Embryonal germ-layer antigens: target for autoimmunity

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seen in the lesions that already form the greatest proportion of all lesions-namely, the superficial spreading melanoma. Thus, campaigns to educate the public about the clinical appearance of these lesions are the most likely to be successful. Concern that guidelines published in both the USA and the UK to help the public recognise early melanoma do not adequately describe nodular melanomas is probably unfounded because nodular melanomas form a small proportion of all melanomas, and because this proportion has fallen over the past decade. However, many nodular melanomas are in the greater than 3-5 mm category-a fmding that points to either rapid growth or poor recognition of early nodular lesions. It is encouraging for public education programmes that the main publichealth issue is the rapid increase in incidence of superficial spreading melanomas, which have a clearly recognised preinvasive or radial growth phase with obvious clinical characteristics. The sustained and significant shift towards thinner primary tumours beginning in 1985 is an encouraging intermediate audit measure of the effect of the public education campaigns.6,7 In addition to the shift in favour of thinner tumours there is, from 1990, a reduction in the absolute number of thick melanomas in women, but not in men, compared with all years from 1979 onwards.8 Our finding that most recurrences of thicker tumours are seen in the first year after surgery to the primary site, but that recurrences of thinner tumours tend to be seen after a longer interval could be used to devise logical follow-up and review programmes for patients after surgery. The difference in rates of increasing incidence in patients with tumours of different clinicopathological types indicates that the division into these four main subsections first suggested by Clark9 in 1969 is biologically relevant. Since 1969, Ackerman10 has suggested that clinicopathological subsets do not exist. Our data do not support this viewpoint but suggest that in Scotland factors associated with the initiation

anu

promouon

oi

supernciai spreauing

melanomas snumu

be the most important public-health issue, whereas those related to acral lentiginous melanoma are of lesser importance in this geographic area. The large number of patients in our study makes detailed anaylsis possible, and also makes it likely that observations are biologically relevant and are not minor statitistical aberrations. In conclusion, a decade of data collection in Scotland and collaboration between specialties has led to the availability of a detailed profile of the changing pattern of incidence of and mortality from cutaneous melanoma. We thank all clinicians and pathologists who provide data for the SMG; the Scottish Home and Health Department and the Cancer Research Campaign for financial support; and Miss Evelyn Salt and Mrs Jenny Stewart for their invaluable assistance with this project.

REFERENCES 1. MacKie RM, Smyth JF, Soutar DS, et al. Malignant melanoma in Scotland 1979-83. Lancet 1985; ii: 859-62. 2. Cox DR. The analysis of binary data. London: Methuen, 1970. 3. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34: 187-220. 4. Magnus K. The nordic profile of skin cancer incidence. A comparative epidemiological study of the three main types of skin cancer. Int J Cancer 1991; 47: 12-19. 5. Osterlind A, Engholm G, Moller Jensen O. Trends in cutaneous melanoma in Denmark 1943-1982 by anatomic site. APMIS 1988; 96: 953-63. 6. Doherty VR, MacKie RM. Reasons for poor prognosis in British patients with malignant melanoma. Br Med J 1986; 292: 987-89. 7. Doherty VR, MacKie RM. Experience of a public education campaign on early detection of cutaneous malignant melanoma. Br Med J 1988; 297: 388-91. 8. MacKie RM, Hole D. Clinical audit of a public education campaign to encourage ealier detection of malignant melaoma. Br Med J (in press). 9. Clark WH, From L, Bemardino EA, et al. The histogenesis and biologic behaviour of primary human malignant melanomas of the skin. Cancer Res 1969; 29: 705-26. 10. Ackerman AB. Malignant melanoma: a unifying concept. Human Pathol 1980; 11: 591-95.

