The mosaic of autoimmunity.

Autoimmunity is a normal event, while autoimmune diseases result from an aberration of this normal phenomenon. The etiology of this switch is considered multifactorial with the final common pathway being the loss of normal self-tolerance in a particular organ or group of organs. Genetic, environmental, hormonal and immunologic factors (along with probably other yet unrecognised factors) are considered important in the development of these disorders. The particular autoimmune disease which any patient develops is most likely a result of which combination of factors the patient has accumulated. We begin with a brief review of immunobiology in order to arrive at a suitable definition of autoimmunity. This is followed by a concise description of the current theories regarding the development of autoimmune disease and the factors known to be associated with these illnesses. Concluding remarks address the factors that normally prevent the progression of autoimmunity to autoimmune disease and the application of current knowledge to future therapeutic approaches.

Hypersensitivity reaction to carboplatin. Results of skin tests.

Four patients with hypersensitivity reaction to carboplatin of variable severity, after previous uneventful cisplatin and carboplatin treatment, are described. Skin testing performed in two of the patients suggests a cross-reaction with cisplatin but was negative with carboplatin in one of them. The mechanism of hypersensitivity reaction to carboplatin is poorly understood and the issue of retreatment with carboplatin is controversial. Physicians should be aware of the possible hypersensitivity reaction to carboplatin and appropriate precautions should be taken.

Nimesulide-induced hepatitis and acute liver failure.

BACKGROUND: Nimesulide is a relatively new non-steroidal anti-inflammatory drug that is gaining popularity in many countries because it is a selective cyclooxygenase 2 inhibitor. Occasionally, treatment is associated with mild elevation of liver enzymes, which return to normal upon discontinuation of the drug. Several cases of nimesulide-induced symptomatic hepatitis were also recently reported, but these patients all recovered. OBJECTIVES: To report the characteristics of liver injury induced by nimesulide. PATIENTS AND METHODS: We report retrospectively six patients, five of them females with a median age of 59 years, whose aminotransferase levels rose after they took nimesulide for joint pains. In all patients nimesulide was discontinued, laboratory tests for viral and autoimmune causes of hepatitis were performed, and sufficient follow-up was available. RESULTS: One patient remained asymptomatic. Four patients presented with symptoms, including fatigue, nausea and vomiting, which had developed several weeks after they began taking nimesulide (median 10 weeks, range 2-13). Hepatocellular injury was observed with median peak serum alanine aminotransferase 15 times the upper limit of normal (range 4-35), reversing to normal 2-4 months after discontinuation of the drug. The remaining patient developed symptoms, but continued taking the drug for another 2 weeks. She subsequently developed acute hepatic failure with encephalopathy and hepatorenal syndrome and died 6 weeks after hospitalization. In none of the cases did serological tests for hepatitis A, B and C, Epstein-Barr virus and cytomegalovirus, as well as autoimmune hepatitis reveal findings. CONCLUSIONS: Nimesulide may cause liver damage. The clinical presentation may vary from abnormal liver enzyme levels with no symptoms, to fatal hepatic failure. Therefore, monitoring liver enzymes after initiating therapy with nimesulide seems prudent.

Cerebrospinal fluid C3a increases with age, but does not increase further in Alzheimer's disease.

Complement activation is present in the brain in Alzheimer's disease (AD), and C1q concentrations are decreased in AD cerebrospinal fluid (CSF). To determine whether concentrations of other complement proteins are also altered in AD CSF, we measured concentrations of C3a and SC5b-9 in CSF from patients with probable AD (n = 19), normal aged controls (n = 11), and normal younger controls (n = 15). C3a concentrations were similar between AD and aged controls, but threefold higher than in younger controls (p < 0.05 vs. both groups). A similar pattern was found with SC5b-9, though the increase was only twofold and statistically significant only for AD vs. younger controls. These results suggest that an increased generation of complement proteins in localized areas of the AD brain does not result in elevated concentrations of these proteins in CSF, compared with age-matched controls. Increased C3a (and, to a lesser extent, SC5b-9) in aged controls may be due to increased complement activation, increased central nervous system production, and/or blood-brain barrier leakage of these proteins.

Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders.

Ceruloplasmin (CP), the major plasma anti-oxidant and copper transport protein, is synthesized in several tissues, including the brain. We compared regional brain concentrations of CP and copper between subjects with Alzheimer's disease (AD, n = 12), Parkinson's disease (PD, n = 14), Huntington's disease (HD, n = 11), progressive supranuclear palsy (PSP, n = 11), young adult normal controls (YC, n = 6) and elderly normal controls (EC, n = 7). Mean CP concentrations were significantly increased vs. EC (P < 0.05) in AD hippocampus, entorhinal cortex, frontal cortex, and putamen. PD hippocampus, frontal, temporal, and parietal cortices, and HD hippocampus, parietal cortex, and substantia nigra. Immunocytochemical staining for CP in AD hippocampus revealed marked staining within neurons, astrocytes, and neuritic plaques. Increased CP concentrations in brain in these disorders may indicate a localized acute phase-type response and/or a compensatory increase to oxidative stress.

Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions.

Oxidant-mediated damage is suspected to be involved in the pathogenesis of several neurodegenerative disorders. Iron promotes conversion of hydrogen peroxide to hydroxyl radical and, thus, may contribute to oxidant stress. We measured iron and its transport protein transferrin in caudate, putamen, globus pallidus, substantia nigra, and frontal cortex of subjects with Alzheimer's disease (n = 14) and Parkinson's disease (n = 14), and in younger adult (n = 8) and elderly (n = 8) normal controls. Although there were no differences between control groups with regard to concentrations of iron and transferrin, iron was significantly increased (p < 0.05) in Alzheimer's disease globus pallidus and frontal cortex and Parkinson's disease globus pallidus, and transferrin was significantly increased in Alzheimer's disease frontal cortex, compared with elderly controls. The transferrin/iron ratio, a measure of iron mobilization capacity, was decreased in globus pallidus and caudate in both disorders. Regional transferrin and iron concentrations were generally more highly correlated (Pearson's correlation coefficient) in elderly controls than in Alzheimer's and Parkinson's disease. The altered relationship between iron and transferrin provides further evidence that a disturbance in iron metabolism may be involved in both disorders.

Ceruloplasmin is increased in cerebrospinal fluid in Alzheimer's disease but not Parkinson's disease.

Although the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD) is unknown, altered brain antioxidative mechanisms have been found in both disorders. Ceruloplasmin (CP) and transferrin (TF) interact to limit concentrations of free ferrous iron (Fe2+), and thus play an important role in antioxidant defense in serum; both proteins are also produced in brain, where their significance as antioxidants is unknown. We quantified concentrations of CP and TF by immunoassay in AD (n = 17) and PD (n = 12) cerebrospinal fluid (CSF) to determine whether these proteins could serve as disease markers. CP was increased versus aged normal subjects (n = 11) in AD (p < 0.05) but not PD CSF, whereas TF concentrations did not differ between groups. CP levels have been reported to be elevated in some brain regions in AD, and increased CP in AD CSF may reflect this finding. Systemic inflammation and oxidative stress are major factors stimulating hepatic CP synthesis, and it remains to be determined whether increased CP concentrations in AD CSF and brain follow from similar mechanisms.

Non-specific binding of normal human IgG, including F(ab')2 and Fc fragments, to embryonic rat brain neurons and human cortex synaptosomes.

Binding of normal human IgG to embryonic rat brain neurons was quantitated by flow cytometry. IgG binding was linear between 0.05 and 1.5 mg/ml; slight binding was detectable even at normal cerebrospinal fluid concentrations. Similar binding curves were obtained for purified Fc and F(ab')2 fragments from normal human IgG. Normal human IgG also bound to synaptosomes (resealed nerve terminals) from human cerebral cortex. However, competition assays utilizing 125I-IgG showed no evidence for specific binding. This study indicates that the specificity of putative anti-neuronal antibodies should be confirmed by competition assays as for other receptor-ligand binding.

A new, simplified method for oxidation of human complement component C2.

