Serum Levels Of Total IgG Research Articles

At-retinal differentially regulates Foxp3+ regulatory and IL-17+ pathogenic T cell in autoimmune arthritis (148.7)

Abstract Retinoids can regulate immune responses. The aim of this study was to determine whether all-trans retinal (at-retinal) improves the inflammation responses and destruction of joints on collagen-induced arthritis (CIA). The arthritis score and incidence of arthritis were lower in the mice treated with at-retinal. Histopathologic evidence of joint damage was lower, and the infiltrations of immune cell were reduced in the mice treated with at-retinal. CII-stimulated proliferation of spleen cells, the expression of cytokines and oxidative stress proteins the serum levels of total IgG and IgG2a anti-CII antibodies, and the expression of osteoclast markers were significantly reduced in the mice treated with at-retinal. In vitro, at-retinal increased Foxp3 expression. At-retinal also inhibits inhibits Th17 development. The proportion of Foxp3+ Treg cells was increased in the spleen of mice treated with at-retinal, whereas the proportion of Th17 cells was reduced. In both mice and human culture system, TRAP positive mononuclear cells and multinucleated cells were significantly reduced in the presence of at-retinal. Taken together, these findings indicate that at-retinal has profound immunoregulatory functions and potential protective values for the treatment of autoimmune inflammatory disorders.

IVIG for Refractory Clostridium difficile Colitis in an Immunosuppressed Patient

Purpose: Background: Clostridium difficile-associated diarrhea (CDAD) is increasing in incidence and severity, with recent outbreaks due to more virulent strains.1 Metronidazole is still considered the first-line therapy, with oral Vancomycin reserved for severe cases.2 CDAD is, however, becoming increasingly refractory to these two therapies. Intravenous immunoglobulin (IVIG) has been reported as an alternative treatment for refractory cases in several case reports and three uncontrolled studies.3 Case Report: A 56 year-old female with a history of multiple sclerosis (MS) presented with sudden bilateral lower extremity weakness, bloody diarrhea, and diffuse abdominal pain. Home medications included monthly Natalizumab and a recent 7 day course of Ciprofloxacin. She was diagnosed with CDAD by positive stool toxin and treated with Metronidazole 500 mg orally three times daily. She also received intravenous Methylprednisolone 1 gram daily for 5 days for MS exacerbation. The diarrhea initially improved, but became increasingly severe and associated with abdominal pain and distention one week after initiating Metronidazole therapy. Oral Vancomycin was added to the regimen, but the patient failed to improve. Stool toxin remained positive at 10 days. Leukocyte count remained persistently high at 35.000-40.000/dl. Abdominal computerized tomography revealed diffuse colonic wall thickening and ileus. On day 11, the patient was transferred to the intensive care unit. Vancomycin enemas were considered, but the patient could not tolerate them due to profuse diarrhea. Serum levels of total IgG, and of IgG1, IgG2, and IgG4 were low. The patient was administered two doses of IVIG 400 mg/kg on days 13 and 14. She had a significant clinical improvement after the IVIG and colectomy was thereby avoided. Discussion: Patients with severe CDAD may have a defective humoral response to toxin A as suggested by finding lower levels of IgG antitoxin A antibodies in these patients4,5. Correction of hypogammaglobulinemia by IVIG administration in the post-transplant period has been shown to decrease the incidence of CDAD6. The currently reported patient was on Natalizumab maintenance therapy, and received high-dose steroids synchronous with treatment for CDAD. Both factors are associated with CDAD development and relapse7,8. She failed both Metronidazole and oral Vancomycin therapy, but improved promptly with administration of IVIG. Colectomy was thereby averted. IVIG therapy may be considered as salvage therapy in immunosuppressed patients with refractory CDAD, especially if they have hypogammaglobulinemia.

