80 immunology to@, May 1981

(rostrum Where do

) mucosal mast cells

acquire IgE ? John Gillon

Gastrointestinal Unit, Western General Hospital, Edinburgh EH4 2XU.

Immedia te hypersensit ivity reactions in the gut are receiving increasing at tent ion and are thought to be involved in a wide spectrum of diseases. The gastro- intestinal tract, like other mucosal surfaces, is rich in sensitized (i.e. IgE-coated) mast cells whose numbers increase not only under specific circumstances such as helminth infections, but also in response to chronic inf lammatory lesions such as peptic ulcers ~. Mas t cells are concentra ted in connective tissues and at mucosal surfaces and are thought to be mobile. However, mucosal mast cells appear to differ from connective tissue mast cells in that they contain in t racytoplasmic IgE as well as the surface IgE which serves as a trigger for mast-cell degranulat ion 2. It is not known whether there are functional differences between the two pop- ulations of mast cells but the observation that the IgE- laden mucosal mast cells, often in the form of so-called 'globule-leukocytes ' , are found not only in the lamina propr ia but also within the epithelial layer of the small intestine of rats infected with Nippostrongylus brasiliensis has led to the suggestion that they may carry IgE for release within the lumen 2. It has long been thought that mast cells or their precursors may circulate 3, and it therefore seems possible that in the case of the mucosal mast cell there is traffic from the gut-associ- ated lymphoid tissues back to the mucosa via the thoracic duct and peripheral circulation.

IgE is normal ly detected in the serum in only very small quanti t ies 4, but raised levels are found in response to helminth infections and in some atopic subjects 5. It has generally been assumed that mast cells are a rmed in situ by IgE from the per ipheral circulat ion and the level of IgE in the blood has been shown to be directly related to the degree of sensitiza- t ion in atopic subjects 6. However, IgE product ion in the case of antigenic challenge at a mucosal surface appears to occur almost exclusively in the regional lymph nodes z and a locally produced lymphokine appears to be the main stimulus ~'. This substance is released from B cells which have surface IgM, IgE and IgD and the release depends on the br idging of surface IgE or IgD 6, implying that antigen is necessary for the ini t iat ion of the cycle of events leading to local IgE production. Little is known about the mechanisms of

mucosal antigen processing and its supposed trans- port to the regional node.

If sensitization of mast cells depended on their acquiring IgE from the circulation the abil i ty to amplify the response and at the same t ime restrict its extent would be lacking. It has been shown, in rats, that the extent of the mast cell response to N. brasiliensis within the intestine is not controlled by the distr ibution of antigen, since both the intestine distant from the main site of infection and isografts of intestine removed from continuity show increased numbers of mast cells 7. Al though these sensitized mast cells are thought to be impor tant in parasi te expul- sion, serum levels of parasite-specific IgE rise only after the worm burden has been el iminated s. New evidence suggests that mast-cell precursors which will differentiate in vitro are present within the regional lymph node of N. brasi/iensis-infected rats 9. Their dif-

As , _ _ ~ A,g I _ LOM N r __I_

to R L N. ~ / M.C. Precursor ..... i / ~ Developing

~ R L N ~ M.C. homes I E f v ~ ~ " " ' r to Mucosa

prlogduct ion ~c c" . ~ y ( ~ . ~ qmres ,gE N= - ie. sensitised |

'spiu-over' ~ L - , - / IgE Y,~ \ [

~','~ v ~ . PERIPHERAL ' r ~ / ~ BLOOD

Fig. 1. Scheme for traffic of mast cell precursors from mucosa to regional l ymph node, where sensit isation with newly formed IgE might occur, back to the mucosa via thoracic duct and per iphera l blood. Ag= antigen; M.C. = mast cell; R .L.N. - regional lymph node; T .D . - thoracic duct; E.P.= epithelium; L.P . - lamina propria

© Elscvicr/Notth-Ho[land Bionlcdical Press 1981

immunology today, May 1981 81

ferentiation appears to depend on the presence of specific helper T cells 9. Mast cells have also been grown in vitro from the thoracic-duct lymph of immunized mice 3.

There is, therefore, convincing evidence that mast- cell p recursors , which may be der ived from a plur ipotent bone marrow stem cell 1°, circulate from the mucosal surface to the regional lymph node, and thence back to the mucosa via the thoracic duct and circulat ion 3,7,9. Since IgE product ion is localized to the regional node z, there is a possibil i ty that the develop- ing mast cell, a l ready pr imed to home to the mucosa, might come into close contact with the IgE-producing B cells. O n teleological grounds it would be logical for the sensitization of the mast cells to occur at this focal point, allowing rapid amplif icat ion of the response in keeping with the term immedia te hypersensitivity, while providing a mechanism for its conta inment within the relevant mucosal surface.

