15 research outputs found
Neonatal molecular pathologies induced by maternal anti-Ro and anti-La antibodies
Maternal antinuclear antibodies with anti-Ro or anti-La specificity might be pathogenic to the fetus and could induce molecular neonatal pathologies, such as neonatal lupus (NL) with or without congenital heart block (CHB). The cutaneous manifestations of neonatal lupus appear at birth or a few weeks later, and skin lesions may persist for weeks. While CHB is characterized by intrauterine bradycardia or low heart rates at birth and may persist for months, depending on the degree of blockage. Clinical and experimental data demonstrated that anti-Ro and anti-La autoantibodies functionally inhibit L-type calcium channels and induce abnormalities in electrical conduction of the cardiac myocytes. It has been 38 years since the first clinical description of CHB. Presently, the pathophysiology of CHB has been clarified through clinical and basic research studie
Cutaneous manifestations of spondyloarthritis
Spondyloarthritis comprises a group of inflammatory rheumatic disorders with a genetic predisposition
involving multiple genes that interact with environmental factors. The skin manifestations of
spondyloarthritis are diverse, particularly psoriatic arthritis related to the overexpression of inflammatory
cytokines such as TNF, IL-6, IL-12, IL-2 and IFN-g; this psoriatic dermatitis is a common skin feature of
spondyloarthritis. Spondyloarthritis mainly affects the spine, sacroiliac joints, ligaments and other tissues.
Psoriatic lesions are erythematous plaques covered with silvery whitish scales distributed on the scalp,
elbows, knees, trunk and gluteus creases, and the fingernails are frequently involved. Individuals with
reactive arthritis and Crohn’s disease may exhibit psoriasiform dermatitis and other manifestations including
ocular inflammation, oral ulceration, erythema nodosum and/or thrombophlebitis. In the case of reactive
arthritis, male patients may exhibit circinate balanitis and keratoderma blennorrhagica. In summary,
dermatological manifestations of spondyloarthritis represent clinical clues and a unique scenario to explore
the related pathophysiology and therapeutic approaches
Pathogenic effects of maternal antinuclear antibodies during pregnancy in women with lupus
Lupus is an autoimmune disease that primarily affects young women of childbearing
age. Fertility rates in lupus patients depend on various factors, including disease activity,
nephritis, and the presence of antiphospholipid antibodies; however, after lupus patients
become pregnant, different factors may affect the course of pregnancy, such as the production of autoantibodies, pre-existing renal disease, and eclampsia, among others. The placenta is a temporary hemochorial organ that prevents immunological conflict due to exposure to alloantigens at the maternal-fetal interface; placental regulatory T cells play a major role in maternal-fetal tolerance. Typically, significant amounts of maternal IgG class antibodies cross the placenta and enter the fetal circulation. This transition depends on the distribution of Fc receptors along the syncytiotrophoblast. The production of antinuclear antibodies (ANA) is a hallmark of lupus, and these autoantibodies can form immune complexes
that are typically trapped in the placenta during gestation. However, the entry of ANA into
the fetal circulation depends on the IgG-ANA concentration and the FcR placental density.
Maternal antinuclear antibodies with anti-Ro or anti-La specificity might be pathogenic to the fetus if transfused by the placental pathway and could induce neonatal pathologies, such as neonatal lupus and congenital heart block. Here, we review the experimental and clinical data supporting a pathogenic role for
maternal autoantibodies transmitted to the fetus
Autoimmune vitiligo in rheumatic disease in the mestizo Mexican population
Vitiligo is a chronic disease characterized
by the dysfunction or destruction of melanocytes with
secondary depigmentation. The aim of the present study
was to determine the prevalence of vitiligo associated with
autoimmune rheumatic diseases. The clinical records from
a 10-year database of patients with rheumatic diseases
and associated vitiligo was analysed, with one group of
patients having autoimmune rheumatic disease and another
non-autoimmune rheumatic disease. Available serum samples
were used to assess the anti-melanocyte antibodies. A total
of 5,251 individual clinical files were archived in the last
10 years, and these patients underwent multiple rheumatology
consultations, with 0.3% of the group presenting with vitiligo.
