2) About 130,000 Americans are now being treated for SLE, although probably as many as a million Americans are affected by some form of this disease (including milder and more temporary forms, and some cases that are not diagnosed, as happened to Charles Kuralt).

3) Just over 90% of lupus victims are women, 90% of these are young women. Lupus also occurs in children, where the sex ratio is only about 1-3 boys to girls, and where the disease progresses more rapidly than in adults, and is usually fatal. In general, the later you get lupus, the less rapidly it will kill you; although even for young adult patients more than half of patients can be effectively treated (the disease being "managed" rather than cured). I have not yet found a number for fatalities per year, but it is somewhere in the thousands per year, perhaps five thousand per year (which would be a seventh or eighth as many fatalities as AIDS in this country, since these have now dropped back below 40,000 per year).

4) Lupus tends to "run in families": studies of sets of identical twins have reported frequencies from 26% to 70% (i.e. if one twin has the disease; in what % of cases does the other twin also get SLE?); immediate family members are thought to have around 5 or 10% probability (lower in males than females) of getting SLE but as much as 20 or 30% chance of getting some autoimmune disease, especially immune thyroiditis, scleroderma and rheumatoid arthritis! Increased frequencies of non-Hodgkins lymphoma have also been reported (but with much smaller %s).

5) "Nearly half the first degree relatives of my lupus patients have a positive ANA blood test" (test for antibodies against DNA and/or RNA-protein particles) quoted from "The Lupus Book" D.J. Wallace, Oxford Univ. Press 1995. About one-third of multiple sclerosis patients have positive ANA blood tests.

6) Higher frequencies of SLE are found among people with certain varieties of type II histocompatibility antigens, specifically DR3 and DR2. These same histocompatibility antigens are also correlated with multiple sclerosis, scleroderma and rheumatoid arthritis

7) Lupus varies in frequency by race, with blacks having a higher rate than whites; it occurs most frequently of all in American Indians, with the Sioux having by far the highest rates. It was said to occur more frequently in Asians than Caucasians, but recent reports contradicted this! "Facts" seem to be unusually unstable in this field!!

8) Diseases very similar to SLE, and perhaps with the same causes, have been found in dogs, mice, rabbits, and certain kinds of mink, among other mammals. Certain strains of mice and rabbits have been found in which lupus occurs at high enough rates so that these have become widely used systems for experimental study of SLE. (e.g. "New Zealand Black" strain mice; and most especially f1 hybrids between NZ Black and NZ White mice!)

9) "Drug induced Lupus" : Symptoms very similar (or identical?) to SLE (including anti-DNA, etc. antibodies in the blood!) are sometimes induced by certain drugs, especially procainamide (used to treat heart arrhythmias), isoniazid (an anti-tuberculosis drug), thorazine (a psychoactive drug), among others. Only around 1 patient per 1,000 treated with such a drug gets the temporary lupus, the symptoms of which almost always disappear when the person stops taking the drug. {A key question is what sort of mechanism eliminates the factors, antibodies in particular as well as the B cells that produce them!!}. There is some interesting evidence about what these different drugs have in common, including some inhibition of your old friend DNA methylation.

10) The "butterfly rash" : Around 30% of lupus victims develop a red rash on their face, especially below the eyes and on the nose (the area of inflamed skin often being shaped like a butterfly). Rashes can also occur on other parts of the skin.

11) Exposure to ultraviolet light (including merely ordinary sunshine) increases the skin rash and also worsens the other symptoms, including damage to blood vessels and kidneys (i.e. it seems not to be just a local effect). It is thought this may be an indirect effect of induced secretion of certain cytokines!

12) Existing treatments for SLE consist mostly of wholesale depression of the whole immune system with heavy doses of corticosteroids, and sometimes also certain "nitrogen mustard" drugs otherwise used for cancer chemotherapy (such as some that cross-link guanines in DNA, hereby blocking cell division and selectively killing faster growing cells). Some anti-malarial drugs related to quinine also produce some improvement, but I haven't yet read any logical explanations for why they should work; they just do.

Some possible features of theories for explaining autoimmunity:

A) Failure to delete anti-self T & B lymphocyte clones B) Failure to induce anergy of antiself clones. (If anergy rather than deletion is how tolerance works) C) Reversal of anergy of some antiself clones. (inactivated antiself lymphocytes become active again) D) Somatic mutations in a lymphocyte's gene for variable sequences. E) Side effect of "affinity maturation" (i.e. resulting from hypermutation of DNA in the VJ&D regions, after these have recombined to form the variable sequence part of the antibody genes). Think what would happen if these mutations included frame-shifts, or even just substitutions of prolines for other amino acids, among other substitutions that would have very major effects on confomation.

*F) Reactivation (later in life) of one or more of the normal diversity-generating mechanisms. (in other words, more VJD recombination events; maybe on the other chromosome?) G) Failure of allelic exclusion , so that both chromosomes undergo VJD recombination, etc. so as to produce two different variable sequence regions for either heavy of light chains or both. Some especially puzzling facts about lupus (& therefore hints as to its causation?): i)* Increased frequency in people with the type II histocompatibility antigen DR3. ii) Increased frequency in certain families (even apart from these DR# etc. antigens). iii) Anti-DNA and phospholipid antibodies can very often be found in the blood of immediate family members of lupus patients, even though they do not have symptoms of lupus!! iv) Strong reaction to UV light, with skin rash and also increase of kidney and circulatory symptoms. / v)* (Apparently) rapid onset with appearance of multiple different anti-self antigens. Why so many different antigens DNA, collagen, (do these antigens have anything in common; or is there just a general loss of tolerance) vi) Temporary versions of lupus are induced (fairly frequently) by certain drugs. (*What was previous state of their b-cells with these specificities??????????????) vii)* Remission (=disappearance) of the drug-induced lupus when patient stops taking the drug.

Each group of 3 students will collaborate with each other to develop a theory as to the causation (including proposals about how to improve treatment!) of the human form of the disease Lupus Erythematosus.

At the beginning of class ?? each group of 3 students will hand in to me an approximately two page summary of the theory that they have jointly invented, and about which they will report orally to the whole class beginning the following week
(Sept 11, and continuing during that class and the following one or two class periods.
During class, ???? and probably continuing the following ?? Sept ?? each group of 3 will stand up at the blackboard in front of the whole class and present their own hypothesis, making arguments in its favor, suggesting future experiments by which it might be tested, as well as possible new strategies for its treatment (based on their hypothesis).

Stages in your progress might consist of making lists or tables of logical implications of each set of facts. For each given fact (or factoid= "fact-like object"), what does it seem to suggest is true? Or what sort of mechanism(s) should produce this result? Or what does it seem to prove couldn't be true? Then, for each of these tentative conclusions/generalization/inferences, make a list of which facts seem to contradict it?

Even when/if you can't yet decide on a clear-cut theory it will be perfectly acceptable for your group to present its tables of tentative conclusions, together with discussions of which other facts seem to contradict these conclusions.

Next, try to think up further experiments and/or questions that you would most like to know the answers to. One kind of experiment that you should try to invent would involve possible future treatments for the disease "If the nature of the disease is "X", then that would imply that treatment of a patient with "Y" should/might be able to amerliorate the symptoms, cure the disease, etc."

After you have been tossing possibilites around for a while, you will be surprised how many wild and nifty ideas can jump into your head! (Turn your brains all the way ON)

Klimas NG. Patarca R. Perez G. Garcia-Morales R. Schultz D. Schabel J. Fletcher MA.
Case report: distinctive immune abnormalities in a patient with procainamide-induced lupus and serositis.
American Journal of the Medical Sciences. 303(2):99-104, 1992 Feb.
To gain insight into the immunopathogenesis of drug-induced autoimmune disorders, lymphocyte and immunoglobulin distributions and cytokine levels were monitored in the peripheral blood and pleural fluid of a patient with procainamide-induced lupus and pleural effusion. Approximately 80% of the B cells in both compartments were CD5+ compared to 10% to 25% in normal adults. CD4/CD8 ratio and percentage CD4 were normal in peripheral blood. Serum levels of IgG (particularly IgG2), IL-6, and soluble IL-2R were slightly elevated, and those of IgA were significantly elevated compared to normal controls. Analysis of the pleural effusion revealed an increased CD4/CD8 ratio because of an increased percentage of CD4+CD29+ helper memory T cells, lack of expression of the resting B-cell marker CD21, immune complex deposition and complement consumption, increased relative levels of ANA, abnormally high levels of IL-6 and soluble IL-2R, and detectable levels of IL-1b, IFN-g and TNF-a. These observations provide evidence for the involvement of CD5+ B cells and differential helper T-cell activity in procainamide-induced lupus and for an association between local lymphocyte activation and organ pathology.

Matsuzaki M. Tsukada Y. Kayahara H. Tadasa K. Ina K.
[Antibodies to poly (adenosine diphosphate-ribose) in systemic lupus erythematosus and drug induced lupus]. [Japanese]
Arerugi - Japanese Journal of Allergology. 41(3):447-53, 1992 Mar.
Abstract The difference between anti poly (ADP-ribose) antibodies was studied in patients with systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS) and drug-induced lupus (DIL). Radioimmunoassay showed that high concentrations of anti poly (ADP-ribose) antibodies (10.3-22.2%) were induced by phenobarbital, phenytoin, valproic acid (anti-epileptic agent) and procainamide (anti-arrhythmic agent). Poly (ADP-ribose) antibodies were separated by hydroxylapatite column chromatography. The average chain length of the polymer consisted of 2.4, 10.8 and 28.2 ADP-ribose units. Anti poly (ADP-ribose) antibodies from patients with SLE and PSS reacted with 2.4, 10.8, and 28.2 ADP-ribose units in RIA, but those from patients with DIL reacted only with 28.2 ADP-ribose units in RIA. The binding specificity of anti poly (ADP-ribose) antibodies from pregnant women was found to be very similar to that of the antibodies from case of DIL. The present results clearly demonstrated that anti poly (ADP-ribose) antibodies found in systemic autoimmune diseases bound not only to poly (ADP-ribose) with an average chain length of more than 20 ADP-ribose units, but also to oligo (ADP-ribose) with an average chain length of about 2 ADP-ribose units. Anti poly (ADP-ribose) antibodies found in DIL cases and pregnant women, however, bound only to poly (ADP-ribose) with an average chain length of more than 20 ADP-ribose units.

