1238
SPECIAL ARTICLE
THIRD INTERNATIONAL CONFERENCE ON SYSTEMIC LUPUS ERYTHEMATOSUS PETER H. SCHUR The Third International Conference on Systemic Lupus Erythematosus was held in London, England, April 12-15, 1992. The meeting was hosted (splendidly) by Dr. Graham Hughes. Almost 1,000 physicians and scientists from all over the world attended. A summary of some of the highlights, compiled by session chairpersons, is presented herein.
of renal disease may result from different sequences of DNA, histone, and anti-DNA deposition. Antiendothelial antibodies may contribute to this process. IgG-N2 is the dominant idiotype found in renal biopsy specimens.
Epidemiology
Normal human keratinocytes pertubated with ultraviolet light or cultured in high concentrations of estrogen synthesize ROBS-A first in the nucleus, then in the cytoplasm, and then the Ro is expressed on the plasma membrane. Thus, the kerotinocyte may become the target of (auto)immune reactions.
The need for standardization of diagnostic criteria for central nervous system (CNS) lupus and for neurologic versus psychiatric events was stressed. The high frequency of cognitive abnormalities detected by psychometric testing was noted repeatedly. Some abnormalities correlate with serologic features: visual spatial deficits with lymphocytotoxic antibodies, verbal memory deficits with antiphospholipid antibodies, and development of subsequent CNS events with neuronal antibodies. Abnormal findings on single-photon emission computed tomography scanning and on magnetic resonance imaging were noted in selected patients. MRLllpr mice were noted to develop behavioral abnormalities even before exhibiting arthritis and lymphadenopathy. P ribosomal antigen was detected on the surface of neuroblastoma cells in culture, and this could (theoretically) be accessed by anti-P antibodies.
Renal involvement
Heart and lung involvement
Immune complex-mediated lupus nephritis may begin with histone binding of heparan sulfate in the glomerular basement membrane, followed by deposition of DNA, and then anti-DNA. Different patterns
Pulmonary hypertension in SLE is associated with a very poor prognosis. While pulmonary hypertension in SLE patients is non-thromboembolic in most cases, in some it is associated with antiphospholipid antibodies. Some patients with acute hypoxemia were described. Patients had serum complement acti-
The prevalence of systemic lupus erythematosus (SLE) is increased among Alaskan Indians and among Asian Indians (in Great Britain), but not in Chinese persons or in natives of Curagao, as compared with Caucasians. The prevalence of SLE is quite low among black Africans, in contrast to a high prevalence among black Americans in the US and the Caribbean.
Skin involvement
From the Editor’s desk, Arthritis und Rheumutism. Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
Central nervous system involvement
THIRD INTERNATIONAL CONFERENCE ON SLE
vation and pulmonary vascular leukocyte aggregation. Response to corticosteroid treatment was reported. Valvular disease is common in SLE and may be associated with antiphospholipid antibodies.
Pregnancy In antiphospholipid antibody-positive SLE mothers whose pregnancies ended in intrauterine fetal death, the placentae showed findings consistent with prolonged placental ischemia (i.e., fibrosis, thrombosis, infarct ion).
Neonatal lupus and childhood lupus La was detected in fetal hearts at 7 weeks, and Ro at I 1 weeks. Congenital complete heart block (CCHB) was associated with maternal anti-Ro (52 kd) and anti-La. Neonatal lupus rash was not associated with any particular maternal antibody profile. No clear guidelines for treatment of CCHB in the fetus were agreed upon. The observation that children often have more severe systemic illness and have a high frequency of renal disease was reaffirmed from centers around the world.
