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Anticardiolipin antibodies (aCL) are found in about 40-50% of patients suffering from systemic lupus erythematosus (SLE) and their presence carries an increased risk of thromboembolism. Since there is a high prevalence of nailfold capillary abnormalities in patients with SLE, we studied the relationship between aCL and skin microcirculatory changes or vascular symptoms in 51 consecutive patients with SLE (49 women, 2 men, 34.8 ± 13.7 years). Twenty-two patients (43.1 %) had positive aCL (IgG 22 (5-60) GPL; IgM 5 (3-16.5) MPL; median titre and range) and 12 (54.5%) of them had abnormal capilloscopic findings. By contrast, among the 29 patients without aCL, only six (20.7%) had an abnormal capillaroscopy (P = 0.027). There was no correlation between either aCL or capillaroscopy and Raynaud's phenomenon. These results show a relationship between aCL and nailfold capillary changes in patients with SLE, suggesting a direct damage of the vascular endothelium by aCL.

Mechanisms of genetic control of murine systemic lupus erythematosus.- The role of cytokines in the immunopathogenesis of lupus.- The cytokine network in the pathogenesis of systemic lupus erythematosus and possible therapeutic implications.- Antibodies to CD45 and other cell membrane antigens in systemic lupus erythematosus.- Antigenic specificities of "antiphospholipid" autoantibodies.- Antiphospholipid antibodies and the antiphospholipid syndrome.- Lupus pregnancies and neonatal lupus.- Systemic lupus erythematosus in children.- Systemic lupus erythematosus - disease management.- Drug combination therapy of systemic lupus erythematosus.- Central nervous system involvement in systemic lupus erythematosus: a new therapeutic approach with intrathecal dexamethasone and methotrexate.- Extracorporeal photochemotherapy for the treatment of lupus erythematosus: preliminary observations.- Immunological intervention reveals reciprocal roles for tumor necrosis factor-? and interleukin-10 in rheumatoid arthritis and systemic lupus erythematosus.- Prognosis in systemic lupus erythematosus.

A dynamic estimation of the involvement of the complement system in various diseases was obtained by the direct quantitation of breakdown products of C3 and of properdin factor B. The methods used were based, first on the separation of native and fragmented molecules according to their molecular size through a precipitation with polyethylene glycol and, secondly, on an immunochemical quantitation, using specific antisera for the major antigens of C3 and factor B. The sensitivity and the specificity of these methods were demonstrated by activation of complement in vitro with generation of C3 and factor B fragments. A clinical investigation was carried out in 41 patients with systemic lupus erythematosus (SLE), 31 with membranoproliferative glomerulonephritis (MPGN), 26 with other types of glomerulonephritis, and 6 with severe alcoholic cirrhosis of the liver. The following observations were made: (a) an elevated plasma level of C3d fragment of C3 was found in 68% of SLE patients, in 87% of MPGN patients, in 62% of patients with other hypocomplementemic nephritis, and in 15% of those with normocomplementemic nephritis, but in only 33% of patients with liver cirrhosis and very low levels of C3; (b) a significant difference was observed between the levels of C3 obtained with either anti-"native" C3 or anti-C3c sera for immunochemical quantitation, in patients with SLE or MPGN, indicating the presence of "altered" or fragmented C3 in plasma; (c) an elevated plasma level of Ba fragment of properdin factor B was found in 46% of SLE patients, in 67% of MPGN patients, in 50% of patients with other hypocomplementemic nephritis, and in 9% of patients with normocomplementemic nephritis, while the level of properdin factor B was only slightly decreased in these diseases; (d) in SLE and MPGN there was an inverse correlation between the levels of C3d and Ba and the level of C3 in plasma. The level of these fragments was directly correlated with the clinical manifestations of SLE; (e) some patients with a normal C3 level exhibited an elevated plasma concentration of C3 and factor B fragments, suggesting the coexistence of an increased synthesis with a hypercatabolism of complement components. Therefore, the quantitation of complement breakdown products by simple immunochemical methods provides additional information concerning the involvement of complement in disease and new features for the evaluation of the intensity of immune reactions during immune complex diseases.

A sensitive and reproducible procedure for the detection of soluble immune complexes in sera from patients with various immunopathological disorders is reported. Radiolabeled C1q is reacted with sera containing immune complexes. Separation of free from complex bound [(125)I]C1q is achieved by selective precipitation with polyethylene glycol (PEG). The method is based on both the large molecular size and the C1q-binding property characterizing immune complexes. The minimal amount of aggregated immunoglobulins thus detected is about 10 mug and that of soluble human IgG-anti-IgG complexes is about 3 mug of complexed antibody. Some immune complexes formed in large antigen excess (Ag(2)Ab) can still be detected by this radiolabeled C1q binding assay. The specificity of the radiolabeled C1q binding test was documented by the inability of antigen-F(ab')(2) antibody complexes to lead to a precipitation of [(125)I]C1q in PEG. In a second step, this radiolabeled C1q binding assay was applied to an experimental model of immune complex disease and was shown to be efficient for the detection of in vivo formed immune complexes.Finally, the technique could be applied to the study of sera from patients with systemic lupus erythematosus (SLE) or to carriers of the hepatitis B antigen (HB-Ag). Significantly increased [(125)I]-C1q binding values were observed in 52 sera from SLE patients when compared to values obtained with healthy blood donors (P

