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Brain neocortex and the i m m u n e system SIR, I read with the utmost interest the review by Besedovsky et aL (Immunol. Today, Vol. 4, pp. 342-346) on the influence of some parts of the brain, particularly the hypothalamus, on the i m m u n e system as assessed by humoral responses. Neocortical brain structures also seem to influence the i m m u n e system and there is evidence for lateralization (a left/right difference). After a left-sided neocortical lesion, the spleen T-cell n u m b e r is reduced to about half that of normal or sham-operated controls; these cells have impaired or inhibited responses to antigens, alloantigens and T-cell mitogens, compared with an equivalent n u m b e r of control cells 1'2. In contrast, b o t h the percentage of T cells and their responsiveness are increased after destruction of the right brain neocortex ~'4'5'6. A n intact brain neocortex is also essential for normal N K activity5 8 and the expression of T-cell surface antigens is altered by neocortical lesions (G. Renoux, unpublished observations). T h e neocortex seems not to affect B cells or macrophages directly. These findings cannot be attributed to the influence of stress or poor health. Unlike some studies on the role of other regions of the central nervous system (CNS) that were performed within a week post-lesion, ten weeks were allowed to elapse between surgery and testing; mice with a unilateral lesion served as controls for symmetrically lesioned mice, together with sham-operated and no-surgery controls. No spontaneous deaths were recorded during the course of the studies. Hemispheric lateralization for the control of T cell-mediated activities in the mouse is present at a population level, as assays assessed over three years in large groups of mice repeatedly gave similar results. Recruitment and functional activity of cells from the T-cell lineage could therefore be due to a balanced brain assymetry in which the right hemisphere may control the inductive ~nfluence of signals emitted by the left hemisphere6. T h e synthesis of factors active on the T-cell lineage is controlled and regulated by the neocortex 9. C u r r e n t studies also suggest that an anterior pituitary pathway is involved. There are now reports of interactions . between the hypothalamus and i m m u n e

system 10,11,and indications that lymphocyte products influence brain activity 12'13 and brain peptides influence lymphocytes 14,15. Furthermore, a pathway has been traced between hypothalmic neurons a n d the neocortex 16. These data suggest that a cascade of interacting signals from brain neocortex may constitute the efferent arc of a physiological network of i m m u n e regulation. Products of macrophages or activated lymphocytes, such as prostaglandins, interferons, interleukins and catecholamines, may represent the efferent link from the i m m u n e system to the CNS. T h e midbrain seems to represent a relay in which neocortically or immunologically induced modification of neurotransmitter levels would, in turn, modify both behaviour and activity of the i m m u n e system. G. RENOUX Department d 'Immunologie, Faculte de Medeeine, 37032 TOURS-Cedex, France.

References 1 Renoux, G., Bizi~re, K. and Guillaumin, j. M. (1980). C. R. Acad. Sci. 290D, 719

'Mucosal' mast cells SIR, W e read with great interest the review by EllenJarrett and David H a i g entitled: 'Mucosal M a s t Ceils in vivo and in vitro' (Imrnunol. Today, Vol. 5, pp. 115-119). These authors have done a fine job of reviewing this rapidly evolving and complicated field. W e would like to emphasize certain issues raised in this review b u t also interject caution in some of the stated or implied central concepts and hypotheses. As the authors stated i n their first sentence, investigations in the rat have provided most of the information about mast cell subpopulations, although evidence is now available in other species including man. In m a n m u c h current knowledge is based upon histochemical studies, although functional assessments of heterogeneity are now appearing in the literature1'2 W h e t h e r histochemical and functional distinctions are as closely linked in m a n and other animals as in the rat 3 is a n important issue in view of its scientific and therapeutic implications. T h e nomenclature of the so-called 'atypical or mucosal' mast cell has already created, and will continue to create conceptual difficulties. As the reviewers point out in their final sentence, 'atypical' as presently used merely reflects the chronology of discovery and indeed this cell m a y represent the characteristics of the predominant mast cell subpopulation. T h e term 'Mucosal'

