- Email: [email protected]
MECHANISMS OF AUTOIMMUNITY
955 Our findings indicate that in the pancreatic beta cell aberrant expression of class II MHC molecules is unlikely to be involved in presentation of autoantigen. They lead us to postulate an alternate hypothesis-namely, that the release of IFN-y by activated T-lymphocytes in an inflammatory islet lesion (? virus or chemical induced) could enhance T-cytotoxic (Tc) lymphocyte-mediated beta cell damage, since Tc-targeting requires co-expression of autoantigen and class I (HLA-ABC) molecules. The discrepant observations on thyroid cells and pancreatic beta cells suggest that the mechanisms of autoimmune recognition and damage may be fundamentally different in these endocrine epithelial cells. Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia n=number of determinations. ’DRX=any DR allotype except DR3. t>15’lo cells posiuve for 4F2 and >10% normal mean.
1. Bottazzo
2.
3.
Department of Diabetes and Immunogenetics, St Bartholomew’s Hospital, London EC1A 7BE, and Department of Endocrinology (I), University of Rome, Rome, Italy
4.
5.
J Immunol 1981; 126: 1409-14. 5 Leonard JJM, Depper T, Uchiyama T, Smith KA, Waldmann TA, Greene C. A monoclonal antibody that appears to recognise the receptor for human T cell growth factor: partial characterisation of the receptor. Nature 1982; 300: 267-69. 6. Bottazzo GF, Pujol Borrell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; ii: 1115-18.
MECHANISMS OF AUTOIMMUNITY
SiR,—The aberrant expression on endocrine epithelial cells of class II molecules of the major histocompatibility complex (MHC), normally required for presentation of antigen to T-helper (Th) lymphocytes, has been postulated by Bottazzo and colleagues as a mechanism for triggering endocrine autoimmunity.These workers observed that HLA-DR molecules were expressed on thyroid cells from patients with Graves’ disease but not on thyroid cells from controls;2 however, HLA-DR expression could be induced on normal thyroid cells by the mitogen phytohaemagglutinin,3 and by the lymphokine interferon-gamma (IFN-y).4 IFN-y, produced by activated T-lymphocytes, is probably the major inducer of MHC molecules in vivo.55 To see if this proposed mechanism also applied to the autoimmune lesion of the pancreatic islets in insulin-dependent diabetes we have examined the effect of IFN-y or conditioned medium from concanavalin-A-activated mouse spleen cells on the expression of MHC molecules on cultured rat beta cells (RIN-m5F line) and mouse and human islet cells. We found no induction of class II molecules (Ia) but a 10-fold increase in the expression of class I molecules (H-2) after culture of murine cells in either
and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; ii: 1115-18. Hanafusa T, Pujol-Borrell R, Chiovato R, Russell RCG, Doniach D, Bottazzo GF. Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: Relevance for autoimmunity. Lancet 1983; ii: 1111-15. Pujol-Borrell R, Hanafusa T, Chiovato, Bottazzo GF. Lectin-induced expression of DR antigen on human cultured follicular thyroid cells. Nature 1983; 304: 71-73. Todd I, Pujol-Borrell R, Hammond LJ, Bottazzo GF, Feldmann M. Interferon-y induces HLA-DR expression in thyroid epithelium. Clin Exp Immunol 1985; 61: 265-73. Rosa F, Fellous M. The effect ofgamma-interferon on MHC antigens. Immunol Today
1984; 5: 261-62. 6.
P. POZZILLI ANNE C. TARN E. A. M. GALE
1. McCombs CC, Michalaski JP. Lymphocyte abnormality associated with HLA-B8 in healthy young adults. J Exp Med 1982; 156: 936-41. 2. Pozzilli P, Zuccarini O, Iavicoli M, et al. Monoclonal antibodies defined abnormalities of T lymphocytes in type 1 diabetes. Diabetes 1983; 32: 91-94. 3. Pozzilli P, Sensi M, AI-Sakkaf L, Tarn A, Zuccarini O, Bottazzo GF. Prospective study of lymphocyte subsets in subjects genetically susceptible to type 1 (insulindependent) diabetes. Diabetologia 1984; 27: 132-35. 4. Haynes BF, Hemler ME, Mann DL, et al. Characterization of a monoclonal antibody (4F2) which binds to human monocytes and to a subset of activated T lymphocytes.
