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2.
Gastroenterology ; 158(1): 151-159.e3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560892

RESUMO

BACKGROUND & AIMS: Celiac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease. METHODS: We analyzed waste blood samples from a community clinic from 15,551 adults for tTGA and, if titer results were above 2 U/mL, for endomysial antibody. The blood samples had been collected at 2 time points (median interval, 8.8 years) from 2006 through 2017. We collected data from the clinic on diagnoses of celiac disease based on duodenal biopsy analysis. RESULTS: Of the serum samples collected at the first time point, 15,398 had negative results for tTGA, and 153 had positive results for tTGA (>4 U/mL). Based on medical records, 6 individuals received a diagnosis of celiac disease, for a cumulative incidence of celiac disease diagnosis of 0.06% (95% confidence interval, 0.01-0.11). Forty-nine (0.32%) individuals with a negative result from the first serologic test for tTGA had a positive result from the second test. Among the 153 adults who were tTGA positive at the first time point, 31 (20%) had a subsequent diagnosis of celiac disease, 81 (53%) remained positive for tTGA without a clinical diagnosis of celiac disease, and 41 (27%) had negative test results for tTGA at the second time point. Higher initial tTGA titers, female sex, and a history of hypothyroidism and autoimmune disease were associated with increased risks of subsequent diagnosis of celiac disease. Interestingly, adults whose first blood sample had a positive test result but second blood sample had a negative result for tTGA were older, had lower-than-average initial tTGA titer results, and had a higher mean body mass index than adults whose blood samples were positive for tTGA at both time points and adults later diagnosed with celiac disease. CONCLUSIONS: In an analysis of serum samples collected from a community clinic an average of 8.8 years apart, we found that fewer than 1% of adults with negative results from an initial test for tTGA have a positive result on a second test. Of adults with positive results from the test for tTGA, only 20% are later diagnosed with celiac disease; the remaining individuals maintain persistent increases in tTGA without diagnoses of celiac disease or have negative results from second tests.


Assuntos
Autoanticorpos/sangue , Autoimunidade , Doença Celíaca/epidemiologia , Centros Comunitários de Saúde/estatística & dados numéricos , Proteínas de Ligação ao GTP/imunologia , Transglutaminases/imunologia , Adulto , Autoanticorpos/imunologia , Biópsia , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Estudos Prospectivos , Estudos Soroepidemiológicos
3.
An Bras Dermatol ; 94(6): 710-712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31789250

RESUMO

Although the association of multiple autoimmune diseases has already been widely described, no reports of the association between vitiligo, primary biliary cirrhosis and Sjogren's syndrome were retrieved in the SciELO and PubMed databases. The authors describe the case of a female patient who was diagnosed with primary biliary cirrhosis and Sjogren's syndrome at age 54. At age 58, she developed vitiligo restricted to the face, associated with significant impairment of self-esteem and quality of life. Antinuclear antibody was negative at the onset of the condition, but became positive after phototherapy initiation. In general, the occurrence of multiple autoimmune diseases in the same patient is known as a mosaic of autoimmunity. However, specific mechanisms appear to interconnect primary biliary cirrhosis and Sjogren's syndrome, such as PDC-E2-mediated generalized epithelitis.


Assuntos
Cirrose Hepática Biliar/complicações , Síndrome de Sjogren/complicações , Vitiligo/complicações , Autoimunidade , Doença Crônica , Feminino , Humanos , Cirrose Hepática Biliar/patologia , Pessoa de Meia-Idade , Síndrome de Sjogren/patologia , Vitiligo/patologia
4.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
5.
Science ; 366(6472): 1445-1446, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31857466
6.
Adv Exp Med Biol ; 1185: 175-179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884608

RESUMO

We present evidence that protein citrullination, a proinflammatory and immune system-activating posttranslational modification (PTM) of arginine residues mediated by peptidyl arginine deiminases (PADs), is elevated in mouse models of retinal degenerations. Together with the fact that the animal models that we investigated (and their human counterparts) exhibit also anti-retinal autoantibodies, we propose that retinal citrullination is an immunogenic trigger that activates the immune system both locally and systemically, contributing to disease pathogenesis. Consistent with this possibility, we show that PAD compromise reduces the severity of Mertk-related retinal degeneration. Thus, PAD inhibition may be as a potential treatment strategy for retinal degenerations.