Mongey AB. Donovan-Brand R. Thomas TJ. Adams LE. Hess EV.
Serologic evaluation of patients receiving procainamide [see comments].
Comment in: Arthritis Rheum 1992 Sep;35(9):1108-9 Arthritis & Rheumatism. 35(2):219-23, 1992 Feb.
This controlled study examined the characteristics of serologic abnormalities in 52 patients receiving procainamide for cardiac arrhythmias, who had no symptoms of a connective tissue disease. Antinuclear antibodies occurred in 43 patients (83%). Significant elevation of antibody binding to single-stranded DNA (mean +/- SEM 30 +/- 2.6%), double-stranded DNA (13 +/- 1.1%), Z-DNA (optical density 0.54 +/- 0.06), and poly A (7.2 +/- 0.6%) was seen (P less than 0.001). Thirty-four patients (65.4%) had antibodies to total histones, most frequently, the H2A/2B dimer. IgG antibodies to H2A/2B correlated with the cumulative procainamide dose. One patient subsequently developed drug-related lupus.

Hay EM. Isenberg DA.
Autoantibodies in central nervous system lupus. [Review]
British Journal of Rheumatology. 32(4):329-32, 1993 Apr.
Central nervous system (CNS) involvement in patients with lupus remains both a diagnostic and a therapeutic challenge. The role of autoantibodies in the pathogenesis of CNS lupus and/or as markers for disease activity is reviewed. Doubt is cast on the value of measuring anti-neuronal antibodies. Those antibodies binding ribosomal-P protein antigens or certain phospholipids appear to have greater utility, although even in these cases there is no uniform agreement as to their precise role in CNS disease induction, or how well antibody levels reflect disease activity.

Erausquin C. Merino R. Izui S. Fernandez-Sueiro L. Saez F. Fernandez F. Rodriguez-Valverde V. Merino J.
Therapeutic effect of early thymic irradiation in (NZB x NZW)F1 mice, associated with a selective decrease in the levels of IgG3 and gp70-anti-gp70 immune complexes.
Cellular Immunology. 161(2):207-12, 1995 Apr 1.
The lupus-prone (NZB x NZW)F1 female mice (NZB/W) develop an autoimmune disease characterized by production of autoAb and fatal glomerulonephritis. Since it has been previously shown that total lymphoid irradiation has a beneficial effect in this model, we have analyzed whether early thymic irradiation (ETI) could improve the course of the lupus-like syndrome in these mice. NZB/W mice received thymic irradiation (4500 rads) beginning at 10 weeks of age, prior to the onset of autoimmune manifestations. Then, they were evaluated for survival, renal histology, and serological markers of autoimmunity, in comparison to nonirradiated NZB/W females. The treatment with ETI improved nephritis and survival in NZB/W mice: 50% mortality was observed at 12 months in irradiated mice and at 9 months in untreated mice. This improved survival could not be attributed to a reduction in the titers of anti-dsDNA Ab nor in the levels of total immune complexes which were essentially identical in both groups. By contrast, this improvement was related to a selective normalization in the serum levels of IgG3 and gp70-anti-gp70 immune complexes (gp70IC) in ETI NZB/W female mice as compared to that seen in nonirradiated NZB/W females. These data show the therapeutical effect of ETI and support the pathogenic role of IgG3 and gp70IC in the development of glomerulonephritis in NZB/W mice.

Mihara M. Katsume A. Takeda Y.
Effect of methotrexate treatment on the onset of autoimmune kidney disease in lupus mice.
Chemical & Pharmaceutical Bulletin. 40(8):2177-81, 1992 Aug.
In this study, we examined the effects of methotrexate (MTX) on the development of autoimmune kidney disease in three kinds of autoimmune prone mice, NZB/NZW F1 (BWF1) mice, MRL/Mp-lpr/lpr (MRL/lpr) mice and NZW/BXSB F1 (WBF1) mice. The results showed that MTX delayed the appearance of proteinuria and prolonged survival of both BWF1 and MRL/lpr mice and inhibited the elevation of blood urea nitrogen (BUN) levels which accompanies the development of lupus nephritis. However, MTX treatment did not affect these in WBF1 mice. Furthermore, MTX could not suppress immunoglobulin G (IgG) class anti-deoxyribonucleic acid (DNA) and anti-trinitrophenol (TNP) antibody production in any variety of mice. These suggest that the therapeutic effect of MTX on BWF1 and MRL/lpr mice does not result in the suppression of IgG autoantibody production.

Bundick RV. Eady RP.
The effects of CP 17193, an immunosuppressive pyrazaloquinoline, on the development of spontaneous lupus disease in NZBW F1 hybrid mice.
Clinical & Experimental Immunology. 89(2):179-84, 1992 Aug.
The effects of the immunosuppressive agent CP 17193 on the development of spontaneous lupus disease in female NZBW F1 hybrid mice were investigated.Long term dosing with CP 17193 markedly delayed the onset of mortality but did not extend the long term survival of the mice. CP 17193 significantly inhibited immune complex deposition in the glomeruli of 30- and 35-week-old mice and also reduced the levels of proteinuria in the 35-week-old mice. There was a slight reduction in the levels of circulating antinuclear antibody to ds DNA in CP 17193-treated mice but this was not statistically significant. Studies on immune cell function of 35-week-old mice dosed with CP 17193 showed significant reduction in the total numbers of spontaneous polyclonal antibody producing cells. Analysis of the results revealed these effects to result from a marked reduction in total spleen cell numbers in CP 17193-treated mice. When results were expressed as activity per cell unit the differences between drug-treated and control mice were small. Spleen cells from mice given a shorter dosing schedule of 7 weeks with CP 17193 showed an augmentation of IL-2 production and responsiveness. These results show CP 17193 having interesting selective immunomodulating activity on the immunopathogenesis of spontaneous murine lupus disease. Furthermore, compounds with this profile of activity may have a potential role in the treatment of some autoimmune diseases.

Connolly MK. Kitchens EA. Chan B. Jardieu P. Wofsy D.
Treatment of murine lupus with monoclonal antibodies to lymphocyte function-associated antigen-1: dose-dependent inhibition of autoantibody production and blockade of the immune response to therapy.
Clinical Immunology & Immunopathology. 72(2):198-203, 1994 Aug.
Monoclonal antibodies (mAb) to lymphocyte function-associated antigen-1 (LFA-1) have been used successfully in vivo to inhibit immune responses and to block inflammatory reactions. To determine whether these effects of anti-LFA-1 could retard autoimmune disease, we treated lupus-prone NZB/NZW F1 (B/W) mice with a rat mAb to LFA-1 (anti-CD11a). Mice received high-dose therapy (500 micrograms twice weekly), low-dose therapy (40 micrograms thrice weekly), or phosphate-buffered saline from age 5 months to age 10 months. Treatment with high doses of anti-CD11a suppressed both the immune response to the rat mAb and the production of autoantibodies to double-stranded DNA. In contrast, treatment with low doses of anti-CD11a elicited an immune response to the rat mAb and did not suppress autoantibody production. The immunosuppressive effects of high doses of anti-CD11a were not due to target cell depletion. In fact, treatment induced a marked lymphocytosis which involved all lymphocyte subsets equally. Despite inhibiting autoantibody production, high-dose therapy had only modest effects on longevity.

Pelkonen P.
Childhood systemic lupus erythematosus, vasculitis, and rheumatic fever and neonatal lupus.
Current Opinion in Rheumatology. 7(5):430-6, 1995 Sep.
Studies on the long-term outcome of patients with systemic lupus erythematosus not only give us survival figures but also uncover flaws in our treatment strategies and reveal both disease-associated and other factors that affect prognosis. Among the latter, compliance with treatment and socioeconomic factors are noteworthy. The pathogenesis of neonatal lupus is under active investigation, and new approaches are being developed. This review also draws attention to a number of vasculitis syndromes that are common in adults but very rarely reported in children. Poststreptococcal reactive arthritis has been described as a new entity; however, such patients should probably receive the same attention as patients with rheumatic fever to avoid recurrences of the disease and cardiac sequelae.

Foster MH. Madaio MP. Barrett KJ.
Variable region sequence analysis of anti-DNA antibodies: evidence for a family of closely related germ-line VH genes encoding lupus autoantibodies.
DNA & Cell Biology. 11(3):175-82, 1992 Apr.
Cloning and sequencing of the V regions of the anti-DNA monoclonal antibodies (mAbs), H438 and H130, indicate that H438 is encoded by a J558 VH gene, a single D region nucleotide, and unmutated JH1, V kappa-1C and J kappa 1 genes, and the H130 L chain is encoded by a V kappa-21 subgroup gene J kappa 1 gene. Identification of VH438, which shared VH hybridization pattern with 6% of a panel of 352 MRL/lpr hybridomas, suggests that the frequency of J558 use among spontaneously activated B cells in MRL/lpr mice is greater than previously reported. The VHH438 J558 family gene is identical to VHPAR, which encodes the independently derived MRL/lpr autoantibody, MRP-2, and is highly homologous to the previously reported VHH130, which is identical to a BALB/c germ-line VH gene. Comparison of consensus sequences of homologous autoantibodies and previously reported restriction mapping suggest that a minimum of three highly related J558 germ-line genes encode lupus autoantibodies.