GF, Pujol-Borrell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR
expression
for anti-Tac represent values 2SD above the
although strongly associated with autoimmune disease, or that the associations are with an as yet unknown HLA class II antigen. Other possibilities could be that there are linked protective factors controlled by other genes or that the environmental "trigger" has not been encountered.
IAIN L. CAMPBELL LEONARD C. HARRISON
Campbell IL, Wong GHW, Schrader JW, Harrison LC. Expression of H-2 antigens on mouse pancreatic islet cells is enhanced by interferon-&ggr;. Diabetes (in press).
FREE RADICALS AND ALCOHOLISM
SIR,-In common with Dr Dormandy and his colleagues (Aug 10,
291),
have been
measuring plasma phospholipid-2-esterified a variety of clinical conditons. Whilst we have been unsuccessful in generating this diene-conjugated non-peroxide in vitro by ultraviolet irradiation or the use of an initiator of free radical activity, we cannot agree with Dr Smith and Dr Thompson (Oct 5, p 774) that the isomer’s presence is not related to free-radical activity. Perhaps the most compelling evidence is to be found in the results from four patients we have studied within 48 h of ingestion of p
we
9,11-linoleic acid (9,11-LA) in patients with
paraquat. In all
cases
the % molar ratio of 9,11
to
9,12 linoleic acid
(R) in plasma phospholipids exceeded at some stage the upper limit of our reference range for this marker established in 143 healthy factory workers (mean + 2SD 3 -27) (see figure). Paraquat undergoes redox cycling with the concomitant production of superoxide anion and an intracellular decline in NADPH:NADP ratio. This will lead to the induction of lipid peroxidation.Thus the appearance of raised R values so soon after ingestion of paraquat supports the hypothesis of an association between increased 9,11-LA and free radical activity rather than a dietary source.
preparation.6 The same results were obtained with cultured human fetal or adult islet cells; recombinant human IFN-y upregulated the expression of class I (HLA-ABC) molecules on beta cells, while HLA-DR molecules remained undetectable (unpublished).
Serial measurements of LA ratio (R).
plasma phospholipid-2-esterified 9,11:9,12
1. Bottazzo
2.
3.
Department of Diabetes and Immunogenetics, St Bartholomew’s Hospital, London EC1A 7BE, and Department of Endocrinology (I), University of Rome, Rome, Italy
4.
5.
J Immunol 1981; 126: 1409-14. 5 Leonard JJM, Depper T, Uchiyama T, Smith KA, Waldmann TA, Greene C. A monoclonal antibody that appears to recognise the receptor for human T cell growth factor: partial characterisation of the receptor. Nature 1982; 300: 267-69. 6. Bottazzo GF, Pujol Borrell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; ii: 1115-18.
MECHANISMS OF AUTOIMMUNITY
SiR,—The aberrant expression on endocrine epithelial cells of class II molecules of the major histocompatibility complex (MHC), normally required for presentation of antigen to T-helper (Th) lymphocytes, has been postulated by Bottazzo and colleagues as a mechanism for triggering endocrine autoimmunity.These workers observed that HLA-DR molecules were expressed on thyroid cells from patients with Graves’ disease but not on thyroid cells from controls;2 however, HLA-DR expression could be induced on normal thyroid cells by the mitogen phytohaemagglutinin,3 and by the lymphokine interferon-gamma (IFN-y).4 IFN-y, produced by activated T-lymphocytes, is probably the major inducer of MHC molecules in vivo.55 To see if this proposed mechanism also applied to the autoimmune lesion of the pancreatic islets in insulin-dependent diabetes we have examined the effect of IFN-y or conditioned medium from concanavalin-A-activated mouse spleen cells on the expression of MHC molecules on cultured rat beta cells (RIN-m5F line) and mouse and human islet cells. We found no induction of class II molecules (Ia) but a 10-fold increase in the expression of class I molecules (H-2) after culture of murine cells in either
and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; ii: 1115-18. Hanafusa T, Pujol-Borrell R, Chiovato R, Russell RCG, Doniach D, Bottazzo GF. Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: Relevance for autoimmunity. Lancet 1983; ii: 1111-15. Pujol-Borrell R, Hanafusa T, Chiovato, Bottazzo GF. Lectin-induced expression of DR antigen on human cultured follicular thyroid cells. Nature 1983; 304: 71-73. Todd I, Pujol-Borrell R, Hammond LJ, Bottazzo GF, Feldmann M. Interferon-y induces HLA-DR expression in thyroid epithelium. Clin Exp Immunol 1985; 61: 265-73. Rosa F, Fellous M. The effect ofgamma-interferon on MHC antigens. Immunol Today
1984; 5: 261-62. 6.
