Cytokines and growth factors in a biologic product obtained from patients' urine as immune-modulators to treat autoimmune and allergic diseases.

At "Instituto de Alergias y Autoinmunidad Dr. Maximiliano Ruiz Castañeda, A.C." in Mexico City, a non-traditional health care center focused on the treatment of autoimmune and allergic diseases using personalized medicine, an alternative treatment referred to as an "immune-modulator" has been developed. In this study, we will refer to this treatment substance as the "immune-modulator." In brief, a urine sample is collected from the patient and processed to obtain the peptide fraction, which is conditioned and then administered sublingually to the patient. Sample processing involves multiple steps aimed at the removal of toxic compounds and enrichment for cytokines, growth factors, and other immune peptides that may contribute to the function of the immune-modulator. This treatment has been administered for many years, and patients testify that it is useful and reliable. Despite the benefits of this treatment, the molecular mechanisms underlying its effects have not been thoroughly investigated. Therefore, this study aims to identify immunoregulatory peptides, such as cytokines and growth factors, in the immune-modulator. Urine and immune-modulator concentrations of cytokines and growth factors were assessed using a Luminex assay. Twenty-one cytokines and growth factors were identified in immune-modulator samples. MCP-1 was identified in 100% of the samples; MIP-1ß, IL-8, RANTES, INF-γ, and IP-10 were identified in approximately 65-70% of samples; IL5, IL-1B, and IL-17 in 50-60%; eotaxin, VEGF, IL-6, and FGF in about 40%; MIP-1α, IL-9, GM-CSF, G-CSF, IL-12, and IL-15 in about 20-30%; and IL-13 and PDGF-bb were identified in <6% of samples. Additionally, patients exhibited significant changes in IL-1ß, IFN-γ, and MCP-1 concentrations after treatment with the immune-modulator, whereas healthy individuals showed no significant change in response to the treatment. The immune-modulator is an alternative treatment based on the administration of cytokines and growth factors obtained from the urine of patients. In this study, its composition was characterized. The isolated products could be responsible for the effects of the immune-modulator. Further trials are required to evaluate the effective delivery of these molecules by the administration route described.

Pediatric Acute-onset Neuropsychiatric Syndrome and Mycoplasma Pneumoniae Infection: A Case Report Analysis with a Metabolomics Approach.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinical condition characterized by a sudden and dramatic obsessive-compulsive disorder with a suggested post-infectious immune-mediated etiology. This condition is accompanied by an extensive series of relatively serious neuropsychiatric symptoms. The diagnosis of PANS is made by "exclusion", as the individual PANS symptoms overlap with a multiplicity of psychiatric disorders with the onset in childhood. A number of researchers accumulated evidence to support the hypothesis that PANS was closely associated with a number of infections. In the last decade, metabolomics played an essential role in improving the knowledge of complex biological systems and identifying potential new biomarkers as indicators of pathological progressions or pharmacologic responses to therapy. The metabolome is considered the most predictive phenotype, capable of recognizing epigenetic differences, reflecting more closely the clinical reality at any given moment and thus providing extremely dynamic data. In the present work, the most recent hypothesis and suggested mechanisms of this condition are reviewed and the case of a 10 - year-old girl with PANS is described, before and after clarithromycin treatment. The main results of this case report are discussed from a metabolomics point of view. The alteration of several metabolic pathways concerning the microbial activity highlights the possible role of the microbiome in the development of PANS. Furthermore, different metabolic perturbations at the level of protein biosynthesis, energy and amino acid metabolisms are observed and discussed. Based on our observations, it is believed that metabolomics is a promising technology to unravel the mysteries of PANS in the near future.

Urinary candidate biomarkers in an experimental autoimmune myocarditis rat model.