HYPOTHESIS Embryonal germ-layer antigens: target for autoimmunity Histopathological analysis of some systemic autoimmune diseases and syndromes led us to the conclusion that the common feature of the organs involved might be their embryonal origin. We suggest that organs derived from the same germ layer express common germ-layer-specific antigens. Such antigens could serve as target antigens for the autoimmune response. Introduction Autoimmune diseases, characterised by specific humoral and cell-mediated immune responses against the constituents of the body’s own tissues, can affect a single organ, a few organs, or many organs. Roitt’ has suggested that these diseases can be regarded as a spectrum ranging from organ-specific diseases accompanied by organ-specific antibodies (eg, primary myxoedema, Hashimoto’s

thyroiditis, and pernicious anaemia) to non-organ-specific disease complexes in which the lesions are widespread and the antigens recognised by the autoantibodies are common to many organs (eg, systemic lupus erythematosus, rheumatoid arthritis). Between the extremes are disorders in which only one organ is damaged (eg, chronic active hepatitis), although the autoantibody is not organ specific (eg, anti-smooth muscle). Despite the appeal of this classification, several questions remain unanswered. Even in the organ-specific diseases, there is some tendency for overlap. Among patients with autoimmune thyroiditis, the frequency of pernicious ADDRESSES Clinical Immunology and Allergy Unit (B Tadmor, MD.Y.Naparstek, MD) and Department of Medicine (C Putterman, MD), Hadassah University Hospital, Ein-Kerem, Jerusalem, Israel. Correspondence to Dr Yaakov Naparstek, Clinical Immunology Unit, Department of Medicine, Hadassah University Hospital, Kiryat Hadassah, PO Box 12000, Jerusalem 91120, Israel.

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Classification of autoimmune organ damage 1.-J by

embryonal

germ

layer.

PAS = polyendocrine autoimmunity syndrome; GI = gastrointestinal. *Connective tissue elements.

anaemia is 50 times that of the general population, whereas among patients with pernicious anaemia, up to 50% have antibodies against thyroid antigens and the frequency of clinical autoimmune thyroid disease (thyroiditis and hyperthyroidism) is unexpectedly high,1 The close association between ulcerative colitis and sclerosing cholangitis is well known.2 Cogan’s syndrome3 consists of two single-organ lesions-interstitial keratitis and

vestibuloauditory damage. However,

no

single antigen

the organs involved in closely associated disorders has been found. Moreover, even when a disease-specific antoantibody is present, it may not satisfactorily explain why some organs are specifically affected in the course of the disease. Identical double-stranded DNA is present in all nucleated cells. Yet the highly specific antibody to double-stranded DNA that spears in systemic lupus erythematosus does not produce common

to

damage in all organ systems. Mitochondria are not limited to any one organ, but primary biliary cirrhosis (associated with antibodies to mitochondrial antigens) mainly affects the bile ducts. We suggest that in some autoimmune diseases and syndromes the pattern of injury is directed by embryonal determinants. Our hypothesis is that these autoimmune disorders specifically affect organs of a certain embryonic lineage, and that the lesions found in them are distributed according to the presence of common antigens that result from identical embryonic origins. The figure shows our disease classification.

Mesodermal autoimmunity The best example of autoantibody-mediated disease that

shows characteristics of

damage

to

mesodermal tissues is

systemic lupus erythematosus. The tissues affected in this

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disorder4 all arise from the embryonal mesoderm. These tissues include the joints, serosal membranes, kidneys, and cellular elements of the haemopoietic system. Other affected organs, which are apparently not of mesodermal origin, show tissue damage only in their mesodermal elements. For example, damage to the skin is predominantly at the dermal/epidermal junction, interfacing with the mesodermally derived dermis.5 The brain is commonly affected but the main histopathological feature is damaged blood vessels, rather than direct damage to the ectodermally derived brain cells.6 The eye can be damaged in several ways in systemic lupus erythematosus, but the tissue element mostly affected in this organ of mixed embryonal origin is the uvea, which is derived from the mesoderm. By contrast, in this multisystem disorder, it is surprising that some organs are protected from the widespread autoimmune process. The liver, gastrointestinal tract, pancreas, thyroid and parathyroid glands, and epidermis are not commonly involved in the disease, even in its active phase. Our hypothesis predicts this protection, since these organs originate from endoderm or ectoderm. Mixed connective tissue disease also shows mesodermal autoimmunity. It involves different combinations of clinical features of systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis, polyarteritis, and polymyositis. The most common manifestations include7 arthritis, Raynaud’s phenomenon, soft-tissue swelling, myalgia, lymphadenopathy, and serositis. All the affected tissues originate from the mesoderm. The oesophagus seems to be an exception, since it is of endodermal origin. However, the main damage in the oesophagus is to the lamina propria, muscularis mucosae, and submucosa,8 all of which originate from the mesoderm.

