IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice.

BACKGROUND: Antibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis. RESULTS: The gamma3 genotype (+/+ vs. +/- vs. -/-) did not appear to significantly affect serum titers of IgG auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin. However, while substantial serum titers of IgG3 auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin were seen in gamma3 +/+ mice, somewhat lower serum titers of these IgG3 auto-antibodies were found in gamma3 +/- mice, and gamma3 -/- mice exhibited baseline concentrations of these auto-antibodies. Analysis of immunoglobulins eluted from snap-frozen kidneys obtained from mice of all three gamma3 genotypes at ~18 weeks of age revealed much higher quantities of IgG in the kidneys from gamma3 +/+ than gamma3 -/- mice, and most IgG eluted from +/+ mice was IgG3. The serum creatinine levels in gamma3 +/+ mice substantially exceeded those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lpr mice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85% of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis. CONCLUSIONS: The available evidence suggests that IgG3 deficiency partially protects MRL/lpr mice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the progression to glomerulosclerosis.

Enhanced immunogenicity of pneumococcal surface adhesin A (PsaA) in mice via fusion to recombinant human B lymphocyte stimulator (BLyS).

BACKGROUND: B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors. BLyS has been shown to enhance the production of antibodies against heterologous antigens when present at elevated concentrations, supporting an immunostimulatory role for BLyS in vivo. METHODS: We constructed a fusion protein consisting of human BLyS and Pneumococcal Surface Adhesin A (PsaA) and used this molecule to immunize mice. The immunostimulatory attributes mediated by BLyS in vivo were evaluated by characterizing immune responses directed against PsaA. RESULTS: The PsaA-BLyS fusion protein was able to act as a co-stimulant for murine spleen cell proliferation induced with F(ab')2 fragments of anti-IgM in vitro in a fashion similar to recombinant BLyS, and immunization of mice with the PsaA-BLyS fusion protein resulted in dramatically elevated serum antibodies specific for PsaA. Mice immunized with PsaA admixed with recombinant BLyS exhibited only modest elevations in PsaA-specific responses following two immunizations, while mice immunized twice with PsaA alone exhibited undetectable PsaA-specific serum antibody responses. Sera obtained from PsaA-BLyS immunized mice exhibited high titers of IgG1, IgG2a, IgG2b, and IgG3, but no IgA, while mice immunized with PsaA admixed with BLyS exhibited only elevated titers of IgG1 following two immunizations. Splenocytes from PsaA-BLyS immunized mice exhibited elevated levels of secretion of IL-2, IL-4 and IL-5, and a very modest but consistent elevation of IFN-γ following in vitro stimulation with PsaA. In contrast, mice immunized with either PsaA admixed with BLyS or PsaA alone exhibited modestly elevated to absent PsaA-specific recall responses for the same cytokines. Mice deficient for one of the three receptors for BLyS designated Transmembrane activator, calcium modulator, and cyclophilin ligand [CAML] interactor (TACI) exhibited attenuated PsaA-specific serum antibody responses following immunization with PsaA-BLyS relative to wild-type littermates. TACI-deficient mice also exhibited decreased responsiveness to a standard pneumococcal conjugate vaccine. CONCLUSION: This study identifies covalent attachment of BLyS as a highly effective adjuvant strategy that may yield improved vaccines. In addition, this is the first report demonstrating an unexpected role for TACI in the elicitation of antibodies by the PsaA-BLyS fusion protein. REVIEWERS: This article was reviewed by Jonathan Yewdell, Rachel Gerstein, and Michael Cancro (nominated by Andy Caton).

Insight into illness and attitudes toward medications among inpatients with schizophrenia.

This study assessed symptoms, severity of illness functional level, insight into illness, and attitudes toward medication in a sample of psychiatric patients who were newly admitted to a state hospital. The patients were evaluated before and after treatment with atypical, conventional, or mixed (atypical plus conventional) antipsychotic medication regimens with the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression, the Global Assessment of Functioning, the Scale to Assess Unawareness of Mental Disorder, and the Drug Attitude Inventory. Overall, the patients showed significant improvement in symptoms, severity of illness, functional level, and insight into their illness during the course of hospitalization. Their attitudes toward medications changed minimally during treatment. Only the patients who were treated with conventional antipsychotics showed significant improvement in their attitudes toward medication. However, the change was not large enough to differentiate the conventional antipsychotic treatment group from the other treatment groups.

Gender related differences in clinical characteristics and hospital based resource utilization among older adults with schizophrenia.

OBJECTIVE: This report is an analysis of gender related differences in clinical characteristics and hospital based health resource utilization among older adults with schizophrenia and schizoaffective disorder in an acute care, state hospital over a one-year period. METHODS: This retrospective record review is an analysis of age of illness onset, psychiatric and medical comorbidity, hospital utilization, and psychotropic medication use. RESULTS: There were a total of 66 individuals with either schizophrenia or schizoaffective disorder. Mean age of this group was 55.2 +/- 4.62 years. Women were significantly over-represented among individuals with late onset schizophrenia and schizoaffective disorder. Men with schizophrenia had more comorbid substance abuse compared to women with schizophrenia (p < 0.05). Women and men did not differ significantly in hospital length of stay, amount or type of antipsychotic medication prescribed, or in utilization of seclusion/restraint in hospital. Both genders had substantial utilization of antipsychotic medication. Use of conventional antipsychotic medication monotherapy was always associated with use of anti-extrapyramidal symptom (anti-EPS) medication, while use of atypical antipsychotic medication monotherapy was more rarely associated with use of anti-EPS medication. CONCLUSIONS: In later life, women and men may have some areas of differing health care needs. Women in particular may benefit from psychoeducational approaches that address the experience of psychiatric illness of relatively recent onset (for example, symptom identification and acceptance of illness). Men may benefit from particular emphasis on treatment of comorbid substance abuse disorders.