- Email: [email protected]
COMPLEMENT FIXATION BY IgA IN SKIN IN DERMATITIS HERPETIFORMIS
624 In general, agents that deplete or block G.A.B.A. tend to produce convulsions, while those that raise its levels tend to produce sedation. Nevertheless, the reduced G.A.D. in the basal ganglia of Huntington’s choreics found in two separate laboratories, coupled with the original report of Perry et al. on reduced G.A.B.A. levels, should leave little
COMPLEMENT FIXATION BY IgA IN SKIN IN DERMATITIS HERPETIFORMIS
doubt that the effect is real. What is paradoxical is that G.A.D. is reduced in extrapyramidal structures in Parkinson’s disease as well. We found a decrease in G.A.D. in the globus pallidus and substantia nigra of such cases,10,111 while Hornykiewicz and colleagues found reduced G.A.D. in the substantia nigra and corpus striatum.12,13 Thus Huntington’s chorea and Parkinson’s disease, two clinical entities with opposite effects on the extrapyramidal motor system, each have reduced levels of G.A.D. Part of this paradox might be explained by secondary or trans-synaptic effects. All of the parkinsonian patients in our study were receiving classical anticholinergic drugs. In this respect, therefore, they were similar to the patients with Huntington’s chorea who had a deficiency of choline acetylase. It is conceivable, therefore, that some of the reduction of G.A.D. in both diseases results from a transneuronal effect secondary to a depressed function of the cholinergic system. The secondary effects of anticholinergic agents on G.A.D. levels are currently being investigated in
laboratory. Lloyd and Hornykiewicz 13 reported
our
on possible transsynaptic effects on G.A.D. in Parkinson’s disease. Patients receiving prolonged treatment with levodopa (1 year or longer) did not have decreased G.A.D. levels in the basal ganglia, while normal rats given high doses of levodopa for a hundred days had elevated G.A.D. levels in the corpus striatum. This may be evidence, therefore, of a transsynaptic response of G.A.D. to elevated dopamine. It is quite possible, of course, that there is a primary loss of G.A.D.-containing cells in Huntington’s chorea. Lesion studies and axoplasmic flow experiments in the basal ganglia of rats suggest that a major G.A.D.-containing tract is one descending from the globus pallidus to the substantia nigra. 14, 15 However, there are probably also some intrinsic
G.A.D. neurons
in the caudate and there may
even
be
a
descending pathway from the caudate to the globus pallidus 16 or the substantia nigra.l’ Cholinergic cells seem to be internally arranged in the caudate and putamen, 18’I so it is likely that the outright destruction of cells in the corpus striatum in Huntington’s chorea would involve cholinergic neurons. Although the exact role of G.A.B.A.-containing cells in extrapyramidal function remains a mystery, the evidence accumulated to date suggests that there may be therapeutic possibilities in drugs which raise or lower G.A.B.A. levels in both Huntington’s chorea and Parkinson’s disease. Laboratory of Neurological Research,
Kinsmen
University of British Columbia, Vancouver 8, Canada. 9.
Perry,
T. L., Hansen, S.,
PATRICK L. MCGEER E. G. MCGEER H. C. FIBIGER.
Kloster, M. New Engl. J. Med. 1973, 288,
337.
McGeer, P. L., McGeer, E. G., Wada, J. A. Neurology, Minneapolis, 1971, 21, 1000. 11. McGeer, E. G., McGeer, P. L., Wada, J. A., Jung, E. Brain Res. 1971, 32, 425. 12. Bernheimer, H., Hornykiewicz, O. Archs exp. Path. 1962, 243, 295. 13. Lloyd, K. G., Hornykiewicz, O. Nature (in the press). 14. Hattori, T., McGeer, P. L., Fibiger, H. C., McGeer, E. G. Brain Res. 1973, 54, 103. 15. McGeer, P. L., Fibiger, H. C., Maler, L., Hattori, T., McGeer, E. G. Adv. Neur. 5 (in the press). 16. McGeer, P. L., Fibiger, H. C., Hattori, T., Singh, V. K., McGeer, E. G., Maler, L. in Neurohumoral Coding and Brain Function (edited by R. D. Myers and R. R. Drucker-Colin). New York (in the press). 17. Kim, J. S., Bak, A. J., Hassler, R., Okada, Y. Exp. Brain Res. 1971, 14, 95. 18. McGeer, P. L., McGeer, E. G., Fibiger, H. C., Wickson, V. Brain Res. 1971, 35, 308.
10.