By far the largest proportion of side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs) belong to the category of so-called PAR (pseudo-allergic reactions). The sensitising potential of a drug is probably connected with its protein-binding capacity. The strongly protein-binding compounds are particularly liable to produce serious immunological complications. The clinical picture depends on the type of immune reaction as well as its location within the organism. Cellular immunity usually leads to skin reactions. However, it is possible that some of the haematological side effects may be caused by T lymphocytes reacting specifically with haemopoietic cells to which a drug adheres. Antibody-mediated immune reactions are more common. Currently we can distinguish five different mechanisms. IgE-mediated drug reactions usually lead to eosinophilia, sometimes with eosinophilic infiltrates in the lung. In such cases, patients frequently develop urticarial rashes. In a number of drug-induced cytopenias the underlying mechanism derives from the action of soluble immune complexes on red cells, leucocytes or platelets as in the case of type I agranulocytosis. IgG and/or IgM may be implicated in the formation of the immune complexes. In this system, blood cells are affected when incubated with the serum from an allergic subject which has previously been incubated with the offending drug or one of its metabolites. Some drugs or drug metabolites have a strong affinity for certain blood cells to which they become attached. If a patient develops antibodies to these drugs, an antibody interaction with the drug-coated cells can lead to the destruction of the cells. This mechanism may be operative not only in the periphery, but also within the bone marrow. On serological testing, preincubation of the serum with the offending drug will inhibit the reaction of the antibody to drug-coated cells. This mechanism may coexist with the immune complex type of blood cell damage. It now appears that patients may develop antibodies whose specificity depends on a drug as well as on a component of the blood cell membrane. The haematological specificity of the immune reaction would then be explained by the autoantigenic constituent of the drug-autoantigen complex. This mechanism has been demonstrated with regard to blood group specificities of certain drug reactions in the case of red cells. In the case of quinidine and quinine thrombocytopenia, the antiplatelet activity has been shown to be connected with the presence of the glycoprotein GP1b which acts as a receptor for platelet factor VIII.(ABSTRACT TRUNCATED AT 400 WORDS)

After injection of lipopolysaccharides (LPS) in mice, there is first a release of DNA into plasma and secondly an induction of anti-DNA antibodies. The circulating DNA was purified from plasma and physico-immunochemically characterized. This DNA has a similar density to mammalian cellular DNA,is 4--6S insize, and probably represents a mixture of single-stranded DNA (SSDNA) and double-stranded DNA (DSDNA) or DSDNA with some single-stranded regions. This purified DNA was shown to react with anti-DNA antibodies which appeared as early as 3 days after a single injection of LPS in mice. In serum, DNA-anti-DNA complexes were not detected, although unidentified circulating immune complex-like material was demonstrated 5-8 days after the injection of LPS. In tissues, particularly in renal glomeruli, fine granular immune complex-type immunoglobulin deposits appeared along the glomerular capillary walls and in the mesangium 3 days after the injection of LPS. There is a direct correlation between the level of anti-DNA antibodies and the intensity of glomerular deposits and about 40% of immunoglobulins eluted from kidneys are anti-DNA antibodies, indicating that some of the immune complexes localized in kidneys are DNA-anti-DNA complexes. Based on these observations, the following hypothetical mechanism for the glomerular localization of DNA-anti-DNA complexes after the injection of LPS in mice is proposed. First, DNA, which has been released in circulating blood after injection of LPS, might bind to renal glomeruli, probably on glomerular basement membranes (GBM) through a high affinity of GBM for DNA; secondly, circulating anti-DNA antibodies, which appear later, might react with the glomerular-bound DNA and form immune complexes independently of circulating immune complexes. However, the possibility of direct deposition of immune complexes is not ruled out.

The present data demonstrate the induction of antisingle-stranded (SS) DNA and antidouble-stranded DNA antibodies in various strains of mice, including athymic C57BL/6 nude mice, after the injection of bacterial lipopolysaccharide (LPS). This anti-DNA response is dose dependent and varies quantitatively according to the strain of the injected mice. It is not correlated to the H-2 histocompatibility locus nor to the immune response to LPS. The lipid A fraction appears to be the active part of the LPS molecule for this particular effect. In addition, it was found that DNA is released in circulating blood a few hours after the injection of LPS. Most of the DNA released has physicochemical and immunochemical characteristics of SS DNA. Therefore, the anti-DNA response induced by injections of LPS may be the result of a release of DNA in a particularly immunogenic form at a time when the immune system, in particular the B lymphocytes, is rendered capable by LPS of developing an immune response to such a soluble antigen. These effects of LPS may account for the triggering or the exacerbation of ante-DNA antibodies during infections with gram-negative bacteria, and a similar mechanism may be involved in the pathogenesis of systemic lupus erythematosus.