Immunology New Zealand black (NZB) mice with the mutation had high-titer anti-DNA antibodies and accelerated glomerulonephritis. T cells that help B cells make anti-DNA were cloned from these mice; the T cells have the phenotype CD4+, T cell receptor dulp, Th2 cytokine. Ninety-two percent of SLE sera contain a 78-kd protein (“Mx”), which can be induced in mononuclear cells by interferon-a (IFNa). Urine, but not serum, of SLE patients contains antibodies to extracellular matrix proteins. SLE T cells have increased interleukin-2 (IL-2) messenger R N A (mRNA) levels, and decreased IL-4 mRNA. These observations suggest that increased B cell activity and depressed cell-mediated immunity could be accounted for by activation of type 2 CD4+ cells, or other T cell subsets. SLE T cells may be down-regulated by transforming growth factor @. Serum levels of type I (p55) and type I1 (p75) tumor necrosis factor (TNF) receptors are elevated, especially in active disease. While there is little increase in serum/plasma levels of IL-6, there is an increase in IL-6 receptors. ~2611112
1239
Molecular biology Antihistone 2A and antihistone 2B may develop sooner than anti-DNA. Anti-DNA and anti-RNP generation are probably mostly antigen driven, while anti-Ro may be driven by molecularly similar (“mimicry”) antigens. The idiotypes (Id) 16/6, 31, 8.12, F4, and 9G4 were found in more than 50% of SLE patients and in tissue lesions from many patients. Id are encoded by V, germline genes. SLE could be induced in mice by immunization with 16/6-Id anti-DNA; the antiphospholipid antibody syndrome could be induced in mice by immunization with anticardiolipin antibodies. The recurrence of shared idiotypes suggests that a limited set of gene segments is used in autoantibodies. Antibodies to heat shock proteins (HSP) are present in low levels in patients with SLE, while hsp70 and hsp90 may be overexpressed on T cells in some patients, especially those with neurologic disease. A search for the role of HSP in SLE continues.
Antiphospholipid antibodies The importance of &-glycoprotein (p,-GP) reacting with cardiolipin in determining antiphospholipid reactivity was extended; &-GP has been cloned and sequenced. The (NZB x BXSB)F, mouse develops antiphospholipid antibody syndrome. Immunization of animals with &-GP was shown to induce antiphospholipid antibody syndrome in one study, but not in another.
Genetics HLA-DR3 positive SLE patients produce high levels of TNF and have a lower frequency of nephritis; DR2 positive patients produce little TNF and have a higher incidence of nephritis. TNF accelerates nephritis in MRLllpr mice, and prolongs survival and delays renal disease in NZB x NZW mice. Local production of TNF (both strains produce it) may have a more important role. One-third of patients with C4A protein deficiency have DR3 and a C4A gene deletion. In C4A null-associated lupus, there is a lower frequency of anti-DNA, renal disease, and complement consumption. C4A null-associated SLE may be due to the B8;DR3 haplotype. DR6 may protect against the development of nephritis. Anti-Ro and anti-La were associated most closely with DQ genes.
SCHUR
1240
Sex hormones Levels of aromatase are increased in skin lesions of patients with SLE. Blood prolactin levels correlate with disease activity in mice and humans, and these levels may be influenced (with concomitant improvement of disease activity in animals) by treatment with bromocriptine. The anti-estrogen, tamoxifen, may be of benefit. Women with SLE have antiovary antibodies, and male patients have antitesticular antibodies. Clinical improvement may occur with menopause.
Treatment Possible new biologic agents for the treatment of S L E were reviewed, including intravenous IgG (thrombocytopenia responds, nephritis worsens), immunoabsorption (treatment needs to be repeated, may
become expensive), photopheresis, monoclonal antibodies, IL-2 receptor, and T cell receptor. Measurement of glucocorticoid receptor density may represent an improved gauge for determination of proper steroid dosage. In one study, cyclosporine was of benefit in nephrotic syndrome. Antibodies to double-stranded DNA were noted to develop in chronic lymphocytic leukemia patients treated with IFNa. I F N a should therefore be used with great caution in patients with SLE.
Summary A Fourth International Conference on Systemic Lupus Erythematosus will be held in Jerusalem in March 1995. We look forward to a better understanding of the molecular, genetic, immunologic, and clinical aspects of the disease and trust that this knowledge will result in improved treatment.