Assuntos
Autoimunidade , Citrulinação , Sistema Imunitário , Inflamação/patologia , Desiminases de Arginina em Proteínas/fisiologia , Degeneração Retiniana/patologia , Animais , Citrulina , Humanos , Camundongos
7.
Nat Rev Drug Discov ; 18(12): 903, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31780854
9.
Adv Exp Med Biol ; 1189: 213-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758536

RESUMO

Co-receptors cooperatively regulate the function of immune cells to optimize anti-infectious immunity while limiting autoimmunity by providing stimulatory and inhibitory co-signals. Among various co-receptors, those in the CD28/CTLA-4 family play fundamental roles in the regulation of lymphocytes by modulating the strength, quality, and/or duration of the antigen receptor signal. The development of the lethal lymphoproliferative disorder and various tissue-specific autoimmune diseases in mice deficient for CTLA-4 and PD-1, respectively, clearly demonstrates their pivotal roles in the development and the maintenance of immune tolerance. The recent success of immunotherapies targeting CTLA-4 and PD-1 in the treatment of various cancers highlights their critical roles in the regulation of cancer immunity in human. In addition, the development of multifarious autoimmune diseases as immune-related adverse events of anti-CTLA-4 and anti-PD-1/PD-L1 therapies and the successful clinical application of the CD28 blocking therapy using CTLA-4-Ig to the treatment of arthritis assure their crucial roles in the regulation of autoimmunity in human. Accumulating evidences in mice and humans indicate that genetic and environmental factors strikingly modify effects of the targeted inhibition and potentiation of co-signals. In this review, we summarize our current understanding of the roles of CD28, CTLA-4, and PD-1 in autoimmunity. Deeper understandings of the context-dependent and context-independent functions of co-signals are essential for the appropriate usage and the future development of innovative immunomodulatory therapies for a diverse array of diseases.


Assuntos
Autoimunidade , Antígenos CD28/metabolismo , Antígeno CTLA-4/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Humanos , Tolerância Imunológica , Imunoterapia , Camundongos
10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 776-782, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750817

RESUMO

Objective To prepare inducible lupus model mice and investigate the effect of nuclear autoantigenic sperm protein (NASP) gene mutation on the autoimmune response of mice with induced systemic lupus erythematosus (SLE). Methods The 3-month wild-type B6 (B6-WT) mice were used as a control group and the NASP mutant B6 (B6-NASPM) mice as an experimental group. Mouse spleen lymphocytes were activated with concanavalin A (ConA), and the DNA was extracted as autoantigen. B6-WT mice and B6-NASPM mice were immunized three times. Serum anti-double stranded DNA (dsDNA) IgG levels were detected by ELISA. Renal lesions were detected by HE staining. Immunohistochemical staining was performed to detect the deposition of IgG and complement C3 in the renal tissues. Flow cytometry was applied to compare the spleen lymphocyte subsets in B6-WT and B6-NASPM mice and to explore the mechanism of NASP gene mutation affecting the immune response in mice. Results Compared with B6-WT mice, B6-NASPM mice showed no significant changes in body weight, kidney index and spleen index; serum anti-dsDNA IgG levels significantly increased; glomerular cell proliferation was obvious and the deposition of IgG and C3 in the renal tissues increased. The proportion of spleen CD3+ T cells and natural killer (NK) cells decreased, while the proportion of CD19+ B cells and regulatory B cells (Breg) increased. Conclusion Mutation in the NASP gene can increase the levels of anti-dsDNA IgG antibodies, promote cell proliferation in the glomerulus of the kidney, deposition of IgG antibodies and complement C3, alter the proportion of immune cells in the spleen and aggravate the autoimmune response in lupus model mice.


Assuntos
Autoantígenos/genética , Autoimunidade , Lúpus Eritematoso Sistêmico/genética , Proteínas Nucleares/genética , Animais , Anticorpos Antinucleares/sangue , Proteínas de Ciclo Celular , Complemento C3/imunologia , Modelos Animais de Doenças , Glomérulos Renais/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Mutação , Baço/imunologia
11.
Presse Med ; 48(11 Pt 1): e307-e315, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31727487

RESUMO

INTRODUCTION: Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease. METHODS: We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected. RESULTS: The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies.