Hofstra AH. Li-Muller SM. Uetrecht JP.
Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus.
Drug Metabolism & Disposition. 20(2):205-10, 1992 Mar-Apr.
The tuberculostatic agent isoniazid has been implicated in inducing various idiosyncratic reactions including drug-induced lupus. The mechanism is unknown but may involve a reactive metabolite of the drug. Isoniazid was oxidized by activated leukocytes to isonicotinic acid. Myeloperoxidase is likely the enzyme in the leukocyte involved, since the oxidation was inhibited by azide, which inhibits myeloperoxidase, and by catalase, which catalyzes the breakdown of hydrogen peroxide. The same metabolic profile was observed when isoniazid was incubated with purified myeloperoxidase and hydrogen peroxide. The rate of the reaction was increased in the presence of chloride. Hypochlorous acid was also able to oxidize isoniazid to isonicotinic acid. Isoniazid, or an oxidative product, inhibited the reaction when high initial substrate concentrations were used. Isoniazid is oxidized by activated leukocytes, possibly to a reactive intermediate, which may have implications for induced lupus.

Bensimon C. Chastagner P. Zouali M.
Human lupus anti-DNA autoantibodies undergo essentially primary V kappa gene rearrangements.
EMBO Journal. 13(13):2951-62, 1994 Jul 1.
We have recently characterized the heavy chain variable region (VH) genes expressed by a panel of human anti-DNA antibodies derived from four patients with systemic lupus erythematosus and expressing an idiotypic marker representative of a subset of pathogenic autoantibodies. Here, we have cloned and sequenced the kappa chain variable region genes (V kappa) of the clones whose VH genes had been previously analysed. All the V kappa genes utilized map to the 280 kb portion of the 3' end of the locus, suggesting that they represent essentially the products of primary rearrangements. This proximal clustering of the V kappa genes used contrasts with the broad distribution of immunization-induced human antibody V kappa genes over 1400 kb of the locus. In addition, lupus autoantibodies show no tendency to express the downstream junctional (J kappa) exons--another indication of infrequent secondary variable gene assembly. Since successive rearrangements may extinguish high-affinity recognition of self antigens, we propose that this bias in V kappa and J kappa expression reflects a low rate of secondary light chain rearrangements among lupus autoantibodies. We also postulate that the corrective mechanism capable of editing potentially aggressive, self-reactive antibodies in these patients may be deficient--a deficit that could be genetically determined and/or somatically acquired.

Burlingame RW. Rubin RL. Balderas RS. Theofilopoulos AN.
Genesis and evolution of antichromatin autoantibodies in murine lupusmplicates T-dependent immunization with self antigen.
Journal of Clinical Investigation. 91(4):1687-96, 1993 Apr.
Autoantibodies reacting with chromatin and its components, histones and DNA, are characteristic of the human autoimmune disease SLE and drug-induced lupus, but the mechanisms of their induction remain unknown. Serial serum samples collected over short intervals from lupus-prone MRL/MP-lpr/lpr and BXSB mice were tested by ELISA on chromatin and its substructures to characterize the initial autoimmune response to these antigens. Direct binding studies demonstrated that the early autoantibodies recognized discontinuous epitopes on native chromatin and the (H2A-H2B)-DNA subnucleosome. As the immune response progressed, native DNA and other chromatin constituents generally became antigenic. Based on adsorption studies and IgG subclass restriction, antibodies to native DNA were more related to chromatin than to denatured DNA. The kinetics of autoantibody appearance and the Ig class distribution were similar to the kinetics and distribution seen in antibodies induced by immunization with an exogenous T-dependent antigen. These results are most consistent with the view that autoantibodies reacting with chromatin are generated by autoimmunization with chromatin, and antibodies to native DNA are a subset of the wide spectrum of antichromatin autoantibodies.

Rubin RL.Bell SA. Burlingame RW.
Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex.
J. Clinical Investigation. 90(1):165-73, 1992
IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.

Nakamura RM. Bylund DJ.
Contemporary concepts for the clinical and laboratory evaluation of systemic lupus erythematosus and "lupus-like" syndromes. [Review]
J. Clinical Laboratory Analysis. 8(6):347-59, 1994.
Systemic lupus erythematosus (SLE) is a nonorgan-specific autoimmune disease which affects multiple organ systems and is multifactorial in etiology. SLE is the prototypic systemic rheumatic disease with immune dysregulation characterized by (1) polyclonal activation of B-cells and (2) production of a large spectrum of autoantibodies with a marked preference for nuclear and intracellular antigens. The clinical and laboratory manifestations and criteria for classification and diagnosis of systemic lupus erythematosus, lupus-like syndromes, and various subsets of systemic lupus erythematosus, are reviewed. The differential diagnosis of SLE and related diseases is described with correlation of specific intracellular autoantibodies.

Vidal S. Gelpi C. Rodriguez-Sanchez JL.
(SWR x SJL)F1 mice: a new model of lupus-like disease.
Journal of Experimental Medicine. 179(5):1429-35, 1994 May 1.
During the study of autoimmune models we found that (SWR x SJL)F1 mice (both parental strains with the V beta a phenotype) spontaneously produced immunoglobulin G (IgG) antibodies directed against Sm/U1 small nuclear ribonucleoproteins (snRNPs). In some of these females, the presence of these autoantibodies was found as early as 10 wk of age. Their frequency increased with age i.e., 70% at 40 wk. At that time, only 10% of males developed anti-Sm/U1snRNP antibodies. Anti-Sm/U1snRNP antibodies from positive mice generally recognized the peptides BB', D, 70 kD, and A from RNPs. These polypeptides are known to bear the autoantigenic epitopes that are recognized by human sera containing anti-Sm and anti-U1snRNP antibodies. Reactivity of IgG antibodies with the octapeptide sequence PPPGMRPP was also found in 30% of anti-Sm/U1snRNP positive (SWR x SJL)F1 mice that precipitated BB' peptides. This octapeptide has been described as the most immunoreactive linear epitope in systemic lupus erythematosus (SLE) patients with anti-Sm and anti-U1snRNP antibodies. Approximately 30% of anti-Sn/U1snRNP positive females, later produced anti-dsDNA antibodies. This fact was accompanied by the development of proteinuria due to glomerulonephritis mediated by immunocomplexes. In addition to the specific autoimmune response, (SWR x SJL)F1 females also showed other immunologic abnormalities such as hypergammaglobulinemia, and an approximately twofold increase in spleen cell number compared with control mice. These results indicate that (SWR x SJL)F1 females develop clinical and serological abnormalities similar to those observed in human SLE and constitute a novel model for the study of the genetic mechanisms that result in autoimmunity.

Schwieterman WD. Wood GM. Scott DE. Steinberg AD.
Studies of bone marrow progenitor cells in lupus-prone mice. I.NZB marrow cells demonstrate increased growth in Whitlock-Witte culture & increased splenic colony-forming unit activity in the Thy-1-, lineage- population.
Journal of Immunology. 148(8):2405-10, 1992 Apr 15.
Previous studies have demonstrated that NZB marrow can transfer features of autoimmunity. Therefore, we undertook a study of NZB marrow to determine whether it demonstrated any phenotypic abnormalities. In Whitlock-Witte cultures, NZB marrow cells generated nonadherent cells at low seeding densities, densities at which marrow from other strains did not generate nonadherent cells. In contrast, NZB marrow grew less well than controls in Dexter cultures. Inasmuch as the latter favor growth of granulocyte-macrophage precursors and the former B cells, these results suggest a possible skewing of NZB marrow cells toward lymphocyte production. Unfractionated marrow cells from NZB mice were found to produce 10-fold more splenic colonies in lethally irradiated recipients than marrow cells from control mice. This result was independent of the genotype of the recipient. When the progenitor Thy-1lo, Lin- marrow subpopulation was studied, NZB mice did not differ substantially from controls regarding splenic CFU. Therefore, Thy-1-, Lin- marrow cells were studied as a possible source of the excess splenic CFU in NZB mice. Indeed, the NZB Thy-1-, Lin- population contained 30-fold more splenic CFU than did the Thy-1-, Lin- population from control mice. These results suggest that NZB mice have unusual marrow progenitor cells; such cells may lay a role in their autoimmune disease.

Sauder DN. Wong D. Laskin C.
Epidermal cytokines in murine lupus.
Journal of Investigative Dermatology. 100(1):42S-46S, 1993 Jan.
Murine lupus and the analogous human disease systemic lupus erythematosus (SLE) in humans are characterized by multisystem disease accompanied by the production of numerous serum autoantibodies. The classic model of murine lupus is the New Zealand black mouse (NZB). In this strain anti-DNA antibodies are the most specific marker for the presence of murine lupus, in that this autoantibody parallels both the development and activity of the disease. Exposure to ultraviolet (UV) radiation is known to exacerbate the disease in both the murine and the human disease. UV irradiation of the skin increases serum levels of certain cytokines including interleukin-1 (IL-1), IL-6, and granulocyte/macrophage-colony stimulating factor (GM-CSF), which can influence B- and T-cell function. Recent studies have focused on the role of cytokines in SLE. We hypothesize that the ultraviolet (UV)-induced exacerbation in NZB mice in part is mediated by UV-induced cytokines such as IL-1. Eight-week-old female NZB and DBA/2 mice were exposed to UV irradiation. Sera and supernatants from spleen cell cultures were assayed for anti-DNA antibodies. After UV exposure, NZB mice showed a marked increase in such antibodies. Skin from both strains of mice was probed for IL-1 alpha mRNA before and after UV irradiation. At 24 h, DBA/2 mice had a slight increase in mRNA coding for IL-1 alpha, whereas a much greater increase in skin IL-1 alpha was seen in the NZB skin. This increase in IL-1 mRNA was associated with similar increases in IL-1 bioactivity. These data suggest that the mechanism underlying the UV-induced exacerbation of lupus is mediated in part by the cutaneous production of IL-1

Molad Y. Sidi Y. Gornish M. Lerner M. Pinkhas J. Weinberger A.
Lupus anticoagulant: correlation with magnetic resonance imaging of brain lesions.
Journal of Rheumatology. 19(4):556-61, 1992 Apr.
Brain magnetic resonance imaging (MRI) was performed in 21 patients with systemic lupus erythematosus (SLE) with and without lupus anticoagulant (LAC), one lupus-like patient and 5 patients with primary antiphospholipid antibody syndrome. Thirteen patients had white matter focal brain lesions on MRI, 10 of whom had LAC (p = 0.03). We found no correlation between these lesions and neurologic manifestations, nor any clinical or serologic indices of activity of SLE. Our MRI lesions were similar to those described in multiple sclerosis and may indicate a similar pathologic process.