SPECIAL ARTICLE
THIRD INTERNATIONAL CONFERENCE ON SYSTEMIC LUPUS ERYTHEMATOSUS PETER H. SCHUR The Third International Conference on Systemic Lupus Erythematosus was held in London, England, April 12-15, 1992. The meeting was hosted (splendidly) by Dr. Graham Hughes. Almost 1,000 physicians and scientists from all over the world attended. A summary of some of the highlights, compiled by session chairpersons, is presented herein.
of renal disease may result from different sequences of DNA, histone, and anti-DNA deposition. Antiendothelial antibodies may contribute to this process. IgG-N2 is the dominant idiotype found in renal biopsy specimens.
Epidemiology
Normal human keratinocytes pertubated with ultraviolet light or cultured in high concentrations of estrogen synthesize ROBS-A first in the nucleus, then in the cytoplasm, and then the Ro is expressed on the plasma membrane. Thus, the kerotinocyte may become the target of (auto)immune reactions.
The need for standardization of diagnostic criteria for central nervous system (CNS) lupus and for neurologic versus psychiatric events was stressed. The high frequency of cognitive abnormalities detected by psychometric testing was noted repeatedly. Some abnormalities correlate with serologic features: visual spatial deficits with lymphocytotoxic antibodies, verbal memory deficits with antiphospholipid antibodies, and development of subsequent CNS events with neuronal antibodies. Abnormal findings on single-photon emission computed tomography scanning and on magnetic resonance imaging were noted in selected patients. MRLllpr mice were noted to develop behavioral abnormalities even before exhibiting arthritis and lymphadenopathy. P ribosomal antigen was detected on the surface of neuroblastoma cells in culture, and this could (theoretically) be accessed by anti-P antibodies.
Renal involvement
Heart and lung involvement
Immune complex-mediated lupus nephritis may begin with histone binding of heparan sulfate in the glomerular basement membrane, followed by deposition of DNA, and then anti-DNA. Different patterns
Pulmonary hypertension in SLE is associated with a very poor prognosis. While pulmonary hypertension in SLE patients is non-thromboembolic in most cases, in some it is associated with antiphospholipid antibodies. Some patients with acute hypoxemia were described. Patients had serum complement acti-
The prevalence of systemic lupus erythematosus (SLE) is increased among Alaskan Indians and among Asian Indians (in Great Britain), but not in Chinese persons or in natives of Curagao, as compared with Caucasians. The prevalence of SLE is quite low among black Africans, in contrast to a high prevalence among black Americans in the US and the Caribbean.
Skin involvement
From the Editor’s desk, Arthritis und Rheumutism. Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
Central nervous system involvement
THIRD INTERNATIONAL CONFERENCE ON SLE
vation and pulmonary vascular leukocyte aggregation. Response to corticosteroid treatment was reported. Valvular disease is common in SLE and may be associated with antiphospholipid antibodies.
Pregnancy In antiphospholipid antibody-positive SLE mothers whose pregnancies ended in intrauterine fetal death, the placentae showed findings consistent with prolonged placental ischemia (i.e., fibrosis, thrombosis, infarct ion).
Neonatal lupus and childhood lupus La was detected in fetal hearts at 7 weeks, and Ro at I 1 weeks. Congenital complete heart block (CCHB) was associated with maternal anti-Ro (52 kd) and anti-La. Neonatal lupus rash was not associated with any particular maternal antibody profile. No clear guidelines for treatment of CCHB in the fetus were agreed upon. The observation that children often have more severe systemic illness and have a high frequency of renal disease was reaffirmed from centers around the world.