Assessment of trichloroethylene (TCE) exposure in murine strains genetically-prone and non-prone to develop autoimmune disease

There is increasing laboratory and epidemiologic evidence relating exposure to trichloroethylene (TCE) with autoimmune disease including scleroderma and lupus. New Zealand Black/New Zealand White (NZBWF1) and B6C3F1 mice were exposed to TCE (0, 1, 400 or 14,000 ppb) via drinking water for 27 or 30 weeks, respectively. NZBWF1 mice spontaneously develop autoimmune disease while B6C3F1 mice, a standard strain used in immunotoxicology testing, are not genetically prone to develop autoimmune disease. During the TCE exposure period, serum levels of total IgG, and autoantibodies (anti-ssDNA, -dsDNA, and -glomerular antigen [GA]) were monitored. At the termination of the study, renal pathology, natural killer (NK) cell activity, total IgG levels, autoantibody production, T-cell activation, and lymphocytic proliferative responses were evaluated. TCE did not alter NK cell activity, or T- and B-cell proliferation in either strain. Numbers of activated T-cells (CD4+/CD44+) were increased in the B6C3F1 mice but not in the NZBWF1 mice. Renal pathology, as indicated by renal score, was significantly increased in the B6C3F1, but not in the NZBWF1 mice. Serum levels of autoantibodies to dsDNA and ssDNA were increased at more time points in B6C3F1, as compared to the NZBWF1 mice. Anti-GA autoantibodies were increased by TCE treatment in early stages of the study in NZBWF1 mice, but by 23 weeks of age, control levels were comparable to those of TCE-exposed animals. Serum levels anti-GA autoantibodies in B6C3F1 were not affected by TCE exposure. Overall, these data suggest that TCE did not contribute to the progression of autoimmune disease in autoimmune-prone mice during the period of 11–36 weeks of age, but rather lead to increased expression of markers associated with autoimmune disease in a non-genetically prone mouse strain.

Gentamicin-attenuated Leishmania infantum: A clinicopathological study in dogs

The clinicopathological changes following infection with an attenuated line of Leishmania infantum ( L. infantum H-line) were evaluated in mixed breed dogs. Two groups of dogs were infected intravenously (i.v.) or intradermally (i.d.) with L. infantum H-line and two control groups were infected i.v. or i.d. with L. infantum wild-type ( L. infantum WT). None of the dogs, which were infected i.v. or i.d. with L. infantum H-line, showed any abnormalities during the observation period. In contrast, two out of three dogs, which were infected i.v. with L. infantum WT, developed clinical signs of disease. In addition, no histopathological changes were seen in the liver and spleen of the dogs infected with the attenuated line of parasite, whereas the histopathological changes in the two dogs infected i.v. with L. infantum WT were severe in form and manifested by infiltration of high numbers of inflammatory cells. No promastigotes were found in cultures set up from spleens and livers of dogs infected with L. infantum H-line at 12 months post-infection, whereas promastigotes were seen in the spleen and liver cultures from 2 dogs infected i.v. with L. infantum WT. Serum levels of total IgG anti- Leishmania antibody were raised in all dogs. The antibody level in the serum of dogs infected i.v. with L. infantum WT was higher than that in dogs infected with L. infantum H-line. These results show no clinicopathological abnormalities in the dogs infected with gentamicin-attenuated L. infantum H-line. Moreover, L. infantum H-line induced IgG anti- Leishmania antibody in the dogs.

Osteoprotegerin modulation of immunefunction during of the atherosclerotic lesion progression

Osteoprotegerin (OPG) is a secreted TNF‐like decoy receptor shown to regulate bone homeostasis. Evidence indicates that serum levels of OPG correlate with the severity of cardiovascular disease. We have shown that in ApoE−/− mice, OPG deficiency worsen the lesion burden, suggesting that OPG is an athero‐protective factor. Recent studies indicate that OPG also plays a role in adaptive immunity. B cells subsets are expanded in OPG−/− mice, and in vivo OPG induces increase of IgM and IgG antibodies titers. Furthermore, DCs isolated from OPG−/− mice were more effective in stimulating T‐cells than WT. Thus, we hypothesize that in ApoE−/− mice OPG stimulates the production of athero‐protective antibodies and dampens the production pro‐atherogenic Th1 cytokines, thus explaining the increased lesion size observed in ApoE−/− mice also lacking OPG. To test this hypothesis we have measured serum levels of total IgG and IgM, and of anti‐ox‐LDL antibodies. We have also measured serum levels for the pro‐atherogeneic IL12 cytokine. We have found that ApoE−/− OPG−/− mice have lower serum levels of IgM and IgG and lower serum levels of the atheroprotective anti‐oxLDL antibodies compared to ApoE−/− OPG+/+. ApoE−/− OPG−/− mice have higher serum levels of IL12 than ApoE−/− OPG+/+. In vitro we found that ApoE−/− OPG−/− DCs and macrophages express more IL12 than ApoE−/− OPG+/+. These results indicate that OPG may modulate key immune factors and cells during the atherosclerosis process. Future studies will be aimed to determine whether OPG in immune cells subsets causatively modulate the atherosclerotic lesion progression.Supported by AHA Grant in Aid #0655677Z