P. POZZILLI ANNE C. TARN E. A. M. GALE
1. McCombs CC, Michalaski JP. Lymphocyte abnormality associated with HLA-B8 in healthy young adults. J Exp Med 1982; 156: 936-41. 2. Pozzilli P, Zuccarini O, Iavicoli M, et al. Monoclonal antibodies defined abnormalities of T lymphocytes in type 1 diabetes. Diabetes 1983; 32: 91-94. 3. Pozzilli P, Sensi M, AI-Sakkaf L, Tarn A, Zuccarini O, Bottazzo GF. Prospective study of lymphocyte subsets in subjects genetically susceptible to type 1 (insulindependent) diabetes. Diabetologia 1984; 27: 132-35. 4. Haynes BF, Hemler ME, Mann DL, et al. Characterization of a monoclonal antibody (4F2) which binds to human monocytes and to a subset of activated T lymphocytes.
GF, Pujol-Borrell R, Hanafusa T, Feldmann M. Role of aberrant HLA-DR
expression
for anti-Tac represent values 2SD above the
although strongly associated with autoimmune disease, or that the associations are with an as yet unknown HLA class II antigen. Other possibilities could be that there are linked protective factors controlled by other genes or that the environmental "trigger" has not been encountered.
IAIN L. CAMPBELL LEONARD C. HARRISON
Campbell IL, Wong GHW, Schrader JW, Harrison LC. Expression of H-2 antigens on mouse pancreatic islet cells is enhanced by interferon-&ggr;. Diabetes (in press).
FREE RADICALS AND ALCOHOLISM
SIR,-In common with Dr Dormandy and his colleagues (Aug 10,
291),
have been
measuring plasma phospholipid-2-esterified a variety of clinical conditons. Whilst we have been unsuccessful in generating this diene-conjugated non-peroxide in vitro by ultraviolet irradiation or the use of an initiator of free radical activity, we cannot agree with Dr Smith and Dr Thompson (Oct 5, p 774) that the isomer’s presence is not related to free-radical activity. Perhaps the most compelling evidence is to be found in the results from four patients we have studied within 48 h of ingestion of p
we
9,11-linoleic acid (9,11-LA) in patients with
paraquat. In all
cases
the % molar ratio of 9,11
to
9,12 linoleic acid
(R) in plasma phospholipids exceeded at some stage the upper limit of our reference range for this marker established in 143 healthy factory workers (mean + 2SD 3 -27) (see figure). Paraquat undergoes redox cycling with the concomitant production of superoxide anion and an intracellular decline in NADPH:NADP ratio. This will lead to the induction of lipid peroxidation.Thus the appearance of raised R values so soon after ingestion of paraquat supports the hypothesis of an association between increased 9,11-LA and free radical activity rather than a dietary source.
preparation.6 The same results were obtained with cultured human fetal or adult islet cells; recombinant human IFN-y upregulated the expression of class I (HLA-ABC) molecules on beta cells, while HLA-DR molecules remained undetectable (unpublished).
Serial measurements of LA ratio (R).
plasma phospholipid-2-esterified 9,11:9,12