Oxy C2 is a valuable immunologic reagent, particularly for investigators whose research or clinical assays require a stable classical pathway C3 and/or C5 convertase or a highly active plasma complement source. To date only one method for the conversion of serum C2 or purified C2 to their respective oxy C2 forms has been published. However, this method has several disadvantages. For example, handling and dissolving the iodine crystals required in this process are difficult and time consuming. Also, the enhancement procedure results in a significant dilution of the original C2 sample. We have, therefore, developed a new, simplified method for oxidation of plasma, serum, or pure C2 which circumvents the difficulties associated with the earlier method. Moreover, this method offers additional flexibility with regard to oxidative conditions (i.e., buffer pH, temperature, and C2 concentrations) and reagent handling and final C2 product stability.

Abdominal pain in hereditary angioedema: the role of acid hypersecretion.

Hereditary angioedema is a familial disorder characterized by recurrent episodes of soft tissue swelling and abdominal pain. Whereas most patients are successfully treated with androgenic steroids, some have abdominal pain unresponsive to therapy. To determine whether acid-peptic disease could account for the abdominal pain unresponsive to androgen therapy, we performed upper gastrointestinal endoscopy and determined basal acid output in 21 consecutive patients with hereditary angioedema and abdominal pain. Mean basal acid output of this group was 6.0 +/- 5.9 mEq/h, with five patients having gastric acid hypersecretion (defined as a basal acid output of greater than 10.0 mEq/h). The abdominal pain in 18 responded to stanozolol, whereas the pain in three patients did not change. Acid-peptic mucosal disease (esophagitis or duodenal ulcer) was present in these three patients with abdominal pain unresponsive to androgen therapy, all of whom had gastric acid hypersecretion (basal acid outputs of 13.7, 19.1, and 21.5 mEq/h, respectively). These three patients were treated with ranitidine but required increased doses to control their gastric acid hypersecretion, and to promote complete relief of abdominal pain and healing of their esophagitis or ulcer disease. These results indicate that there is a subset of patients with hereditary angioedema whose abdominal pain may be secondary to acid-peptic disease and gastric acid hypersecretion. Such individuals may require increased therapeutic doses of antisecretory medication to promote complete healing of esophagitis or ulcer disease. Basal acid output and upper gastrointestinal endoscopy are important determinants when evaluating abdominal pain in patients with hereditary angioedema that fails to respond to standard therapy.

Urine-histamine levels in patients with hereditary angioedema (HAE).

Hereditary angioedema (HAE) is defined clinically by recurrent, self-limited episodes of angioedema. The disease is defined biochemically by a deficiency in the functional activity of C1 esterase inhibitor. To date, the actual serum or tissue mediator(s) responsible for the angioedematous lesion remains controversial. Although antihistaminics have been clearly demonstrated to have no efficacy in the long-term treatment of this disorder, instances of elevated urine-histamine levels in patients with HAE raises the possibility of a role for histamine in the pathophysiology of this disease. Urine samples were collected from 28 asymptomatic and from 11 symptomatic patients with HAE. The urine-histamine levels were compared with levels of 41 normal control subjects. With the exception of one asymptomatic patient with HAE whose diagnoses also included rheumatoid arthritis and secondary Sjögren's syndrome, the urine-histamine levels from asymptomatic patients with HAE were similar to values obtained from normal control subjects. Except for data from two patients with HAE, urine-histamine levels from symptomatic patients with HAE were also indistinguishable from levels of normal volunteers. These data suggest that the vast majority of patients with HAE have normal urine-histamine levels both during and between attacks. Consequently, histamine is unlikely to play a pathophysiologic role in HAE.

Immunoregulatory disorders associated with hereditary angioedema. II. Serologic and cellular abnormalities.