Anti-inflammatory effect of all- trans-retinoic acid in inflammatory arthritis

Objective: To determine whether all- trans-retinoic acid (ATRA) improves the destruction of joints and the effect of cytokines on DBA/1J mice with collagen-induced arthritis (CIA). Methods: Starting from the time of type II collagen injection, DBA/1J mice were injected intraperitoneally with PBS or 0.5 mg of ATRA 3 times per week for 35 days. The effects of treatment were monitored by determining arthritis and histological scores and measuring cellular proliferation, production of cytokines (IL-2, IL-10, IL-12, IL-6, IFN-γ, and TNF-α) and IgG, and the expression of mRNAs for inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), and CXCR3. Results: The arthritis score and incidence of arthritis were lower in the mice treated with ATRA than in those treated with PBS. Histopathologic evidence of joint damage was 34% lower, and the infiltrations of macrophages were reduced in the mice treated with ATRA compared with those treated with PBS. Type II collagen- and ConA-stimulated proliferation of spleen cells, the production of cytokines (IL-6, IL-12, and TNF-α), the serum levels of total IgG and IgG1 anti-collagen antibodies, and the expression of mRNAs for MCP-1 were significantly reduced in the mice treated with ATRA than in those treated with PBS. Conclusion: ATRA improved the clinical course and reduced the production of inflammatory cytokines, immunoglobulin, and chemokines in murine CIA. These data suggest that ATRA might be also effective for the treatment of inflammatory arthritis like human rheumatoid arthritis.

Mice expressing HLA-DQ6α8β transgenes develop polychondritis spontaneously

Relapsing polychondritis (RP) is a human autoimmune disease of unknown etiology in which cartilaginous sites are destroyed by cyclic inflammatory episodes beginning, most commonly, during the fourth or fifth decade of life. We have previously described collagen-induced polychondritis that closely mirrors RP occurring in young (6–8 weeks old) HLA-DQ6αβ8αβ transgenic Aβ0 mice, following immunization with heterologous type II collagen (CII).We present evidence here that transgenic strains expressing the DQ6α8β transgene develop spontaneous polychondritis (SP) at the mouse equivalent of human middle age (4.5–6 months and 40–50 years old, respectively) and display polyarthritis, auricular chondritis and nasal chondritis – three of the most common sites affected in RP. Auricular chondritis in SP, like RP but unlike CII-induced polychondritis, exhibited a relapsing/remitting phenotype, requiring several inflammatory cycles before the cartilage is destroyed. Elevated serum levels of total IgG corresponded with the onset of disease in SP, as in RP and CII-induced polychondritis. No CII-specific immune response was detected in SP, however – more closely mirroring RP, in which as few as 30% of RP patients have been reported to have CII-specific IgG. CII-induced polychondritis displays a strong CII-specific immune response. SP also demonstrated a strong female preponderance, as some workers have reported in RP but has not observed in CII-induced polychondritis. These characteristics of SP allow for the examination of the immunopathogenesis of polychondritis in the absence of an overwhelming CII-specific immune response and the strong adjuvant-induced immunostimulatory influence in CII-induced polychondritis.This spontaneous model of polychondritis provides a new and unique tool to investigate both the initiatory events as well as the immunopathogenic mechanisms occurring at cartilaginous sites during the cyclic inflammatory assaults of polychondritis.

Specific antibody levels in the aqueous humor and serum of two distinct populations of patients with ocular toxoplasmosis

The population of Erechim, Southern Brazil, is characterized by a high incidence of ocular toxoplasmosis, which is presumed to be of acquired origin. We wished to compare the local specific humoral immune response of individuals from this region with that of Swiss patients suffering from the same disease. Paired samples of aqueous humor and serum were withdrawn from 27 Brazilian and 50 Swiss patients presenting consecutively with active ocular toxoplasmosis. The total and specific levels of IgG in each of these were determined. The populations did not differ with respect either to age or sex. The serum levels of total IgG in Brazilian (10.8 g/l) and Swiss patients (11.1 g/l) were similar ( p = 0.499 ), but the aqueous humor ones were higher in the former group (95 vs. 20 mg/l; p = 0.0001 ). The systemic and local levels of specific IgG were likewise higher in Brazilian patients [206 i.u. vs. 72 i.u. ( p = 0.001 ) and 14 i.u. vs. 4 i.u. ( p = 0.005 ), respectively] and the number of individuals without detectable levels of local specific IgG was correspondingly lower (11% vs. 54%; p = 0.0005 ). The Goldmann–Witmer coefficient (an index of local specific antibody production) did not differ between Brazilian and Swiss patients (2.1 vs. 0.08, respectively; p = 0.107 ). Our findings are indicative of a more pronounced uveovascular barrier breakdown in Brazilians than in Swiss patients with active ocular toxoplasmosis. That the systemic and local specific immune response is weaker in Swiss than in Brazilian patients has not been hitherto documented. This finding may reflect differences in the immunological handling of the infection.

