These studies were carried out to examine the presence of the inflammatory cytokines IL-6 and TNFalpha in kidneys of patients with lupus nephritis as an indicator of their possible role in its pathogenesis. A total of 19 kidney biopsies from patients with type III or IV lupus nephritis were processed by direct immunofluorescence using monoclonal anti-IL-6 and TNFalpha antibodies. Local expression of these genes was demonstrated both by in situ hybridization and by reverse transcriptase-PCR amplification of total RNA isolated from kidney tissue. Fifty-two percent of the biopsies exhibited IL-6 and TNFalpha deposited along the glomeruli and tubules; in situ expression of these cytokines was demonstrated in 6 biopsies with type IV, and 1 with type III nephritis. Inflammatory cytokines are actively synthesized in the kidneys of patients with lupus nephritis and therefore, may play a role in its pathogenesis.
This paper presents the morphological evidence that apoptosis and acantholysis are linked. Therefore, the Fas pathway is associated with CD8 cells in pemphigus lesions.
Apoptosis plays a role in pemphigus IgG-dependent acantholysis; theoretically, the blockade of the caspase pathway could prevent the blistering that is caused by pemphigus autoantibodies. Using this strategy, we attempted to block the pathogenic effect of pemphigus IgG in Balb/c mice by using the caspase inhibitor Ac-DEVD-CMK. This inhibitor was administrated before the injection of pemphigus IgG into neonatal mice. The main results of the present investigation are as follows: (1) pemphigus IgG induces intraepidermal blisters in Balb/c neonatal mice; (2) keratinocytes around the blister and acantholytic cells undergo apoptosis; (3) the caspases inhibitor Ac-DEVD-CMK prevents apoptosis; (4) the inhibition of the caspase pathway prevents blister formation. In conclusion, inhibition of the caspase pathway may be a promising therapeutic tool that can help in the treatment of pemphigus flare ups.
Idiotypes are molecular clues used to explore the specificity and diversity of immune response. In the present study, anti-idiotype antibodies were used to neutralize the pathogenic effects induced by the injection of pemphigus immunoglobulin(Ig)G into BALB/c mice. To achieve our goal, antidesmoglein 1 IgG was obtained from a patient with pemphigus foliaceus with high titer of antiepithelial antibodies. The IgG was isolated by ion exchange chromatography, then digested by pepsin. F(ab H ) 2 fragments were purified in Sephacryl S-300 and injected in rabbits to produce anti-idiotype antibodies. The rabbit sera reacted with the pemphigus F(ab H ) 2 fragments. Eleven pemphigus foliaceus sera were recognized by the anti-idiotype serum at the light or heavy chains whereas bullous pemphigoid and normal IgG were negative. Neonatal BALB/c mice injected with pemphigus IgG developed intraepidermal blisters, mimicking the clinical and immunopathological features of the pemphigus. In contrast, the animals treated with anti-idiotype antibodies and pemphigus IgG did not develop blisters. Thus, anti-idiotype antibodies neutralize in vivo the pathogenic effects of pemphigus IgG.Dr E. Avalos-Dõ Âaz, Chepinque 306, Col. Lomas de la Soledad, Zacatecas, 98040 Me Âxico.
Phosphorylation is the most important post-translational event at a cellular level that is regulated by protein kinases. MAPK is a key player in the important cellular signaling pathway. It has been hypothesized that phosphorylation might have a role in the induction of break tolerance against some autoantigens such as SRP72. The aim of this study was to explore the pathways of phosphorylation and overexpression of the SRP72 polypeptide, using an in vitro model of Jurkat cells stimulated by recombinant human (rh)IL-1β in the presence of MAPK inhibitors. We used Jurkat cells as a substrate stimulated with rhIL-1β in the presence of MAPK inhibitors at different concentrations in a time course in vitro experiment by immunoprecipitation, immunoprecipitation-Western blotting, and real time PCR. Our results showed that rhIL-1β causes up-regulation of protein expression and phosphorylation of SRP72 in Jurkat cells. Inhibitors of the MAPK pathway ERK1/2 or p38α/β down-regulate the expression of SRP72 autoantigen in Jurkat cells stimulated by rhIL-1β. Our results highlight the importance of studying the pathways of activation and overexpression of autoantigens. It will be necessary to perform careful research on various kinases pathways, including MAPK in dermatomyositis and other rheumatic diseases, to help to explain the routes of activation and inhibition of autoantigens. The understanding of this process may help to develop new therapies to prevent and control the loss of tolerance toward own normal proteins.
The current studies were carried out to determine the expression of Fas ligand and Bax in kidneys from lupus nephritis as possible indicators of apoptosis. Twenty-four kidney biopsies from patients with lupus nephritis and 30 normal controls were studied for FasL and Bax gene expression by fluorescent in situ hybridization. Seventy percent of the lupus biopsies displayed FasL or Bax mRNAs. These genes were mainly expressed in biopsies with higher activity indices. In contrast, neither of these mediators was detected in normal glomeruli. These data suggest that FasL and Bax are up-regulated in lupus nephritis and may play a pathogenic role through apoptotic cascades.
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