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Available techniques for detection of anti-nuclear antibodies are here briefly reviewed. The relatively insensitive LE cell test has been largely supplanted by the indirect immunofluorescent ANA test which should be reported in terms of titre and pattern. Specific measurement of nDNA antibodies is now a regular technique in SLE diagnosis and management.
PROBLEM: The immunologic mechanisms of pregnancy loss in habitual aborters with antiphospholipid and antinuclear antibodies have not been fully clarified. The possible association of antineutrophil cytoplasmic antibodies (ANCAs) with recurrent miscarriage was examined. METHOD OF STUDY: In a prospective, controlled trial of 59 women with recurrent abortion, the prevalence of pANCA (antimyeloperoxidase), cANCA (antiproteinase-3), and immunoserologic abnormalities of systemic lupus erythematosus (SLE) anti double-stranded DNA, anti-SSA, anti-SSB, anti-U1RNP, anti-Sm, anticardiolipin and antinuclear antibodies, LE-cell, lupus anticoagulant, and complement-3 were investigated. RESULTS: pANCA occurred in 2, and cANCA in 6 of 59 case patients, but neither was observed in the controls (P = 0.09 for cANCA). cANCA levels were significantly higher in patients than in controls (P = 0.028). Six recurrent aborters were identified as having a group of immunoserologic abnormalities characteristic of SLE. CONCLUSIONS: Immunologic mechanisms detectable in SLE may operate in a subgroup of habitual aborters with suspected immunologic cause. ANCAs occur more frequently in patients with recurrent miscarriage than in controls.
Two types of lymphocyte tubular structures were studied by electron microscopy in 80 patients with classic or definite rheumatoid arthritis (RA). Fifteen patients with unequivocal systemic lupus erythematosus (SLE) and 10 healthy persons were studied as controls. Lymphocyte tubulo-reticular structures were found in 13 of the 80 patients with RA and in 10 of the 15 patients with SLE. No tubuloreticular structures were found in any of the healthy subjects. In the RA patients antinuclear antibodies, LE cell phenomenon, and chlorambucil treatment were associated significantly with these inclusions but disease activity was not related to their presence. In cases in which tubuloreticular structures were present the number of cells containing inclusions was on average much lower in patients with RA than in those with SLE. Lymphocyte tubular parallel arrays were found in all the patients with RA and SLE and in all the healthy persons. In all three groups the average number of cells containing parallel tubular arrays was similar.
In 1948, the observation of the LE cell phenomenon in a patient with systemic lupus erythematosus (SLE) began the discovery of a broad variety of autoantibodies directed to nuclear antigens called antinuclear antibodies (ANA). Nowadays, different ANA serve as important diagnostic parameters for differentiating most of the connective tissue diseases, such as SLE, neonatal lupus syndromes, Sjögren's syndrome, scleroderma, autoimmune myositis, mixed connective tissue disease and other overlaps. This overview summarizes the history of ANA and their detection methods, in part to introduce the subsequent papers dealing with special topics of ANA-related diseases in this issue. Furthermore, the pathogenic role of these autoantibodies in targeting non-organ-specific intracellular antigens as a functional important constituent of a subcellular particle or multimolecular complex is addressed. Notably, some of these autoantibodies have functioned as significant tools for cell biologists to elucidate the subcellular structures and functions of these autoantigens. In the future, we can expect further advances to answer such important questions as why these antigens are targets of autoantibodies, what is their pathogenic impact and what are the triggers of autoimmunity?
Asymptomatic autoimmune thyroiditis (AAT), especially prevalent in elderly women and associated with the presence of thyroid antibodies (HT), is recognized as a precursor of hypothyroidism and is an intermediate between euthyroidism and hypothyroidism. This paper is concerned with the possible modifications of biochemical variables - some of which are not directly related to the thyroid - in patients with AAT. Thirty-seven serum factors were investigated in euthyroid, AAT, and HT subjects over 69 years of age. They were thyroglobulin; microsomal, gastric and adrenal antibodies; LE cells, and thyroid, lipid and immunological variables linked to the inflammatory process. In women the only variable, other than those related to the thyroid, which showed any modification in the AAT state was the cholesterol level. Wholly different observations were made in men, stressing the necessity of separate analysis of male and female data: the thyroid-related variables which were modified in the AAT state are not the same as in women, the cholesterol is not increased but triglycerides, HDL, albumin and inflammatory variables are modified. Furthermore, the lipid variables showed an unexpected age dependency in AAT, but not in euthyroid women (between 69-90 years of age).