Today's concept of the pathogenesis of RA permits the establishment of rational treatment regimens, the goal of which is to prevent irreparable tissue damage by an early and rapid induction of remission. Awareness of a genetic predisposition to the disease permits the clinician and patient to be realistic about the risk of relapse and the need for maintenance therapy in severe cases.

Quantitative determination of the small C3 breakdown product, C3d, was used to investigate complement activation in 45 plasma samples from 30 patients with rheumatoid arthritis (RA). The mean plasma C3e level in these samples (3.0 +/- 1.3 mg/100 ml) was significantly increased (P less than 0.001) as compared to patients with degenerative joint disease (0.9 +/- 0.4 mg/100 ml) and healthy blood donors (0.8 +/- 0.5 mg/100 ml). C3d levels were increased by more than s SD in 79% of RA samples. Plasma C3d levels were compared with C3d concentrations in synovial fluid. In most RA patients, the C3d levels were higher in synovial fluid than in plasma. A very significant correlation between plasma C3d levels and circulating immune complexes, as measured by determination of Clq binding activity (Clq BA), was observed (P less than 0.001). C3d levels were more elevated in RA patients with extra-articular disease manifestations (3.8 +/- 1.2 mg/100 ml) as compared to patients with joint disease alone (2.2 +/- 1.0 mg/100 ml). C3d levels and Clq BA were also significantly correlated (P less than 0.001) with the RA disease activity expressed by an index derived from sedimentation rate, joint score, and duration of morning stiffness. A close relationship between C3d levels, Clq BA, and the clinical activity further appeared during follow-up studies. The present observations suggest that a parallel but rather independent activation of the complement system may be induced by immune complexes in circulating blood and in the joint spaces during the course of rheumatoid arthritis.

The occurrence of circulating immune complexes was investigated in 467 serum samples from 230 leukemia patients using the [(125)I]Clq-binding test. There was an increased serum [(125)I]Clq-binding activity in 40% of patients with acute myeloid leukemia, 23% with acute lymphatic leukemia, 46% in blastic crisis of chronic myeloid leukemia, 12% with chronic lymphatic leukemia, and 13% with chronic myeloid leukemia. In 48 patients, serum was also tested for soluble immune complexes by the Raji cell radioassay; the correlation between results of the two tests was significant. The Clq-binding material had properties identical with those of immune complexes. It sedimented as 14-28s material on sucrose density gradient. It contained IgG which could be dissociated at acid pH. Its Clq-binding properties could be removed after passage through anti-IgG immuno-absorbant or after a mild reduction-alkylation treatment, but were not sensitive to deoxyribonuclease treatment. Circulating immune complexes were found most commonly during the blastic stage of leukemia.Remission took place in 75.4% of patients with no detectable circulating immune complexes at the onset of acute leukemia, but in only 32.7% of those with detected complexes during this period. Median survival times of the former group of patients were more than 18 mo in acute myeloid leukemia and acute lymphatic leukemia and more than 8(1/2) mo in blastic crisis of chronic myeloid leukemia. The corresponding median survival times in the latter patient group were 64, 135, and 90 days. These findings were unrelated to prognostic features already known.

Immune complex formation during Plasmodium berghei infection of OF1 mice was investigated. Circulating immune complexes (CIC) were detected by the Clq-binding assay and the conglutinin-binding solid-phase assay in lethal or drug-limited infections. CIC appeared on day 9 of infection, peaked on day 11, and disappeared only after complete cure of the infection. Analysis of the immune complexes detected by the Clq-binding assay revealed the following characteristics: sedimentation coefficients of 13S to 21S, resistance to DNAse, and selective removal by filtration through protein A bound to Sepharose. Glomerular deposits of IgM preceded the appearance of CIC, whereas deposits of IgG and C3 were concomitant with the appearance of CIC. Tissue-bound immunoglobulins were also found in the choroid plexus. The appearance of anti-malarial antibodies and malarial antigens in the serum was closely associated with a depression of C3 levels and the presence of CIC. Drug treatment was followed by normalization of C3 levels, and clearance of both CIC and malarial antigens.