Decreased Expression of the Ets Family Transcription Factor Fli-1 Markedly Prolongs Survival and Significantly Reduces Renal Disease in MRL/lpr Mice

Increased Fli-1 mRNA is present in PBLs from systemic lupus erythematosus patients, and transgenic overexpression of Fli-1 in normal mice leads to a lupus-like disease. We report in this study that MRL/lpr mice, an animal model of systemic lupus erythematosus, have increased splenic expression of Fli-1 protein compared with BALB/c mice. Using mice with targeted gene disruption, we examined the effect of reduced Fli-1 expression on disease development in MRL/lpr mice. Complete knockout of Fli-1 is lethal in utero. Fli-1 protein expression in heterozygous MRL/lpr (Fli-1(+/-)) mice was reduced by 50% compared with wild-type MRL/lpr (Fli-1(+/+)) mice. Fli-1(+/-) MRL/lpr mice had significantly decreased serum levels of total IgG and anti-dsDNA Abs as disease progressed. Fli-1(+/-) MRL/lpr mice had significantly increased splenic CD8(+) and naive T cells compared with Fli-1(+/+) MRL/lpr mice. Both in vivo and in vitro production of MCP-1 were significantly decreased in Fli-1(+/-) MRL/lpr mice. The Fli-1(+/-) mice had markedly decreased proteinuria and significantly lower pathologic renal scores. At 48 wk of age, survival was significantly increased in the Fli-1(+/-) MRL/lpr mice, as 100% of Fli-1(+/-) MRL/lpr mice were alive, in contrast to only 27% of Fli-1(+/+) mice. These findings indicate that Fli-1 expression is important in lupus-like disease development, and that modulation of Fli-1 expression profoundly decreases renal disease and improves survival in MRL/lpr mice.

Serum Levels of Th2-Type Immunoglobulins are Increased in Weanling Mice Subjected to Acute Wasting Protein-Energy Malnutrition.

The bulk of our knowledge on immunosuppression in malnutrition comes from the experiments done on cell-mediated immunity. However, malnutrition-induced modifications of humoral immunity have been less understood. The objective of this study was to determine the effects of acute protein-energy malnutrition on serum levels of immunoglobulins and their subclasses in murine models. Male and female C57BL/6J mice were allocated to one of the four groups: (1) zero-time control (ZC) (19 days of age); (2) ad libitum intake of a complete purified diet (control group [CG]); (3) restricted intake of the complete diet (restricted group [RG]); and ad libitum intake of an isocaloric low-protein diet (low-protein group [LP]). The three groups other than the zero-time control were maintained on their respective regimens for 14 days, i.e. from 19 through 33 days of age. The restricted intake protocol produced weight loss through energy deficiency (marasmic-type malnutrition), whereas the low-protein diet caused wasting through inadequate protein nitrogen and induced a condition mimicking incipient kwashiorkor. Though serum levels of IgG1 and IgE (Th2-type immunoglobulins) in RG and LP mice were significantly higher than those in CG mice, serum levels of IgG2a and IgG3 (Th1-type immunoglobulins) did not show any significant difference between those three groups. Interestingly, serum levels of IgG2b (another Th2-type immunoglobulin) in LP mice were significantly higher than those in CG and RG mice. In ZC mice serum levels of total IgG, IgG1, IgG2b and IgG3 were significantly higher than those in the other three groups. We concluded that during acute malnutrition, Th1/Th2 balance is apparently shifted towards Th2 arm. This deviation seems to be more prominent during acute protein deficiency. The increased serum levels of immunoglobulins in ZC mice were probably due to the intestinal uptake of those proteins from maternal milk.