SIR,-Dr Seah and others (July 28, p. 175) suggested IgA activates complement by the " alternate " complement pathway in cutaneous lesions of dermatitis herpetiformis. We agree that IgA is not considered an immunoglobulin capable of classical complement pathway activation and that the absence of Clq in the presence of C3 is probably suggestive of alternate complement pathway activation; but without the demonstration of factors associated with the alternate pathway (properdin, C3 pro-
that
activator [C3PA]), this may be presumptive. The mere absence of Clq does not exclude classical complement pathway activation since, after activation of C4 and C2 to form C3 convertase, C1 probably dissociates from the complex.1 Clq, therefore, may or may not be present, despite classical pathway activation. Recent data in patients with bullous pemphigoid, in which the classical pathway appears to be the primary pathway that is activated,2,3 tend to support this contention (unpublished observations). Clq is sometimes absent in the presence of C4 and C3. Provost and Tomasi 3,4 have convincingly demonstrated activation of the alternate pathway in cutaneous lesions of dermatitis herpetiformis using antisera specific for C3PA and properdin. One of us (R. E. J.) has confirmed this finding, using antisera to these same alternate pathway In addition, components (unpublished observations). Provost and Tomasi4 have reported the absence of Clq and C4 while demonstrating the presence of C3, C3PA, and properdin. Whether dermatitis herpetiformis is a disease due to an immunological disturbance, as Dr Seah and his associates state, remains to be resolved. Mayo Clinic, Rochester, Minnesota 55901, U.S.A.
IF
SiR,—The
R. S. ROGERS, III R. E. JORDON.
NOT, WHY NOT ?
resources
available for biomedical research
becoming inadequate for the funding of promising research proposals. It is therefore increasingly important in the public interest to optimise the selection and allocation procedures. As there is room for a great variety of opinion on this matter as a whole, I merely draw attention here to one of its least controversial aspects-the question of feed-
are
back.
Should reasons for the decision made on a grant be given to the applicant ? The reasons given could either be the referees’ comments alone (with their anonymity preserved if necessary, and perhaps reinforced by editing) or, preferably, these comments supplemented by policy arguments. The advantages of such an open system include:
application
(1) The majority of referees are conscientious and skilled and their scientific comments are often as valuable as those brought out at scientific meetings. Therefore, when comments are made available to the applicant, his research stands to benefit, should his application be successful or, if it be unsuccessful, his resubmission elsewhere stands to benefit (or be scrapped even). (2) Such an open system imposes a degree of discipline on referees and provides some safeguard against " simple errors of fact and logic " which, on occasion, they have been known to make in the past.5 (3) There is no cause for uncertainty among applicants and no unnecessary
puzzlement.
Rapp, H. J., Borsos, T. Molecular Basis of Complement Action. New York, 1970. 2. Jordon, R. E., Day, N. K., Sams, W. M., Jr., Good, R. A. J. clin. Invest. 1973, 52, 1207. 3. Provost, T. T., Tomasi, T. B., Jr. ibid. p. 1779. 4. Provost, T., Tomasi, T. B., Jr. Clin. Res. 1973, 21, 481. 5. Horrobin, D. F. Lancet, 1972, ii, 323. 1.
COMPLEMENT FIXATION BY IgA IN SKIN IN DERMATITIS HERPETIFORMIS
doubt that the effect is real. What is paradoxical is that G.A.D. is reduced in extrapyramidal structures in Parkinson’s disease as well. We found a decrease in G.A.D. in the globus pallidus and substantia nigra of such cases,10,111 while Hornykiewicz and colleagues found reduced G.A.D. in the substantia nigra and corpus striatum.12,13 Thus Huntington’s chorea and Parkinson’s disease, two clinical entities with opposite effects on the extrapyramidal motor system, each have reduced levels of G.A.D. Part of this paradox might be explained by secondary or trans-synaptic effects. All of the parkinsonian patients in our study were receiving classical anticholinergic drugs. In this respect, therefore, they were similar to the patients with Huntington’s chorea who had a deficiency of choline acetylase. It is conceivable, therefore, that some of the reduction of G.A.D. in both diseases results from a transneuronal effect secondary to a depressed function of the cholinergic system. The secondary effects of anticholinergic agents on G.A.D. levels are currently being investigated in
laboratory. Lloyd and Hornykiewicz 13 reported
our
on possible transsynaptic effects on G.A.D. in Parkinson’s disease. Patients receiving prolonged treatment with levodopa (1 year or longer) did not have decreased G.A.D. levels in the basal ganglia, while normal rats given high doses of levodopa for a hundred days had elevated G.A.D. levels in the corpus striatum. This may be evidence, therefore, of a transsynaptic response of G.A.D. to elevated dopamine. It is quite possible, of course, that there is a primary loss of G.A.D.-containing cells in Huntington’s chorea. Lesion studies and axoplasmic flow experiments in the basal ganglia of rats suggest that a major G.A.D.-containing tract is one descending from the globus pallidus to the substantia nigra. 14, 15 However, there are probably also some intrinsic
G.A.D. neurons
in the caudate and there may
even
be
a
descending pathway from the caudate to the globus pallidus 16 or the substantia nigra.l’ Cholinergic cells seem to be internally arranged in the caudate and putamen, 18’I so it is likely that the outright destruction of cells in the corpus striatum in Huntington’s chorea would involve cholinergic neurons. Although the exact role of G.A.B.A.-containing cells in extrapyramidal function remains a mystery, the evidence accumulated to date suggests that there may be therapeutic possibilities in drugs which raise or lower G.A.B.A. levels in both Huntington’s chorea and Parkinson’s disease. Laboratory of Neurological Research,
Kinsmen
University of British Columbia, Vancouver 8, Canada. 9.
