sign in sign up
<<
Home , Immune system

Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

Gut, 1989, 30, 1679-1685

The intestinal immune system

WILLIAM F DOE

(This article is one of a series linked with the Festschrift for Christopher Boot/i. See Gut Festschrift 1989; 30.) The concept of localised intestinal has its contain the largest accumulation of lymphoid tissues origins in Besredka's observation that oral immunisa- in the body' in the form of lymphoid aggregates in tion using killed provided solid Peyer's patches and in the lamina propria (solitary protection against dysenteric irrespective of lymphoid nodules) and as the scattered the titres of serum .' But the clinical benefits populations found in the and in the lamina were variable and short lived and interest lapsed. propria. Little further progress was made until Heremans' Although nascent Peyer's patches are evident in discovery of IgA and the marked predominance of the newborn, the epithelium and lamina propria are IgA-containing plasma cells in normal intestinal devoid of mononuclear cells. T mi- mucosa.2 The differences between the antigenic grating from the rapidly populate the thymus determinants of serum and secretory IgA led to the - dependent areas of Peyer's patches and the identification of an additional polypeptide chain, the epithelium but exposure to micro-organisms in the secretory component (SC), which is essential to the normal environment is necessary to develop the B and function of IgA antibody at mucosal cell population and their germinal follicles as shown surfaces.' by experiments conducted in germ free .6 The importance of the mucosal immune system to the of intestinal was swiftly Induction of the secretory immune response recognised by Chris Booth. When I arrived as a houseman at Hammersmith in 1969, several pio- Non-immune and immune mechanisms protect the neering immunological studies of had privileged environment of the lamina propria from

been published. The clinical research ethos at challenge by foreign . Gastric acidity, diges- http://gut.bmj.com/ Hammersmith stimulated the study of disease tive proteases in the , intestinal not only by applying basic scientific knowledge and mobility, the commensal microflora and the mucous techniques but also by recognising that careful study coat or glycocolyx comprise some of the non-specific of human disease can also provide opportunities for protective barriers. The immune mechanisms may advancing our understanding of human . I operate within the lumen of the gut, at the mucosal recall the outpatient clinic in 1969 when Chris handed surface or within the lamina propria. The inter- me the referral letter for a new patient he had not epithelial lymphocyte (IEL) population are pre- on September 30, 2021 by guest. Protected copyright. seen: 'Fascinating, sounds like alpha chain disease.' dominantly suppressor lymphocytes (Ts) in contrast Several months later Heremans came to Hammer- with the lamina propria and show evidence of smith to deliver a series of outstanding lectures on the whereas most of the lamina propria secretory immune system. Grand rounds that week lymphocytes belong to the helper-inducer subset included the presentation of what was to be one of the (Th). Class II MHC determinants which represent a earliest published cases of alpha chain disease.4 restriction element in dependent immune In the decades since these early discoveries, major responses are expressed on normal small intestinal advances in understanding the physiology of the epithelial cells but not colon epithelial cells unless the intestinal immune response and the advent of mole- colon is inflamed. Expression of class II antigens is cular biology have helped to elucidate the induction modulated by products of activated T and regulation of the secretory antibody and cellular cells especially y (IFNy). Bland and responses at mucosal surfaces. Warren7 reported that MHC class Il positive villous epithelial cells can present soluble to primed Gut associated lymphoid (GALT) T cells leading to antigen specific suppression. Although human colonic epithelial cells have been The exposed surface of the intestinal mucosa is under reported to act as stimulators in autologous and constant challenge by ingested foreign antigens in allogeneic responses8 others have been unable to micro-organisms, products of digestion and stimulate T cells in an allogeneic system using an . It is therefore not surprising that the intestines MHC class II positive colon cell line.' 1679 Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