Mesodermal-endodermal autoimmunity We suggest that a second group of autoimmune diseases those syndromes manifesting both mesodermal and endodermal autoimmunity. Polyendocrine autoimmunity syndromes9 are typical of this group of diseases. Type 1 is present in patients who have at least two of autoimmune Addison’s disease, hypoparathyroidism, and mucocutaneous candidiasis. Type 2 is diagnosed when a patient has Addison’s disease with autoimmune thyroid disease and/or insulin-dependent diabetes mellitus. The chief components of these syndromes are injury to the adrenal cortex (mesodermal origin) with associated damage also to the pancreas, thyroid, and parathyroid (all of endodermal origin). Primary biliary cirrhosis also shows mixed endodermalmesodermal autoimmunity. Commonly associated features include autoimmune thyroid disease, sicca syndrome, and pernicious anaemia (endoderm) with arthritis, systemic sclerosis, and renal tubular acidosis (mesoderm).lo Endodermal-mesodermal autoimmunity is shown also by the enteropathic arthropathies." Extraintestinal organs affected in inflammatory bowel disease (endoderm), for instance, include the vertebral column (mesoderm), uvea (mesoderm), and dermis (erythema nodosum; mesoderm). Other syndromes in this group, such as pernicious anaemia with thyroiditis, or sclerosing cholangitis with inflammatory bowel disease, affect organs of endodermal origin only. The nature of the pathogenetic process that leads to these autoimmune syndromes is unclear. Immunoglobulin deposits are not a common finding in affected organs but evidence points to pathogenetic autoreactive T-cells as agents of the damage to these organs of endodermal origin,12,13 are

Ectodermal There

autoimmunity

few autoimmune diseases that affect ectodermally derived tissues. They tend to involve isolated organs, in contrast to the mesodermal group of autoimmune diseases. Examples include multiple sclerosis, pemphigus, and Guillain-Barré syndrome. Cogan’s syndrome seems an exception, since it affects both the cornea (interstitial keratitis) and the eighth cranial nerve (vestibuloauditory disturbances), but the damage to these organs could be a systemic vascular process rather than autoreactivity to ectodermal antigens on two tissues.3 are

Germinal layer

antigens?

In an early stage of embryogenesis, the spherical blastula is transformed into a three-layered structure ,14 The endoderm gives rise to the pharynx, oesophagus, stomach, intestines, liver, pancreas, lungs, and endocrine glands. The mesodermal layer gives rise to the vertebral column, bone, cartilage, muscle, fibrous tissue, and the dermis. Most of the urogenital system (excluding the bladder) comes from the mesoderm, as do the vascular system, heart, and blood cells, including the lymphocytes. The epidermis and the whole nervous system, including most parts of the sensory organs, arise from the ectoderm. The embryonic layers are physically distinct from each other, but within each layer the cells are tightly packed. One possible way this packing could be brought about is by the expression by cells in each layer of membrane adhesion molecules specific to that layer. Such molecules could enable recognition of "sister" cells and cause aggregation of similar cells into exclusively separate layers. These primordial germ-layer-specific adhesion molecules could persist as self-antigens on the cells and remain in adult tissue; alternatively, they could disappear but be expressed later in a disease process. One example of such antigens is the neural-cell adhesion family of molecules (N-CAM), which mediate specific neuronal contacts. The embryonal form of these molecules differs from their adult formY Infection with Neisseria meningitidis induces autoantibodies directed specifically at the embryonal N-CAM, in vitro, these antibodies can lyse cells that express this embryonal antigen.16 We suggest that microbial antigenic mimicry could induce the pathological self-recognition of such embryonal molecules after birth. This might result in an autoimmune response that would affect tissue organs (or parts of those tissues) of common ontogenic ancestry that express the antigen. This autoimmune response would not affect cells originating from the other germ layers, which do not express this putative antigen. The presence of separate antigens for each germinal layer could lead, under conditions of disturbed immunological function, to diseases predominantly affecting specific organs with a shared antigen.