The prevalence of vitiligo in the autoimmune rheumatic
disease group was 0.672%, which was mainly associated with
lupus and arthritis. However, patients with more than one
autoimmune disease had an increased relative risk to develop
vitiligo, and anti-melanocyte antibodies were positive in 92%
of these patients. By contrast, the prevalence was 0.082% in
the group that lacked autoimmune rheumatic disease and
had negative autoantibodies. In conclusion, the association
between vitiligo and autoimmune rheumatic diseases was
relatively low. However, the relative risk increased when there
were other autoimmune comorbidities, such as thyroiditis or
celiac disease. Therefore, the presence of multiple autoimmune
syndromes should be suspected
Apoptosis and cell proliferation: the paradox of salivary glands in sjögren’s disease
Este estudo avalia a apoptose e a proliferação nas glândulas salivares dos doentes com SĂndroma de Sjögren primária.
MĂ©todos: A apoptose foi estudada por imunohistoquĂmica utilizando anticorpos monoclonais anti-
-Fas, FasL e Caspase 3 e as caracterĂsticas apoptĂłticas por TUNEL. Os estudos foram executados em
vinte e quatro glândulas salivares minor de doentes com SĂndroma de Sjögren primária e num igual nĂşmero de controlos. A proliferação foi avaliada com anticorpos monoclonais anti-PCNA e anti-Ki67.
Resultados:Todas as glândulas salivares dos doentes com Sjögren apresentavam moléculas apoptoticas no epitélio dos ductos salivares, e menos no tecido acinar, consequentemente a presença do caspase 3, Fas/FasL eram concordantes com a expressão da apoptose por TUNEL. Os marcadores de proliferação foram encontrados nas células inflamatórias presentes, mas não no epitélio ductal nem nos acinos. A expressão de marcadores de apoptose ou de proliferação nos tecidos das biopsias dos controlos foi escassa.
ConclusĂŁo: Os dados actuais sugerem que as cĂ©lulas do epitĂ©lio ductal e dos acinos das glândulas salivares dos doentes com doença de Sjögren tĂŞm aumento da apoptose. A proliferação foi observada principalmente no infiltrado celular linfĂłide. Em conjunto, estes eventos constituem um paradoxo biolĂłgico relacionado com o processo inflamatĂłrio das glândulas salivares na SĂndrome de Sjögren.Aim: To assess apoptosis and proliferation in salivary glands of patients with primary Sjögren’s syndrome.
Methods: Studies were performed in twenty four minor salivary glands from patients with primary
Sjögren’s syndrome and an equal number of controls. Apoptosis was studied by immunohistochemistry using monoclonal antibodies anti-Fas, FasL and Caspase 3 and apoptotic features by TUNEL. Proliferation was assessed with monoclonal anti-PCNA and anti-Ki67 antibodies.
Results: All salivary glands from Sjögren’s display apoptotic molecules along the epithelia of salivary
ducts, and in a smaller amount in acinar tissue. The presence of Caspase 3, Fas/FasL was concordant
with the expression of apoptosis by TUNEL. Proliferation markers were encountered in inflammatory emigrant cells, but not in ductal epithelia nor in acini. Control biopsies poorly expressed apoptotic or proliferation markers.
Conclusion: Present data suggests that the ductal epithelial and acinar cells of salivary glands from
Sjögren’s disease patients exhibit increased apoptosis. Proliferation was mainly observed in infiltrating lymphoid cells. Both events constitute a biological paradox related to the inflammatory process of salivary glands in Sjögren’s disease
Camptothecin induces the transit of fASl trimers to the cell surface in apoptotic heP-2 cells
Fas ligand (L) is a membrane protein from the tumor necrosis factor
(TNF) family. It induces apoptosis upon contact with its Fas/CD95/APO1
receptor. Trimerization of FasL on the surface of effector cells is essential in the
binding of the Fas trimer of the target cells. The receptor then recruits an adaptor
and caspase-like proteins which lead apoptosis. This paper reports on the fate of
FasL in HEp-2 cells committed to apoptosis by induction with campthotecin.