2 Bizibre, K., Renoux, G., Renoux, M. et aL (1980) Neurosci. Abst. 6, 31 3 Bizibre, K, Renoux, M. and Renoux, G. (1982) Neuroscience 7, 528 4 Renoux, G., Bizi~re, K., Renoux, M. et aL (1982) Int. J. Immunopharm. 4, 290 5 Renoux, G., Bizibre, K., Renoux, M. et aL (1982) Immunobiology 163, 148 6 Renoux, G., Bizi~re, K., Renoux, M. etal, (1983)J. Neuroimmunol. 5, 227 7 Bardos, P., Degenne, D., Lebranchu, Y. et al. (1981) Scand. J. ImmunoL 13, 609 8 Renoux, G., Bizi~re, K., Bardos, P. et aL (1982) In N K cellsand otherEffector Cells(R. B. Herberman, ed.), pp. 639-643, Academic Press, New York 9 Renoux, G., Bizi~re, K., Renoux, M. et aL (1983) Scand. J. Immunol. 17, 45 10 Cross, R. J., Markesbery, W. R., Brooks, W. H. et al. (1980) Brain Res. 196, 79 11 Roozman, T. L., Cross, R. J., Brooks, W. H. et al. (1982) Immunology 45,737 12 Blalock, J. E. and Smith, E. M. (1981) Biochem. Biophys. Res. Commun. 101,472 13 Oppenheim, J. J. and Gery, I. (1982) ImmunoL Today 3, 13 14 Gilman, S. C., Schwartz, J. M., Milner, R.J. etal. (1982) Proc. NatlAcad. Sci. USA 79, 4226 15 Johnson, H. M., Smith, E. M., Torres, B. et aL (1982) Proc. Natl Acad. Sc£ USA 79, 4171 16 Vincent, S. R., H6kfelt, T., Skirboll, L. R. et aL (1983) Science 220, 1309 despite its current wide usage, is inaccurate because: (a) both mast cell types are present in mucosal tissues, and (b) the histochemically 'atypical' type is found, often as frequently as the 'typical' type, in sites other than the mucosa, e.g., smooth muscle of intestine 4, pulmonary p a r e n c h y m a (Shanahan, MacNiven, Bienenstock and Befus, unpublished) and skin 5. Given existing knowledge, which is restricted both in the diversity of tissues surveyed and in the species studied, it is premature to provide an acceptable nomenclature for mast cell subpopulations based upon functional characteristics or tissue distribution. T o minimize the potential impact of a misleading nomenclature, perhaps arbitrary categories, type I, II etc., would be appropriate. Moreover, these categories would have to be species specific until ontogenetic and functional analogies are firmly established. For example, 'typical' mast cells derived from the mouse peritoneal cavity are functionally distinct from rat peritoneal mast cells in their responsiveness to secretagogues 6, dependence upon phosphotidylserine 6'7 (Befus and Neilson unpublished observations) and responsiveness to anti-allergic compounds (disodium cromoglycate inhibits rat peritoneal mast cell secretion but is inactive against mouse peritoneal mast cells) a. T h e spectrum of such mast cell heterogeneity must be defined. This is not the forum to establish a new nomen" clature. Perhaps such a task can be

Immunology Today, voL 5, No. 8, 1984 accomplished at the meeting on mast cell heterogeneity which will be held in early 1985 in Canada. O n e current example where species differences may be seriously misleading is in the definition of the cultured mast cell from murine bone marrow. For various reasons outlined by Jarrett and Haig, these cultured murine mast cells have been tentatively labeled 'mucosal'. However, to a large extent this is based upon cross-species analogies with rat, but not with mouse peritoneal mast cells. In the absence of homogeneic data, together with the lack of data on direct comparisons between cultured 'mucosal' and cultured 'non-mucosal' mast cells, it is difficult to assess the significance of the differences described. Such comparisons of distinct mast cell subtypes in culture are essential to assess the effects of the culture procedures, but have not yet been performed. After such investigations it may be clear that the mast cells grown from rat mesenteric lymph node by ourselves 9 and more recently by Haig andJarrett, and known to be analogous to the mast cell in the rat intestinal mucosa, may not be analogous to the mast cells cultured from murine bone marrow. O n e widely cited difference between mast cell subtypes, namely the T-cell dependency of the 'atypical or mucosal' type has never been properly substantiated as being restricted to this mast cell type. It is clear that proliferation of 'mucosal' mast cells is T-cell dependent ~0 and that in the absence of thymic (T-cell) influence, numbers are subnormal. However, in such T-cell deficient animals both mast dell populations are present. T h e T-cell dependency of the typical mast cell subtype has only been studied in nonproliferative conditions. The essential study, yet to be done, is to establish under conditions where 'typical, non-mucosal' mast cell proliferation is occurring, whether such proliferation is T-cell dependent. If this is the case, the arguments relating T-cell dependency to 'atypical' mast cells lose their significance and must be reassessd. It is important that the concepts surrounding mast cell heterogeneity not be restricted to two subtypes, 'mucosal and non-mucosal' because heterogeneity is certain to be more extensive than this and may involve not only related lineages, but encompass cell size 1, phase of cell cycle 11, and recent cellular secretory activity. At one extreme, heterogeneity may be fully site specific as micro-environmental factors regulate the phenotypic expression of different portions of the genome. W e are optimistic that the review by Jarrett and Haig, together with the reservations we have raised, will

219 aid in an efficient advancement of knowledge in this field and in important therapeutic developments for allergic and other diseases. D. BEFUS T. LEE J. DENBURG J. BIENENSTOCK Host Resistance Programme, Departments of Pathology and Medicine, McMaster University, Hamilton, Ontario, Canada, L 8 N 3Z5.

