaeg, P.: Induction of secretory immunity and memory at mucosal surfaces. Vaccine 2007, 25:5467–5484.

• ■ Czerkinsky, C. and Holmgren, J.: Mucosal delivery routes for optimal immunization: targeting immunity to the right tissues. Curr. Top. Microbiol. Immunol. 2012, 354:1–18.

• ■ Ruane, D., Brane, L., Reis, B.S., Cheong, C., Poles, J., Do, Y., Zhu, H., Velinzon, K., Choi, J.H., Studt, N., et al.: Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J. Exp. Med. 2013, 210:1871–1888.

1.2.7 Abschnitt 12.1.7

• ■ Cerovic, V., Bain, C.C., Mowat, A.M., and Milling, S.W.F.: Intestinal macrophages and dendritic cells: what’s the difference? Trends Immunol. 2014, 35:270–277.

• ■ Goto, Y., Panea, C., Nakato, G., Cebula, A., Lee, C., Diez, M.G., Laufer, T.M., Ignatowicz, L., and Ivanov, I.I.: Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014, 40:594–607.

• ■ Guilliams, M., Lambrecht, B.N., and Hammad, H.: Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013, 6:464–473.

• ■ Jaensson-Gyllenback, E., Kotarsky, K., Zapata, F., Persson, E.K., Gundersen, T.E., Blomhoff, R., and Agace, W.W.: Bile retinoids imprint intestinal CD103⁺ dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunol. 2011, 4:438–447.

• ■ Matteoli, G.: Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut 2010, 59:595–604.

• ■ Schlitzer, A., McGovern, N., Teo, P., Zelante, T., Atarashi, K., Low, D., Ho, A.W., See, P., Shin, A., Wasan, P.S., et al.: IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 2013, 38:970–983.

• ■ Scott, C.L., Bain, C.C., Wright, P.B., Schien, D., Kotarsky, K., Persson, E.K., Luda, K., Guilliams, M., Lambrecht, B.N., Agace, W.W., et al.: CCR2⁺CD103^-intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells. Mucosal Immunol. 2015, 8:327–239.

• ■ Travis, M.A., Reizis, B., Melton, A.C., Masteller, E., Tang, Q., Proctor, J.M., Wang, Y., Bernstein, X., Huang, X., Reichardt, L.F., et al.: Loss of integrin α_Vβ₈ on dendritic cells causes autoimmunity and colitis in mice. Nature 2007, 449:361–365.

• ■ Vicente-Suarez, I., Larange, A., Reardon, C., Matho, M., Feau, S., Chodaczek, G., Park, Y., Obata, Y., Gold, R., Wang-Zhu, Y., et al.: Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol. 2015, 8:141–151.

• ■ Watchmaker, P.B., Lahl, K., Lee, M., Baumjohann, D., Morton, J., Kim, S.J., Zeng, R., Dent, A., Ansel, K.M., Diamond, B., et al.: Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat. Immunol. 2014, 15:98–108.

1.2.8 Abschnitt 12.1.8

• ■ Bain, C.C., Bravo-Blas, A., Scott, C.L., Geissmann, F., Henri, S., Malissen, B., Osborne, L.C., Artis, D., and Mowat, A.M.: Constant replenishment from circulating monocytes maintains the macrophage pool in adult intestine. Nat. Immunol. 2014, 15:929–937.

• ■ Guilliams, M., Lambrecht, B.N., and Hammad, H.: Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013, 6:464–473.

• ■ Hadis, U., Wahl, B., Schulz, O., Hardtke-Wolenski, M., Schippers, A., Wagner, N., Muller, W., Sparwasser, T., Forster, R., and Pabst, O.: Intestinal tolerance requires gut homing and expansion of FoxP3⁺ regulatory T cells in the lamina propria. Immunity 2011, 34:237–246.

• ■ Mortha, A., Chudnovskiy, A., Hashimoto, D., Bogunovic, M., Spencer, S.P., Belkaid, Y., and Merad, M.: Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 2014, 343:1249288.