The study of serum from a patient with C2 deficiency is described. The patient had an episode of pneumococcal meningitis at 5 mo of age with seizures and transient hemiparesis and apparent purpuric skin lesions. He was first admitted to the University of Minnesota Hospitals at 10 yr of age following the discovery of proteinuria accidentally by his mother. Since then he has been admitted repeatedly to this hospital with numerous clinical findings including arthralgia, recurrent abdominal pain, proteinuria, membranous nephropathy, malar butterfly rash, seizures, personality aberrations, and recurrent fever. In June 1971, the patient developed positive DNA and DNP antibodies and positive LE cells. When the C profile was studied before and after recognition of lupus, C1q, C1s, and C4 dropped. C3 levels were elevated as were C5, C6, and C7, C3 proactivator had been reduced in the patient even before he developed lupus. Also because of a traumatic renal biopsy leading to a perirenal hematoma, he required surgery and a blood transfusion. 1 h after blood transfusion, a C2 titer of 23 hemolytic units was detected. Almost immediately levels of C3, C5, C6, and C7 dropped, C8 and C9 remained elevated. The addition of C2 from normal blood permitted dramatic activation of C3. These findings support the view that the rare deficiency in production of C2 predisposes to serious susceptibility to infection, vascular and mesenchymal disease as well as to renal disease and a lupus syndrome.
Neuropathologic examination of an autopsy series of 54 patients of various types of CVD revealed a very high frequency of pathologic changes both in brain parenchyma (in 81%) and vessels (in 78%). A broad but continuous spectrum of primary vascular alterations was observed, ranging from fibrinoid deposits in intact or necrotizing vessel walls to fibrohyalinosis and endothelial proliferations. In acute SLE showing LE cells within brain tissues, immune complex deposits were observed for the first time in brain vessels, in addition to similar deposits in the plexus chorioideus and in hematoxylin bodies. Secondary complications are frequently affecting the brain in CVD; they are mainly sequels of systemic atherosclerosis, hypertension, thromboemboli from SLE endocarditis, cardiac, hepatic or renal dysfunctions, or infections and should be clinically differentiated from primary brain involvement in CVD to ensure the appropriate therapeutic measures.
This study was performed in 60 patients with the following connective tissue diseases: rheumatoid arthritis (RA--20 patients), systemic lupus erythematosus (SLE--20), and progressive systemic sclerosis (scleroderma = PSS--20). Twenty normal persons served as controls. All patients and controls were subjected to complete history taking, complete physical examination, and laboratory investigations including: rheumatoid factor, anti-DNA, LE cell test, antinuclear factor (ANF), and ECG. Finger arterial blood pressure (FABP) readings using an 8 MHz Doppler flow detector with a 24-mm-diameter cuff at a temperature of 24 degrees C were made in all cases and controls. The mean age of incidence in patients with RA was 37.8 years; in those with SLE, 21.5 years; in those with PSS 34.6 years; and in the control group, 33.7 years. Women were predominant both in the diseases and the control groups. The FABP was measured in all groups and the range of difference between the brachial and finger arterial blood pressure in each group was estimated. In the control group the mean difference was 27.7 mm Hg; in the RA group, 45.8 mm Hg; in the SLE group, 58.1 mm Hg; and in the PSS group, 70.9 mm Hg. There were no significant peripheral vascular changes in the small arteries in the RA group, whereas in the SLE and PSS groups there was a significant difference, which suggests different underlying microvascular changes. The FABP appears to be a diagnostic tool in the diagnosis of PSS and it helps in differentiation between various types of collagen disease in equivocal cases.