Perry,
T. L., Hansen, S.,
PATRICK L. MCGEER E. G. MCGEER H. C. FIBIGER.
Kloster, M. New Engl. J. Med. 1973, 288,
337.
McGeer, P. L., McGeer, E. G., Wada, J. A. Neurology, Minneapolis, 1971, 21, 1000. 11. McGeer, E. G., McGeer, P. L., Wada, J. A., Jung, E. Brain Res. 1971, 32, 425. 12. Bernheimer, H., Hornykiewicz, O. Archs exp. Path. 1962, 243, 295. 13. Lloyd, K. G., Hornykiewicz, O. Nature (in the press). 14. Hattori, T., McGeer, P. L., Fibiger, H. C., McGeer, E. G. Brain Res. 1973, 54, 103. 15. McGeer, P. L., Fibiger, H. C., Maler, L., Hattori, T., McGeer, E. G. Adv. Neur. 5 (in the press). 16. McGeer, P. L., Fibiger, H. C., Hattori, T., Singh, V. K., McGeer, E. G., Maler, L. in Neurohumoral Coding and Brain Function (edited by R. D. Myers and R. R. Drucker-Colin). New York (in the press). 17. Kim, J. S., Bak, A. J., Hassler, R., Okada, Y. Exp. Brain Res. 1971, 14, 95. 18. McGeer, P. L., McGeer, E. G., Fibiger, H. C., Wickson, V. Brain Res. 1971, 35, 308.
10.
SIR,-Dr Seah and others (July 28, p. 175) suggested IgA activates complement by the " alternate " complement pathway in cutaneous lesions of dermatitis herpetiformis. We agree that IgA is not considered an immunoglobulin capable of classical complement pathway activation and that the absence of Clq in the presence of C3 is probably suggestive of alternate complement pathway activation; but without the demonstration of factors associated with the alternate pathway (properdin, C3 pro-
that
activator [C3PA]), this may be presumptive. The mere absence of Clq does not exclude classical complement pathway activation since, after activation of C4 and C2 to form C3 convertase, C1 probably dissociates from the complex.1 Clq, therefore, may or may not be present, despite classical pathway activation. Recent data in patients with bullous pemphigoid, in which the classical pathway appears to be the primary pathway that is activated,2,3 tend to support this contention (unpublished observations). Clq is sometimes absent in the presence of C4 and C3. Provost and Tomasi 3,4 have convincingly demonstrated activation of the alternate pathway in cutaneous lesions of dermatitis herpetiformis using antisera specific for C3PA and properdin. One of us (R. E. J.) has confirmed this finding, using antisera to these same alternate pathway In addition, components (unpublished observations). Provost and Tomasi4 have reported the absence of Clq and C4 while demonstrating the presence of C3, C3PA, and properdin. Whether dermatitis herpetiformis is a disease due to an immunological disturbance, as Dr Seah and his associates state, remains to be resolved. Mayo Clinic, Rochester, Minnesota 55901, U.S.A.
IF
SiR,—The
R. S. ROGERS, III R. E. JORDON.
NOT, WHY NOT ?
resources
available for biomedical research
becoming inadequate for the funding of promising research proposals. It is therefore increasingly important in the public interest to optimise the selection and allocation procedures. As there is room for a great variety of opinion on this matter as a whole, I merely draw attention here to one of its least controversial aspects-the question of feed-
are
back.
Should reasons for the decision made on a grant be given to the applicant ? The reasons given could either be the referees’ comments alone (with their anonymity preserved if necessary, and perhaps reinforced by editing) or, preferably, these comments supplemented by policy arguments. The advantages of such an open system include:
application
(1) The majority of referees are conscientious and skilled and their scientific comments are often as valuable as those brought out at scientific meetings. Therefore, when comments are made available to the applicant, his research stands to benefit, should his application be successful or, if it be unsuccessful, his resubmission elsewhere stands to benefit (or be scrapped even). (2) Such an open system imposes a degree of discipline on referees and provides some safeguard against " simple errors of fact and logic " which, on occasion, they have been known to make in the past.5 (3) There is no cause for uncertainty among applicants and no unnecessary
puzzlement.
Rapp, H. J., Borsos, T. Molecular Basis of Complement Action. New York, 1970. 2. Jordon, R. E., Day, N. K., Sams, W. M., Jr., Good, R. A. J. clin. Invest. 1973, 52, 1207. 3. Provost, T. T., Tomasi, T. B., Jr. ibid. p. 1779. 4. Provost, T., Tomasi, T. B., Jr. Clin. Res. 1973, 21, 481. 5. Horrobin, D. F. Lancet, 1972, ii, 323. 1.