Yung RL. Johnson KJ. Richardson BC.
New concepts in the pathogenesis of drug-induced lupus. [Review]
Laboratory Investigation. 73(6):746-59, 1995 Dec.
Although the importance of DNA methylation in normal cellular development and hereditary disease states has been appreciated for some time, the role of environmental agents in causing DNA methylation abnormalities and the effects of DNA hypomethylation on T cells have only recently been examined. This review summarizes current knowledge about the role of DNA methylation in regulating T function and gene expression and highlights a novel mechanism causing autoimmunity, in which epigenetic modification of T cell DNA by environmental agents plays an important role in triggering lupus-like diseases. The observations that DNA methylation inhibitors modify gene expression and induce autoreactivity in cloned, Ag-specific CD4+ cells in vitro, that the modified cells cause autoimmunity in vivo, and that similar changes are found in patients with active lupus provide a new approach to understanding how some forms of autoimmunity develop and may lead to new and more effective treatments.

Adams LE. Balakrishnan K. Roberts SM. Belcher R. Mongey AB. Thomas TJ. Hess EV.
Genetic, immunologic and biotransformation studies of patients on procainamide.
Lupus. 2(2):89-98, 1993 Apr.
This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.

Harley JB. Scofield RH. Reichlin M.
Anti-Ro in Sjogren's syndrome and systemic lupus erythematosus. [Review]
Rheumatic Diseases Clinics of North America. 18(2):337-58, 1992 May.
Anti-Ro autoantibodies are frequently found in the sera of patients with Sjogren's syndrome, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus as well as in the sera of mothers of infants with the neonatal lupus syndrome. Close associations have been found between anti-Ro and a number of clinical manifestations, particularly including hematologic cytopenias, heart block, and photosensitive skin rashes. Serologic and genetic associations have been found between anti-Ro and anti-La, rheumatoid factor, hypergammaglobulinemia, the histocompatibility alleles DQ1 and DQ2, and alleles of the T-cell receptor beta chain gene. The origin of anti-Ro and other autoantigens is thought to relate to the etiology of Sjogren's syndrome and systemic lupus erythematosus and remains the most fundamental unanswered question preventing a comprehensive understanding of these diseases.

Elkon KB. Bonfa E. Brot N.
Antiribosomal antibodies in systemic lupus erythematosus. [Review]
Rheumatic Diseases Clinics of North America. 18(2):377-90, 1992 May.
ARA occur in approximately 10% of randomly selected SLE patients but in up to 40% of patients with active disease. Anti-P antibodies appear to be a highly specific diagnostic marker for SLE because they are rarely detected in other multisystem autoimmune disorders. ARA are most frequently directed against the P proteins, and the shared conserved C-terminus of the P proteins is immunodominant in almost all sera tested. Anti-P antibodies increase in titer in patients with active disease and have been reported to be detected more frequently in patients with severe behavioral disturbances. This may be particularly true of patients with affective disorders. The clinical utility of serologic tests for anti-P in central nervous system lupus must await large, prospective studies. Other ARA antibodies have been detected in patients with SLE. These antibodies include anti-28S rRNA, anti-S10, and anti-L12. In all cases, the frequency with which these antibodies are detected is increased in sera containing anti-P. The P proteins and the 28S rRNA epitope play essential, but as yet undefined, roles in GTPase activity on the ribosome. The L12 protein is the mammalian homologue of the E. coli and yeast proteins known to bind to the 28S rRNA epitope. These findings indicate that some SLE patients produce autoantibodies against multiple components of a functionally related domain of the ribosome. This, in turn, supports the notion that the ribosome initiates and/or maintains autoantibody production. Despite these findings, attempts to induce anti-P antibodies by immunization with autologous ribosomes in the autoimmune strain of mouse, MRL, have been unsuccessful. It therefore seems likely that the ribosomal components must be altered to break tolerance or that other abnormalities of the immune system are necessary for autoantibody production.

Gonzalo JA. de Alboran IM. Kroemer G.
Dissociation of autoaggression and self-superantigen reactivity [editorial]. [Review]
Scandinavian Journal of Immunology. 37(1):1-6, 1993 Jan.
Self-superantigens have been described as products of endogenous retroviruses of the mouse ('minor lymphocyte stimulating loci') that are capable of interacting without prior processing with conserved domains of TCR V beta chains, causing the activation and deletion of most T cells expressing products of determined V beta gene families [1-4]. The fact that superantigens activate a far higher percentage of T cells (1-20%) than conventional, peptidic antigens (< 0.1%) provides the methodological advantage that the degree of clonal deletion may be measured by the analysis of the TCR repertoire using appropriate anti-V beta antibodies. Although much information on the spatio-temporal organization of repertoire-purging has been gathered by virtue of self-superantigens, serious doubts exist as to the possibility that such structures serve as pathogenetically relevant autoantigens. Thus, certain inbred mice spontaneously develop autoimmune diseases, although they bear T-cell repertoires that appear to be purged from self-superantigen-reactive V beta products. In addition, therapeutic interventions targeted to V beta gene products that are not specific for self-superantigens are successful in preventing disease development. The lack of correlation between superantigen-related V beta deletions and autoimmune disease development is substantiated in further models of murine autoimmunity. Based on these observations, we formulate the hypothesis that self-superantigen-reactive T cells are not involved in the development of autoimmune diseases.

Yui MA. Brissette WH. Brennan DC. Wuthrich RP. Rubin-Kelley VE.
Increased macrophage colony-stimulating factor in neonatal and adult autoimmune MRL-lpr mice.
American Journal of Pathology. 139(2):255-61, 1991 Aug.
Abnormal macrophages in MRL-lpr mice are implicated in the pathogenesis of autoimmune disease. These mice die of lupus nephritis by 5 to 6 months of age. This study reports that MRL-lpr mice have an increased level of circulating macrophage colony-stimulating factor (M-CSF) detectable as early as 1 week of age. Macrophage colony-stimulating factor decreased between 2 and 4 months and then steadily increased beginning at 4 months of age. In contrast, M-CSF was not detected in sera from congenic MRL-++ mice, normal C3H/FeJ mice, two other mouse strains with the lpr gene (B6-lpr and C3H-lpr), or another lupus model, the NZB/W mouse. These observations indicate that the lpr gene alone is not responsible for inducing this growth factor, and elevated M-CSF is not required for all forms of murine lupus. The entire source of serum M-CSF is not clear. The unique T cells regulated by the lpr gene are not responsible for the increased serum M-CSF levels, as no M-CSFs could be detected in supernatants from cultured lymph nodes from MRL-lpr mice, and the steady-state levels of M-CSF mRNA in lymph nodes and spleens in MRL-lpr, C3H-lpr mice and in their respective congenic strains were similar. The steady-state M-CSF mRNA transcripts in liver, lung, and bone marrow in MRL-lpr, MRL-++, and C3H/FeJ mice were also similar. Macrophage colony-stimulating factor transcripts were clearly elevated in the kidneys of MRL-lpr mice, suggesting a renal source of circulating M-CSF. The increase of M-CSF might be responsible for the increased numbers and enhanced functions of macrophages, which in turn cause tissue destruction in MRL-lpr mice.

Roujeau JC. Andre C. Bertolus S. Lemann M. Touraine R.
[Subacute cutaneous lupus: critical study]. [French] Lupus cutane subaigu: etude critique.
Annales de Medecine Interne. 138(8):592-4, 1987.
Subacute cutaneous lupus erythematosus has been identified as a bioclinical entity associating particular clinical signs (diffuse superficial cutaneous lesions evolving without atrophy or scarring), biological markers (anti-Ro/SSA, HLA A1 B8 DR3) and a good prognosis. We assessed the reality of this entity: 1) all the anti-Ro/SSA sera at H.-Mondor Hospital was examined over a 2 year period; 58 of the 963 sera tested were positive. Thirty one of the 58 positive patients had lupus (53 p. 100), but only 12 (21 p. 100) had subacute cutaneous lupus; 2) a photographic dossier was examined by three dermatologists who classified the photos of 74 patients independently. All three observers agreed on the diagnosis of subacute cutaneous lupus erythematosus in only 32 p. 100 of cases. The 17 patients in whom the diagnosis was retained did not differ clinically from the 23 cases of systemic lupus. Anti-Ro/SSA antibodies were found in 42 p. 100 of cases of subacute cutaneous lupus and in 23 p. 100 of cases of systemic lupus erythematosus (not significant). The results of this double blind study indicate that the reality of subacute cutaneous lupus erythematosus as a separate entity is debatable.