A number of drugs have recently been implicated in a syndrome that resembles systemic lupus erythematosus. One of the difficulties in many of these patients is that the signs, symptoms and serological abnormalities reported in these patients may be a natural consequence of the primary diseases rather than the incriminated drug. A second problem with the studies is a lack of uniform reporting of the techniques used to detect autoantibodies. For example, a patient that has a highly positive ANA with a homogeneous pattern of staining or a positive LE cell test usually has antibodies directed against chromatin components (DNA, histones, high mobility group (HMG) proteins). The discrepancies in clinical criteria and the serological techniques in many of these reports, emphasize the importance of using guidelines for the diagnosis of drug-induced or drug-related lupus. In the future, it appears that the increased use of biological response modifiers such as interferon-alpha and other cytokines may prompt more reports of lupus syndromes associated with their use.
Autoantibodies to DNA were discovered over 40 years ago following the discovery a few years earlier of the 'LE' cell phenomenon by Hargraves and colleagues in 1948. These investigators noted that, when leucocytes were incubated with serum from lupus patients, changes in the nucleus could be seen together with phagocytosis of nuclear remnants by polymorphonuclear leucocytes. Since that time numerous studies in many laboratories have investigated almost every aspect of anti-DNA antibodies, partly to identify what determines their pathology. Whilst a subset of anti-DNA antibodies, especially anti-native, or double-stranded DNA (dsDNA) antibodies constitutes a hallmark of lupus disease and a diagnostic criterion, it is now clear that not all anti-DNA autoantibodies are of pathogenic relevance. Moreover, anti-DNA autoantibodies may also be found in other connective tissue disorders. Here we briefly review studies presented at the fifth international workshop on anti-DNA autoantibodies held in London to highlight relevant properties of pathogenic anti-DNA antibodies.
This Festschift by his former trainees is dedicated to the memory of Dr Henry G Kunkel. Dr Kunkel spent most of his academic life at The Rockefeller University. He has been called the father of Clinical Immunology. His trainees became professors and leaders in this field. Dr Kunkel's laboratory led to the elucidation of the immunology of the LE cell, the significance of anti-DNA and immune deposits in lupus nephritis, the recognition of antibodies to other nucleic acids and cellular constituents, the role of complement, genetics, hormones and cellular immunology--in the area of lupus and other rheumatic diseases.
A personal account is given: 1) of my early work with lupus erythematosus including the first observation of formation of the LE cell and the experimental production in animal renal glomeruli of hematoxyphil bodies, the pathognomonic lesion of lupus; and, 2) of how discontinuation of work on lupus--by decree--diverted my life in science away from immunology into another area of human genetics, namely cytogenetics, the discovery of genetically determined genomic instability and the choice of Bloom's syndrome as an investigational model for human cancer.
We studied 24 patients (18 women, 6 men), aged 29 to 54, with Sneddon's syndrome. The clinical picture of Sneddon's syndrome was characterized by cerebrovascular disorders, livedo reticularis, disturbance of peripheral circulation, arterial hypertension, cardiac pathology (ischemic heart disease, heart murmurs), complicated obstetric history in women, and disturbed sexual function in men. In 6 of 17 examined patients with Sneddon's syndrome there was a high concentration of anticardiolipin antibodies (ACA) but no antibodies to native DNA and LE cells. The course of the disease in the patients with a high ACA level, when compared with normal ACA level patients, was characterized by a more rapid progression and more severe clinical manifestations. The study demonstrates the similarity of clinical symptoms and immunologic disturbances in Sneddon's syndrome and the antiphospholipid syndrome and suggests the importance of ACA in the pathogenesis of some cases of Sneddon's syndrome.
A 78-year-old man presented with acute lupus pleuritis due to procainamide. The pleural fluid was a turbid, yellow exudate with a WBC count of 53,200/cu mm (70 percent polymorphonuclear leucocytes), LDH of 4,296 IU/L, and pH of 7.195. Although these fluid characteristics suggested pleural space infection, they were due to pleural inflammation from drug-induced lupus. LE cells were present in the fluid and results of microbiologic studies were negative. Clinical and roentgenographic improvement followed discontinuation of procainamide.