1.2.9 Abschnitt 12.1.9

• ■ Farache, J., Zigmond, E., Shakhar, G., and Jung, S.: Contributions of dendritic cells and macrophages to intestinal homeostasis and immune defense. Immunol. Cell Biol. 2013, 91:232–239.

• ■ Jang, M.H., Kweon, M.N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P.D., et al.: Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 2004, 101:6110–6115.

• ■ Mazzini, E., Massimiliano, L., Penna, G., and Rescigno, M.: Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1⁺ macrophages to CD103⁺ dendritic cells. Immunity 2014, 40:248–261.

• ■ McDole, J.R., Wheeler, L.W., McDonald, K.G., Wang, B., Konjufca, V., Knoop, K. A., Newberry, R.D., and Miller, M.J.: Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012, 483:345–349.

• ■ Schulz, O. and Pabst, O.: Antigen sampling in the small intestine. Trends Immunol. 2013, 34:155–161.

• ■ Yoshida, M., Claypool, S.M., Wagner, J.S., Mizoguchi, E., Mizoguchi, A., Roopenian, D.C., Lencer, W.I., and Blumberg, R.S.: Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 2004, 20:769–783.

1.2.10 Abschnitt 12.1.10

• ■ Fritz, J.H., Rojas, O.L., Simard, N., McCarthy, D.D., Hapfelmeier, S., Rubino, S., Robertson, S.J., Larijani, M., Gosselin, J., Ivanov, II, et al.: Acquisition of a multi-functional IgA⁺ plasma cell phenotype in the gut. Nature 2012, 481:199–203.

• ■ Kawamoto, S., Maruya, M., Kato, L.M., Suda, W., Atarashi, K., Doi, Y., Tsutsui, Y., Qin, H., Honda, K., Okada, T., et al.: Foxp3 T cells regulate immunoglobulin A selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 2014, 41:152–165.

• ■ Lin, M., Du, L., Brandtzaeg, P., and Pan-Hammarstrom, Q.: IgA subclass switch recombination in human mucosal and systemic immune compartments. Mucosal Immunol. 2014, 7:511–520.

• ■ Woof, J.M. and Russell, M.W.: Structure and function relationships in IgA. Mucosal Immunol. 2011, 4:590–597.

1.2.11 Abschnitt 12.1.11

• ■ Barone, F., Vossenkamper, A., Boursier, L., Su, W., Watson, A., John, S., Dunn-Walters, D.K., Fields, P., Wijetilleka, S., Edgeworth, J.D., et al.: IgA-producing plasma cells originate from germinal centers that are induced by B-cell receptor engagement in humans. Gastroenterology 2011, 140:947–956.

• ■ Fagarasan, S., Kawamoto, S., Kanagawa, O., and Suzuki, K.: Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 2010, 28:243–273.

• ■ Lin, M., Du, L., Brandtzaeg, P., and Pan-Hammarstrom, Q.: IgA subclass switch recombination in human mucosal and systemic immune compartments. Mucosal Immunol. 2014, 7:511–520.

• ■ Tezuka, H., Abe, Y., Asano, J., Sato, T., Liu, J., Iwata, M., and Ohteki, T.: Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 2011, 34:247–257.

1.2.12 Abschnitt 12.1.12

• ■ Karlsson, M.R., Johansen, F.E., Kahu, H., Macpherson, A., and Brandtzaeg, P.: Hypersensitivity and oral tolerance in the absence of a secretory immune system. Allergy 2010, 65:561–570.

• ■ Yel, L.: Selective IgA deficiency. J. Clin. Immunol. 2010, 30:10–16.

1.2.13 Abschnitt 12.1.13

• ■ Buonocore, S., Ahern, P.P., Uhlig, H.H., Ivanov, I.I., Littman, D.R., Maloy, K.J., and Powrie, F.: Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 2010, 464:1371–1375.

• ■ Satpathy, A.T., Briseño, C.G., Lee, J.S., Ng, D., Manieri, N.A., Kc, W., Wu, X., Thomas, S.R., Lee, W.L., Turkoz, M., et al.: Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat. Immunol. 2013, 14:937–948.

