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IgE AND THE NEPHROTIC SYNDROME
1299
Bacteriological studies on opened tins of more than one type of tulle, which had been in use for one month or less, have shown that these tins do become contaminated with airborne organisms. The use of such tins can therefore be regarded as a breach in normal septic procedures. We have found this breach can be effectively closed by the use of individually foil-packed and sterilised antibiotic tulle. Individually packed items are certainly more expensive, but are probably less expensive in the long run than the treatment of any resulting infection. Sources of infection are always difficult to trace in hospitals, and anything which will help to eliminate or diminish the human error, such as an individually packed dressing, is in my opinion worthy of consideration. Amersham, Bucks.
K. G. WESTCOMBE.
IgE AND THE NEPHROTIC SYNDROME SIR,-We were particularly interested to note the findings of Dr. Gerber and Professor Paronetto (May 29, p. 1097) regarding the presence of IgE in the glomeruli of patients with the nephrotic syndrome. During the past eighteen
Fig
2.
epigastric pain and back pain followed by jaundice. Investigations revealed cholestatic jaundice (bilirubin 7-5 mg. per 100 ml., alkaline phosphatase 28 King-Armstrong units, serum-aspartate-aminotransferase 250 units). A straight radiograph of the abdomen was normal. Cholangiography was not done because of the hyperbilirubinaemia. Duodenoscopy was performed under light sedation and the ampulla of Vater visualised. The ampulla was cannulated under direct vision and contrast medium injected into the biliary system, under screening control. With this procedure a dilated biliary system was discovered with a filling defect in the common bileduct near the ampulla (fig. 1) and multiple filling defects in a dilated cystic duct (fig. 2). Not only was one able to substantiate a diagnosis of gallstones but also additional information was provided suggesting the presence of stones in the common bileduct. P. R. SALMON P. BROWN T. HTUT R. BURWOOD A. E. READ.
Departments of Medicine and Radiology,
University
of Bristol.
BACTERIA ON ANTIBIOTIC TULLE SIR,-We have been facing a mild epidemic of superficial infection in patients attending our hand clinic, and have been trying to eliminate possible causes. At the time we were using tins of antibiotic tulle. Following my inquiries into what were regarded as normal procedures for using this tulle, the following practices emerged: 1. Pieces of tulle were being removed from the tin and placed on the lid or put to one side for an indefinite period. Tins were often incompletely closed. 2. Portions of tulle were being placed on the dressing
trolley and,
if
not
used
later,
were
being replaced
in the
tin. 3. At times, pieces were cut from the tulle squares and the remainder replaced in the tin. 4. Attempts have been made by staff to have opened and partially used tins of tulle resterilised by normal hospital procedures. Were this to have succeeded the antibiotic would presumably have been inactivated.
months we have been studying three patients who have a steroid-sensitive nephrotic syndrome in association with grass-pollen allergy and seasonal hayfever. The feature which is of particular interest to us is the annual relapse of their proteinuria, which occurs during the pollen season. Two of these patients remain in remission for most of the year; the third has persistent proteinuria which becomes more severe in May and June. On one of these patients (a boy aged 13) we now have serial estimations of a number of variables extending over a full twelve-month period. With the help of Dr. S. G. 0. Johansson we have been able to study the variation in the serum level of IgE-both the total amount and that specifically reacting with grass-pollen. These measurements were made using the radio-immunosorbent assay (R.I.S.T.) and the radio-allergosorbent test (R.A.S.T.) respectively. 1.,The total IgE levels are within the normal range for the large part of the year but rise quite steeply with the advent of the pollen season. The level reaches a maximum of about five times the winter level and the peak coincides with a similar peak in the grass-pollen-specific IgE level, the air-borne-pollen count, the 24-hour urinary protein excretion, hypoalbuminxmia, and the onset of oedema. This patient is just commencing his fourth seasonal relapse and each has been readily sensitive to corticosteroid therapy. There is no associated elevation of total IgG, IgA, or IgM levels. Prick tests produce pronounced reactions to all grasses but none of the other common allergens. These results will be published in full in the near future. Although a nephrotic syndrome in association with atopic allergy has been described previously 3,4 we feel that it may be more common than is at first apparent. Those patients with a steroid-sensitive " minimal-change " nephrotic syndrome, who do not show a seasonal variation, may be producing reaginic antibody against other allergens-e.g., moulds, animal dander, dusts, or dietary factors. In view of the importance of detecting atopic sensitivity in these patients it seems to us that skin-testing with a full range of common allergens should be done in all patients with this kind of nephrotic syndrome. Urine-testing of all patients with atopic disorders should be carefully recorded and repeated when they are in full relapse. Johansson, S. G. O., Bennich, H., Wide, L. Immunology, 1968, 14, 265. 2. Wide, L., Bennich, H., Johansson, S. G. O. Lancet, 1967, ii, 1105. 3. Hardwicke, J., Soothill, J. F., Squire, J. R., Holti, G. ibid. 1959, i, 500. 4. Wittig, H. J., Goldman, A. S. ibid. 1970, i, 542. 1.