Andjaparidze OG. Chaplygina NM. Bogomolova NN Koptyaeva IB. Nevryaeva EG. Filimonova RG. Tareeva IE.
Detection of measles virus genome in blood leucocytes of patients with certain autoimmune diseases.
Archives of Virology. 105(3-4):287-91, 1989.
RNA isolated from lymphocytes of peripheral blood was dot-hybridized to a hybrid plasmid containing specific sequences for measles virus nucleocapsid protein. Viral RNA was detected in the lymphocytes of 28 of 34 (82%) patients with systemic lupus erythematosus (SLE) and of 40 of 68 (59%) patients with chronic glomerulonephritis (CGN), and was not detected in 29 control patients.

Grosse-Wilde H. Genth E. Grevesmuhl A. Vogeler U. Zarnowski H. Mierau R. Doxiadis G. Doxiadis I. Maas D.
HLA-DR4 and Gm 1;21 haplotypes are associated with pseudolupus induced by venopyronum dragees.
Arthritis & Rheumatism. 30(8):878-83, 1987 Aug. The phenotypic frequencies of human major histocompatibility complex class I, II, and III antigens and immunoglobulin allotypes (Gm factors) were determined in 56 patients (55 women, 1 man) who had lupus-like disease induced by venopyronum dragees. The findings in these patients were compared with those of a control group. We found a significant increase of HLA-DR4 (57.1% versus 26.5%, relative risk [RR] 3.7) and a decrease of HLA-DR3 (3.6% versus 19.1%, RR 0.16) in the patient group. In addition, the haplotype Gm 1;21 (60.7% versus 32.9%, RR 3.2), and the phenotype Gm 1,3;5,21 (46.4% versus 25.8%, RR 2.5) were significantly increased. Both the haplotype Gm 1;21 and the phenotype Gm 1,3;5,21 are associated with HLA-DR4 in pseudolupus patients but not in controls. The coincidence of HLA-DR4 and Gm 1;21 markedly increases the risk of acquiring pseudolupus (RR 6.9). We conclude that the pathogenesis of pseudolupus is influenced by at least 2 independent genetic factors. A similar HLA association has been described in hydralazine-induced lupus, and this suggests a common pathogenic mechanism.

Uetrecht J.
Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions.
Critical Reviews in Toxicology. 20(4):213-35, 1990.
This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABST TRUNCATED 400 WORDS) and not a word too soon, either!

Tucker LB.
Systemic lupus erythematosus, dermatomyositis, scleroderma, vasculopathies, and other connective tissue disorders in children.
Current Opinion in Rheumatology. 3(5):844-53, 1991 Oct.
The diverse disorders discussed in this review share the underlying features of multisystem involvement and vasculitis as a part of their pathophysiology. A review of morbidity seen in childhood-onset systemic lupus erythematosus reveals the need for careful monitoring for complications secondary to treatment and infections. Current understanding of the pathophysiology and risks of developing the neonatal lupus syndrome are reviewed, with the important recognition of the association of specific maternal autoantibodies with affected offspring. A review of current management issues in the treatment of juvenile dermatomyositis is discussed. Kawasaki disease, one of the most common childhood vasculitides, continues to provoke interest in the areas of accurate diagnosis, potential etiologic role of common viruses, management, and late morbidity. Interesting case reports of children with unusual features of the more rarely described disorders of Sjogren's syndrome, scleroderma, and Behcet's syndrome are discussed.

Hess EV.
Drug-related lupus. [Review] Current Opinion in Rheumatology. 3(5):809-14, 1991 Oct.
All physicians should be alerted to the many drugs and other agents that are associated with drug-related lupus, as there is an increasing number of such drugs. A wide range of immune responses and antibodies are being reported with this syndrome. A new concern is the perceived ability of new biologic treatments to induce these autoimmune phenomena. More in-depth studies of various environmental factors are providing new insights into possible mechanisms. These include the immune responses to the drugs, their metabolites, and drug-altered conjugates; bioactivation mechanisms of drug protein conjugation; the role of macrophages in antigen recognition and processing; and lastly, the important role of the acetylation of various drugs and the relationship to immunogenetic factors. Continued study of this human experimental model of lupus will help to clarify the etiology and mechanisms of systemic lupus erythematosus itself.

Adams LE. Hess EV.
Drug-related lupus. Incidence, mechanisms and clinical implications. [Review]
Drug Safety. 6(6):431-49, 1991 Nov-Dec.
Adverse side effects to drugs and chemicals in which immune mechanisms may be responsible have been described in drug-related lupus (DRL). The spectrum of drugs that may elicit DRL includes such classes as the hydrazines, arylamines, and chemicals that can be metabolised to amines. The 2 major pathways of metabolism--acetylation and N-hydroxylation--are described in detail. The events leading to autoantibody production are not well understood; however, specific consideration of the genetic makeup of patients who are candidates for treatment with these drugs may help identify those at risk of developing DRL.

Cornacchia E. Golbus J. Maybaum J. Strahler J. Hanash S. Richardson B.
Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity.
Journal of Immunology. 140(7):2197-200, 1988 Apr 1.
Inhibitors of DNA methylation, such as 5-azacytidine, induce gene expression. We have previously reported that cloned T cells treated with 5-azacytidine lose the requirement for Ag and can be activated by autologous HLA-D molecules alone, thus becoming auto-reactive. This phenomenon could potentially mediate an autoimmune disease in vivo. Inasmuch as several drugs are known to cause autoimmune disease, we asked whether they exert the same effects on T cells as 5-azacytidine. We report that hydralazine and procainamide, two drugs associated with a lupus-like autoimmune disease, also inhibit DNA methylation and induce self-reactivity in cloned T cell lines. These results suggest that drug-induced autoimmune disease may be due to activation of as yet unidentified genes through mechanisms involving DNA methylation.

Furukawa F. Kashihara-Sawami M. Lyons MB. Norris DA.
Binding of antibodies to the extractable nuclear antigens SS-A/Ro and SS-B/La is induced on the surface of human keratinocytes by ultraviolet light (UVL): implications for the pathogenesis of photosensitive cutaneous lupus [see comments].
Comment in: J Invest Dermatol 1991 Sep;97(3):604-5
Journal of Investigative Dermatology. 94(1):77-85, 1990 Jan.
Autoantibodies to the non-histone nucleoprotein antigens SS-A/Ro, SS-B/La, and RNP are highly associated with photosensitive cutaneous lupus erythematosus (LE). In order to better understand the potential mechanisms of ultraviolet (UV) light on photosensitivity in patients with cutaneous LE, we designed immunopathologic in vitro and in vivo experiments to evaluate the effects of UV on the binding of such autoantibodies to the surface of human keratinocytes, one major target of immunologic damage in photosensitive LE. Short-term 2% paraformaldehyde fixation of suspensions of cultured human keratinocytes previously incubated with monospecific antiserum probes enabled the detection of ENA expression on the cell surface by flow-cytometry analysis. UVB light (280-320 nm) induced the binding of monospecific antibody probes for SS-A/Ro and SS-B/La on keratinocytes in a dose-dependent pattern with maximal induction observed at the dose of 200 mJ/cm2 UVB. Binding of SS-A/Ro, SS-B/La, and RNP antibody was augmented strongly, but binding of anti-Sm was very weak. In contrast, UVA (320-400 nm) light had no effect on the induction of binding of these antibody probes. Identical results were seen by standard immunofluorescence techniques. Hydroxyurea-treated keratinocytes showed similar induction of those antigens by UVB irradiation, which suggested that ENA expression on cultured keratinocytes by UVB were cell-cycle independent. Tunicamycin, an inhibitor of glycosylation of proteins, reduced UVB light effect on the SS-A/Ro and SS-B/La antigen's expression. These in vitro FACS analyses revealed that ENA augmentation on the keratinocyte cell surface was dose dependent, UVB dependent, glycosylation dependent, and cell-cycle independent. In vivo ENA augmentation on the keratinocyte surface was examined in suction blister epidermal roofs. Specific antibody probes for SS-A/Ro, SS-B/La, RNP, and Sm bound to human keratinocytes in intact suction blister epidermis following UVL irradiation in vivo. Using three different protocols, we have demonstrated that antibodies to SS-A/Ro, SS-B/La, and U1RNP bind to UVL-irradiated human keratinocytes. We speculate that this antibody binding is an important inducer of antibody dependent keratinocyte damage in photosensitive cutaneous lupus.

Ermak TH. Steger HJ. Wofsy D.
Treatment of murine lupus with monoclonal antibody to L3T4. II. Effects on immunohistopathology of thymus, spleen, and lymph node.
Laboratory Investigation. 61(4):447-56, 1989 Oct.
Monoclonal antibody to L3T4 has been used successfully to suppress autoimmunity in the New Zealand black/New Zealand white F1 (B/W) mouse model for systemic lupus erythematosus. To clarify the immunopathology of murine lupus and determine the effects of anti-L3T4 treatment on the cellular composition and histopathology of lymphoid organs, we examined the distribution of lymphocyte subsets in cryostat sections of the thymus, spleen, and lymph nodes of B/W mice. Immunohistologic specimens were obtained from female B/W mice that had received weekly intraperitoneal injections of either rat monoclonal antibody to L3T4 (2 mg/mouse/week) or phosphate buffered saline (200 microliters/mouse/week) from age 5 months until euthanasia at 8 months. B and T cell domains in each organ were identified on serial sections with monoclonal antibody directed against B220 (all B cells), Thy-1.2 (all T cells), L3T4 (helper T cells), and Ly-2 (cytotoxic/suppressor T cells). In control mice, striking cytoarchitectural abnormalities were identified in the thymuses, and the spleen and lymph nodes were hypertrophied relative to anti-L3T4 treated mice. Thymic abnormalities included amplification of medulla, formation of thymomas, and cortical atrophy. Amplified medullary regions and thymomas in B/W mice contained numerous B cells and L3T4+ T cells but few Ly-2+ T cells. The enlarged spleens and lymph nodes of control mice consisted of numerous secondary follicles with germinal centers containing an unusual subpopulation of T cells that expressed L3T4 but not Thy-1.2. In contrast, mice treated with anti-L3T4 did not develop histopathologic changes characteristic of systemic lupus erythematosus in any organ. However, treatment depleted L3T4+ cells from the spleen and lymph nodes, and it modulated the expression of L3T4 by thymocytes. These observations demonstrate that treatment with anti-L3T4 not only interferes with L3T4-dependent T cell functions, but it also prevents progressive abnormalities in lymphoid tissue in lupus-prone B/W mice. This preservation of normal lymphoid structure may contribute to the beneficial effects of anti-L3T4 on autoimmunity.