The 125I-C1q binding test was modified in order to allow for the detection of immune complexes in native unheated human serum. Indeed, heat-inactivation (56°, 30 min) was found to reduce the C1q-binding activity of immune complexes mixed with native serum. This effect was not observed when EDTA was added to the native serum before mixing with immune complexes. The modified 125I-C1q binding test was performed in two steps: first, the tested native serum sample was incubated for 30 min at 37°C with 0.13 M EDTA in order to prevent the integration of 125I-C1q into the intrinsic C1qrs complex, second, 125I-C1q and polyethylene glycol (final concentration 2.5%) were added to this mixture, and further incubated for 1 hr at 4°C. Under these conditions, free C1q remained soluble whereas C1q bound to macromolecular complexes was precipitated. The competitive effect of intrinsic C1q and the interference of other substances such as DNA or bacterial LPS were very limited. The modified C1q binding test was applied to the clinical investigation of 44 patients with systemic lupus erythematosus; and increased C1q binding activity (C1q-BA) was observed in 91% of the samples. The level of C1q-BA was found to be significantly correlated to the DNA-binding capacity and to the decrease of the level of some complement components.

When administered orally, both acetylsalicylic acid and acetylsalicylic acid lysinate produced an increased bleeding time, reduced platelet adhesiveness and inhibition of the second phase of ADP-induced platelet aggregation in the majority of subjects. The effects on bleeding time and adhesiveness were similar for both drugs. Platelet aggregation studies demonstrated slight differences between smokers and non-smokers, in both control samples and in response to the two drugs. It is concluded that aspirin lysinate should provide a good candidate for clinical investigation, to assess its value in the treatment of thrombotic disease.

In vitro, collagen and collagen-like material in GBM, were demonstrated to have a particular high affinity for any DNA tested (mammalian, bacterial, viral, and plant). GBM fixed DNA 40-80 times more than HGG and BSA and 10-40 times more than bacterial LPS. GBM has a higher affinity for SSDNA than for DSDNA. This binding was inhibited at low pH, low ionic strength, and in the presence of anionic detergents, indicating that the highly negatively charged DNA may interact with the basic site on collagen or GBM by electrostatic forces. This interaction was competitively interfered with by DNA-binding proteins such as Clq. Complexes formed of DNA and anti-DNA antibodies did not exhibit the same binding property as free DNA. However, DNA which was already bound to GBM or to collagen could very efficiently bind anti-DNA antibodies and form immune complexes which would remain on these structures. The biological significance of the binding of DNA to GBM or to collagen should be particularly considered in relation to the pathogenesis of SLE. It is possible that DNA released from disrupted or degenerating cells would bind to surrounding collagen fibers or to basement membranes and then act as an immunoabsorbant for circulating anti-DNA antibodies. Some evidence for an in vivo binding of SSDNA to renal structures was obtained in mice treated with bacterial LPS 2 days before the injection of SSDNA.

Administration of DNP-BGG to newborn guinea pigs resulted, in more than half of the animals, in the specific suppression of delayed hypersensitivity to DNP-BGG and BGG, as shown after immunization with DNP-BGG in complete Freund's adjuvant. In contrast, all animals formed antibodies to DNP-BGG, whether or not delayed hypersensitivity to this antigen was present. No difference in antibody titers was found between pretreated and control animals. All animals had antibodies reacting specifically to the hapten DNP, and most of them to the carrier protein BGG, whether or not delayed hypersensitivity to the carrier protein was present. Furthermore, some animals with and without positive 24 hr skin test to DNP-BGG had antibodies with a combined hapten-carrier protein specificity to this antigen, i.e., a specificity which is similar to that of delayed hypersensitivity. Thus, delayed hypersensitivity and antibody formation to similar antigenic determinant were differently affected by injection of antigen in the neonatal period. The finding that delayed hypersensitivity and antibody formation could be dissociated by the induction of immunologic tolerance supports the assumption that delayed hypersensitivity and antibody formation are different immune processes which are not necessarily linked together.

Cryoglobulin precipitates of the mixed type, containing 19 S IgM and 7 S IgG gamma globulin, were isolated from a patient serum and the interaction with serum C was studied. Loss of C activity in human serum incubated with cryoprecipitate was accompanied by the generation of C3 activity in the cryoglobulin aggregates. Complete dissociation of cryoprecipitation and the interaction of the precipitates with C was achieved at temperatures below 22°C and above 32°C respectively. The normal C titre in fresh serum of a cryoglobulinaemic patient was significantly reduced in vitro by first cooling and then rewarming the serum. The possible pathogenic role of the bithermic C activation in cryoglobulinaemic vascular lesions is discussed.

Resume Le traitement au mercaptoethanol de trois anticorps 7 S (1 serum de lapin anti-erythrocyte de rat, 2 serums anti-nucleoproteine humaine) reduit leurs capacites de fixer le complement «opsonisant» et dans deux cas le complement «hemolytique». Un serum humain d'un patient souffrant de lupus erythemateux dissemine etait fortement anticomplementaire. La diminution du complement responsable de l'opsonisation ne peut etre evaluee que si on teste des dilutions progressives de complement. Zusammenfassung Die ME-Behandlung von drei 7S-Antikorpern (Anti-Ratten-Erythrozyten-Immunserum von Kaninchcn, zwei menschliche Anti-Nukleoproteinseren) setzte ihr Vermogen zur Bindung von «opsonisierendem» und in zwei Fallen auch von «hamolytischem» Komplement herab. Ein Serum eines Patienten mit SLE war stark antikomplementar. Der Schwund der komplementabhangigen Opsonisation kann nur beurteilt werden, wenn Verdunnungsreihen vom Komplement untersucht werden.