Urine is a better source than plasma for biomarker studies, as it can accumulate all changes in the body. Various candidate urinary biomarkers of physiological condition, kidney disease and even brain dysfunction, have been detected in urine; however, urine has rarely been used to reflect cardiac diseases. In this study, urine at day 0, 14, 21 and 28 were collected from the myosin-induced autoimmune myocarditis rat models. The candidate urinary biomarkers were then characterized using the isobaric tandem mass tag labeling approach coupled with offline two-dimensional reverse-phase liquid chromatography and high-resolution mass spectrometry. Compared with controls, forty-six urinary proteins were significantly changed in the myocarditis rats; among them, ten had previously been associated with myocarditis, twelve corresponding gene products had annotated as mainly cardiovascular network genes by the Ingenuity Pathway Analysis, four urinary proteins were validated by western blot, thirteen were reported in previous urine proteome studies of other diseases and twenty-six were reported the first time to be related to myocarditis. SIGNIFICANCE: This is the first study to use isobaric tandem mass tag labeling approach in the urine proteome analysis of experimental autoimmune myocarditis. These findings may provide clues for the pathogenesis of myocarditis. And the study showed that urine can be a good source of myocarditis biomarkers.

Pregnancy in immunoglobulin M nephropathy.

Immunoglobulin M nephropathy is an uncommon glomerular disease and a relatively less recognized clinico-immunopathological entity in the domain of glomerulonephritis, often thought to be a bridge between minimal change disease and focal segmental glomerulosclerosis. It is characterized by asymptomatic hematuria, episodes of macroscopic hematuria and proteinuria. Corticosteroids remain the mainstay of therapeutic strategies for such patients. We present what we believe to be the first known case of successful pregnancy in a 40-year-old woman with a 12-year history of underlying immunoglobulin M nephropathy. In view of the rarity of this disease we hope this report will assist professionals managing such cases.

Urine metabolome profiling of immune-mediated inflammatory diseases.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. METHODS: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. RESULTS: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (P FDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an over-representation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. CONCLUSIONS: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.

Proteomics and autoimmune kidney disease.

Proteomics has long been considered an ideal platform, and urine an ideal source for biomarker discovery in human autoimmune kidney diseases. A number of studies have examined the urine proteome to identify biomarkers of disease activity, kidney pathology, and response to therapy. Increasingly, proteomic studies of kidney disease have expanded to include blood, circulating cells and kidney tissue. Recently the clinical potential of renal proteomics has been realized through a handful of investigations whose results appear to be applicable to patient care. In this review, approaches to the proteomic evaluation of autoimmune kidney diseases will be considered in the context of developing clinically useful disease biomarkers.

Hypocomplementaemic urticarial vasculitis syndrome: a mimicker of systemic lupus erythematosus.

A middle aged female patient presented with generalised palpable purpura associated with intense pruritus along with subconjunctival haemorrhage and orbital inflammation. There was extensive dermographism. Other systemic examinations were within normal limits. Haematological profile was normal except raised D-dimer. Skin biopsy revealed the presence of leucocytoclastic vasculitis. Antinuclear antibody was positive in a titre of 1 : 160, but antidouble-stranded DNA was negative. Urine examination revealed haematuria and proteinuria. Complement C3, C4 and C1q levels were decreased with the presence of anti-C1q antibody. There was a diagnostic dilemma between systemic lupus erythematosus and hypocomplementaemic urticarial vasculitis syndrome. However, as the patient did not fulfil the American College of Rheumatology criteria for systemic lupus erythematosus, but fulfilled all the criteria for hypocomplementaemic urticarial vasculitis syndrome, the case was finally diagnosed as hypocomplementaemic urticarial vasculitis syndrome and treated accordingly with favourable outcome.

[Personalized reamberin therapy in patients with decompensated LADA 1.5 diabetes mellitus].

The aim of the study was to develop a new strategy of dosing a Reamberine 1,5% infusion solution on an individual basis for patients with LADA 1.5 diabetes mellitus (DM) and new methods for estimating the regulation and functioning of metabolic pathways associated with the production and transformation of succinic acid. The use of Reamberin led to the reduction of average, maximum and minimum blood glucose and HBA1c levels. The study revealed a decrease of proteinuria, serum creatinine level, and albumin/creatinine ratio in urine Patients given intensive therapy with insulin and Reamberin underwent significant reduction of blood Na', K+ and chlorine levels and increased Na+/K+, Mg++ and Ca++ ratios. Morning and evening concentrations of ACTH decreased while cortisol levels increased at 8.00 and 18.00. IRI level decreased, T3 and T4 levels increased both at 8.00 and 18.00 when TSH concentration was reduced The percentage of patients unsatisfied with QL (based on the Diabetes QL scale) among those taking Reamberine diminished while that of the patients satisfied with QL increased. The first data on dynamics of plasma protein expression during Reamberin therapy are presented

Relationship between mercury levels in blood and urine and complaints of chronic mercury toxicity from amalgam restorations.