Expression of embryonic antigens on adult tissues

colleagues17 suggested as a mechanism for organ-specific autoimmunity pathological local expression of HLA-DR antigens on epithelial cells. These cells can present autoantigens on their surface (eg, thyroglobulin) to T lymphocytes, thus initiating an autoimmune cascade. In other words, the autoimmunity is initiated not by the lymphocytes but the expression of aberrant molecules by the target organs. We extend this idea to aberrantly expressed embryonic antigens; the result is organ involvement according to early embryonic development. Bottazzo and

978

Can mature cells express embryonic antigens in adult life? Well-known examples are the production of alphafetoprotein by hepatoma cells and of carcinoembryonic antigens by malignant cells of gastrointestinal tumours. These fetal antigens re-expressed during cellular dedifferentiation can serve as targets of T cells, leading to an immune response against cancer cells.18 Similarly, Kupffer cells express fetal-cell-surface carbohydrate molecules in chronic hepatitis that can serve as the target for the autoimmune response directed at the liver cells,19 Signals that induce neoexpression of these fetal antigens have not been clarified. However, local interferon production or the viral infection itself could be the cause. Indeed, it is conceivable that expression of embryonic antigens in adult life could accompany the processes of inflammation, healing, and regeneration triggered by many different agents or accidents. To test our hypothesis, interaction of autoantibodies and T cells with cells derived from the different embryonal germ layers, as well as the embryonal germ-layer-specific molecules, should be studied. In addition, tissues from patients with systemic autoimmune diseases should be tested for the expression of embryonal antigens. Our classification calls attention to the need for embryonal, rather than adult, tissues to be examined for the presence of target antigens in various autoimmune diseases. The detection of such novel autoantigens defined by the T cells or antibodies of patients would prove our hypothesis. Y. N. holds the Leifferman Chair m Arthritis. This study was supported by the Gablinger Fund for Research in Autoimmunity. We thank Prof I. Cohen (Weizmann Institute for Science, Rehovot) for help and suggestions in preparing the paper.

REFERENCES IM, ed. Autoimmune diseases. In: Essential immunology, 6th ed. Oxford: Blackwell, 1988: 238-53. 2. Chapman RWG, Arborgh BAM, Rhodes JM, et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography and hepatic histology. Gut 1980; 21: 870-77. 3. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan syndrome: studies in 13 patients, long-term follow up and a review of the literature. Medicine 1980; 59: 426-41. 4. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 1. Roitt

25: 1271-77. 5. Rothfield NF, Marino C. Studies of repeat biopsy of non lesional skin in patients with systemic lupus erythematosus. Arthritis Rheum 1982; 25: 624-28. 6. Bryant GL, Weinblatt ME, Rumbaugh C, Coblyn JS. Cerebral vasculopathy: an analysis of sixteen cases. Semin Arthritis Rheum 1986; 15: 297-302. 7. Prystowsky SD, Tuffanelli DL. Speckled (particulate) epidermal nuclear IgG deposition in normal skin: correlation of clinical features and laboratory findings in 46 patients with a subset of connective tissue disease characterized by autoantibody to extractable nuclear antigen. Arch Dermatol 1978; 114: 705-10. 8. D’Angelo WA, Fries JF, Masi AT, Shulman LF. Pathologic observations in systemic sclerosis (scleroderma): a study of 58 autopsy cases and 58 matched controls. Am J Med 1969; 46: 428-40. 9. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine 1981; 60: 355-62. 10. Christensen E, Crowe J, Doniach D, et al. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 230 patients. Gastroenterology 1980; 78: 236-46. 11. Aldo-Benson MA. Enteropathic arthritis. In: McCarty DJ, ed. Arthritis and allied conditions, 11th ed. Philadelphia: Lea & Febiger, 1989: 972-79. 12. Geczy AF, McGuigan LE, Sullivan JS, Edmons JP. Cytotoxic T-lymphocytes against disease associated determinant(s) in ankylosing spondylitis. J Exp Med 1986; 164: 932-37. 13. MacDonald TT, Spencer J. Evidence that mucosal T-cells play a role in the pathogenesis of enteropathy in human small intestine. J Exp Med 14.