• ■ Klose, C.S., Kiss, E.A., Schwierzeck, V., Ebert, K., Hoyler, T., d’Hargues, Y., Goppert, N., Croxford, A.L., Waisman, A., Tanriver, Y., et al.: A T-bet gradient controls the fate and function of CCR6-RORγt⁺ innate lymphoid cells. Nature 2013, 494:261–265.

• ■ Kruglov, A.A., Grivennikov, S.I., Kuprash, D.V., Winsauer, C., Prepens, S., Seleznik, G.M., Eberl, G., Littman, D.R., Heikenwalder, M., Tumanov, A.V., et al.: Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science 2013, 342:1243–1246.

• ■ Le Bourhis, L., Dusseaux, M., Bohineust, A., Bessoles, S., Martin, E., Premel, V., Core, M., Sleurs, D., Serriari, N.E., and Treiner, E.: MAIT cells detect and efficiently lyse bacterially-infected epithelial cells. PLoS Pathog. 2013, 9:e1003681.

• ■ Spits, H. and Cupedo, T.: Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 2012, 30:647–675.

1.2.14 Abschnitt 12.1.14

• ■ Agace, W.W., Roberts, A.I., Wu, L., Greineder, C., Ebert, E.C., and Parker, C.M.: Human intestinal lamina propria and intraepithelial lymphocytes express receptors specific for chemokines induced by inflammation. Eur. J. Immunol. 2000, 30:819–826.

• ■ Cheroutre, H., Lambolez, F., and Mucida, D.: The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 2011, 11:445–456.

• ■ Eberl, G. and Sawa, S.: Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 2010, 31:50–55.

• ■ Hayday, A., Theodoridis, E., Ramsburg, E., and Shires, J.: Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2001, 2:997–1003.

• ■ Jiang, W., Wang, X., Zeng, B., Liu, L., Tardivel, A., Wei, H., Han, J., MacDonald, H.R., Tschopp, J., Tian, Z., et al.: Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med. 2013, 210:2465–2476.

• ■ Li, Y., Innocentin, S., Withers, D.R., Roberts, N.A., Gallagher, A.R., Grigorieva, E.F., Wilhelm, C., and Veldhoen, M.: Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 2011, 147:629–640.

• ■ Pobezinsky, L.A., Angelov, G.S., Tai, X., Jeurling, S., Van Laethem, F., Feigenbaum, L., Park, J.H., and Singer, A.: Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 2012, 13:569–578.

1.2.15 Abschnitt 12.2.1

• ■ Clevers, H.C. and Bevins, C.L.: Paneth cells: maestros of the small intestinal crypts. Annu. Rev. Physio. 2013, 75:289–311.

• ■ Conway, K.L., Kuballa, P., Song, J.H., Patel, K.K., Castoreno, A.B., Yilmaz, O.H., Jijon, H.B., Zhang, M., Aldrich, L.N., Villablanca, E.J., et al.: Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 2013, 145:1347–1357.

• ■ Geddes, K., Rubino, S.J., Magalhaes, J.G., Streutker, C., Le Bourhis, L., Cho, J.H., Robertson, S.J., Kim, C.J., Kaul, R., Philpott, D.J., et al.: Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat. Med. 2011, 17:837–844.

• ■ Lassen, K.G., Kuballa, P., Conway, K.L., Patel, K.K., Becker, C.E., Peloquin, J.M., Villablanca, E.J., Norman, J.M., Liu, T.C., Heath, R.J., et al.: Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl Acad. Sci. USA 2014, 111:7741–7746.

• ■ Prescott, D., Lee, J., and Philpott, D.J.: An epithelial armamentarium to sense the microbiota. Semin. Immunol. 2013, 25:323–333.

• ■ Song-Zhao, G.X., Srinivasan, N., Pott, J., Baban, D., Frankel, G., and Maloy, K.J.: Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen. Mucosal Immunol. 2014, 7:763–774.

1.2.16 Abschnitt 12.2.2

• ■ Bain, C.C. and Mowat, A.M.: Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 2014: 260:102–117.

• ■ Farache, J., Koren, I., Milo, I., Gurevich, I., Kim, K.W., Zigmond, E., Furtado, G.C., Lira, S.A., and Shakhar, G.: Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 2013, 38:581–595.