AIM: To determine whether patients complaining of oral and medical symptoms perceived to be associated with chronic mercury toxicity have elevated mercury levels in their blood and urine. METHODS: The study group in this audit were 56 patients presenting to an oral medicine unit with complaints perceived to be related to chronic mercury toxicity. Their symptoms and co-morbidity were charted and mercury levels in blood and urine were biochemically tested by atomic absorption spectrophotometry. RESULTS: None had elevated mercury levels in blood or urine above the normal threshold level. Subgroup analysis showed subjects with oral lesions, autoimmune disorders and multiple sclerosis had relatively and significantly higher mercury levels within this cohort, but within the threshold values. When tested by multiple logistic regression adjusted for age and gender, mercury levels in blood or urine, numbers of amalgams were not significant for multiple sclerosis or previously diagnosed autoimmune disease. CONCLUSION: Mercury levels in blood and urine of this cohort of patients with perceived chronic mercury toxicity were within the normal range in accordance with a national laboratory threshold value.

Adenylyl cyclase-associated protein-1/CAP1 as a biological target substrate of gelatinase B/MMP-9.

Matrix metalloproteinases (MMPs) are classically associated with the turnover of secreted structural and functional proteins. Although MMPs have been shown to process also a kaleidoscope of membrane-associated substrates, little is known about the processing of intracellular proteins by MMPs. Physiological and pathological cell apoptosis, necrosis and tumor lysis by chemotherapy, radiotherapy or immunological cytotoxicity, are examples of conditions in which an overload of intracellular proteins becomes accessible to the action of MMPs. We used a model system of dying human myelomonocytic cells to study the processing of intracellular protein substrates by gelatinase B/MMP-9 in vitro. Adenylyl cyclase-associated protein-1 or CAP1 was identified as a novel and most efficient substrate of gelatinase B/MMP-9. The presence of CAP1 in the extracellular milieu in vivo was documented by analysis of urine of patients with systemic autoimmune diseases. Whereas no active MMP-9 could be detected in urines of healthy controls, all urine samples of patients with clinical parameters of renal failure contained activated MMP-9 and/or MMP-2. In addition, in some of these patients indications of CAP1 cleavage are observed, implying CAP1 degradation in vivo. The high turnover rate of CAP1 by MMP-9, comparable to that of gelatin as the natural extracellular substrate of this enzyme, may be critical to prevent pathological conditions associated with considerable cytolysis.

Excess urinary iodine is associated with autoimmune subclinical hypothyroidism among Egyptian women.

Excessive iodine exposure was reported to be associated with thyroid dysfunctions. The aim of this study is to evaluate the link between excess urinary iodine as the prime indicator of excessive iodine intake and autoimmune subclinical hypothyroidism (SCH) among Egyptian women. Seventy three women with autoimmune SCH and 60 age- matched healthy women as controls were enrolled in this study. TSH, FT4, urinary iodine concentrations (UIC) and thyroid peroxidase antibody (TPOAb) were estimated. The levels of urinary iodine were significantly higher in patients with SCH as compared with control subjects, (326.97 112.98 vs. 274.45 98.75 microg/l, p<0.01). In patients with SCH, there was a significant correlation between UIC and TSH levels. Also, a significant correlation between UIC and TPOAb was found. We conclude that excessive iodine intake may trigger thyroid autoimmunity and eventually thyroid hypofunction among Egyptian women.

[Is decreased thyroid echogenity a good indicator of thyroid autoimmune disorder?]. / Je snízená echogenita stítné zlázy dobrým ukazatelem jejího autoimunitního postizení!