1300 The mechanism by which IgE antibody can give rise to proteinuria is obscure, if in fact the two are causally related. Ideally one would like to know the grass-pollenspecific antibody levels of each of the five immunoglobulin classes, but this has not yet been accomplished with either the R.A.S.T. or the red-cell-linked antigen antiglobulin reaction which has proved useful for other antigens.5 The IgE in the kidney, detected by Gerber and Paronetto, is presumably either present on mast cells or within plasma cells, yet neither of these cells are characminimal-change " teristically seen in glomeruli in nephrosis. Mast cells, in the form we usually know them, seem to be relatively scarce in renal tissue, although they s are readily found in the renal pelvis and urinary tract. However, it is possible that cells having a different appearance in the kidney may be the site of fixation of IgE and "
that mediators such as histamine are released producing a local increase in glomerular permeability. This would parallel the known effects of such mediators on capillary permeability elsewhere in the body. A third possibility is that pollen/IgE complexes are formed, and although current evidence suggests that they do not fix complement it is still possible that such complexes could lodge in the kidney and give rise to positive results with immunofluorescence for IgE. In this context it would be of interest to know whether the pollen antigen is also present in the glomeruli. In addition to IgG, IgA, IgM, and now IgE, antibodies belonging to the class IgD have been detected in the glomeruli of patients with glomerulonephritis.’7 We would stress that in future studies an attempt should be made to ascertain the presence or absence of each of these classes of antibody. Although IgD was recognised as a new class of antibody in 1965, some time elapsed before its presence was detected in specific immune responses.7-10 It is possible that both IgD and IgE are yet to be implicated in a number of other situations. W. G. REEVES J. S. CAMERON Guy’s Hospital, C. S. OGG. London S.E.1.
TESTOSTERONE-BINDING PROTEIN PROBABLY NOT Y-LINKED
SIR,-Dr. Gross and Dr. Horton (Feb. 13, p. 346) have presented beautiful evidence for the dominant transmission of the gene of low testosterone-binding protein (T.B.P.), but their assignment of T.B.P. to the Y chromosome should be considered highly speculative. What is needed now are sufficient data to feel secure at the biological level-i.e., with P < 0-05-that T.B.P. is Y-linked and not, as appears more likely, an autosomal dominant trait. Eliminating the proband and his father from consideration because of ascertainment bias, the probability that the gene T.B.P. is on the Y chromosome is 16/1. Since the a-priori probability of a gene being on the Y is 0.02 (it represents only about 2% of the human male haploid genome), the final odds ratio for T.B.P. being Y-linked is approximately 1/3-that is to say, there is still a three times greater probability that T.B.P. is autosomal than Y-linked. Division of Medical
Genetics, University of Oregon Medical School, FREDERICK HECHT WILLIAM KIMBERLING. Portland, Oregon 97201. 5. 6. 7. 8. 9. 10.
Coombs, R. R. A., Hunter, A., Jonas, W. E., Bennich, H., Johansson, S. G. O., Panzani, R. ibid. 1968, i, 1115. Selye, H. The Mast Cell. Washington, 1965. Kantor, G. L., Van Herle, A. J., Barnett, E. V. Clin. exp. Immun. 1970, 6, 951. Ritchie, R. F. Arthritis Rheum. 1968, 11, 506. Gleich, G. I., Bieger, R. C., Stankievic, R. Science, 1969, 165, 606. Devey, M., Carter, D., Sanderson, C. J., Coombs, R. R. A. Lancet, 1970, ii, 1280.