• ■ Persson, E.K., Scott, C.L., Mowat, A.M., and Agace, W.W.: Dendritic cell subsets in the intestinal lamina propria: Ontogeny and function. Eur. J. Immunol. 2013, 43:3098–3107.

• ■ Salazar-Gonzalez, R.M., Niess, J.H., Zammit, D.J., Ravindran, R., Srinivasan, A., Maxwell, J.R., Stoklasek, T., Yadav, R., Williams, I.R., Gu, X., et al.: CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches. Immunity 2006, 24:623–632.

• ■ Uematsu, S., Jang, M.H., Chevrier, N., Guo, Z., Kumagai, Y., Yamamoto, M., Kato, H., Sougawa, N., Matsui, H., Kuwata, H., et al.: Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c⁺ lamina propria cells. Nat. Immunol. 2006, 7:868–874.

1.2.17 Abschnitt 12.2.3

• ■ Cliffe, L.J., Humphreys, N.E., Lane, T.E., Potten, C.S., Booth, C., and Grencis, R.K.: Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 2005, 308:1463–1465.

• ■ Kinnebrew, M.A., Buffie, C.G., Diehl, G.E., Zenewicz, L.A., Leiner, I., Hohl, T.M., Flavell, R.A., Littman, D.R., and Pamer, E. G.: Interleukin 23 production by intestinal CD103⁺CD11b⁺ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 2012, 36:276–287.

• ■ Sokol, H., Conway, K.L., Zhang, M., Choi, M., Morin, B., Cao, Z., Villablanca, E.J., Li, C., Wijmenga, C., Yun, S.H., et al.: Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 2013, 145:591–601.

• ■ Sonnenberg, G.F., Fouser, L.A., and Artis, D.: Functional biology of the IL-22-IL-22R pathway in regulating immunity and inflammation at barrier surfaces. Adv. Immunol. 2010, 107:1–29.

• ■ Turner, J.E., Stockinger, B., and Helmby, H.: IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS Pathog. 2013, 9:e1003698.

1.2.18 Abschnitt 12.2.4

• ■ Cassani, B., Villablanca, E.J., Quintana, F.J., Love, P.E., Lacy-Hulbert, A., Blaner, W.S., Sparwasser, T., Snapper, S.B., Weiner, H.L., and Mora, J.R.: Gut-tropic T cells that express integrin α4β7 and CCR9 are required for induction of oral immune tolerance in mice. Gastroenterology 2011, 141:2109–2118.

• ■ Coombes, J.L., Siddiqui, K.R., Arancibia-Carcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., and Powrie, F.: A functionally specialized population of mucosal CD103⁺ DCs induces Foxp3⁺ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 2007, 204:1757–1764.

• ■ Du Toit, G., Roberts, G., Sayre, P.H., Bahnson, H.T., Radulovic, S., Santos, A. F., Brough, H.A., Phippard, D., Basting, M., Feeney, M., et al.: Randomized trial of peanut consumption in infants at risk for peanut allergy. N. Engl. J. Med. 2015, 372:803–813.

• ■ Huang, G., Wang, Y., and Chi, H.: Control of T cell fates and immune tolerance by p38α signaling in mucosal CD103⁺ dendritic cells. J. Immunol. 2013, 191:650–659.

• ■ Mowat, A.M., Strobel, S., Drummond, H.E., and Ferguson, A.: Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide. Immunology 1982, 45:105–113.

1.2.19 Abschnitte 12.2.5 und 12.2.6

• ■ Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J.R., Pfeffer, K., Coffer, P.J., et al.: Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013, 504:451–455.

• ■ Atarashi, K., Tanoue, T., Oshima, K., Suda, W., Nagano, Y., Nishikawa, H., Fukuda, S., Saito, T., Narushima, S., Hase, K., et al.: T_reg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013, 500:232–236.

• ■ Belkaid, Y. and Hand, T.W.: Role of the microbiota in immunity and inflammation. Cell 2014, 157:121–141.