Summary Heterospecific antiplatelet sera were demonstrated to have a direct action on coagulation, as manifest by the inhibitory effect on thromboplastin generation. This effect is distinct from the previously demonstrated ability to agglutinate platelets and inhibit clot retraction. Platelet phospholipid represents the antigenic platelet constituent responsible for this phenomenon. This constituent is not unique to platelets, but is also present in red cells since erythrocyte phospholipid cross reacts with antiserum directed against platelet phospholipid. Brain cephalin, which contains another phospholipid active in thromboplastin generation, exhibited no cross reaction. Fibrinogen is another antigenic substance intricately associated with platelets. It was confirmed that the precipitin action with sonicated platelets is due to fibrinogen. A platelet protein constitutes a third antigenic constituent which was found to be responsible for the immunological specificity of platelets. Platelet agglutination and inhibition of clot retraction are the result of an immune reaction involving this platelet protein as the specific substrate. Resume Les serums anti-plaquettaires heterospecifiques ont une action directe sur la coagulation se manifestant par un effet inhibiteur de la thromboplastinogenese. Cet effet est different de celui deja demontre qui se manifeste par une tendance a agglutiner les plaquettes et a inhiber la retraction du caillot. Left phospholipides plaquettaires representent le constituent plaquettaire antigenique responsable de ce phenomene. Ce constituant n'est pas le seul apanage des plaquettes, mais il est aussi present sur les erythrocytes puisque les phospholipides erythrocytaires presentent une reaction croisee avec l'anti-serum anti-phospholipide plaquettaire. Avec la cephaline cerebrale, autre phospholipide active dans la thromboplastinogenese, on n'observe pas de reaction croisee. Le fibrinogene est une autre substance antigenique intimement associee aux plaquettes. II a ete confirme que la reaction de precipitation des plaquettes traitees par les ultra-sons est due au fibrinogene. Une proteine plaquettaire forme un troisieme constituant antigenique qui s'est avere comme etant responsable de la specificite immunologique des plaquettes. L'agglutination plaquettaire et l'inhibition de la retraction du caillot sont le resultat d'une reaction immunitaire component cette proteine plaquettaire comme substrat specifique. Zusammenfassung Heterospezifische Antiplattchenseren hemmen die Thromboplastinbildung und beeinflussen auf diese Weise die Blutgerinnung. Diese Wirkung ist verschieden von der Fahigkeit solcher Seren, Plattchen zu agglutinieren und Gerinnselretraktion zu hemmen. Bei dem an diesem Phanomen beteiligten Antigen handelt es sich um Plattchenphospholipid. Diese Substanz kommt nicht nur in Plattchen, sondern auch in Erythrozyten vor, was daraus zu ersehen ist, das Erythrozytenphospholipid mit Antiseren gegen Plattchenphospholipid Kreuzreaktionen zeigt. Mit Hirnkephalin, einem anderen an der Thromboplastinbildung beteiligten Phospholipid wurden hingegen keine Kreuzreaktionen beobachtet. Fibrinogen ist ein anderes Plattchenantigen. Es wurde bestatigt, das bei der Prazipitationsreaktion mit Ultraschall zertrummerten Plattchen Fibrinogen das Antigen darstellt. Ein Plattchenprotein bildet das dritte Antigen; es ist verantwortlich fur die immunologische Spezifitat der Plattchen. Bei der Plattchenagglutination, wie auch bei der Retraktionshemmung zufolge von Immunreaktionen bildet dieses Plattchenprotein das spezifische Substrat.