Saito K. Tanaka Y. Ota T. Eto S. Yamashita U.
B-B cell interactions in the spontaneous activation of B cells in autoimmune NZB mice.
Microbiology & Immunology. 35(9):741-53, 1991.
We analyzed the mechanism of spontaneous B cell activation in lupus mice by using anticlass-II antibody in vitro. The in vitro culture of B cells from old NZB mice markedly produced Ig without any stimulation, while B cells from NZW mice did not. The addition of anticlass-II antibody (anti-Iad antibody) to the culture inhibited Ig production of NZB B cells in a concentration-dependent manner. On the other hand, the addition of anticlass-I antibody (anti-H-2Dd antibody) and anticlass-II antibody with different specificity (anti-Iak) gave no effect on the Ig production of NZB B cells. When mitomycin C-treated B cells were added to in vitro culture of responder B cells as a stimulator, Ig production of responder B cells was enhanced in a concentration-dependent manner. However, the enhancing effect of the stimulator B cells was abrogated by the pretreatment with anticlass-II antibody. The stimulator B-cell activity to NZB B cells was marked in NZB B cells, moderate in NZB/W F1 B cells, and weak in NZW B cells. Furthermore, the stimulator B-cell activity with regard to NZB B cells was marked in old female NZB B cells, moderate in old male NZB B cells, and weak in young NZB B cells. The expression of class II antigens on the surface of old female NZB B cells was significantly higher than that of old male NZB and young NZB B cells. These results suggest that in lupus mice the spontaneous B-cell activation is induced by an abnormal B-B cell interaction mediated by class II antigens.

The butterfly rash and the malar flush. What diseases do these signs reflect? [see comments].
Comment in: Postgrad Med 1991 Oct;90(5):38, 40 Postgraduate Medicine. 89(1):225-8, 233-4, 1991 Jan.
The butterfly rash and malar flush are common facial manifestations of several disorders. Systemic lupus erythematosus may produce a transient rash before any other signs. In pellagra, symmetric keratotic areas on the face are always accompanied by lesions elsewhere on the body. Erysipelas produces brawny, fiery red facial lesions, and scarlet fever causes facial eruptions as part of a generalized eruption. Lupus vulgaris and lupus pernio produce nodules that may spread in a butterfly pattern, and seborrheic dermatitis has a predilection for the malar prominences and other areas of the face. Carcinoid syndrome often causes flushing attacks that vary in duration, and facial flushing that lasts throughout treatment may accompany chemotherapy if the patient has a hypersensitivity reaction. Deep-red rashes and/or lichenoid lesions may be caused by graft-versus-host disease in a patient undergoing bone marrow transplantation.

Kluger J. Drayer DE. Reidenberg MM. Lahita R.
Acetylprocainamide therapy in patients with previous procainamide-induced lupus syndrome.
Annals of Internal Medicine. 95(1):18-23, 1981 Jul.
Acetylprocainamide was used to treat 11 patients with previous procainamide-induced lupus syndrome for their cardiac arrhythmias. Three patients from whom procainamide had been withdrawn and whose lupus was in remission did not have a recurrence during a course of acetylprocainamide therapy of a longer average duration than their prior procainamide therapy. Lupus symptoms subsided during treatment in two patients who had symptoms when acetylprocainamide was started. Drug fever developed in one patient, and another had a mild recurrence of lupus symptoms during high-dose acetylprocainamide therapy that regressed with dosage reduction. All patients had small amounts of circulating procainamide from in-vivo deacetylation of acetylprocainamide. These observations strongly support the hypothesis that the aromatic amino group on procainamide is important for induction of the lupus syndrome and that acetylating this amino group blocks the lupus-inducing effect.

Gioud M. Kaci MA. Monier JC.
Histone antibodies in systemic lupus erythematosus. A possible diagnostic tool.
Arthritis & Rheumatism. 25(4):407-13, 1982 Apr.
Antibodies to total histones and histone fractions H1, H2a-H4, H2b, and H3 were measured in serum samples from 61 patients with systemic lupus erythematosus (SLE), 33 with rheumatoid arthritis, 17 with systemic sclerosis, and 20 with various other diseases by use of a sensitive immunoenzymatic assay. Histone antibodies were present in 52.4% of the SLE samples whereas only 1 of the samples from other diseases was positive (systemic sclerosis). The presence of these antibodies in SLE patients was not associated with any specific clinical manifestations, but was correlated with activity of the disease: 87% (20 of 23) of patients with active SLE, in particular 9 of 9 not yet treated, showed histone antibody whereas only 18% (4 of 22) of samples from patients with inactive SLE were positive. We believe that the measurement of histone antibodies would be a useful addition to the present laboratory parameters (antinuclear and double-stranded DNA antibodies and circulating immune complexes) for the diagnosis and progression of systemic lupus erythematosus, particularly since they seem to appear during or just before the onset of an activy phase and tend to be absent during remission.

Knight JG. Adams DD.
Genes determining autoimmune disease in New Zealand mice.
Journal of Clinical & Laboratory Immunology. 5(3):165-70, 1981 May.
The genetic basis of autoimmune haemolytic anaemia in NZB mice has been investigated using crosses and backcrosses with the NZC strain. These mating combinations reveal two dominant or co-dominant genes governing occurrence of the disorder. One of these, Aia-2, is common to both the NZB and the NZC strains. The other gene, Aia-1, is peculiar to the NZB strain and is linked to the b (black/brown) coat colour locus on chromosome 4. The cross-over value of 37+/-4% places this gene in the neighbourhood of the minor histocompatibility locus H-18, provided it is on the same side of the b locus. Previously, we have obtained evidence that the lupus nephritis of the (NZB X NZW)F(1) mice is determined by three dominant or co-dominant genes, Lpn-1, Lpn-2 and Lpn-3. Lpn-2 appears to be tightly linked to the H-2 complex, Lpn-1 has a cross-over frequency of 33+/-3% with H-2 placing it in the neighbourhood of a hybrid histocompatibility (Hh) locus on chromosome 17, and Lpn-3 is on a separate, unknown chromosome. In this paper we present data from an out-cross study between (NZW X NZC)F(1) and NZB mice, which indicate that Lpn-3 is not linked to Igh-C and is therefore not an immunoglobulin heavy chain V gene. Whilst it remains possible that Lpn-3 is a kappa or lambda light chain V gene and that Aia-2 is a V gene, Lpn-1 and Aia-1 are clearly not H or kappa V genes, nor are they in the major histocompatibility gene complex. Their apparent association with the Hh and H-18 loci suggests that they may be genes coding for minor histocompatibility loci. Such genes could influence immune response repertoire, and hence genetic predisposition to autoimmune disease, through the clonal deletion and paratope-idiotope network reactions which we have postulated to be the mechanisms mediating the effect of the major histocompatibility antigen genes.

Alarcon-Segovia D.
Drug-induced antinuclear antibodies and lupus syndromes. [Review]
Drugs. 12(1):69-77, 1976.
Drugs capable of triggering the onset of systemic lupus erythematosus may be divided into those that do so by pharmacological properties of their own and those that do so by eliciting allergic reactions which bring about lupus. Drugs in the first group vary in their potency to activate lupus. They all elicit antinuclear antibodies in the majority of patients who receive them but they only cause lupus in a small percentage of patients. This dichotomy suggests that a predisposition is required for the development of lupus upon intake of these drugs. The mechanism whereby these drugs elicit antinuclear antibodies seems to relate to coupling to and/or modification of, nuclear antigens. The patterns of antinuclear antibodies elicited by these drugs in individuals who receive them correlate well with their known reactivity with various nuclear antigens.

Leslie RD. Hawa M.
Twin studies in auto-immune disease. [Review]
Acta Genet Med Gemellol (Roma). 43(1-2):71-81, 1994.
Immune-mediated diseases affect up to 5% of the population and are a major cause of morbidity and mortality. These diseases can be organ specific, such as insulin-dependent diabetes (IDDM) and non-organ specific, such as Rheumatoid Arthritis (RA). Identical and non-identical twins have been used to establish whether these diseases are determined by genetic or environmental factors. The results of these studies have been collated in a new section of the Mendel Institute in Rome. Diseases included in these studies included IDDM, RA, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and Myasthenia. Striking differences in concordance rates between identical and non-identical twins in all these studies suggest that genetic factors are important in causing these diseases. All the diseases are known to be associated with HLA genes on chromosome 6 which may account for some or all of the genetic susceptibility. However, in the majority of pairs the affected twin has an unaffected co-twin. These observations suggest that non-genetically determined factors, probably environmental factors and not somatic mutations, are critical. The study of unaffected co-twins, who are at high disease-risk, has allowed the identification of changes which precede and predict the clinical disease. The immune-mediated destruction in many of these diseases is probably caused by T-lymphocytes. Twin studies have shown the importance of genetic factors in determining T-cell responses. Identical twins should, therefore, provide the perfect test bed to assess the role of T-cells in immune-mediated diseases.