Immunology New Zealand black (NZB) mice with the mutation had high-titer anti-DNA antibodies and accelerated glomerulonephritis. T cells that help B cells make anti-DNA were cloned from these mice; the T cells have the phenotype CD4+, T cell receptor dulp, Th2 cytokine. Ninety-two percent of SLE sera contain a 78-kd protein (“Mx”), which can be induced in mononuclear cells by interferon-a (IFNa). Urine, but not serum, of SLE patients contains antibodies to extracellular matrix proteins. SLE T cells have increased interleukin-2 (IL-2) messenger R N A (mRNA) levels, and decreased IL-4 mRNA. These observations suggest that increased B cell activity and depressed cell-mediated immunity could be accounted for by activation of type 2 CD4+ cells, or other T cell subsets. SLE T cells may be down-regulated by transforming growth factor @. Serum levels of type I (p55) and type I1 (p75) tumor necrosis factor (TNF) receptors are elevated, especially in active disease. While there is little increase in serum/plasma levels of IL-6, there is an increase in IL-6 receptors. ~2611112
1239
Molecular biology Antihistone 2A and antihistone 2B may develop sooner than anti-DNA. Anti-DNA and anti-RNP generation are probably mostly antigen driven, while anti-Ro may be driven by molecularly similar (“mimicry”) antigens. The idiotypes (Id) 16/6, 31, 8.12, F4, and 9G4 were found in more than 50% of SLE patients and in tissue lesions from many patients. Id are encoded by V, germline genes. SLE could be induced in mice by immunization with 16/6-Id anti-DNA; the antiphospholipid antibody syndrome could be induced in mice by immunization with anticardiolipin antibodies. The recurrence of shared idiotypes suggests that a limited set of gene segments is used in autoantibodies. Antibodies to heat shock proteins (HSP) are present in low levels in patients with SLE, while hsp70 and hsp90 may be overexpressed on T cells in some patients, especially those with neurologic disease. A search for the role of HSP in SLE continues.
Antiphospholipid antibodies The importance of &-glycoprotein (p,-GP) reacting with cardiolipin in determining antiphospholipid reactivity was extended; &-GP has been cloned and sequenced. The (NZB x BXSB)F, mouse develops antiphospholipid antibody syndrome. Immunization of animals with &-GP was shown to induce antiphospholipid antibody syndrome in one study, but not in another.
Genetics HLA-DR3 positive SLE patients produce high levels of TNF and have a lower frequency of nephritis; DR2 positive patients produce little TNF and have a higher incidence of nephritis. TNF accelerates nephritis in MRLllpr mice, and prolongs survival and delays renal disease in NZB x NZW mice. Local production of TNF (both strains produce it) may have a more important role. One-third of patients with C4A protein deficiency have DR3 and a C4A gene deletion. In C4A null-associated lupus, there is a lower frequency of anti-DNA, renal disease, and complement consumption. C4A null-associated SLE may be due to the B8;DR3 haplotype. DR6 may protect against the development of nephritis. Anti-Ro and anti-La were associated most closely with DQ genes.
SCHUR
1240
Sex hormones Levels of aromatase are increased in skin lesions of patients with SLE. Blood prolactin levels correlate with disease activity in mice and humans, and these levels may be influenced (with concomitant improvement of disease activity in animals) by treatment with bromocriptine. The anti-estrogen, tamoxifen, may be of benefit. Women with SLE have antiovary antibodies, and male patients have antitesticular antibodies. Clinical improvement may occur with menopause.
Treatment Possible new biologic agents for the treatment of S L E were reviewed, including intravenous IgG (thrombocytopenia responds, nephritis worsens), immunoabsorption (treatment needs to be repeated, may
become expensive), photopheresis, monoclonal antibodies, IL-2 receptor, and T cell receptor. Measurement of glucocorticoid receptor density may represent an improved gauge for determination of proper steroid dosage. In one study, cyclosporine was of benefit in nephrotic syndrome. Antibodies to double-stranded DNA were noted to develop in chronic lymphocytic leukemia patients treated with IFNa. I F N a should therefore be used with great caution in patients with SLE.
Summary A Fourth International Conference on Systemic Lupus Erythematosus will be held in Jerusalem in March 1995. We look forward to a better understanding of the molecular, genetic, immunologic, and clinical aspects of the disease and trust that this knowledge will result in improved treatment.