Summary Polynuclear leukocytes have been separated into (1) whole cytoplasma, (2) mitochondria, (3) nucleoproteins, (4) nuclear reticulum minus the nucleoproteins; and respective antisera have been prepared by immunization of guinea-pigs with the separated fractions. These investigations showed that the cytoplasm (most likely the mitochondria) and not the nucleus are responsible for the antigenic specificity of the leukocytes. To a certain extent there exists an antigenic relationship between human and rabbit granulocytes. The leukocyte nucleus possesses antigenic properties which differ from those of the cytoplasm, but which coincide with the antigenic properties of other nuclei of the organism and so are not specific for leukocytes. Nucleoproteins are indispensable for the antigenic properties of the nucleus. Again a certain immunological relationship was observed between rabbit and human nuclei. The differentiation between cytoplasm and nucleus as different antigenic complexes of leukocytes has also proved useful in the clinic, since pathological serum proteins have been detected which are directed against these leukocyte constituents. Firstly, we know that there is a specific antileukocytic factor which is active against the cytoplasm of leukocytes, and that it occurs in the form of auto-antibodies in rare cases of idiopathic neutrophilic leukopenia, as well as in the form of posttransfusional iso-antibodies among certain patients who have received numerous transfusions. Secondly, there is the L.E. factor, which is active against Ieukocytes inasmuch as they contain a nucleus, and which likewise reacts on the nuclei of other cells. The L.E. factor is thus not really an antileukocytic, but an antinuclear antibody. Whereas the auto-antibody character of the antigranulocytic serum factors has been generally accepted, doubts were raised for a long time with regard to the lupus erythematosus factor as a nuclear auto-antibody. In comparative investigations it has been found, however, that serologically the lupus erythematosus factor behaves like an experimental antinuclear antibody. It has been found to be a gamma-globulin which can be adsorbed specifically and quantitatively upon nuclei, and which is eluted again only with difficulty. Isolated leukocytic nuclei sensitized with this gamma-globulin are phagocytized by functional leukocytes even if the sensitized nuclei have been washed repeatedly with physiological saline. This phagocytosis of nuclear material (L.E. phenomenon) has its parallel in an experimental nuclear phagocytosis as induced by antinuclear sera. In the same way as a potent antiserum against nuclei, the L.E. factor likewise reacts with nuclei of different animal species. These facts make it possible to identify the L.E. factor as a serum protein with the character of an antinuclear auto-antibody, and thus to include it among other auto-antibodies. Resume Les elements suivants ont ete prepares a partir de leucocytes polynucleaires: 1. cytoplasme, 2. mitochondries, 3. nucleoproteines, 4. reticulum nuckaire sans nucleoproteines. Des anticorps contre ces divers elements ont ete produits chez le cobaye, et leurs reactions avec les leucocytes efitiers ont ete etudiees. Ces etudes ont conduit aux conclusions suivantes. C'est le cytoplasme (et tres probablement la mitochondrie ellememe) et non le noyau cellulaire, qui est responsable de la specificite antigenique du leucocyte. Il y a entre le cytoplasme leucocytaire de l'homme et du lapin un rapport d'antigenicite de faible degre. Le noyau leucocytaire presente des proprietes antigeniques nettement differentes de celles du cytoplasme et qui sont les memes que chez d'autres noyaux cellulaires. Les nucleoproteines sont indispensables a cette specificite nucleaire. Les noyaux leucocytaires du lapin et de l'homme sont etroitement apparentes antigeniquement. Ces constatations ont un interet clinique, puisque certaines substances de serums pathologiques ont une affinite specifique pour differents elements du leucocyte. Ainsi nous connaissons un «auto-anticorp» present dans de rares cas de neutropenie idiopathique, qui est specifique pour le cytoplasme des leucocytes neutrophiles. Ce facteur serique antileucocytaire peut aussi se presenter comme iso-anticorps chez des malades ayant recu des transfusions multiples. D'autre part, le facteur L.E. est une substance specifique pour le noyau leucocytaire et aussi pour d'autres noyaux cellulaires. Il est generalement reconnu que le facteur serique anti-granulocytaire est bien un anticorps, tandis que le meme caractere a souvent ete conteste au facteur L.E. Les faits suivants demontrent cependant que le facteur L.E. se comporte effectivement comme un anticorps antinucleaire. Le facteur L.E. est une gammaglubuline qui se fixe quantitativement a des noyaux cellulaires et qui peut en etre elue. Des noyaux cellulaires «sensibilises» avec le facteur L.E. sont phagocytes par des granulocytes vivants. Cette phagocytose est entierement comparable a la nucleo-phagocytose provoquee par un anticorps antinucleaire experimental. De meme qu'un tel anticorps experimental reagit avec des noyaux cellulaires de differentes especes, de meme le facteur L.E. n'a aucune specificite propre a l'espece humaine. En conclusion, nous pouvons donc considerer le facteur L.E. comme un «auto-anticorps antinucleair» avec autant de droit que nous designons comme auto-anticorps certaines substances seriques antierythrocytaires. Zusammenfassung Polynukleare Leukozyten wurden in folgende Bestandteile aufgeteilt: 1. Ganzes Cytoplasma, 2. Mitochondrien, 3. Nukleoproteine, 4. Kerngelust ohne Nukleoproteine. Die immunologischen Besonder-heiten dieser Leukozyten-Bestandteile wurden anhand der Reaktion entsprechender Antiseren mit ganzen Leukozyten untersucht. Aus diesen Versuchen geht hervor, das das Cytoplasma (Mitochon-drien) und nicht der Zellkern fur die antigene Leukozytenspezifitat verantwortlich ist. Es konnte eine geringgradige antigene Verwandt-schaft zwischen menschlichen und Kaninchen-Leukozyten festgestellt werden. Der Zellkern der Leukozyten zeigt von denjenigen des Cytoplasmas verschiedene antigene Eigenschaften. Diese stimmen weitgehend mit den antigenen Eigenschaften anderer Zellkerne uberein und sind damit nicht fur Leukosyten spezilfisch. Nukleproteine sind fur diese antigene «Kernspesifitat» unerlaslich. Esbesteht eine ausgesprochene antigene Verwandtschaft zwischen Kaninchen- und Menschen-Zellkernen. Die Differenzierung der Leukozyten in Cytoplasma und Zellkern als in zwei verschiedene antigene Komplexe hat sich auch in der Klink als nutzlich erwiesen, da pathologische Serumkorper aufgedeckt werden konnten, die gegen diese Leukozyten-Bestandteile gerichtet sind. Erstens kennen wir einen spezifischen antileukozytaren Serumfaktor, der gegenuber dem Leukozyten-Cytoplasma aktiv ist und als sog. «Autoantikorper» in seltenen Fallen von idiopathischer neutrophiler Leukopenie vorkommt sowie als posttransfusioneller Isoantikorperbei gewissen Patienten, denen zahlreiche Transfusionen verabreicht worden sind. Zweitens stellt der sogenannte L.E.-Faktor einen Serumkorper dar, der gegenuber Leukozyten als Trager eines Zellkerns aktiv ist und ebenso mit Zellkernen anderer Provenienz reagiert. Der L.E.-Faktor ist also keine eigentliche antileukozytare, sondern eine gegen Zellkerne gerichtete Substanz. Wahrenddem die Antikorper-Natur des antigranulozytaren Serumfaktors allgemein anerkannt wird, wurde immer wieder an der Antikorper-Natur des L.E.-Faktors gezweifelt. Es konnte jedoch gezeigt werden, das sich dieser L.E.-Faktor serologisch tatsachlich wie ein gegen Zellkerne gerichteter Antikorper verhalt. Es handelt sich um ein Gammaglobulin, das spezifisch und quantitativ auf Zellkerne fixiert und darauf wieder von diesen Kernen eluiert werden kann. Mit diesem Serurnkorper «sensibilisierte» Zellkerne werden durch vitale Granulozyten phagozytiert. Diese Phagozytose von Kernmaterial ist vergleichbar mit einor durch ein experimentelles Anti-Kernserum induzierten Nukleophagozytose. In gleicher Weise, wie ein durch Immunisierung gewonnenes Anti-Kernserum mit Zellkernen verschiedener Spezies-Herkunft reagiert, weist auch die Aktivitat des L.E.-Faktors keine Humanspezies-Spezifitat auf. Auf Grund dieser Tatsachen kann dem L.E.-Faktor der Charakter eines gegen Zellkerne gerichteten («antinuklearen») «Autoaatikorpers» zugeschxieben werden, und zwar mit der gleichen Berechtigung, mit der wir gewisse antierythrozytare Serurnfaktoren als «Autoantikorper», bezeichnen.