Ilan Y. Naparstek Y.
Pure red cell aplasia associated with systemic lupus erythematosus: remission after a single course of intravenous immunoglobulin.
Acta Haematol. 89(3):152-4, 1993.
Pure red cell aplasia is characterized by severe anemia, with reticulocytopenia and absence of precursor cells in the bone marrow. Many modes of treatment have been described, including the use of immunosuppressive agents. Recently repeated courses of high-dose intravenous immunoglobulins have been used successfully in patients with idiopathic pure red cell aplasia. We here describe a 22-year-old woman who developed pure red cell aplasia in the course of systemic lupus erythematosus. After failure of corticosteroid therapy the patient was treated with one course of high-dose intravenous immunoglobulins with complete remission. No further therapy was required.

Rasmussen HB. Perron H. Clausen J.
Do endogenous retroviruses have etiological implications in inflammatory and degenerative nervous system diseases?.
Acta Neurol Scand. 88(3):190-8, 1993 Sep.
Vertebrates carry large numbers of endogenous retroviruses (ERVs) and related sequences in their genomes. These retroviral elements are inherited as Mendelian traits. Generally, ERVs are defective without the ability of being expressed as viral particles. However, ERV sequences often have a potential for expression of at least some proteins. So far, the possible biological significance of ERVs is not clear. Nonetheless, there are observations suggesting a connection between ERVs and various diseases. This is the case with murine lupus and a spinal cord disease of certain mouse strains. In the present review, we discuss possible mechanisms by which ERVs could contribute to the development of human degenerative and inflammatory nervous system diseases, including direct effects on nervous system cells and immune cells. Interactions between ERVs and infectious viruses are also discussed. Finally, we review a possible retroviral etiology of multiple sclerosis.

Kinnunen E. Jarvinen P. Ketonen L. Sepponen R.
Co-twin control study on cerebral manifestations of systemic lupus erythematosus.
Acta Neurol Scand. 88(6):422-6, 1993 Dec.
All available twin pairs systemic lupus erythematosus (SLE) derived from the Finnish Twin Cohort were studied by clinical evaluation, magnetic resonance imaging (MRI), anticardiolipin (aCL), and antineurofilament (ANFA) antibodies. One of the five monozygotic and one of the eight dizygotic pairs were concordant for SLE. 10 of the 15 patients showed clinical neurological abnormalities, and 11 had abnormal MRI of the brain. Altogether, 12 patients were considered to have neuropsychiatric lupus (NPSLE). Seven of the 11 patients with long-term corticosteroid treatment had either central or cortical atrophy. High or moderate aCL level was found in eight patients and two co-twins. Of them, six patients had at least two manifestations of the antiphospholipid syndrome. ANFAs were found in five patients and four co-twins. Five co-twins fulfilled some of the SLE criteria. Of them, three MZ twins and one additional DZ co-twin with no ARA criteria had findings suggesting central nervous system (CNS) involvement. The results indicate that the majority of SLE patients has cerebral abnormalities either as a result of SLE, or concomitant risk factors. The co-twins without clinical SLE often have minor signs of SLE, and even they may have neurological and MRI abnormalities. However, their aCL and ANFA levels seem not to correlate with MRI abnormalities.

Cucurull E. Gharavi AE. Diri E. Mendez E. Kapoor D. Espinoza LR.
Department of Medicine, Louisiana State University Medical Center, New Orleans 70112-2822, USA.
IgA anticardiolipin and anti-beta2-glycoprotein I are the most prevalent isotypes in African American patients with systemic lupus erythematosus.
American Journal of the Medical Sciences. 318(1):55-60, 1999 Jul.
BACKGROUND: Ethnicity plays a role in the prevalence, isotype distribution, and clinical significance of anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies in patients with systemic lupus erythematosus (SLE). Few studies have been done in the African American population. METHODS: Serum samples from 100 African American patients with SLE were tested for IgG, IgM, and IgA aCL and anti-beta2-GPI antibodies by enzyme-linked immunosorbent assay (ELISA). Computerized clinical data on these patients were reviewed with a specific focus on clinical manifestations of antiphospholipid syndrome (APS). RESULTS: Positivity for at least one isotype of aCL antibodies was found in 33% of the patients, whereas 28% were positive for at least one isotype of anti-beta2-GPI antibodies. IgA was the most prevalent isotype for both antibodies; 24% of the patients in the aCL ELISA and 19% in the anti-beta2-GPI ELISA were positive for IgA. Positivity for both aCL and anti-beta2-GPI in the same patient was seen more frequently with the IgA isotype. Fewer than half of the patients positive for aCL antibodies had medium-to-high levels of antibodies. A few patients had presented thrombotic manifestations, and these patients were positive for aCL (P = 0.01) and anti-beta2-GPI antibodies (P = 0.02). No other manifestations of APS could be significantly correlated with the presence of these antibodies. CONCLUSIONS: Our results show that IgA is the most prevalent isotype among the African American patients with SLE studied. The predominance of the IgA isotype and the low prevalence of medium-to-high levels of aCL antibodies may account for the low frequency of clinical manifestations of APS in these patients.

Dorner T. Farner NL. Lipsky PE.
Department of Internal Medicine, The Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235
Ig lambda and heavy chain gene usage in early untreated systemic lupus erythematosus suggests intensive B cell stimulation.
Journal of Immunology. 163(2):1027-36, 1999 Jul 15.
To determine the distribution of Vlambda and Jlambda as well as VH and JH gene usage in a patient with systemic lupus erythematosus (SLE), productive and nonproductive VJ and V(D)J rearrangements were amplified from individual peripheral CD19+ B cells and were analyzed. No differences in the Vlambda and Jlambda or the VH and JH gene usage in the nonproductive gene repertoire of this SLE patient were found compared with the distribution of genes found in normal adults, whereas marked skewing of both Vlambda and VH was noted among the productive rearrangements. The distribution of productive Vlambda rearrangements was skewed, with significantly greater representation of the Jlambda distal cluster C Vlambda genes and the Vlambda distal Jlambda7 element, consistent with the possibility that there was receptor editing of the Vlambda locus in this patient. Significant bias in VH gene usage was also noted with VH3 family members dominating the peripheral B cell repertoire of the SLE patient (83%) compared with that found in normal subjects (55%; p < 0.001). Notably, a clone of B cells employing the VH3-11 gene for the heavy chain and the Vlambda1G segment for the light chain was detected. These data are most consistent with the conclusion that extreme B cell overactivity drives the initial stages of SLE leading to remarkable changes in the peripheral V gene usage that may underlie on fail to prevent the emergence of autoimmunity.

Frank MB.
Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, 73104, USA. frank@omrf.ouhsc.edu
Characterization of DNA binding properties and sequence specificity of the human 52 kDa Ro/SS-A (Ro52) zinc finger protein.
Biochemical & Biophysical Research Communications. 259(3):665-70, 1999
The Ro52 protein is an autoantigen in Sjogren's Syndrome and systemic lupus erythematosus. Although its function is not yet known, sequence similarities to other proteins suggest that it binds to DNA. In this study, the hypothesis that Ro52 recognizes particular nucleic acid sequences was tested. Ro52 bound to double stranded but not single stranded DNA. 1,10-Phenanthroline, a chelater of zinc, was found to inhibit this interaction, suggesting that the zinc fingers of Ro52 are functional. DNA sequences were selected from an oligonucleotide library by binding to Ro52 followed by amplification by Taq DNA polymerase in order to characterize the DNA sequence-binding motif for this protein. These studies support the hypothesis that Ro52 is functionally a member of a family of zinc finger proteins, many of which are known to bind to DNA or regulate gene expression. We speculate that Ro52 functions as a transcription factor, and that its disregulation may have important consequences in the expression or susceptibility of certain autoimmune diseases.

Jouanne C. Avrameas S. Payelle-Brogard B.
Unite d'Immunocytochimie, CNRS URA 1961, Departement d'Immunologie, Institut Pasteur, Paris, France.
A peptide derived from a polyreactive monoclonal anti-DNA natural antibody can modulate lupus development in (NZBxNZW)F1 mice.
Immunology. 96(3):333-9, 1999 Mar.
In lupus-prone (NZBxNZW)F1 (B/W) mice, elevated levels of polyreactive autoantibodies bearing the D23 idiotype (Id), characteristic of natural antibodies, were detected before and after the appearance of pathological anti-DNA antibodies. While these D23 Id+ antibodies were able to regulate anti-DNA antibodies in the early stage of the disease, we found that during disease evolution they had lost their normal ability to regulate anti-DNA antibodies and furthermore could participate in the lupus-like syndrome. To explore further the role of the D23 Id+ antibodies, we injected young B/W mice with a peptide corresponding to the VH CDR3 region of the D23 monoclonal natural antibody (mNAb). High levels of monospecific antipeptide, as well as polyreactive antibodies, were induced. Among them, the most markedly enhanced antibody population was DNA-reactive immunoglobulin G1 (IgG1). Compared with controls, these immunized mice had a delayed 50% survival rate and proteinuria developed later. Furthermore, IgG1 able to react with IgG2a anti-DNA monoclonal antibodies derived from IgG1 able to react with IgG2a anti-DNA monoclonal antibodies derived from B/W mice were also produced after peptide immunization. Thus, a peptide corresponding to the CDR3 of the D23 mNAb antibody might play a role in the regulation of murine lupus.