Dichotomous effects of complete versus partial class II major histocompatibility complex deficiency on circulating autoantibody levels in autoimmune-prone mice

To assess the effects of altered class II major histocompatibility complex (MHCII) expression on circulating autoantibody levels in C57BL/6 (B6) mice congenic for the Sle1 (B6.Sle1 mice) or Nba2 (B6.Nba2 mice) regions. H-2Ab(+/+) (MHCII-intact), H-2Ab(+/-) (MHCII-intermediate), and H-2Ab(-/-) (MHCII-deficient) littermate B6.Sle1 and B6.Nba2 mice were evaluated for spleen cell phenotype, numbers of splenic Ig-secreting cells, and serum levels of total IgM, total IgG, IgG antichromatin, IgG antihistone, and IgG anti-double-stranded DNA (anti-dsDNA). Compared with their MHCII-intact littermates, MHCII-deficient B6.Sle1 and B6.Nba2 mice developed markedly decreased circulating levels of IgG autoantibodies, along with decreased circulating levels of total IgG. In sharp contrast, MHCII-intermediate mice developed increased circulating levels of IgG autoantibodies. This was associated with increased numbers of splenic Ig-secreting cells and serum levels of total IgG in B6.Sle1 mice, but it occurred without concomitant increases in the numbers of splenic Ig-secreting cells or serum total IgG levels in B6.Nba2 mice. In 2 clinically healthy strains of mice with a genetic proclivity for developing autoantibodies, the effects of class II MHC expression on levels of circulating IgG autoantibodies were found to be complex. In the absence of MHCII expression, circulating IgG autoantibody levels were minimal. With full MHCII expression, circulating IgG autoantibody levels were considerable. With intermediate MHCII expression, circulating IgG autoantibody levels were even greater. These last findings may help explain why heterozygosity at the H-2 locus is associated with increased autoantibody titers and aggravated disease in certain lupus-prone mice.

Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen.

To investigate the role of CD26 in the immune system, CD26 gene knockout mice with C57BL/6 background were used to study the immune response after stimulation with PWM. CD26(-/-) mice display an apparently normal phenotype. However, in their spleen lymphocyte population the percentage of CD4(+) T cells is lower, and that of NK cells is higher, than that in CD26(+/+) mice. In their peripheral blood, CD26(-/-) mice present a conspicuously decreased proportion of CD4(+) NKT lymphocytes. In vitro, the PWM-stimulated IL-4 production was decreased by 60-80% in the supernatants of spleen lymphocytes of CD26(-/-) mice compared to that of CD26(+/+) mice, whereas levels of IL-10 and IFN-gamma were increased. No significant differences were found in the production of IL-2, IL-5, IL-6 and IL-13 between knockout and wild-type mice. After immunization of mice with PWM in vivo, serum levels of total IgG, IgG1, IgG2a and IgE were markedly lower in CD26(-/-) mice than those in CD26(+/+) mice, while no difference was found in IgM production. Further analysis of cytokine levels in vivo revealed a reduced IL-4, IL-2 and delayed IFN-gamma production in sera of CD26(-/-) mice upon immunization with PWM. These results indicate that CD26 contributes to the regulation of development, maturation and migration of CD4(+) T, NK and NKT cells, cytokine secretion, T cell-dependent antibody production and immunoglobulin isotype switching of B cells.

The Changes of Mite-Specific Immunoglobulin A and Transforming Growth Factor-β1 During Immunotherapy of Children with Dust Mite Allergy

Immunoglobulin A (IgA) is the most important immunoglobulin of the mucosa. It can protect the mucosal surface from invasion by foreign pathogens. However, only a few studies have mentioned the changes of allergen-specific IgA after immunotherapy in patients with bronchial asthma. In this study, we sought to investigate the levels of mite-specific IgA, IgE, and IgG4 as well as total IgE, IgG, IgA, and IgM, before and after immunotherapy. Serum levels of transforming growth factor β1 (TGF-β1), the major cytokine secreted by type 3 T helper (TH3) cell and a contributing factor for IgA isotype switch, was also assayed. A total of 19 patients were enrolled in this study. The serum levels of total IgG, IgA, and IgM were measured by rate nephelometry. Total IgE, Dermatophagoides pteronyssinus (Der-p), and Dermatophagoides farinae (Der-f)-specific IgE, and mite-specific IgG4 were determined with commercial radioallergosorbent test (RAST) system. Mite-specific IgA and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA). The results showed a significant increase of mite-specific IgA and IgG4 mean of 7 months after immunotherapy (p < 0.05). TGF-β1 decreases significantly (p < 0.05). There were no significant differences in total IgG, IgE, IgA, and IgM or mite-specific IgE after immunotherapy (p > 0.05). We hypothesized that the increased allergen-specific IgA and IgG4 might work as blocking antibodies at the mucosa and in serum, respectively, after immunotherapy. It might prevent the allergen from penetrating the mucosa or from competing with allergen specific IgE. However, further studies are needed to clarify the role of allergen-specific IgA and TGF-β in the working mechanisms of immunotherapy.

