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

The Caspase Pathway as a Possible Therapeutic Target in Experimental Pemphigus

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

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 Redistribution of the Ro Autoantigen in Balb/c Mouse Like in Subacute Cutaneous Lupus Erythematosus

In subacute cutaneous lupus eryhematosus (SCLE) the cutaneous antigens constitute the main source of Ro and La autoantigens. The aim of this investigation was to demonstrate if UV light increases the availability of Ro autoantigen in the skin, also the blocking effect of Ac-DEVD-CMK a caspase inhibitor was assessed. For this purpose newborn Balb/c mice were UVB irradiated (5–30 mJ/cm2) equivalent to a moderate to severe sunburn. Animals were injected with monoclonal anti-Ro antibodies from SCLE patients. Apoptosis was also induced by anti-Fas antibody injection. Skin samples were examined by direct immunofluoresence, by TUNEL, and the expression of caspase 3 by RT-PCR. Major findings of present studies were: 1. UVB irradiation and anti-Fas induced apoptosis of keratinocytes. 2. Apoptosis redistribute the Ro antigen on cell surface and is better triggered by Ro antibody. 3. The caspase 3 inhibitor Ac-DEVD-CMK decreases the availability of Ro autoantigen in epidermis and prevents deposition of anti-Ro. In conclusion, the caspase pathway would be blocked to avoid anti-Ro deposition along skin; this finding would be a prospect in the treatment of SCLE patients

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 Síndroma de Sjögren primária. Métodos: A apoptose foi estudada por imunohistoquímica utilizando anticorpos monoclonais anti- -Fas, FasL e Caspase 3 e as características apoptóticas por TUNEL. Os estudos foram executados em vinte e quatro glândulas salivares minor de doentes com Síndroma de Sjögren primária e num igual número 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. Conclusão: Os dados actuais sugerem que as células do epitélio ductal e dos acinos das glândulas salivares dos doentes com doença de Sjögren têm aumento da apoptose. A proliferação foi observada principalmente no infiltrado celular linfóide. Em conjunto, estes eventos constituem um paradoxo biológico relacionado com o processo inflamatório das glândulas salivares na Síndrome 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

shRNA targeting caspase-3 inhibits apoptosis and cell detachment induced by Pemphigus Vulgaris autoantibodies

Pemphigus is an organ-specific autoimmune disease that affects the skin and mucous membranes. It is induced by the deposition of pemphigus IgG autoantibodies, which mainly target Dsg1 and 3 and cause a loss of cell adhesion in a phenomenon known as acantholysis, and clinically is reflected as intraepidermal blistering. The present work assessed the effect of pemphigus vulgaris IgG (PV-IgG) on cell adhesion and caspase 3- dependent apoptosis in HaCaT cells. The expression of caspase-3 induced by PV-IgG was silenced in cells pre-treated with caspase 3-shRNA. PV-IgG induced cell detachment and apoptotic changes as demonstrated by the annexin-FITC assays. Treatment of cell cultures with normal IgG (control; N-IgG) did not have relevant effects on the aforementioned parameters. Then, the effect of PV-IgG on cells previously treated with shRNA was tested. The results demonstrated that shRNA reduced apoptotic features and the relative expression of caspase-3 measured by qRT-PCR, which showed a decrease of 96%. In conclusion shRNA prevented cell detachment and apoptosis of HaCaT cells induced by PV-IgG. The presented results further our understanding of the molecular pathophysiologic mechanisms involved in pemphigus diseases.Pemphigus is an organ-specific autoimmune disease that affects the skin and mucous membranes. It is induced by the deposition of pemphigus IgG autoantibodies, which mainly target Dsg1 and 3 and cause a loss of cell adhesion in a phenomenon known as acantholysis, and clinically is reflected as intraepidermal blistering. The present work assessed the effect of pemphigus vulgaris IgG (PV-IgG) on cell adhesion and caspase 3- dependent apoptosis in HaCaT cells. The expression of caspase-3 induced by PV-IgG was silenced in cells pre-treated with caspase 3-shRNA. PV-IgG induced cell detachment and apoptotic changes as demonstrated by the annexin-FITC assays. Treatment of cell cultures with normal IgG (control; N-IgG) did not have relevant effects on the aforementioned parameters. Then, the effect of PV-IgG on cells previously treated with shRNA was tested. The results demonstrated that shRNA reduced apoptotic features and the relative expression of caspase-3 measured by qRT-PCR, which showed a decrease of 96%. In conclusion shRNA prevented cell detachment and apoptosis of HaCaT cells induced by PV-IgG. The presented results further our understanding of the molecular pathophysiologic mechanisms involved in pemphigus diseases