Our main results demonstrated that in non-apoptotic cells, FasL aggregates in
the cytoplasm forming trimers of 120 kDa. Apoptosis increases the trimeric
FasL species, but also induces its dissociation into monomers of 35 kDa. In
conclusion, camptothecin appears to perturb the Fas and FasL segregation in the
cytoplasm by promoting the transit of FasL to the cell surface, thus fostering
a process of autocrine or paracrine apoptosis. FasL is trimerized prior to
Fas/FasL complex formation, and after apoptosis, FasL undergoes an intense
turnover
An Activin Receptor IA/Activin-Like Kinase-2 (R206H) Mutation in Fibrodysplasia Ossificans Progressiva
Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disease that is characterised by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomical areas.This disease is caused by a mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2). A Mexican family with one member affected by FOP was studied. The patient is a 19-year-old female who first presented with symptoms of FOP at 8 years old; she developed spontaneous and painful
swelling of the right scapular area accompanied by functional limitation of movement. Mutation analysis was performed in which genomic DNA as PCR amplified using primers flanking exons 4 and 6, and PCR products were digested with Cac8I and HphI restriction enzymes.The most informative results were obtained with the exon 4 flanking primers and the Cac8I restriction enzyme, which generated a 253 bp product that carries the ACVR1 617G>A mutation, which causes an amino acid substitution of histidine for arginine at position 206 of the glycine-serine (GS) domain, and its mutation results in the dysregulation of bone morphogenetic
protein (BMP) signalling that causes FO
Activation of Peptidylarginine Deiminase in the Salivary Glands of Balb/c Mice Drives the Citrullination of Ro and La Ribonucleoproteins
The goal of the present study was to determine whether peptidylarginine deiminase PAD2 and PAD4 enzymes are present in Balb/c mouse salivary glands and whether they are able to citrullinate Ro and La ribonucleoproteins. Salivary glands from Balb/c mice were cultured in DMEM and supplemented with one of the following stimulants: ATP, LPS, TNF, IFNÎł, or IL-6. A control group without stimulant was also evaluated. PAD2, PAD4, citrullinated peptides, Ro60, and La were detected by immunohistochemistry and double immunofluorescence. PAD2 and PAD4 mRNAs and protein expression were detected by qPCR and Western blot analysis. PAD activity was assessed using an antigen capture enzyme-linked immunosorbent assay. LPS, ATP, and TNF triggered PAD2 and PAD4 expression; in contrast, no expression was detected in the control group (p < 0 001). PAD transcription slightly increased in response to stimulation. Additionally, PAD2/4 activity modified the arginine residues of a reporter protein (fibrinogen) in vitro. PADs citrullinated Ro60 and La ribonucleoproteins in vivo. Molecular stimulants induced apoptosis in ductal cells and the externalization of Ro60 and La ribonucleoproteins onto apoptotic membranes. PAD enzymes citrullinate Ro and La ribonucleoproteins, and this experimental approach may facilitate our understanding of the role of
posttranslational modifications in the pathophysiology of Sjögren’s syndrome
An Animal Model Using Metallic Ions to Produce Autoimmune Nephritis
Autoimmune nephritis triggered by metallic ions was assessed in a Long-Evans rat model. The parameters evaluated included antinuclear autoantibody production, kidney damage mediated by immune complexes detected by immunofluorescence, and renal function tested by retention of nitrogen waste products and proteinuria. To accomplish our goal, the animals were treated with the following ionic metals: HgCl2, CuSO4, AgNO3, and Pb(NO3)2. A group without ionic metals was used as the control. The results of the present investigation demonstrated that metallic ions triggered antinuclear antibody production in 60% of animals,
some of them with anti-DNA specificity. Furthermore, all animals treated with heavy metals developed toxic glomerulonephritis with immune complex deposition along the mesangium and membranes. These phenomena were accompanied by proteinuria and increased concentrations of urea. Based on these results, we conclude that metallic ions may induce experimental autoimmune nephritis
Apoptosis in chronic cutaneous lupus erythematosus, discoid lupus, and lupus profundus
: Introduction: Lupus erythematosus is a multisystemic disease that is characterized by autoantibody
production and immune complex deposition in such tissues as the mucosa, joints, the central nervous system,
and skin. Cutaneous lupus erythematosus is categorized as acute, subacute, and chronic. Chronic cutaneous lupus erythematosus comprises discoid lupus erythematosus (DLE) and lupus profundus (LP). Aim: To analyze the expression of proapoptotic molecules in patients with lupus erythematosus discoid and lupus profundus. Material and methods: Descriptive study, the study groups comprised 10 cases of LP and 10 cases of DLE, and a control. Skin samples of cases and controls were processed for immunohistochemistry and by TUNEL technique. The database and statistical analysis was performed (statistical test X2) SPSS (Chicago, IL, USA). Results: Apoptotic features were broadly distributed along the skin biopsies in epidermal keratinocytes as well as at dermis. By immunohistochemistry the expression of Fas receptor and Fas-L was higher in the skin of lupus patients compared with controls. We also noted differences in Fas-L, -Fas, and -Bax proteins expression intensity in discoid lupus erythematosus patients in the epidermis, and hair follicles. Conclusions: Fas and Fas-L are expressed similarly in LP and DLE