INTRODUCTION: Thyroid gland with mildly decreased or significantly decreased echogenity is indicating possible autoimmune disorder even before first symptoms, i.e. change in laboratory tests measuring the level of thyroid hormones and antibodies to thyroid antigens occur. TARGET: to consider changes in thyroid gland echogenity suspecting thyroid autoimmune disorder and to determine antibodies to thyroid antigens in the respective type of thyroid echogenity (increased, normal, mildly decreased or significantly decreased) to consider the activity of autoimmune thyropathies related to echogenity and to compare these factors. METHODS: Echogenity of the thyroid gland was examinated in randomly selected population (n = 1 055, 360 male, 695 female) in 11 regions of the Czech republic, all presented with urinary iodine concentration > 100 microg/L of urine. The echogenity was determined in 4-level scale as increased (1), normal (0), mildly decreased (-1) and significantly decreased (-2). Texture of thyroid was evaluated in 2-level scale as homogenous or non-homogenous. For the evaluation of the relation between echogenity type (1 to -2) and TgAb, and between the type of echogenity and TOPAb frequence analysis (logarithm-linear modules) was used, i.e. the complete module was compared with the measured values. RESULTS: The selected adults (695 female, 360 male) with urinary iodine concentration > 100 microg/L of urine presented with increased echogenity in 2 females (0.28%) and 1 male (0.28%), normal echogenity in 281 females (40.42%) and 206 males (57.22%), mildly decreased echogenity in 288 females (41.43%) and 128 males (35.56%) and significantly decreased echogenity in 124 females (17.84%) and 25 males (6.95%). The biggest group, both in males and in females, presented with normal and mildly decreased echogenity. Homogenous thyroid gland structure was found in 223 females (32.08%) and 220 males (61.11%). Non-homogenous texture was found in 472 females (67.92 %) and 140 males (38.89%). Frequence analysis both in males and in females was focused on: 1. relation between the echogenity (ECHO) and TgAb: in females with positive TgAb (14.23%), significant relation to ECHO can be seen (p < 0,0001), in contradiction to males; 2. relation between the echogenity (ECHO) and TPOAb: this relation is very significant both in males and in females (p < 0.0001); 3. mutual relation between TgAb and TPOAb: both in males and in females very significant (p < 0.0001); positive relation between antibodies can be seen. Positive presence of antibodies can be found less frequent, negative presence of both antibodies is more frequent; 4. relation between the echogenity, TgAb and TPOAb: no statistic significance was found. CONCLUSION: Homogenous thyroid gland structure was mainly found in males and, on the contrary, non-homogenous structure in females. In 52.7% of adults with significantly decreased echogenity, autoimmune disorder was confirmed in laboratory tests at the same time. With echogenity increasing, TgAb and TPOAb decreased, vice versa. Sonography, evaluating decreased echogenity, can be an early indicator of serious thyropathies before function parameters and clinical symptoms appear. Detected risky adults with sonographic signs of autoimmune disorder have to be monitored and respective treatment considered and started at the very first occurence of positive antibodies even if the function is still normal.

Bone and calcium metabolism in subclinical autoimmune hyperthyroidism and hypothyroidism.

Bone turnover is reported to increase in favour of resorption in overt hyperthyroidism and the rate of resorption is associated with the levels of thyroid hormones. Hypothyroidism, on the other hand, was shown to cause no disturbance of calcium kinetics and found to associate lower trabecular resorption surfaces and increased bone cortical thickness. Similar studies are very rare in subclinical thyroid disorders and consequently we aimed to examine calcium and bone metabolism in subclinical thyroid disorders. Thirteen patients with subclinical hyperthyroidism secondary to untreated Graves' disease, 20 patients with subclinical hypothyroidism and 10 healthy subjects participated in this survey. Briefly calcium, phosphorus, and creatinine (Cre), urinary deoxypyridinoline (U-DPD) and serum osteocalcin (OC) were measured as biochemical markers for calcium metabolism. Concerning serum Ca and phosphorus levels, there were no differences between three of the groups, but urinary Ca excretion was higher in subclinical hyperthyroid patients compared to control and hypothyroid subjects. Hypothyroid patients had similar U-DPD levels with control subjects (p = 0.218). Serum OC and U-DPD were higher in subclinical hyperthyroid compared to control subjects (p<0.001 and p<0.001 respectively). We demonstrated a higher bone turnover and greater calcium excretion in subclinical hyperthyroid patients. Additionally, we found that subclinical hypothyroidism is not associated with disturbed calcium metabolism. As persistent increase in bone turnover is responsible for accelerated bone loss, patients with Graves' disease may have increased risk for osteoporosis.