1680 William F Doe

Whether IEL require a second signal from a mucosal surface relates to separation of the T and B accessory cells in the lamina propria remains to be cell zones in Peyer's patches from antigen presenting answered. cells is not known. Mestecky and McGhee'` have Most studies of isolated GALT cells have been speculated that to lymphocytes performed using Peyer's patch cells. Whether these does occur in GALT resulting in an 'initial induction' reflect the function of all organised GALT is un- of immune responses and that the 'terminal inductive known. The dome of Peyer's patches is covered by a stimuli' may occur at distant mucosal sites after these unique epithelium comprising cuboidal epithelial committed lymphocytes have migrated there. cells which express class II MHC antigens, very few The migratory characteristics of IgA-committed goblet cells and specialised antigen-sampling cells lymphoblasts and memory cells are quite distinct. called M (for microfold) cells."' M cells pinocytose Unlike memory lymphocytes, IgA-containing soluble antigens such as ferritin and horse-radish lymphoblasts do not recirculate but 'home' to the peroxidase or phagocytose particulate foreign of antigenic stimulation, secrete antibody, antigens including and whole , and remain associated with the mucosal target tissue and transport them intact across the epithelium to the probably die within a few days.'` In rats primed and underlying lymphoreticular cells in the dome." challenged by intraintestinal injection of cholera and dendritic cells are present in the , specific antibody - containing lymphoblasts dome region, and MHC class II positive cells dis- were found three to five days later in the thoracic duct playing morphology are also found in from where they entered the circulation and the T and zones. Dendritic cells found in cell then populated distant mucosal sites. The number of suspensions of Peyer's patches are fully able to lymphoblasts in the thoracic duct greatly diminished present antigen in vitro"' and those present in the after five days but the number of small lymphocytes lamina propria of the small and in capable of transferring specific immunity to naive mouse and man are also competent to present animals (memory cells) peaked after two weeks and antigens. Whether Peyer's patch macrophages also persisted. The memory cells, which will produce T- function as antigen presenting cells, however, is and B-lymphoblasts when stimulated by specific uncertain, as lamina propria macrophages suppress antigen, enter the circulation from the lymph, 'home' antigen presentation by dendritic cells.'1 to distant mucosal sites and then re-enter the lymph Peyer's patches contain a higher proportion of B to recirculate.'7 Peripheral lymphoid tissues were not cells than nodes. B peripheral While IgM-bearing examined in these experiments but other studies http://gut.bmj.com/ cells predominate, there is significant enrichment for suggest that memory lymphocytes from the thoracic B cells displaying surface lgA and committed to IgA duct also 'home' preferentially to mucosal lymphoid synthesis consistent with the role of GALT as a major tissue. site for the induction of IgA responses. Peyer's Lymphocyte 'homing' is not dependent on the patches are also greatly enriched for T cells of the presence of antigen. IgA lymphoblasts migrate to helper-inducer subset (Th) although suppressor- fetal isografts of transplanted under- cytotoxic T cells (Ts) and the regulatory contra- neath the capsule of an adult mouse.'` When suppressor T cells (Tcs) which appear to potentiate rats primed by intracolonic injection of cholera toxin on September 30, 2021 by guest. Protected copyright. immune responses to orally presented antigen, are were challenged 14 days later by injecting antigen also found. The high degree of preferential localis- into a surgically isolated loop of jejunum with an ation of B cells and IgA specific Th cells in Peyer's intact and lymph supply, blast cells appeared in patches is probably determined by the specificity of comparable numbers in the stimulated intestinal loop binding of these lymphocytes to the high endothelial and in the unstimulated jejunum. By cannulating and venule receptors present in postcapillary venules in draining the thoracic duct, the researchers confirmed Peyer's patches'4 which determine their represen- that antigen stimulation of memory cells in the tation in Peyer's patches and ultimately regulate the isolated jejunal loop resulted in the production of nature of the immune response generated. lymphoblasts that entered the lymph and circulated Yet induction ofmucosal immunity and the delivery to populate the entire jejunum.'7 Although memory of the immune response is not entirely localised to the cells recirculate to populate the mucosal tissues, intestine. After antigen exposure, Th cells and B cells general mucosal dissemination of lymphoblasts com- committed to specific IgA synthesis are rapidly mitted to IgA synthesis does not occur after secondary generated in Peyer's patches and travel via the challenge. When thoracic duct lymphoblasts from mesenteric node into the thoracic duct to enter the animals both primed and challenged by intracolonic circulation before selectively migrating to mucosal injection of cholera toxin were transferred into naive surfaces. Whether this inability to mount a completely recipients, large numbers of antibody specific plasma localised immune response to antigen encountered at cells populated the colon but there were virtually Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