Summary1. Among each of 2 groups of guinea pigs immunized with 50 μg and 500 μg of picrylated thyroglobulin in Freund's adjuvant respectively, 57.2% (63 of 110 animals) developed thyroiditis 17 days following the initial dose of antigen. Delayed skin reactivity to intradermal thyroglobulin was observed in 72.7% of the animals. There was no significant difference in incidence of thyroiditis and delayed skin reactivity in the 2 groups of animals. However, circulating antithyroglobulin antibody as determined by passive hemagglutination, was found in 4.6% (2 of 43 animals) in the low antigen group and 30% (18 of 60 animals) in the high antigen group.

Summary Soluble antigen-antibody-complexes have been prepared with rabbit anti-ovalbumin serum and three times recrystallized hen ovalbumin. The complexes prepared in the range of slight antigen excess (2 « and 4 « equivalence ratio) were shown to agglutinate rabbit platelets. With the aid of the fluorescent antibody technique, fixation of the complexes upon the agglutinated platelets has been demonstrated. Resume Des complexes antigene-anticorps ont ete prepare avec du serum anti-ovalbumine de lapin et de l'ovalbumine cristallisee. Les complexes solubles, prepares avec un excks d'antigene (2 « a 4 « equivalence) ont agglutine des plaquettes de lapin. La fixation des complexes sur les plaquettes agglutinees a ete mise en evidence a l'aide de la methode d'anticorps fluorescents. Zusammenfassung Losliche Antigen-Antikorper-Komplexe wurden mit einem Kaninchen-Antiovalbuminserum und kristallisiertem Ovalbumin hergestellt. Wurden die Komplexe mit der 2 bis 4 fachen Menge Ovalbumin die fur die Aquivalenzzone benotigt wird, zubereitet, so fuhrten sie zu einer Agglutination von Kaninchen-Thrombocyten. Mit Hilfe der Antikorper-Fluoreszenz-Methode konnte gezeigt werden, das die Komplexe den agglutinierten Thrombocyten fest anhaften

THE relation of chronic discoid lupus erythematosus to systemic lupus erythematosus has always been controversial. Studies reporting a frequent occurrence of clinical and laboratory abnormalities have led some authors to conclude that there is a high incidence of systemic involvement in patients with chronic discoid lupus and that the two diseases may represent different manifestations of the same conditio,.1 , 2 However, the lack of suitable control groups in these studies makes the data difficult to evaluate. To clarify this problem we have studied 65 patients with chronic discoid lupus erythematosus and 65 patients with other dermatologie disorders matched for age, sex . . .