• ■ Harig, J.M., Soergel, K.H., Komorowski, R.A., and Wood, C.M.: Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 1989, 320:23–28.

• ■ Hirota, K., Turner, J.E., Villa, M., Duarte, J.H., Demengeot, J., Steinmetz, O.M., and Stockinger, B.: Plasticity of Th17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat. Immunol. 2013, 14:372–379.

• ■ Kato, L.M., Kawamoto, S., Maruya, M., and Fagarasan, S.: The role of the adaptive immune system in regulation of gut microbiota. Immunol. Rev. 2014, 260:67–75.

• ■ Macia, L., Thorburn, A.N., Binge, L.C., Marino, E., Rogers, K.E., Maslowski, K.M., Vieira, A.T., Kranich, J., and Mackay, C.R.: Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 2012, 245:164–176.

• ■ Maynard, C.L., Elson, C.O., Hatton, R.D., and Weaver, C.T.: Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012, 489:231–241.

• ■ Peterson, D.A., McNulty, N.P., Guruge, J.L., and Gordon, J.I.: IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2007, 2:328–339.

• ■ Round, J.L. and Mazmanian, S.K.: Inducible Foxp3⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 2010, 107:12204–12209.

• ■ Scher, J.U., Sczesnak, A., Longman, R.S., Segata, N., Ubeda, C., Bielski, C., Rostron, T., Cerundolo, V., Pamer, E. G., Abramson, S.B., et al.: Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2013, 2:e01202.

• ■ Zigmond, E., Bernshtein, B., Friedlander, G., Walker, C.R., Yona, S., Kim, K.W., Brenner, O., Krauthgamer, R., Varol, C., Müller, W., et al.: Macrophage-restricted interleukin-10 receptor deficiency, but not IL10 deficiency, causes severe spontaneous colitis. Immunity 2014, 40:720–733.

1.2.20 Abschnitte 12.2.7 und 12.2.8

• ■ Adolph, T.E., Tomczak, M.F., Niederreiter, L., Ko, H.J., Bock, J., Martinez-Naves, E., Glickman, J.N., Tschurtschenthaler, M., Hartwig, J., Hosomi, S., et al.: Paneth cells as a site of origin for intestinal inflammation. Nature 2013, 503:272–276.

• ■ Alexander, K.L., Targan, S.R., and Elson, C.O.: Microbiota activation and regulation of innate and adaptive immunity. Immunol. Rev. 2014, 260:206–220.

• ■ Arenas-Hernández, M.M., Martínez-Laguna, Y., and Torres, A.G.: Clinical implications of enteroadherent Escherichia coli. Curr. Gastroenterol. Rep. 2012, 14:386–394.

• ■ Chung, H., Pamp, S.J., Hill, J.A., Surana, N.K., Edelman, S.M., Troy, E.B., Reading, N.C., Villablanca, E.J., Wang, S., Mora, J.R., et al.: Gut immune maturation depends on colonization with a host-specific microbiota. Cell 2012, 149:1578–1593.

• ■ Coccia, M., Harrison, O.J., Schiering, C., Asquith, M.J., Becher, B., Powrie, F., and Maloy, K.J.: IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4⁺ Th17 cells. J. Exp. Med. 2012, 209:1595–1609.

• ■ Knights, D., Lassen, K.G., and Xavier, R.J.: Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 2013, 62:1505–1510.

• ■ Kullberg, M.C., Jankovic, D., Feng, C.G., Hue, S., Gorelick, P.L., McKenzie, B.S., Cua, D.J., Powrie, F., Cheever, A.W., Maloy, K.J., et al.: Intestinal epithelial cells: regulators of barrier function and immune homeostasis. J. Exp. Med. 2006, 203:2485–2494.

• ■ Peterson, L.W. and Artis, D.: Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 2014, 14:141–153.

• ■ Shale, M., Schiering, C., and Powrie, F.: CD4⁺ T-cell subsets in intestinal inflammation. Immunol. Rev. 2013, 252:164–182.

• ■ Zelante, T., Iannitti, R.G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D’Angelo, C., Massi-Benedetti, C., Fallarino, F., et al.: Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013, 39:372–385.