1988; 167: 1341-49. Langman J. Medical embryology, 6th ed. Baltimore: Williams & Wilkins, 1988.

15.

Rougon G, Marshak D. Structural and immunological characterization of

the amino-terminal domain of mammalian neural cell adhesion molecules. J Biol Chem 1986; 261: 3396-401. 16. Nedelec J, Boucraut J, Garnier JM, Bernard D, Rougon G. Evidence for autoimmune antibodies directed against neural cell adhesion molecules (N-CAM) in patients with group B meningitis. J Neuroimmunol 1990; 29: 49-56. 17. Bottazzo GF, Pujok-Borrell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; ii: 1115-19. 18. Mendelsohn J. Principles of neoplasia. In: Braunwald E, Isselbacher K,

19.

PetersdorfR, et al, eds. Harrison’s principles of internal medicine, 11th ed. New York: McGraw-Hill, 1988: 430-31. Okada Y, Tsuji T. Neoexpression of sialyl oligomeric Lewis X by Kupffer cells in chronic hepatitis. Lancet 1990; 335: 1302-06.

BOOKSHELF Eukaryotic Transcription Factors David S. Latchman. London: Academic Press. 1991. 14.95. ISBN 0-12437171X.

Pp 270.

It is a common complaint, particularly from clinicians, that molecular biology is made to seem unnecessarily difficult by the impenetrability of its jargon. Yet the discipline has a very honourable record in terms of a mission to explain: among major textbooks and shorter specialist works alike there are numerous examples of clearly written, well illustrated, and genuinely helpful books that compare favourably with corresponding texts in most other specialties. Latchman’s latest is a case in point. The format, some 250 profusely illustrated pages in soft covers, has become almost a standard for the genre. The title may not seem particularly gripping but the subject matter-how gene expression is regulated-is a major issue if ever there was one. Latchman identifies a target audience of undergraduates, postgraduate students, and those gingerly approaching molecular biology from other disciplines. Although clinicians are not singled out for individual mention there is little doubt that gene regulation, which determines organogenesis, cellular differentiation, and cell function, is of more fundamental relevance to medicine

than, say, gene mapping. A little background knowledge of molecular biology is assumed but the theoretical and practical aspects of transcription factors are handled in a logical progression, with carefully presented examples from yeast, Caenorhabditis elegans, drosophila, and mice as well as from man. Virtually every point is made twice, in different ways, the two descriptions usually separated by a diagram to drive the message home. For good measure, major topics are summarised at the end of each chapter. Throughout the book, as new concepts are introduced, there are constant reminders of examples cited earlier to emphasise correlations or contrasts. This overtly didactic approach occasionally irritates, but much more often it illuminates. In common with almost all biochemists or molecular biologists, however, the author assumes familiarity with the singleletter code for the aminoacids; a brief table would have been welcome. Starting with definitions of transcription, transcription factors, promotors, and enhancers, Latchman discusses methods to study interactions between nuclear proteins and DNA, gradually introducing the concept of increasingly complex arrays of positive and negative signals that appear to depend upon a limited number of biochemical processes. Even the most reluctant student should be impressed by the beauty of a system whereby immense