The intestinal immune system 1681 none found in the jejunum. These studies suggest chains of one of the monomers in dimeric IgA. The that the lymphoblasts can distinguish between high regions of SC are structurally related to the endothelial cell receptors in the colon and jejunum variable domain of immunoglobulin light chains and indicating that the colon receptors have their own probably have a similar tertiary structure. Since the 'homing' specificity. The presence of antigen, how- secondary structure of J chain also shows immuno- ever, profoundly affects the magnitude and persist- globulin like folding, the interactions of a, ,u and J ence of the response due to antigen-driven clonal chains with SC may be based on the complementaries expansion of antibody forming cells and their precur- of their domain-like structures.2" Both the additional sors.I' peptides SC and J chain bind covalently to the Fc region of IgA and IgM. Intestinal fluid immunoglobulins The constant domains of the a chains of the two subclasses of IgA, IgA, and IgA2 are very similar. A specialised form of IgA, secretory IgA, represents The C terminus of the a chain resembles that of the ,u the predominant antibody in intestinal fluid chain and extends further than the C termini of the y, where the relative concentrations of the major £ and o chains of IgG, IgE and IgD strongly suggest- immunoglobulin isotypes mirror their relative ing that this extension is implicated in the ability of distribution in the antibody-containing cells of the IgA and IgM to form polymers." intestinal mucosa.' Unlike IgA in the serum and The predominant structural differences between cerebrospinal fluid which largely comprises 7S mono- IgA, and lgA2 occur in the hinge region where IgA, mers, secretory IgA is an 11S dimer made up of two has a unique sequence of 13 amino that are IgA monomers joined by a covalently linked peptide susceptible to cleavage by highly specific bacterial named J chain.' Both IgA and IgM plasma cells IgA proteases. The corresponding sequence is lacking synthesise J chain which greatly enhances the binding in IgA2 which are therefore resistant to of an additional polypeptide, secretory component nearly all known bacterial proteases with the excep- (SC), thereby completing the assembly of secretory tion of a clostridial IgA protease that cleaves a IgA and IgM molecules. The details of secretory IgA peptide bond in the hinge region of both IgA1 and structure have recently been reviewed." J chain is an IgA2 of the A2m(1) .2' acidic peptide of 137 residues which may be involved Plasma cells producing 1OS IgA are found in all in the intracellular polymerisation of IgA. One mucosal tissues especially in the intestinal lamina of J chain joins two IgA monomers whereas propria whereas plasma cells in the marrow, http://gut.bmj.com/ three or more J chain molecules are involved in and peripheral lymph nodes secrete mono- forming the IgM pentamer within the meric (7S) lgA. There is also a selective distribution before secretion. of cells producing the IgAI and IgA2 subclasses. IgA1 Secretory component (SC) is a plasma cells form the majority in all tissues apart molecule synthesised by epithelial cells in secretory from the colon but there is marked variation in the glandular tissue and mucosal surfaces. In some ratio of lgA, to IgA2 plasma cells between lymphoid mammalian species, but not man, hepatocytes also tissues from different sites. That IgA2 is the prepon- synthesise and display SC. Secretory component derant subclass in the colon may relate to local on September 30, 2021 by guest. Protected copyright. exists in three molecular forms; as a membrane stimulation by endotoxins from commensal gram expressed on the outer surface of epithelial negative organisms which mainly induce an IgA2 cells, it acts as a for polymeric immuno- subclass antibody response resistant to bacterial globulins. Secretory component forms part of proteases." secretory IgA and IgM molecules in mucosal fluids where it is also found as a free . Secretory component interacts with a specific binding site on Secretory IgA function the Fc region of SIgA and IgM, stabilises their quaternary structures, and increases their resistance The protective role of secretory IgA against a variety to proteolytic digestion.' Structural studies of human of foreign antigens, including food antigens bacteria SC reveal a characteristic composition, comprising viruses and , is well established. S-lgA blocks 549 to 558 amino acids and a high the access of potentially allergenic molecules derived content (20%). Twenty cysteine residues create 10 from food or drugs. S-IgA mediated responses at intrachain disulphide bridges in a single polypeptide mucosal surfaces to locally encountered antigens are chain that has five regions of remarkable homology. readily detected but prolonged topical exposure to The fifth homology region contains an additional protein or particulate antigens is required to induce labile disulphide bond that is involved in the for- serum .`2 Antibodies of all three major mation of a disulphide bridge linking SC to the two isotypes specific for food and microbial antigens are Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