In N. brasiliensis-infected rats, the worm count in the intestine is greatest at a round day 12, and worm expul- sion is complete by day 20 in a p r imary infection 7. Mast cells are most numerous in the intestinal mucosa between day 16 and day 20 (Ref. 7), and at the same time mast-cell precursors can be isolated in large numbers from the mesenteric lymph nod&. However, specific homocytotropic ant ibody is not found con- sistently in the serum before day 20, and even at day 42 may be present in only low titre 2. It seems unlikely, therefore, that the mucosal mast cells acquire IgE from the circulation. Sensit ization of the circulat ing mast-cell precursors in the regional lymph nodes w h e r e IgE is s y n t h e s i z e d w o u l d e x p l a i n the appearance of large numbers of mature sensitized mast cells in the mucosae at the time of worm expul- sion but before a 'spill over ' effect of IgE is detectable in the serum.

The model I propose is i l lustrated in the accom-

panying figure. It should be easy to test with existing animal models of immedia te hypersensit ivity and if correct it provides an explanat ion for the localized nature of most immedia te hypersensit ivity reactions even in the presence of systemic exposure to antigen. For example, it has been shown that antigen absorbed from the small intestine, and thus present in t hepe r i - pheral circulation, can produce localized anaphylact ic reactions at other sites such as the bronchial mucosa 11. Absorbed antigen (ovalbumin) was also found to form complexes with specific IgE. The complexes ' main function in the serum might be to mop up antigen gaining access to the circulation. If, on the other hand, mast cells in the per ipheral tissues were sensitized by IgE from the circulation, systemic anaphylaxis is likely to be much more frequent in atopic or as thmatic subjects with raised serum IgE levels because mast cells throughout the body would be sensitized and not just those at the mucosal surface where the antigenic challenge first occurred. Refe rences

1 Brown, W. R., Borthistle, B. K. and Chen, S. T. (1975) Clin. Exp. hnmuno120, 227-237

2 Mayrhofer, G., Bazin, H. and Gowans, J. L. (1976) Eur. J. Immunol. 6, 537-545

3 Ginsburg, H. and Lagunoff, D. (1967) J. Cell. Biol. 35, 685-697 4 Johannson, S. G. O. (1967) Lancet ii, 951-953 5 Stenius, B., Wide, L., Seymour, W. M., Holford-Stevens, V.

and pepys,J. (1971) Clin. Allergy 1, 37-55 6 Urban, J. F., Ishizaka, K. and Bazin, H. (1980) J. Immunol.

124, 527-532 7 MacDonald, T. T., Murray, M. and Ferguson, A. (1980) Exp.

Parctsitol. 49, 9-14 8 Jarrett, E. E. E., Haig, D. M. and Bazin, H. (1976) Clin. Exp.

Immunol. 24, 346-351 9 Denburg, J. A., Befus, A. D. and Bienenstock, J. (1980)

Immunology 41,195-202 10 Kitamura, Y., Go, S. and Hatanaka, K. (1978) Blood 52,

447-452 11 Brostott, J., Carini, C., Wraith, D. G., and Johns, P. (1979)

Lancel i, 1268-1270

K] (,°.,°., Lymphocyte migration and tissue specificity

In recent years it has become apparent that certain lymphocyte classes show well defined and predic table pat terns of migrat ion in vivo, and that their pa t te rn of migrat ion appears to be determined by their tissue of origin. The capacity of small lymphocytes from thor- acic duct lymph of rats and mice to re-circulate is well documented 12. Thus, when thoracic-duct lympho- cytes are labelled in vitro with a radioisotope which labels all lymphocytes (such as 51Cr) and the cells are

infused into syngeneic recipients the lymphocytes dis- t r ibute themselves evenly among the lymph nodes, and the majori ty can be recovered in the lymph 18-20h later 12. Qui te different results are obtained if the lymphocytes are labelled with 3H-thymidine or 125I-iodinated deoxyuridine (12~IUdR) which selec- tively label lymphoblasts . 12sIUdR- or 3H-thymidine- labelled cells from thoracic-duct lymph disappear from fhe blood soon after IV infusion, few cells are

© Elsevier/North-Holland Biomedical Press 1981