References 1 Sehulman, E. 8., Kagey-Sobotka, A., MacGlashan, D. W. Jr., Adkinson, N. F. Jr., Peters, S. P., Sehleimer, R. P. and Lichtcnstein, L. M. (1983)dr. Immunol. 131, 1936-1941 2 Befus, A. D., Goodacre, R., Dyck, N. and Bienenstoek,J. (1984) Fed. Proc. 43, 1973

Molecules in the immunoglobulin superfamily SIR, In a recent review (Immunol. Today 1984, Vol. 5, 133) Marchalonis et aL analysed the similarities between major histocompatibility ( M H C ) antigens, Thy-1 antigen and immunoglobnlins (Igs) and concluded that there was little evidence for evolutionary relationships between these molecules and that the data for a T h y - l : I g relationship was particularly unconvincing. In m y view this conclusion is incorrect and was arrived at largely because the comparisons were made without taking into account the structural features and conserved sequence patterns of Ig domains. Below, I discuss the issues mainly with reference to ht'.,~Thy-1 data although the same arguments could be made for the homology with Ig of the M H C antigens 1'2, the T-cell receptor 3'4 and the poly-Ig receptor 5. Homologies with Igs can only sensibly be made at the level of single Ig domains which consist of a sequence of about 100 amino acids. In these domains the sequence is folded into anti-parallel/3strands that form two/3-sheets that are held together by inpointing hydrophobic residues and a conserved disulphide bond 6'7. This is shown in Fig. 1 where the E-strands are labelled with the letters along the sequence and are marked on domain structures as they are seen by x-ray crystallography. The V-domain and C - d o m a i n folding patterns are shown and it can be seen that these share a common core structure made up offlstrands A , B , E and G , F , C but that they differ in the middle of the domains where the V-domains have an extra loop of sequence (labelled/3-strands C ' and C").

3 Befus, A. D., Pearce, F. L., Gauldie, J., Horsewood, P. and Bienenstock, J. (1982) J. ImmunoL 128, 2475-2480 4 Befus, A. D., Pearce, F. L., Goodacre, R. and Bienenstoek, J. (1982) in In-vivo Immunology (Nieuwenhuis, P., van den Brock, A. A. and Hanna, M. G. Jr., eds), 521-527 5 Becker, B., Chung, K. F., McDonald, D., Frick O. L. and Gold, W. M. (1984) Fed. Proc. 43, 1935 6 Barrett, K. E. and Pearce, F. L. (1983) Int. Arch. AllergyAppL Immunol. 72, 234-238 7 Siraganian,-R. P. and Hazard, K. A. (1979) J. Immunol. 122, 1719-1725 8 Barrett, K. E., Leung, K. B. P. and Pearce, F. L. (1983) Br. J. Phammcol. 78, 58 9 Denburg, J. A., Befus, A. D. and Bienenstock, J. (1980) Immunology 41,195-202 10 Ruitenberg, E. J. and Elgersma, A. (1976) Nature (London) 264, 258-260 11 Meyer, C., Wahl, L. M., Stadler, B. M. and Sirang-anian, R. P. (1983)J. Immunol. 131, 911-914 Within the Ig domains conserved p a t t e r n s of sequence are seen and these occur particularly in the/3-strand segments 7. Some of these conserved patterns are c o m m o n to V and C domains while others are specific for each domain type (Refs 7, 8; see below). To argue convincingly that a sequence is related in evolution to Ig domains the following points should be taken into account: (1) The comparisons should be made over segments of sequence of about 100 amino acids. (2) These segments must contain cysteine residues that could form the conserved disulphide b o n d - b e t w e e n /3strands B and F and ultimately this linkage should be established. (3) Secondary structure predictions should be consistent with fl-strands along the sequence as for V and C domains and ideally the circular dichroism spectrum of the molecule should indicate a high content offl-structure and little a-helix. (4) Sequence similarities that fit with the conserved patterns o f Ig domains should be observed. (5) The sequence similarities should be statistically significant. Marchalonis et al. dealt only with point (5) and used statistical analyses based on amino acid compositions and sequence. Analysis of amino acid compositions is inadequate given that the level of identity is only 20-30% and that the sequences involved vary from about 100 amino acids (/32-microgtobulin and T h y - 1 ) to 755 amino acids (poly-Ig receptor). Comparison at the level of domain segments is impossible with this method unless the bizarre procedure of converting sequence to amino acid composition is contemplated. In their statistical analysis based on sequences 1V~,~.~_halonis et al. did find