1682 William F Doe detectable in the sera of normal individuals. They are and Th cells to provide cell mediated antibacterial mostly IgA, class and very high serum titres are activity.2' found in IgA deficient patients. S-IgA may also block The secretory component (SC) displayed on the reaginic sensitivity reactions at the surface of the basolateral membrane of mucosal epithelial cells acts as reported for nasal epithelium. as a receptor for polymeric IgA and IgM by binding Because some dietary antigen is clearly absorbed by to a J chain-related site. The SC-polymeric IgA normal subjects, the importance of S-IgA antibody complex is internalised by the epithelial cell and may lie in reducing the amount of antigen that gains transported as a vesicle to its apical surface where the access to the lamina propria. SC-IgA complex is released.' Although human S-IgA can neutralise biologically active antigens, hepatocytes do not express surface SC they do have including viruses and toxins and , prevent surface membrane receptors specific for asialoglyco- adherence of bacterial to epithelial sur- called hepatic binding proteins that bind faces and enhance the antibacterial efficiency of human polymeric IgA, and to a lesser extent mono- other immune effector systems. The effectiveness of meric lgAl. lgA2 does not inhibit this interaction. S-IgA as a neutralising antibody against viruses is The human rapidly clears S-IgAl from the shown by the responses to the Sabin oral live circulation indicating that the hepatic binding protein where protection correlates with acts as a receptor for S-IgA, uptake.29 Unlike those levels of secretory antibody.` The four antigen species that have hepatocytes bearing SC, do combining sites of S-lgA also allow it to function not transport large quantities of circulating IgA efficiently as an agglutinin and the capacity of S-IgA across the hepatocyte and into the bile. In human to protect by inhibiting bacterial adherence to the bile, only about 50% of the polymeric IgA is derived mucosal epithelium is exemplified by S-lgA anti- from the plasma. bodies to Vibrio cholera. There is also evidence that IgA has bacteriocidal potential in cooperation with Regulation of S-IgA immune responses complement and and S-lgA can opsonise bacteria as outlined below. Many characteristics of the S-IgA system clearly Unlike IgM or IgG, however, secretory IgA does distinguish it from systemic immunity. GALT con- not recruit the powerful mediator systems that are tains all the cells required for local responses and is activated in systemic immune responses. In partic- constantly exposed to antigenic stimulation and to ular, sIgA-antigen do not complexes activate the biological active bacterial components such as http://gut.bmj.com/ classical or alternative pathways of complement.'4 endotoxin, but a number of negative regulatory Chemically aggregated IgA in high concentration factors suppress the induction of a localised immune does activate the alternative pathway but the bio- response. There is selective of GALT B cells logical relevance of the finding is questionable. leading to marked restriction of the isotype potential IgA and IgA-containing immune complexes are of B cells to IgA expression.29 Endogenous gut capable of interacting with , mononuclear endotoxin appears to enhance the host's resistance to , epithelial cells lining mucous mem- gram negative possibly by interacting with branes, T, B and NK cells. The Fc receptors for Cot2 lymphoreticular cells in GALT resulting in induction on September 30, 2021 by guest. Protected copyright. domain of polymeric and monomeric IgA and for of innate host immunity to infection. sIgA of both subclasses that are displayed by sub- The IgA response to antigens including carbo- populations of neutrophils and mononuclear hydrate antigens is controlled by T cells. Peyer's phagocytes increase in number when these cells are patch T cells stimulated by Conconavalin A help IgA exposed to high levels of IgA. These findings may expression but suppress IgM and IgG in LPS-driven explain the enhanced phagocytic activity of mucosal B cell cultures whereas similarly treated splenic T neutrophils compared to those from the circulation.'` cells suppress all three isotypes.90 Oral administration The functional significance of Fco receptors on of soluble or particulate antigens induces Th cells in phagocytes is uncertain. Earlier reports suggested GALT which are specific for the IgA isotype and that IgA had little capacity as an , but recent probably account for the IgA isotype response that studies indicate that particles coated with IgA are results from oral immunisation. readily phagocytosed by neutrophils from the oral Two separate modes of T cell regulation for the cavity." Neutrophils may also clear IgA complexes IgA response apparently exist in GALT. T cells may from the blood. Macrophages in and milk induce B cells to switch isotypes (Tsw)3' by promoting contain large amounts of S-IgA suggesting that they the switch of B cells bearing surface IgM (sIgM+) to provide the means for transporting S-IgA into the cells expressing surface IgA (sIgA) - events that are lower gastrointestinal tract of breastfed . influenced by factors released by activated T cells There is also evidence that IgA can 'arm' neutrophils including 4 and 5. A second mode of T Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