The authors describe the case of a young Brazilian woman who was treated of ileocolonic Crohn's disease sparing rectum, as confirmed by colonoscopy and histopathological examination. After a 4-year course of sulfasalazine treatment, she presented with skin facial lesions in vespertilio, fever, arthralgias and high titers of anti-ANA and LE cells. A sulfasalazine-induced lupus syndrome was diagnosed, because after sulfasalazine withdrawal and a short course of prednisone, the clinical symptoms disappeared and the laboratory tests returned to normal. Mesalazine 3 g/day was started and the patient remained well for the next 3 years, when she was again admitted with fever, weakness, arthralgias, diplopy, strabismus and hypoaesthesia in both hands and feet, microhematuria, haematic casts, hypocomplementemia and high titers of autoimmune antibodies. A diagnosis of associated systemic lupus erythematosus was made. Although a pulsotherapy with methylprednisolone was started, no improvement was noticed. A cyclophosphamide trial was tried and again no positive results occurred. The patient evolved to severe clinical manifestations of general vasculitis affecting the central and peripheral nervous system and lungs, having a fatal evolution after 2 weeks. Although uncommon, the association of both disease may occur, and the authors call attention to this possibility, making a brief review of literature.
OBJECTIVE: To report and assess the incidence of cardiac tamponade in systemic lupus erythematosus as a cardiac manifestation of the disease. METHODS: We reviewed the medical records of 325 patients diagnosed with systemic lupus erythematosus according to the American Rheumatism Association and their complementary laboratory tests compatible with cardiac tamponade. RESULTS: In the 325 medical records reviewed, we found 108 patients with pericardial effusions corresponding to 33.2% of the total and 54% of the patients studied in the active phase of the disease. Clinical assessment and transthoracic echocardiogram allowed the clinical diagnosis of cardiac tamponade in only 4 (1.23%) patients, 3 of whom were females, white, with ages ranging from 25 to 44 years. The pericardial fluid was hemorrhagic or serosanguineous with high levels of FAN and positivity for LE cells. In the treatment, we successfully used pericardiocentesis associated with high doses of corticosteroids. In clinical and laboratory follow-up performed for a period of 3 years, neither recrudescence of the pericardial effusion nor evolution to constriction occurred. CONCLUSION: Even though rare (1.23%), cardiac tamponade in patients with systemic lupus erythematosus has a benign evolution when properly treated, according to our experience.
A 35-year-old woman was diagnosed as autoimmune hepatitis 12 years ago by abnormal findings of liver tests including lupus erythematosus (LE) cell phenomenon and liver biopsy. She was admitted in May 1990 with a history of lower gastrointestinal bleeding. Colonoscopy with biopsy and barium enema revealed chronic ulcerative colitis along the entire colon. Since liver tests did not respond well to prednisolone treatment, liver biopsy was again performed and it revealed periductal inflammation with small duct proliferation, a finding compatible with pericholangitis. We herein report this patient who was initially diagnosed as autoimmune hepatitis and thereafter found to be pericholangitis associated with ulcerative colitis.
A portion of anticardiolipin antibodies is defined as phospholipid-dependent anti-beta 2-glycoprotein I (beta 2-GPI) antibodies and recognizes the conformationally altered beta 2 GPI which interacts with anionic phospholipids. We studied the clinical significance of IgG phospholipid-dependent anti-beta 2-GPI antibodies in patients with antiphospholipid syndrome (APS). The subjects consisted of 60 APS patients. IgG phospholipid-dependent anti-beta 2-GPI antibodies were detected by ELISA in 32 of the 60 patients (53%). Significantly higher incidences of prolonged APTT and lupus anticoagulants were found in patients with these anti-beta 2-GPI antibodies. Moreover, significantly lower incidences of malar rash, serositis, LE cell preparation and anti-Sm antibodies were found in patients with these anti-beta 2-GPI antibodies. It was found that 88% of the patients with these anti-beta 2-GPI antibodies satisfied less than five of the revised criteria items for the classification of SLE. These findings indicate the clinical characteristics of APS patients with IgG phospholipid-dependent anti-beta 2-GPI antibodies.