Serum osteocalcin levels in premenopausal rheumatoid arthritis patients.

The objective of this study was to assess the occurrence of generalized bone loss in rheumatoid arthritis (RA) patients and to evaluate the factors influencing bone loss, in particular, the usefulness of bone turnover markers. Twenty-five premenopausal patients (mean age, 40 x 5 years) with active RA were compared with 27 age-matched premenopausal patients with RA but without active disease and 30 age-matched healthy premenopausal controls. Serum concentrations of osteocalcin, intact parathyroid hormone (PTH), spot urine concentrations of crosslinked N-telopeptidases of type 1 collagen (NTX), and deoxypyridinoline (DPD) were detected by ELISA and radioimmunoassay. Serum osteocalcin levels were found to be significantly lower (p < 0.001) in patients with active RA compared with patients without active RA and controls. Similarly, serum intact PTH was significantly lower (p < 0.01) in patients with active RA than in patients with RA without active disease and controls. Spot urine concentrations of NTX and DPD were significantly higher (p < 0.01) in active RA patients than in patients with nonactive RA and controls. Positive correlations between osteocalcin and marker of disease activity were found to be significant (p < 0.01). There were no significant correlations between serum intact PTH, urine concentrations of NTX and DPD, and markers of inflammation. This study suggests that generalized bone loss occurs in active RA and is characterized by an evident bone resorption correlated with the high levels of inflammation.

Treatment with cytotoxic immunosuppression agents increases urinary excretion of JCV in patients with autoimmune disease.

Human JC virus is ubiquitous in human populations and is reactivated frequently in immunosuppressed patients. Fifty-one patients with autoimmune disease receiving immunomodulating therapy were evaluated to study the possible relationship between immunosuppression and JCV viruria. Patients were divided into cytotoxic and noncytotoxic treatment groups based on their prescription. The incidence of JCV viruria in the cytotoxic treatment group was significantly higher than that in the noncytotoxic group (67% vs. 28%; P < 0.05). Most patients with JCV viruria were receiving corticosteroid (P = 0.03 for any dose and P < 0.001 for higher-dose treatments) and cytotoxic agents (P = 0.02). Age, disease duration, and medication duration appeared not to be the precipitating factors of JCV viruria in this study. The results of clinical evaluation indicate that cytotoxic immunosuppression may play an important role in JC virus reactivation.

Can serum amyloid A or macrophage colony stimulating factor serve as marker of amyloid formation process?

Amyloid formation depends on amyloid precursor production and is influenced by the activity of the underlying disorder and mediated by some proinflammatory cytokines. In this pilot study we tried to find some specific markers that could establish the activity of the disease. We investigated 45 samples of sera and 38 samples of urine from patients (pts) with secondary amyloidosis (AA), primary amyloidosis (AL), systemic autoimmune diseases with renal impairment (Vasc) and healthy controls (Co). Pts with AA had increased plasma levels of TNF alpha (9.97 +/- 4.22 vs. 2.63 +/- 1.34 pg/mL, p < 0.001) and SAA (43.14 +/- 16.0 vs. 3.42 +/- 0.7 ng/mL, p < 0.05) in comparison with Co. Plasma levels of M-CSF in the AA group were significantly increased in comparison with Co (1077.34 +/- 238.6 vs. 137.71 +/- 19.6, pg/mL, p < 0.001) and also in comparison with Vasc (482.24 +/- 86.7 pg/mL, p < 0.05). Urinary excretions of TNF alpha (8.92 +/- 8.1 vs. 0.17 +/- 0.11 microgram/mol creatinine, p < 0.01), sIL-6R (1.39 +/- 1.14 vs. 0.07 +/- 0.05 g/mol creatinine, p < 0.01) and M-CSF (650.2 +/- 153.7 vs. 33.3 +/- 8.6 micrograms/mol creatinine, p < 0.01) in AA were significantly increased in comparison with Co. Pts with AL had increased plasma levels of M-CSF (819.83 +/- 264.2 vs. 137.71 +/- 19.6 pg/mL, p < 0.05) and urinary excretion of M-CSF (865.0 +/- 188.4 vs. 33.3 +/- 8.6 micrograms/mol creatinine, p < 0.01) in comparison with Co. SAA has a low specificity for amyloidosis but is a sensitive acute phase reactant. TNF alpha, a proinflammatory cytokine, may reflect the activity of the underlying diseases in secondary amyloidosis. M-CSF was increased both in plasma and urine in amyloidosis groups and seems to be the most promising (possibly specific) marker of amyloidosis.