The intestinal immune system 1683 cell regulation of IgA responses may involve Th cells Mucosal cellular responses bearing Fc receptors for IgA (Fcca) which preferen- tially interact with sIgA'B cells and differentiate Studies of effector cell populations in isolated lamina them into IgA-producing plasma cells.32 In mice, Fcct propria mononuclear cells have identified marked receptors (FcaR) are also found on some Ts cells that differences in their relative frequency, functional can release the FcaR as an IgA-binding factor (IBFa) state and phenotype in comparison to corresponding resulting in suppression of IgA synthesis in pokeweed cell populations in the peripheral blood. Lamina mitogen driven spleen cell cultures. On exposure to propria lymphocytes show enhanced proliferation lgA, activated FcctRT cells released IBFa and after exposure to 2 (IL-2), a much higher suppressed IgA responses. Supernatants of FcaIR proportion of IL-2 receptor-bearing cells in the Th hybrids created by fusing Peyer's patch Th cells with a and Ts subpopulations and an increased proportion T cell lymphoma line, supported antigen-dependent of T cells expressing class II antigens of the major IgA responses in cultures of normal Peyer's patch B histocompatibility complex. Moreover, IL-2 receptor cells whereas FccR- supernatants did not. mRNA is detectable in unstimulated lamina propria When IBFa was purified from the supernatants, high lymphocytes. But there is no evidence of IL-2 mRNA concentrations suppressed T cell-dependent IgA expression. Peripheral blood lymphocytes do not responses while low levels of IBFa enhanced IgA express either mRNA.33 Mucosal T cells therefore responses.33 These results indicate that T cell selec- selectively express some of the associated with tion and induction of sIgA+ B cells involves FcaR and T cell activation resulting in 'partial' activation or that high concentrations of IBFct have a paradoxical 'primed' mucosal T cells that may result from unique, suppressor effect. Whether these effects derive from possibly environmental activation signals in the intes- different concentrations of the same IBFa molecule tine or altered regulation of T cell function at mucosal or whether, as has been shown for IgE, there are two surfaces. classes of IBF, one suppressor the other helper, that Mucosal cell mediated unrestricted by differ in their carbohydrate moieties,34 has not been the MHC is also markedly distinct from that found in established. Thus clones of T cells may produce both peripheral blood. Natural killer cells represent 2-3% surface Fca receptors and a secretory form(s) of of dispersed lamina propria cells, as identified by the IBFct which markedly influence the responses of NKH-1 , but are Leu 11`. sIgA+ cells in a complex network to generate IgA Natural killer activity is very low or undetectable in specific immunoregulation at exposed mucosal sites unseparated lamina propria cells4`4 but can be http://gut.bmj.com/ involving selective homing mechanisms for redistri- discerned in purified NKH-1+ cells. Mucosal bution of IgA-committed cells. lymphokine activated killer (LAK) cells also express a different phenotype to those in peripheral blood T cell networks and oral tolerance being T11+, NKH-1-, Leu 11-, T4-, T3-, T11-, and T8- 33 41 and high levels of cytotoxicity to cell lines and Two separate immune responses follow oral admini- to freshly isolated cells can be generated after stration of antigen in large doses; S-IgA antibodies exposure of lamina propria lymphocytes to IL-2 in are generated at mucosal surfaces and unresponsive- culture for 72h.4" 4' Non-specific cytolytic cells on September 30, 2021 by guest. Protected copyright. ness to the same antigen - that is, tolerance, develops activated by which are also present may well systemically. The simultaneous generation of Th and be a variant of the LAK cell. Although the numbers Ts cells specific for the same antigen implies another and cytotoxic activity of mucosal NK cells are very level of control which is apparently provided by the limited, it remains possible that other NK cell contra-suppressor T cell (Tcs). Indeed Tcs, which are capabilities, including resisting viral infection, and enriched along with Th cells in Peyer's patches, can immunoregulation may be relevant to mucosal abolish oral tolerance when adoptively transferred to homeostasis. Lymphokine activated killer cells lyse an orally immunised by the same antigen. IgA solid tumour cells in vitro but whether the conditions isotype-specific Tcs cells have recently been reported exist to generate this population in vivo is unclear. in Peyer's patches. These Tcs bind to immobilised Markers of T cell activation are markedly increased FcaR+ helper cells and, when adoptively transferred, in lamina propria lymphocytes compared to those also abolish oral tolerance. from peripheral blood. These include proliferative Although circulating immune complexes33 and responses to IL-2, IL-2 receptor expression and anti-idiotypic antibodies37 have also been proposed as function and expression of class II MHC antigens but mechanisms mediating oral tolerance, the evidence there is no enhancement of IL-2 synthesis. Mucosal suggests that a T cell suppression network plays the NK cells and other Fc-bearing cells including macro- major part in the downregulation of systemic immune phages may mediate antibody-dependent cytotoxicity responses. (ADCC). Antibody-dependent cytotoxicity has been Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