Clinical relevance of autoimmune-related pancreatitis

Recently, a concept of ‘autoimmune pancreatitis’ (AIP) was proposed. Computed tomography, magnetic resonance imaging or ultrasonography show a diffusely enlarged pancreas with a so-called ‘sausage-like’ appearance. Hypergammaglobulinaemia, increased serum levels of total IgG or IgG4, positive autoantibodies such as antinuclear antibody, anti-lactoferrin antibody, anti-CA-II antibody, rheumatoid factor and anti-smooth muscle antibody, were often observed in patients with AIP. Microscopic findings showed fibrotic changes with infiltration of lymphocytes, plasmacytes and sometimes eosinophils in the pancreas. Major subgroups of lymphocytes infiltrating areas around pancreatic ducts were CD4+ T-cells producing IFN-γ. HLA-DR was expressed on pancreatic duct cells as well as CD4+ cells. The diagnosis is made by a combination of clinical, laboratory and morphological findings. Laboratory data, pancreas images and diabetes mellitus in most patients do respond to steroid treatment. In conclusion, autoimmune-related pancreatitis appears to be a unique clinical entity. However, its importance in clinical practice needs further characterization.

Abnormal immunoglobulin subclass patterns in women with a history of recurrent miscarriage

Objective: To determine whether IgG subclass patterns differed between nonpregnant women, healthy pregnant women, and pregnant women with a history of recurrent miscarriage. Design: Controlled clinical study. Setting: An academic setting. Patient(s): Group 1 was comprised of 10 nonpregnant women, group 2 of 10 healthy pregnant women, group 3 of eight pregnant women with a history of recurrent miscarriage and whose pregnancies on this occasion went to term, and group 4 of 10 women with a history of recurrent miscarriage whose pregnancies again failed later in the first trimester. Intervention(s): None of the patients received any medication. Main Outcome Measure(s): Serum levels of total IgG and IgG 1, 2, 3, and 4. Result(s): The results obtained showed that normal pregnancy was associated with a significant increase in total IgG production and an increase in IgG subclasses 1, 2, and 3. Women with a history of miscarriage, but who had a successful pregnancy on this occasion, showed a similar pattern of IgG subclasses. Women with a history of miscarriage and whose pregnancy again ended in miscarriage showed a different IgG subclass pattern. Conclusion(s): Pregnancies that ended in miscarriage showed a different pattern of IgG subclasses than those that continued to term. The changes seen in immunoglobulin patterns could be linked to changes in cytokine production.

Reduction in the incidence and severity of collagen-induced arthritis in DBA/1 mice, using exogenous dehydroepiandrosterone.

This study examined the effect of exogenous dehydroepiandrosterone (DHEA) on the onset, incidence, and severity of collagen-induced arthritis (CIA). DHEA was administered subcutaneously prior to arthritis induction in DBA/1 mice, and the severity of the subsequent arthritis was monitored. Serum levels of total IgG and IgG isotype-specific anti-murine type II collagen were measured. Repeated administration of DHEA during arthritis induction delayed the onset and decreased the severity of arthritis in male and female DBA/1 mice. DHEA failed to have an observable effect on established arthritis. IgG isotype autoantibody levels were found to be decreased in the sera of DHEA-treated mice. Administration of exogenous DHEA offered protection against the development of CIA. These data support the results of human studies in which low DHEA levels have been identified as a potential risk factor for the development of rheumatoid arthritis. These findings also highlight DHEA as a potential therapy worthy of further investigation.