TUMOUR IMMUNOTHERAPY SIR,-Although there are good theoretical and experimental grounds for treating malignant tumours by immunotherapy,’,’ this method has not yet been widely used clinically. 3-7 This may be because the tumour-specific antigens on the membrane (T.S.T.A.) and inside (T antigens) the neoplastic cells are associated with strong antigens of the HL-A typing system-the normal histocompatibility antigens. When vaccinotherapy is attempted using Freund’s adjuvant, antibodies may be produced against the host’s histocompatibility antigens as well as the tumour antigens. Thus, the immunological reaction against the tumour could be small or absent. On the other hand, immunotherapy by administration of large amount of lymphocytes ’’* should be moderately effective, since the homologous lymphocytes have as their main target the HL-A type antigen. Until it is possible to isolate and purify tumourspecific antigens 10 the best way to overcome the HL-A difficulty may be to isolate the tumour-specific antigens by coating the neoplastic cells with anti-HL-A antibodies (polyspecific antiserum). Tumour cells treated in this way could be used for (a) preparation of autogenous vaccines; (b) cross-immunisation by lymphocyte exchange; (e) selection in vitro of clones of immunocompetent cells; and (d) immunisation of a xenogeneic host and lymphocyte transfer to the patient. Laboratorio di Ricerca " Charles Huggins ", Genzano di Roma, Italy.
Cancerologica
VINCENZO RUSSO LUIGI RUSSO.
RELATIONSHIP OF TORULOPSIS TO CANDIDA SIR,-Our experience of vaginal mycoses over the past five years suggests that Torulopsis glabrata is associated with superficial infections. It is isolated from 3-5% of patients with yeast-associated vaginitis, and is second to Candida albicans (93-95%). We were therefore interested to read the report by Dr. Lees and his colleagues (May 8, p. 943) on endocarditis due to T. glabrata. The part that the fungus plays in the causation of disease in man has not been fully defined, but in their well-documented case its aaiological role seems unassailable. Dr. Lees and his colleagues do not state their criteria of identification; and their first isolate was identified, possibly erroneously, as C. albicans. The genera Candida
Torulopsis are closely related, being distinguished primarily on morphological grounds, and secondarily on physiological criteria. Some may think these distinctions too nice, and they are not easily made by those untrained in mycological techniques. We have shown this in our own laboratories, where trainees regularly identify T. glabrata as C. krusei. The probable close relationship between the two genera was brought home forcibly to one of us in the course of an experiment. An isolate of T. glabrata, from an impeccable source, was identified upon receipt in our laboratory and injected into a series of and
Southam, C. M. Indian J. Cancer, 1967, 4, 3. Southam, C. M. Perspective in Leukemia. New York, 1968. Humphrey, L. J., Jewell, W. R., Murray, D. R., Griffen, W. 0. Ann. Surg. 1971, 173, 47. 4. Moton, D., Eilben, F., Joseph, W., Wood, W., Tiahan, E., Ketcham, A. ibid. 1970, 172, 740. 5. Cunningham, C. J., Olson, K. B., Zaffin, R., Hoton, J., Sullivan, J. Paper given at Meeting of American Association for Cancer Research, Atlantic City, New Jersey, April, 1968. 6. Czajkowski, N. P., Rosenblatt, M., Wolf, P. L., Griffen, W. 0. Lancet, 1967, ii, 905. 7. Ikonu-Pisou, R. L., Lewis, M. G., Hunter-Craig, J. D., Bodenham, D. C., Phillips, T. M., Cooling, C. I., Proctor, I., Hamilton Fairley, G., Alexander, P. Br. med. J. 1970, i, 752. 8. Moore, E. G., Moore, M. B. N.Y. St. J. Med. 1969, 69, 460. 9. Moore, E. G., Gerner, R. E. Ann. Surg. 1970, 172, 733. 10. Viza, D., Davies, D. A. L., Todd, R., Bernard-Degani, O., Bernard, C., Harris, R. Presse méd. 1970, 78, 2259. 1. 2. 3.