1684 William F Doe shown in lamina propria cells but its importance to technology to engineer micro-organisms not only to mucosal remains to be assessed. produce large quantities of previously unavailable An indirect measure of in vitro primed cytotoxic T natural peptides in pure form but also to create cell activity that is not MHC restricted may be recombinant for oral immunisation against obtained using antibodies to the CD3 component of intestinal infection and infestation. Besredka's vision the human T cell receptor.4" High levels of cyto- of oral vaccines is now being realised. were found in lamina propria cells from histologically normal colon possibly reflecting the Division of Clinical Sciences, exposure of the mucosa to consistent and diverse John Curtin School of Clinical Research, antigenic challenges. These effector cells display the Australian National University, CD2+, CD3+, CD8+, CD4-, CD16- and Leu Canberra. 7-phenotype and the pattern of target cell specificity may be determined by the CD45 antigen which is References coupled to the trigger process for NK of some target cells.43 This cell population may represent in I Besredka A. De la contra les ctats typhoid vitro primed T par la voic buccale. Ann Inst Pasteur 1919; 33: 882. cytotoxic cells reactive against un- 2 Crabbc PA, Heremans JF. Etude immunohistochem- determined antigens including viruses. ique des plasmocytes de la muqucse intestinale humaine normale. Rev Fran( Etudes Clin biol 1966; 11: 484-92. Conclusion 3 Tomasi TB. Structure and function of mucosal anti- bodies. Ann Rev, Med 1970; 21: 281-98. Clinical research involving the detailed study of 4 Doc WF, Henry K, Hobbs JR. Dowling RH. Alpha individual patients has made many important and chain disease. QJ Med 1970; 39: 619. original contributions to understanding of the 5 Brandtzaeg P. Role of J chain and secretory component physiology of the intestinal immune system in health in receptor-mediated glandular and hepatic transport of immunoglobulins in man. Scand J Immnunol 1985; 22: and disease. In this context, the study of individual 111-46. patients suffering from alpha chain disease (ctCD) 6 Crabb6 PA, Nash DR, Bazin H, Eyssen H, Heremans represents a paradigm. The importance of diffuse, JF. Immunohistochemical observations on lymphoid small intestinal lymphomas called Mediterranean tissuc from conventional and germ-free mice. Lab Invest lymphomas (ML) as a cause of malabsorption in the 1970; 22: 448-57. Middle East had been recognised for years, but 7 Bland PW, Warren LG. Antigen presentation by