Thyroid autoimmunity is associated with higher urinary iodine concentrations in an iodine-deficient area of Northwestern Greece.

Northwestern Greece was identified in the 1960s for its high prevalence of endemic goiter and iodine deficiency. Although iodized salt has been commercially available since then, a recent epidemiological survey of 3916 schoolchildren found that low-grade goiter is still prevalent in endemic proportions (21%). The aim of this study was to further assess the cause of goiter and the severity of iodine deficiency in children from this endemic area of Greece. Of the 800 children with clinically detectable goiter, 97 children (60 girls and 37 boys, 8-15 years) were recruited for determination of urinary iodine excretion, as well as assessment of thyroid volume and function and detection of antithyroid antibodies. The median urinary iodine concentration was 8.4 microg/dL, indicative of a mild iodine deficiency. Thyroid function was normal in all but 11 children who had subclinical hypothyroidism. Sixteen children (16.5%), including all those with subclinical hypothyroidism, were positive for antithyroid antibodies. Their median urinary iodine concentration (20.6 microg/dL) was higher compared to children who were negative for antibodies (7.4 microg/dL; p<0.001). The mean thyroid volume by ultrasonography (12.2+/-4.1 mL) was above the upper limit of normal for this age group. Thyroid volume was inversely related to the urinary iodine content in the children with negative antithyroid antibodies. Iodine deficiency is still prevalent in northwestern Greece although of mild severity and constitutes the primary cause of goiter among schoolchildren. However, it appears that autoimmune thyroiditis is emerging as a frequent cause of goiter in those children with sufficient iodine intake.

Silicone gel enhances the development of autoimmune disease in New Zealand black mice but fails to induce it in BALB/cAnPt mice.

Anecdotal evidence links silicone gel breast implants with the development of autoimmune connective tissue disease in women. To investigate whether silicone gel is capable of directly inducing and/or enhancing the development of autoimmune disease, female BALB/cAnPt (BALB/c) and New Zealand Black (NZB) mice were injected subcutaneously with silicone gel, pristane, a nonmetabolizable substance that can cause plasmacytomas in BALB/c and NZB mice, or saline and monitored for the development of glomerulonephritis and autoantibody production. NZB, but not BALB/c, mice spontaneously develop autoantibodies and an autoimmune hemolytic anemia by 12 months of age. Over a period of 10 months, biweekly screening for proteinuria revealed increases in urinary protein in NZB mice that received multiple injections of either silicone gel or pristane. In contrast, urinary protein was unaffected in identically treated BALB/c mice. Although, silicone gel had no effect on serum titers of antierythrocyte antibodies in NZB mice, the hematocrits were significantly decreased. Moreover, silicone gel both increased the concentration of IgM anti-type I collagen antibodies and skewed the immunofluorescent staining pattern of serum autoantibodies on HEp-2 cells. In contrast, silicone gel failed to induce the production of anti-erythrocyte or antinuclear antibodies in BALB/c mice and induced only slight increases in IgG anti-type I collagen antibodies. These results suggest that silicone gel can exacerbate the development of autoimmune disease in autoimmune NZB mice, but fails to induce disease in normal BALB/c mice. This is consistent with several epidemiological studies failing to demonstrate an increase in the incidence of autoimmune disease in women with breast implants. However, because silicone gel was able to exacerbate autoimmune disease in NZB mice, it may play a similar role in the development of autoimmune disease in a small percentage of women who are genetically susceptible to such diseases.