Trapani S. Ermini M. Falcini F.
Department of Pediatrics, University of Florence, Italy.
Human parvovirus B19 infection: its relationship with systemic lupus erythematosus. [Review]
Seminars in Arthritis & Rheumatism. 28(5):319-25, 1999 Apr.
OBJECTIVES: The clinical presentation and outcome of four cases of human parvovirus-B19 (HPV-B19) infection, initially diagnosed as systemic lupus erythematosus (SLE), were reviewed and compared with similar cases previously reported in the literature. The relationship between HPV-B19 infection and SLE is discussed. METHODS: The medical records of four patients with documented HPV-B19 infection, initially diagnosed as SLE, were reviewed and studied in detail. A Medline search from 1985 to 1997 was performed to identify other cases reported in the literature in which a relationship between HPV-B19 and SLE had been identified in both adults and children. RESULTS: In all of our cases, the clinical findings (fever, rash, arthritis and malaise) and hematologic data (leukopenia, thrombocytopenia, anemia, presence of autoantibodies, hypocomplementemia, etc.) had initially suggested a diagnosis of juvenile SLE. Subsequently, evidence of HPV-B19 infection at the time of clinical presentation was ascertained. In three of these cases, the disease course was self-limiting with complete clinical remission and normalization of hematologic abnormalities within 18 months; one case, however, had persistent disease activity and repeated exacerbations. CONCLUSIONS: The occurrence of HPV-B19 infection has been documented in patients with SLE, in particular in relation to disease onset. Similarities in clinical and immunological features of viral infections and SLE at presentation may hinder the differential diagnosis between these two conditions. The family history, a self-limiting disease course and certain disease specific clinical aspects may help the pediatrician formulate an accurate diagnosis. In our patients, HPV-B19 infection may have mimicked the onset of SLE in three cases, but triggered the disease in one. [References: 27]

Radic MZ. Cocca BA. Seal SN.
Department of Microbiology and Immunology, MCP Hahnemann University, Philadelphia, PA
Initiation of systemic autoimmunity and sequence specific anti-DNA autoantibodies. [Review]
Critical Reviews in Immunology. 19(2):117-26, 1999.
Antibodies to double-stranded DNA (dsDNA) are a defining feature of Systemic Lupus Erythematosus (SLE). The molecular characterization of anti-dsDNA autoantibodies reveals that they are actively selected for binding to antigen. Evidence for antigen selection includes the use of suitable rearrangement products, the switching of IgM isotype to IgG, and the acquisition of somatic mutations that raise the affinity for dsDNA. Through a process of specificity maturation, anti-dsDNA antibodies can arise from anti-single stranded DNA (ssDNA) antibodies that also occur in nonautoimmune individuals. To clarify circumstances leading to the initiation of systemic autoimmunity, we compare features of immune responses to nucleic acids that operate before and after disease develops. Evidence indicating that anti-dsDNA antibodies bind with DNA sequence preference is highlighted to propose that sequence-specific anti-dsDNA antibodies may be induced by an infectious agent and in turn may extend the response to endogenous nuclear antigens. Thus, sequence-specific anti-dsDNA B cells may provide an important stimulus to break the tolerance to self. [References: 76]

Kowal C. Weinstein A. Diamond B.
Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus.
European Journal of Immunology. 29(6):1901-11, 1999 Jun.
The importance of microbial infection as a trigger for the induction of systemic lupus erythematosus is frequently debated. Clinical observations indicate that anti-viral and antibacterial responses are often accompanied by self reactivity, and anti-pneumococcal antibodies elicited in non-autoimmune individuals by pneumococcal vaccine express lupus-associated anti-DNA idiotypes. To explore the relationship between protective and pathogenic antibodies in humans, we have used the phage display immunoglobulin expression system to generate a combinatorial library from spleen cells of a lupus patient immunized with a polyvalent pneumococcal polysaccharide vaccine prior to splenectomy. From this library, monovalent antigen-binding fragments expressing the 3I Vkappa1-associated idiotype were isolated. This idiotype is expressed on up to 90% of anti-DNA antibodies in the serum of lupus patients and on anti-pneumococcal antibodies in the serum of non-autoimmune individuals. Eight 3I+ monovalent antigen-binding fragments reacting with pneumococcal polysaccharide, DNA or both were analyzed. Four of these fragments were cross-reactive with both foreign and self antigen, demonstrating that a high percentage of anti-bacterial antibodies produced in a patient with lupus bind double-stranded DNA. These studies provide support at the molecular level for a potential role of molecular mimicry in the generation of anti-DNA antibodies. In addition, this is, to our knowledge, the first panel of fully sequenced human anti-pneumococcal antibodies.

Theofilopoulos AN. Kono DH.
Immunology Department, The Scripps Research Institute, La Jolla, CA, USA.
The genes of systemic autoimmunity. [Review] [97 refs]
Proceedings of the Association of American Physicians. 111(3):228-40, 1999 May-Jun.
Autoimmune diseases include a wide spectrum of disorders, which have been divided into systemic and organ-specific disorders. Lupus, the prototypic systemic autoimmune disease, is characterized by female predominance, multiorgan pathology, and autoantibodies, primarily directed against nuclear antigens. The disease is heterogeneous, with variable organ involvement, serology, and clinical course. Susceptibility to lupus is inherited as a polygenic trait with added contributions from environmental and stochastic variance. Concerted efforts have recently been made by several laboratories to define the genetic basis of this disease in predisposed mice and humans. The identification of the Fas/FasL defects in lpr and gld lupus mice was the first example of spontaneous mutations of apoptosis-promoting genes being associated with systemic autoimmunity. This research was instrumental in clarifying the roles of these genes in tolerance and immunoregulation, and in extrapolating these results to other autoimmune diseases, as well as cancer and transplantation. To these findings have been added those from transgenic and gene knockout mouse studies that have helped to define the systemic autoimmunity-inducing or -modifying effects of specific genes in normal background and lupus-congenic mice. In addition, the findings from genome-wide searches have begun to identify predisposing loci (and ultimately genes) for the spontaneous lupus-like diseases in various mouse strains and in humans. The emerging picture is that multiple genetic contributions can independently lead to systemic autoimmunity in mice, which reinforces the view that human lupus may be similarly composed of diverse genotypes. This complexity underscores the importance of defining the predisposing alleles and mechanisms of action, an undertaking that is certainly feasible given current technologies and future advances in the definition of mammalian genomes. [References: 97]

Maeda N. Sekigawa I. Iida N. Matsumoto M. Hashimoto H. Hirose S.
Relationship between CD4+/CD8+ T cell ratio and T cell activation in systemic lupus erythematosus.
Scandinavian Journal of Rheumatology. 28(3):166-70, 1999.
We investigated the relationship between the ratio of CD4+ to CD8+ T cells (CD4/CD8 ratio) and T cell activation, indicated by human leukocyte antigen (HLA)-DR expression, in patients with systemic lupus erythematosus (SLE). We found that the ratio was decreased in SLE patients and that this was significantly related to expression of HLA-DR by CD8+ (but not CD4+) T cells. These findings may assist in understanding the pathogenesis of SLE. In some SLE patients, the CD4/CD8 ratio and HLA-DR expression may be good indicators of therapeutic efficacy.

Shinde S. Gee R. Santulli-Marotto S. Bockenstedt LK. Clarke SH.& Mamula MJ.
Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA.
T cell autoimmunity in Ig transgenic mice.
Journal of Immunology.162(12):7519-24, 1999 Jun 15
Autoantibodies directed at a diverse group of proteins of the U1/Sm ribonucleoprotein (snRNP) are characteristic of systemic lupus erythematosus and are found in the MRL murine model of this disease. This study examines the role of transgenic B lymphocytes in the regulation of autoreactive T cells to the snRNP autoantigen. Transgenic mice were developed bearing an Ig heavy chain gene specific for the D protein component of murine snRNP. B lymphocytes in these mice are neither deleted nor anergic and are of an immature (heat-stable Aghigh) phenotype. T lymphocytes from anti-snRNP transgenic mice were examined using a recombinant form of the D protein of the murine snRNP complex. Our results revealed that transgenic anti-snRNP B cell APCs stimulated CD4 T cells from wild-type C57BL/6 and MRL lpr/lpr mice, while nonspecific APCs failed to stimulate CD4 T cells. This study demonstrates that autoreactive T cells are not deleted from wild-type mice, although their activation is facilitated by autoantigen-specific APCs. The snRNP-reactive T cells in C57BL/6 transgenic mice are tolerized, in contrast to those T cells from MRL lpr/lpr transgenic mice. These studies implicate a role for autoreactive B lymphocytes in the in vivo activation and/or diversification of autoreactive T cells.

Seery JP. Wang EC. Cattell V. Carroll JM. Owen MJ. Watt FM.
Keratinocyte Lymphocyte Molecular Biology Laboratory, Imperial Cancer Research, London, UK
A central role for alpha beta T cells in the pathogenesis of murine lupus.
J. Immunology. 162(12):7241-8, 1999 Jun 15.
We have previously shown that female transgenic mice expressing IFN-gamma in the epidermis, under the control of the involucrin promoter, develop inflammatory skin disease and a form of murine lupus. To investigate the pathogenesis of this syndrome, we generated female IFN-gamma transgenic mice congenitally deficient in either alpha beta or gamma delta T cells.TCR delta-/- transgenics continued to produce antinuclear autoantibodies and to develop severe kidney lesions. In contrast, TCR beta-/- IFN-gamma transgenic mice failed to produce antinucleosome, anti-dsDNA, or antihistone autoantibodies, and kidney disease was abolished. Both alpha beta- and gamma delta-deficient transgenics continued to develop IFN-gamma-associated skin disease, lymphadenopathy, and splenomegaly. The data show that the autoantibody-mediated pathology of murine lupus in IFN-gamma transgenic mice is completely alpha beta T cell dependent and that gamma delta T cells cannot drive autoantibody production. These results imply that production of antinuclear autoantibodies in IFN-gamma transgenic animals is Ag driven, and we identified clusters of apoptotic cells in the epidermis of the mice as a possible source of self Ags. Our findings emphasize the relevance of this murine lupus model to the human disease.

Steinberg AD. Huston DP. Taurog JD. Cowdery JS. Ravechee ES.
The cellular and genetic basis of murine lupus. [Review] Immunological Reviews. 55:121-54, 1981.