many http://gut.bmj.com/ understanding was limited to descriptive accounts of epithelial cells of the rat small intestine. I Kinetics, the morphology of the cellular infiltrate as seen in antigen specificity and blocking by anti la antisera. stained paraffin sections of intestinal tissue. When Immunology 1986; 58: 1-7. in 8 Mayer L, Schlien R. Evidence for function of la mole- individual patients Paris' and at Hammersmith44' cules on gut epithelial cells in man. J Exp Med 1987: 166: were investigated, it was discovered that the diffuse 147 1-83. cellular infiltrate represented a monoclonal expan- 9 Sollid LM, Brandtzaeg P, Kvale D, etal. Teell epithelium sion of benign appearing plasma cells which interactions in relation to gut immunity. Monogr , synthesised, and usually secreted, a marker protein 1988; 24: 60-65. on September 30, 2021 by guest. Protected copyright. comprising a heavy chain fragment of IgA, devoid of 10 Owen RL, Joncs AL. Epithelial cell specialization light chains. Analysis of the Fca fragment found in within human Peyer's patches: An ultrastructural study serum, and intestinal fluid revealed that it of intestinal lymphoid follicies. Gastroenterology 1974; bound secretory component (SC), providing the first 66: 189-203. 11 Owcn RL. Sequential uptake of horseradish peroxidase evidence for the binding site of SC to the IgA dimer. by lymphoid follicle epithelium of Peyer's patches in the Left untreated, axCD progresses to a frankly invasive normal unobstructed mousc intestinc: An intestinal lymphoma. The discovery of ctCD, has ultrastructural study. Gastroenterology 1977; 72: 440-5. provided a unique and important opportunity to 12 Spalding DM, Koopman WJ, Eldridge JH, McGhee JR, study the natural history of a B cell lymphoma as well Steinman RM. Accessory cells in murine Peycr's patch. as offering the prospect of early diagnosis by detection I Identification and Enrichment of a functional dendritic of the marker protein and of cure.4" cell. J Exp Med 1983; 157: 1646-59. The molecular analysis of immune and inflam- 13 Pavli P, Hume DA, Doe WF. Isolation and enrichment matory events at the mucosal surface in human of human colonic antigen-presenting dendritic cells (DCs). Gastroenterology 1989: 5: A385. beings has been greatly enhanced by the improved 14 Stevens SK, Weissman IL, Butcher EC. Differences in access to tissue provided by developments in fibre- the migration of B and T lymphocytes: organ-selective optics and in ultrasound, microassay systems localization in vivo and the rolc of including HPLC, fluorimetry, monoclonal antibodies lymphocyte-cndothelial cell recognition. J Immunol and DNA probes, and the use of recombinant DNA 1982; 128: 844-5 1. Gut: first published as 10.1136/gut.30.12.1679 on 1 December 1989. Downloaded from