The influence of 6-mercaptopurine and aminopterin was studied on immune response and immune thyroiditis in guinea pigs immunized with thyroid extract. 1. Both compounds depressed delayed hypersensitivity to thyroglobulin and immune thyroiditis. 2. Antibody formation to thyroglobulin was strongly depressed by aminopterin but not significantly influenced by 6-mercaptopurine. 3. Immune response and thyroiditis were suppressed as long as the compounds were administered; after discontinuation of treatment, immune response and thyroiditis appeared in the same time intervals as observed in control animals after initiation of immunization. 4. Treatment with 6-mercaptopurine and aminopterin 10 days after immunization lead to suppression of delayed hypersensitivity and thyroiditis. 5. Treatment with 6-mercaptopurine of animals after onset of thyroiditis lead to suppression of delayed hypersensitivity and disappearance or diminution of round cell infiltration in the thyroid. 6. The results are discussed in terms of the pathogenesis of experimental immune thyroiditis, the mode of action of these antimetabolites on this experimental immune disease, and in view of the potential value of these compounds in human diseases.

The correlation between the incidence and level of immune complexes in serum and synovial fluid and the various clinical and biological manifestations of rheumatoid arthritis has been studied. Immune complexes were quantitated using a sensitive radioimmunoassay, the 125I-Clq binding test, in unheated native sera and synovial fluids from 50 patients with seropositive (RA +) and 45 with seronegative (RA -) rheumatoid arthritis, 17 with other inflammatory arthritis, and 37 with degenerative and post-traumatic joint disease. The following observations were made: (a) when compared to the results from patients with degenerative and post-traumatic joint diseases, the 125I-Clq binding activity (Clq-BA) in synovial fluid was found to be increased (by more than 2 SD) in most of the patients with RA + (80%) and RA - (71%) and in 29% of patients with other inflammatory arthritis; the serum Clq-BA was also frequently increased in both RA + (76%) and RA - (49%) patients, but only exceptionally in patients with other inflammatory arthritis (6%); (b) a significant negative correlation existed between the Clq-BA and the immunochemical C4 level in synovial fluids from patients with RA + and RA -; (c) neither the serum nor the synovial fluid Clq-BA in rheumatoid arthritis significantly correlated with the erythrocyte sedimentation rate, the clinical stage of the disease, or the IgM rheumatoid factor titer; and (d) the serum Clq-BA in patients with rheumatoid arthritis and extra-articular disease manifestations (40 +/- 34% in those with RA +,32 +/- 29% in those with RA -) was significantly increased as compared to the serum Clq-BA in patients with joint disease alone (24 +/- 30% in those with RA +, 10 +/- 13% in those with RA -). Experimental studies were carried out in order to characterize the Clq binding material in rheumatoid arthritis. This material had properties similar to immune complexes: it sedimented in a high molecular weight range on sucrose density gradients (10-30S) and lost the ability to bind Clq after reduction and alkylation, or after acid dissociation at pH 3.8, or after passage through an anti-IgG immunoabsorbant. DNase did not affect the Clq BA. These results support the hypothesis that circulating as well as intra-articular immune complexes may play an important role in some pathogenetic aspects of rheumatoid arthritis. The 125I-Clq binding test may also be of some practical clinical value in detecting patients who have a higher risk of developing vasculitis.

Als visceraler Erythematodes wird eine nicht infektiose, nicht neoplastische, in Schuben verlaufende, generalisierte entzundliche Erkrankung unbekannter Atiologie mit genetisch determinierter Pradisposition benannt, die praktisch jedes Organ befallen kann, und die mit einer Reihe abnormaler immunologischer Vorgange einhergeht. Die klinischen Manifestationen sind mannigfaltig; folgende Symptome werden in den meisten Fallen festgestellt: intermittierendes Fieber, Arthritis, weniger regelmasig nephritische Zeichen und Hauteruptionen. Im Blut treten im Verlauf der Krankheit antinucleare Sarumantikorper auf. Eine Vielfalt weiterer autoimmunitarer Vorgange kommen vor, meistens ohne Organ- und Species-Spezifitat. Pathologisch-anatomisch sind die sog. hamatoxyphilen Korperchen (alteriertes Nucleoprotein) pathognomonisch. Andere Gewebsveranderungen („wireloop“Nephritis, vasculare „onion skin lesions“, atypische verrukose Endokarditis, fibrinoide Degeneration) sind charakteristisch, ohne fur den visceralen Lupus erythematodes pathognomonisch zu sein.