Bacteriological studies on opened tins of more than one type of tulle, which had been in use for one month or less, have shown that these tins do become contaminated with airborne organisms. The use of such tins can therefore be regarded as a breach in normal septic procedures. We have found this breach can be effectively closed by the use of individually foil-packed and sterilised antibiotic tulle. Individually packed items are certainly more expensive, but are probably less expensive in the long run than the treatment of any resulting infection. Sources of infection are always difficult to trace in hospitals, and anything which will help to eliminate or diminish the human error, such as an individually packed dressing, is in my opinion worthy of consideration. Amersham, Bucks.
K. G. WESTCOMBE.
IgE AND THE NEPHROTIC SYNDROME SIR,-We were particularly interested to note the findings of Dr. Gerber and Professor Paronetto (May 29, p. 1097) regarding the presence of IgE in the glomeruli of patients with the nephrotic syndrome. During the past eighteen
Fig
2.
epigastric pain and back pain followed by jaundice. Investigations revealed cholestatic jaundice (bilirubin 7-5 mg. per 100 ml., alkaline phosphatase 28 King-Armstrong units, serum-aspartate-aminotransferase 250 units). A straight radiograph of the abdomen was normal. Cholangiography was not done because of the hyperbilirubinaemia. Duodenoscopy was performed under light sedation and the ampulla of Vater visualised. The ampulla was cannulated under direct vision and contrast medium injected into the biliary system, under screening control. With this procedure a dilated biliary system was discovered with a filling defect in the common bileduct near the ampulla (fig. 1) and multiple filling defects in a dilated cystic duct (fig. 2). Not only was one able to substantiate a diagnosis of gallstones but also additional information was provided suggesting the presence of stones in the common bileduct. P. R. SALMON P. BROWN T. HTUT R. BURWOOD A. E. READ.
Departments of Medicine and Radiology,
University
of Bristol.
BACTERIA ON ANTIBIOTIC TULLE SIR,-We have been facing a mild epidemic of superficial infection in patients attending our hand clinic, and have been trying to eliminate possible causes. At the time we were using tins of antibiotic tulle. Following my inquiries into what were regarded as normal procedures for using this tulle, the following practices emerged: 1. Pieces of tulle were being removed from the tin and placed on the lid or put to one side for an indefinite period. Tins were often incompletely closed. 2. Portions of tulle were being placed on the dressing
trolley and,
if
not
used
later,
were
being replaced
in the
tin. 3. At times, pieces were cut from the tulle squares and the remainder replaced in the tin. 4. Attempts have been made by staff to have opened and partially used tins of tulle resterilised by normal hospital procedures. Were this to have succeeded the antibiotic would presumably have been inactivated.
months we have been studying three patients who have a steroid-sensitive nephrotic syndrome in association with grass-pollen allergy and seasonal hayfever. The feature which is of particular interest to us is the annual relapse of their proteinuria, which occurs during the pollen season. Two of these patients remain in remission for most of the year; the third has persistent proteinuria which becomes more severe in May and June. On one of these patients (a boy aged 13) we now have serial estimations of a number of variables extending over a full twelve-month period. With the help of Dr. S. G. 0. Johansson we have been able to study the variation in the serum level of IgE-both the total amount and that specifically reacting with grass-pollen. These measurements were made using the radio-immunosorbent assay (R.I.S.T.) and the radio-allergosorbent test (R.A.S.T.) respectively. 1.,The total IgE levels are within the normal range for the large part of the year but rise quite steeply with the advent of the pollen season. The level reaches a maximum of about five times the winter level and the peak coincides with a similar peak in the grass-pollen-specific IgE level, the air-borne-pollen count, the 24-hour urinary protein excretion, hypoalbuminxmia, and the onset of oedema. This patient is just commencing his fourth seasonal relapse and each has been readily sensitive to corticosteroid therapy. There is no associated elevation of total IgG, IgA, or IgM levels. Prick tests produce pronounced reactions to all grasses but none of the other common allergens. These results will be published in full in the near future. Although a nephrotic syndrome in association with atopic allergy has been described previously 3,4 we feel that it may be more common than is at first apparent. Those patients with a steroid-sensitive " minimal-change " nephrotic syndrome, who do not show a seasonal variation, may be producing reaginic antibody against other allergens-e.g., moulds, animal dander, dusts, or dietary factors. In view of the importance of detecting atopic sensitivity in these patients it seems to us that skin-testing with a full range of common allergens should be done in all patients with this kind of nephrotic syndrome. Urine-testing of all patients with atopic disorders should be carefully recorded and repeated when they are in full relapse. Johansson, S. G. O., Bennich, H., Wide, L. Immunology, 1968, 14, 265. 2. Wide, L., Bennich, H., Johansson, S. G. O. Lancet, 1967, ii, 1105. 3. Hardwicke, J., Soothill, J. F., Squire, J. R., Holti, G. ibid. 1959, i, 500. 4. Wittig, H. J., Goldman, A. S. ibid. 1970, i, 542. 1.