Effects of steroids with different endocrine profiles on the development, morphology and function of the bursa of Fabricius in chickens

This paper describes the effect of various steroids on the anlage of the bursa of Fabricius in chickens. The steroids were administered by dipping embryonated eggs on the third day of incubation in ethanolic solutions of these steroids. The results with about 30 different steroids show that the capacity to inhibit the development of the bursa does not correlate with the endocrine properties of these steroids as measured in routine screening tests for androgenic, anabolic, progestational and oestrogenic activities or with the relative binding affinities for various endocrine receptors. More elaborate studies with several representative steroids show that testosterone (10 mg/ml), nandrolone (10 mg/ml), 11α-hydroxy-nandrolone (10 mg/ml), ethylestrenol (1 mg/ml), lynestrenol (1 mg/ml), and Org OD14 [tibolone] (0.1 mg/ml) induce also histomorphological changes in the remaining bursa tissue still present in 10 day-and 53-day old chickens and in the bursa-dependent sites of their spleens (53-day old chickens only). Testosterone and lynestrenol induced smaller changes than nandrolone or ethylestrenol. Tibolone and 11α-hydroxynandrolone were more effective than nandrolone. All drugs, except testosterone and lynestrenol, impaired antibody formation to Newcastle Disease Virus and decreased the serum levels of total IgG, but not of total IgM. Also these effects were not correlated with endocrine properties. In other studies (for references, see text) we found that several of these steroids, notably tibolone, favourably influence the course of spontaneous autoimmune diseases of NZB/W mice and Obese Strain chickens. Since this autoimmunosuppression is likely to be caused by inhibitory effects on bursa or bursa equivalent, we may use this approach for developing medically useful autoimmunosuppressive steroids with minimal endocrine effects.

Autoimmunization in murine graft-vs-host disease. I. Selective production of antibodies to histones and DNA.

A lupus-like disease characterized by a severe immune complex glomerulonephritis and IgG autoantibody production was induced in (C57BL/6 X DBA/2)F1 mice by injection of parental DBA/2 lymphoid cells. The ensuing graft-vs-host (GVH) reaction resulted in a 10- and a 100-fold increase in serum IgG antibody levels to denatured DNA and total histones, respectively, compared with that in F1----F1 control mice. The level of anti-DNA antibodies peaked 2 wk after injection of DBA/2 cells and preceded peak anti-histone levels by approximately 2 wk. Anti-histone antibodies were generated predominantly to histones H1, H2A, and H2B, a profile different from that observed in NZB/NZW and MRL-lpr/lpr mice. The marked increase in IgG antinuclear antibodies did not correlate with increases in total IgG serum levels and was not associated with comparable increases in antibodies to transferrin, hemoglobin, fibrinogen, or thyroglobulin. Selective autoantibody production was also observed in vitro, wherein GVH spleen cells produced high levels of IgG antibodies to total histones and denatured DNA but not to these non-nuclear protein antigens. In contrast, spleen cells stimulated in vitro with lipopolysaccharide produced equivalent amounts of antibodies to all antigens tested. Our results are in agreement with those of other investigators and collectively suggest that IgG autoantibodies in GVH disease, and possibly in spontaneous lupus-like disease, are not secondary to a generalized B cell activation, but may be selectively generated in response to self antigens with unique configurational properties.

Serology of paracoccidioidomycosis. II. Correlation between class-specific antibodies and clinical forms of the disease

Untreated and previously treated patients with paracoccidioidomycosis were studied for: (i) serum levels of total IgG, IgM and IgA immunoglobulins, by radial immunodiffusion and Paracoccidioides brasiliensis (Pb) antibodies, by indirect immunofluorescence; (ii) correlation between their levels with the clinical forms of the disease; (iii) correlation between the serum titres obtained by tube precipitin with those of anti- Pb IgG, IgM and IgA. In the untreated group, serum IgG levels were significantly increased in patients with the more systemic forms of the disease, especially the acute progressive form. Serum IgA levels were significantly increased in all patients with no statistical difference between clinical forms. Serum IgM levels were normal in all patients. Anti- Pb IgG, IgA and IgM were detected in 97·5%, 32·5% and 45·0% of all cases, respectively. There was a sharp tendency towards higher levels of anti- Pb IgG among those with the acute progressive form (83·4%) in relation to the chronic, more localized forms, mixed form (68·0%) and isolated organic form (55·5%). In the untreated and previously treated group sera, there was positive correlation between the level of anti- Pb IgG and positivity for the tube precipitin test, suggesting that the precipitin-type antibodies are of the IgG class. Broadly, the present data demonstrate a polyclonal activation of the humoral immune system in paracoccidioidomycosis, with a positive relationship between serological results and severity of the disease.