The intestinal immune system 1685

15 Mestecky J, McGhee JR. (IgA): regulating IgA class-specific immunoglobulin produc- Molecular and cellular interactions involved in IgA tion in murine gut-associated lymphoid tissues 11. Biosynthesis and Immune response. Adv Immunol Terminal differentiation of postswitch sIgA-bearing 1987; 40: 153-245. Peyer's patch B cells. J Fxp Med 1983; 158: 649-69. 16 Husband A, Gowans JL. The origin and antigen- 32 Kiyono H, Cooper MD, Kearney JF, et al. Isotype dependent distribution of IgA-containing cells in the specificity of helper T cell clones. Peyer's patch Th cells intestine. J Exp Med 1978; 148: 1146-60. prefcrentially collaborate with maturc IgA B cells for 17 Pierce NF, Cray WC Jr. Determinants of the local- IgA responses. J Exp Med 1984; 159: 798-811. ization, magnitude and duration of a specific mucosal 33 Kiyono H, Mostellar-Barnum LM, Pitts AM, IgA plasma cell response in enterically immunised rats. J Williamson SI, Michalek SM, McGhee JR. Isotype- Immunol 1982; 128: 1311-5. specific immunoregulation: IgA binding factors pro- 18 Ferguson A, Parrott DMV. The effect of antigen duced by Fcu receptor positive T cell hybridomas deprivation on thymus dependent and thymus inde- regulate IgA responses. J Exp Med 1985; 161: 731-47. pendent lymphocytes in the small intestine of the mouse. 34 Ishizaka K. Regulation of IgE synthesis. Ann Rev Clin Exp Immunol 1972; 17: 477-88. Immunol 1984; 2: 159-82. 19 Halpern MS, Koshland ME. Novel subunit in secretory 35 Suzuki 1, Kitamura J, Kiyono H, et al. Isotype-specific IgA. Nature (Lond) 1970; 228: 1276-8. immuno-regulation. Evidence for a distinct subset of T 20 Zikan J, Novotny J, Trapane TL, et al. Secondary contrasuppressor cells for IgA responses in murine structure of the immunoglobulin J chain. Proc Natl Acad Peyer's patches. J Exp Med 1986; 164: 501-16. Sci USA 1985; 8: 5905-9. 36 Andre C, Heremans JF, Vaerman JP, Cambiasco CL. A 21 Fujiyama Y, Kobayashi K, Senda S, et al. A novel IgA mechanism for induction of immunological tolerance by protease from Clostridium sp. capable of cleaving IgAj antigen feeding: antigen-antibody complexes. J Exp and IgA2 A2m(1) allotype but not IgA2 A2m(2) Med 1975; 142: 1509-19. allotype paraproteins. J Immunol 1985; 134: 573-6. 37 Kagnoff MF. Effects of antigen-feeding on intestinal 22 Heremans JF, Bazin H. Antibodies induced by local and systemic immune responses. III. Antigen-specific antigenic stimulation of mucosal surfaces. Ann NYAcad serum-mediated suppression of humoral antibody Sci 1972; 190: 268-75. responses after antigen feeding. Cell Immunol 1978; 40: 23 Ogra PL, Karzon DT. Poliovirus antibody response in 186-203. serum and nasal following intranasal inocu- 38 Zeitz M, Greene WC, Peffer NJ, James SP. Lympho- lation with inactivated poliovaccine. J Immunol 1969; cytes isolated from the intestinal lamina propria of 102: 15-23. normal nonhuman primates have increased expression 24 Colten H, Bienenstock J. Lack of C3 activation through of genes associated with T cell activation. Gastroenter- classical or alternate pathways by human secretory IgA ology 1988; 94: 647-55. anti-blood-group-A antibody. In: Mestecky J, Lawton 39 Shanahan F, Brogan M, Targan S. Human mucosal http://gut.bmj.com/ AR, eds. The Immunoglobulin A system New York: cytotoxic effector cells. Gastroenterology 1987; 92: Plenum, 1974; 45: 305. 1951-7. 25 Fanger MW, Goldstine SN, Shen L. Cytofluorographic 40 Hogan PG, Hapel AJ, Doe WF. Lymphokine-activated analysis of receptors for IgA on human polymorpho- and activity in human intestinal nuclear cells and and the correlation of mucosa. J Immunol 1985; 135: 1731-8. receptor expression with . Mol Immunol 41 Fiocchi C, Tubbs RR, Youngman KR. Human intestinal 1983; 20: 1019-27. mucosa mononuclear cells exhibit lymphokine-activated 26 Tagliabue A, Boraschi D, Villa L, et al. IgA-dependent killer cell activity. Gastroenterology 1985; 88: 625-37. on September 30, 2021 by guest. Protected copyright. cell-mediated activity against enteropathogenic bacteria: 42 Phillips JH, Lanier LL. -dependent and anti CD-3 distribution, specificity and characterisation of the induced cytotoxicity are preferentially mediated by effector cells. J Immunol 1984; 133: 988-92. peripheral blood cytotoxic T lymphocytes expressing 27 Nagura H, Nakane PK, Brown WR. Translocation of Lcu-7 antigen. J Immunol 1986; 136: 1579-85. dimeric IgA through neoplastic colon cells in vitro. J 43 Shanahan F, Deem R, Nayersina R, Leman B, Targan Immunol 1979; 123: 2359-68. S. Human mucosal T-cell cytotoxicity. Gastroenterology 28 Tomana M, Phillips JO, Kulhavy R, Mestecy J. Carbo- 1988; 94: 960-7. hydrate-mediated clearance of secretory IgA from the 44 Seligman A, Hurez D, Mihaesco D, et al. Alpha chain circulation. Mol Immunol 1985; 22: 887-92. discase; a new immunoglobulin abnormality. Science 29 Cebra J, Komisar JL, Schweitzer PA. CH isotype 1968; 162: 1396-7. "switching" during normal B-lymphocyte development. 45 Doe WF, Hobbs J, Henry K, et al. Five cases of alpha Ann Rev Immunol 1984; 2: 493- 548. chain disease. Gut 1972; 13: 947-57. 30 Elson CO. Heck JA, Strober W. T cell regulation of 46 WHO Alpha chain disease and related small intestinal murine IgA synthesis. J Exp Med 1979; 149: 632-43. lymphome. Revue Generale, Arch Franc Mal Appar 31 Kawanishi H, Saltzman L, Strober W. Mechanisms Dig 1976; 65: 591-607.