1300 The mechanism by which IgE antibody can give rise to proteinuria is obscure, if in fact the two are causally related. Ideally one would like to know the grass-pollenspecific antibody levels of each of the five immunoglobulin classes, but this has not yet been accomplished with either the R.A.S.T. or the red-cell-linked antigen antiglobulin reaction which has proved useful for other antigens.5 The IgE in the kidney, detected by Gerber and Paronetto, is presumably either present on mast cells or within plasma cells, yet neither of these cells are characminimal-change " teristically seen in glomeruli in nephrosis. Mast cells, in the form we usually know them, seem to be relatively scarce in renal tissue, although they s are readily found in the renal pelvis and urinary tract. However, it is possible that cells having a different appearance in the kidney may be the site of fixation of IgE and "
that mediators such as histamine are released producing a local increase in glomerular permeability. This would parallel the known effects of such mediators on capillary permeability elsewhere in the body. A third possibility is that pollen/IgE complexes are formed, and although current evidence suggests that they do not fix complement it is still possible that such complexes could lodge in the kidney and give rise to positive results with immunofluorescence for IgE. In this context it would be of interest to know whether the pollen antigen is also present in the glomeruli. In addition to IgG, IgA, IgM, and now IgE, antibodies belonging to the class IgD have been detected in the glomeruli of patients with glomerulonephritis.’7 We would stress that in future studies an attempt should be made to ascertain the presence or absence of each of these classes of antibody. Although IgD was recognised as a new class of antibody in 1965, some time elapsed before its presence was detected in specific immune responses.7-10 It is possible that both IgD and IgE are yet to be implicated in a number of other situations. W. G. REEVES J. S. CAMERON Guy’s Hospital, C. S. OGG. London S.E.1.
TESTOSTERONE-BINDING PROTEIN PROBABLY NOT Y-LINKED
SIR,-Dr. Gross and Dr. Horton (Feb. 13, p. 346) have presented beautiful evidence for the dominant transmission of the gene of low testosterone-binding protein (T.B.P.), but their assignment of T.B.P. to the Y chromosome should be considered highly speculative. What is needed now are sufficient data to feel secure at the biological level-i.e., with P < 0-05-that T.B.P. is Y-linked and not, as appears more likely, an autosomal dominant trait. Eliminating the proband and his father from consideration because of ascertainment bias, the probability that the gene T.B.P. is on the Y chromosome is 16/1. Since the a-priori probability of a gene being on the Y is 0.02 (it represents only about 2% of the human male haploid genome), the final odds ratio for T.B.P. being Y-linked is approximately 1/3-that is to say, there is still a three times greater probability that T.B.P. is autosomal than Y-linked. Division of Medical
Genetics, University of Oregon Medical School, FREDERICK HECHT WILLIAM KIMBERLING. Portland, Oregon 97201. 5. 6. 7. 8. 9. 10.
Coombs, R. R. A., Hunter, A., Jonas, W. E., Bennich, H., Johansson, S. G. O., Panzani, R. ibid. 1968, i, 1115. Selye, H. The Mast Cell. Washington, 1965. Kantor, G. L., Van Herle, A. J., Barnett, E. V. Clin. exp. Immun. 1970, 6, 951. Ritchie, R. F. Arthritis Rheum. 1968, 11, 506. Gleich, G. I., Bieger, R. C., Stankievic, R. Science, 1969, 165, 606. Devey, M., Carter, D., Sanderson, C. J., Coombs, R. R. A. Lancet, 1970, ii, 1280.