Hereditary angioedema is defined biochemically by a deficiency in the functional activity of the inhibitor of Cl, Cl esterase inhibitor (Cl INH). Deficiency of this regulator of the early classic pathway of complement results in chronic activation of this cascade with a resultant deficiency of C4 and C2. Ninety-seven patients with either complicated (associated with autoimmune disorders) or uncomplicated hereditary angioedema were evaluated for laboratory evidence of immunoregulatory defects. Specific cellular and humoral abnormalities were found and included increased mean total lymphocyte counts, increased mean Leu 4+ (total) and Leu 3+ (helper) T cells, an increased mean Leu 3/Leu 2 (helper/suppressor T cell) ratio, polyclonal B cell activation, and evidence of circulating immune complexes. C4 functional titers were negatively correlated with percent Leu 3+ cells and absolute Leu 3+ cell numbers. We failed to detect any evidence of immune deficiency in this population, and yet a statistically significant number of patients demonstrated elevated levels of antibodies to Epstein-Barr virus antigens when patients were compared to a control group. Thus, early classic complement pathway activation and/or partial complement component deficiency may effect T cell subpopulations and B cell activation. However, additional predisposing factors (e.g., genetic or viral) appear necessary for the development of a particular autoimmune disease in hypocomplementemic patients.

Immunoregulatory disorders associated with hereditary angioedema. I. Clinical manifestations of autoimmune disease.

Occasional reports have appeared linking hereditary angioedema (HAE) with autoimmune diseases. We have systematically evaluated 157 patients for manifestations of autoimmunity. Nineteen of these patients (12%) had clinical immunoregulatory diseases including glomerulonephritis (five patients), Sjögren's syndrome (three), inflammatory bowel disease (three), thyroiditis (two), systemic lupus erythematosus (one), drug-induced lupus (one), rheumatoid arthritis (one), juvenile rheumatoid arthritis with IgA deficiency (one), incipient pernicious anemia (one), and sicca syndrome (one). All eight patients with HAE who developed an autoimmune disease with a known human histocompatibility antigen association developed a disease associated with their histocompatibility antigen haplotype (p = 0.014). Although only four patients developed Sjögren's syndrome or sicca syndrome, an additional nine manifested part of the sicca complex. We also found patients with HAE with features suggestive of an immune-based abnormality. These features included idiopathic pancreatitis (three patients), Raynaud's disease (two), partial lipodystrophy (one), chronic chorioretinitis (one), and alopecia universalis (one).

Abnormal clearance of immune complexes from the circulation of patients with primary sclerosing cholangitis.

The ability of fixed macrophages of the reticuloendothelial system to clear circulating immune complexes was studied in 6 patients with primary sclerosing cholangitis, 5 patients with various other forms of chronic liver disease, and 12 normal control subjects. Autologous red cells were radiolabeled with 51Cr and sensitized with anti-Rh(D) immunoglobulin G in vitro. After intravenous infusion of the labeled antibody-coated red cells, the radioactivity content of timed blood specimens was measured. The time required by the reticuloendothelial system to clear one-half the labeled cells from the circulation (t1/2) was then determined. The t1/2 clearance times were significantly prolonged in all 6 patients with primary sclerosing cholangitis, whereas the clearance times in 4 of the 5 liver disease control patients were either normal or shortened. Serum immunoglobulin G and immunoglobulin M immune complex levels did not correlate with t1/2 clearance times. These results suggest that in primary sclerosing cholangitis there is a defect in the ability of fixed macrophages of the reticuloendothelial system to mediate clearance of circulating particles that have been opsonized with immunoglobulin G. This finding further supports recent data that incriminates the immune system in the pathogenesis of primary sclerosing cholangitis.

Monocyte receptors for the Fc portion of IgG increase in number in autoimmune hemolytic anemia and other hemolytic states and are decreased by glucocorticoid therapy.

Peripheral blood monocyte receptors for the Fc portion of IgG were quantitatively studied in 43 normal subjects, in 14 patients with warm antibody autoimmune hemolysis (AIHA), and in nine individuals with nonantibody-mediated hemolysis. Monocytes of normal females expressed significantly greater numbers of Fc gamma receptors than did similar cells from male subjects, with no difference in affinity for the IgG1 probe. Monocyte Fc gamma receptor number was increased in patients of both sexes with AIHA; a similar, but smaller, increase in monocyte Fc gamma receptor number was noted in patients with nonantibody-mediated hemolysis. Glucocorticoid administration was associated with a dose-dependent decrease in monocyte Fc gamma receptor number in normal volunteers and patients. Possible etiologic mechanisms and pathogenetic consequences of enhanced monocyte Fc gamma binding in AIHA are discussed.