TUMOUR IMMUNOTHERAPY SIR,-Although there are good theoretical and experimental grounds for treating malignant tumours by immunotherapy,’,’ this method has not yet been widely used clinically. 3-7 This may be because the tumour-specific antigens on the membrane (T.S.T.A.) and inside (T antigens) the neoplastic cells are associated with strong antigens of the HL-A typing system-the normal histocompatibility antigens. When vaccinotherapy is attempted using Freund’s adjuvant, antibodies may be produced against the host’s histocompatibility antigens as well as the tumour antigens. Thus, the immunological reaction against the tumour could be small or absent. On the other hand, immunotherapy by administration of large amount of lymphocytes ’’* should be moderately effective, since the homologous lymphocytes have as their main target the HL-A type antigen. Until it is possible to isolate and purify tumourspecific antigens 10 the best way to overcome the HL-A difficulty may be to isolate the tumour-specific antigens by coating the neoplastic cells with anti-HL-A antibodies (polyspecific antiserum). Tumour cells treated in this way could be used for (a) preparation of autogenous vaccines; (b) cross-immunisation by lymphocyte exchange; (e) selection in vitro of clones of immunocompetent cells; and (d) immunisation of a xenogeneic host and lymphocyte transfer to the patient. Laboratorio di Ricerca " Charles Huggins ", Genzano di Roma, Italy.
Cancerologica
VINCENZO RUSSO LUIGI RUSSO.
RELATIONSHIP OF TORULOPSIS TO CANDIDA SIR,-Our experience of vaginal mycoses over the past five years suggests that Torulopsis glabrata is associated with superficial infections. It is isolated from 3-5% of patients with yeast-associated vaginitis, and is second to Candida albicans (93-95%). We were therefore interested to read the report by Dr. Lees and his colleagues (May 8, p. 943) on endocarditis due to T. glabrata. The part that the fungus plays in the causation of disease in man has not been fully defined, but in their well-documented case its aaiological role seems unassailable. Dr. Lees and his colleagues do not state their criteria of identification; and their first isolate was identified, possibly erroneously, as C. albicans. The genera Candida
Torulopsis are closely related, being distinguished primarily on morphological grounds, and secondarily on physiological criteria. Some may think these distinctions too nice, and they are not easily made by those untrained in mycological techniques. We have shown this in our own laboratories, where trainees regularly identify T. glabrata as C. krusei. The probable close relationship between the two genera was brought home forcibly to one of us in the course of an experiment. An isolate of T. glabrata, from an impeccable source, was identified upon receipt in our laboratory and injected into a series of and
Southam, C. M. Indian J. Cancer, 1967, 4, 3. Southam, C. M. Perspective in Leukemia. New York, 1968. Humphrey, L. J., Jewell, W. R., Murray, D. R., Griffen, W. 0. Ann. Surg. 1971, 173, 47. 4. Moton, D., Eilben, F., Joseph, W., Wood, W., Tiahan, E., Ketcham, A. ibid. 1970, 172, 740. 5. Cunningham, C. J., Olson, K. B., Zaffin, R., Hoton, J., Sullivan, J. Paper given at Meeting of American Association for Cancer Research, Atlantic City, New Jersey, April, 1968. 6. Czajkowski, N. P., Rosenblatt, M., Wolf, P. L., Griffen, W. 0. Lancet, 1967, ii, 905. 7. Ikonu-Pisou, R. L., Lewis, M. G., Hunter-Craig, J. D., Bodenham, D. C., Phillips, T. M., Cooling, C. I., Proctor, I., Hamilton Fairley, G., Alexander, P. Br. med. J. 1970, i, 752. 8. Moore, E. G., Moore, M. B. N.Y. St. J. Med. 1969, 69, 460. 9. Moore, E. G., Gerner, R. E. Ann. Surg. 1970, 172, 733. 10. Viza, D., Davies, D. A. L., Todd, R., Bernard-Degani, O., Bernard, C., Harris, R. Presse méd. 1970, 78, 2259. 1. 2. 3.