Assuntos
Autoanticorpos/sangue , Autoimunidade , Infertilidade Feminina/imunologia , Anticorpos Antinucleares/sangue , Anticorpos Antifosfolipídeos/sangue , Autoantígenos/imunologia , Implantação do Embrião , Endometriose/imunologia , Feminino , França , Humanos , Imunomodulação , Infertilidade Feminina/sangue , Infertilidade Feminina/terapia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Gravidez , Estudos Retrospectivos
12.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(9): 550-554, nov. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-184377

RESUMO

Introducción: La hipertirotropinemia aislada se describe como un a elevación de la hormona estimulante del tiroides (TSH) con niveles normales de hormonas tiroideas y autoinmunidad negativa en pacientes asintomáticos y sin hallazgos en la exploración. Dado el aumento no justificado del análisis de la función tiroidea en niños asintomáticos, el objetivo principal es analizar la evolución de estos pacientes. Como objetivo secundario se realiza un análisis de costes asociado. Material y métodos: Estudio longitudinal observacional retrospectivo de los pacientes derivados a endocrinología de un hospital de tercer nivel por hipertirotropinemia aislada (TSH 5-20 mUI/l). Se recogieron variables clínicas, analíticas, número de visitas hasta el alta, necesidad de tratamiento, tiempo de seguimiento, así como variables económicas. Resultados: Se obtuvo una muestra de 155 pacientes, con edad media de 7,8 años ± 3,6 DE. La derivación a endocrinología representó el 4% de las consultas de primera visita. La cifra media de TSH inicial fue de 7,8 mU/l (5,03-15,8 mU/l). Los niveles de TSH se normalizaron tras la primera repetición durante el mes posterior, en el 60% de los casos. En un intervalo máximo de 3años fueron dados de alta el 83,6%, con un seguimiento medio de 8,14 ± 6,8 meses y 2,4 visitas/paciente. Se obtuvo un coste medio de 251,27 €/paciente (rango 143,49-444,21 €). Conclusión: Es fundamental no generar alarma familiar ante una hipertirotropinemia, dado que se trata de una situación bioquímica que, en la mayoría de los casos, se normaliza. Este hecho, junto con el coste medio derivado de la asistencia especializada, pone de manifiesto que el primer paso debería ser la repetición de la misma en atención primaria


Introduction: Subclinical hypothyroidism is defined as elevation of thyroid-stimulating hormone (TSH) levels, with normal thyroid hormone levels and negative autoimmunity, in asymptomatic patients with no findings on examination. Because of the unwarranted increase in thyroid function tests in asymptomatic children, the main objective of this review was to analyze the course of these patients. Analysis of associated costs was a secondary objective. Material and methods: A longitudinal, observational, retrospective study of patients referred to the endocrinology department of a tertiary hospital for high TSH levels (TSH 5-20 mIU/L). Clinical and laboratory variables, number of visits until discharge, need for treatment, monitoring time, and economic variables were collected. Results: The study sample consisted of 155 patients with a mean age of 7.8 years ± 3.6SD. Referrals to endocrinology accounted for 4% of first office visits. Baseline mean TSH level was 7.8 mU/L (5.03-15.8 mU/L). TSH levels normalized after the first repeated measurement during the subsequent month in 60% of cases. A total of 83.6% of patients were discharged within a maximum of 3years, with a mean follow-up of 8.14 ± 6.8 months and 2.4 visits/patient. Average cost per patient was € 251.27 (range € 143.49-444.21). Conclusion: It is essential not to alarm the family when subclinical hypothyroidism is detected, because this is a biochemical situation which normalizes in most cases. This fact, together with the mean cost of specialized care, suggests that the first step should be repeated TSH measurements in primary care


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Evolução Clínica , Hipotireoidismo/economia , Atenção Primária à Saúde/economia , Tireotropina/sangue , Estudos Longitudinais , Estudos Retrospectivos , Autoimunidade , Custos e Análise de Custo
13.
Scand J Immunol ; 90(6): e12821, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31589347

RESUMO

As a result of the cancer immunotherapy revolution, more than 2000 immuno-oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co-inhibitory signals. Unfortunately, manipulation of the co-inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune-related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA-4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self-tissues. The irAEs are very similar to that of a chronic graft-versus-host-disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft-versus-malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto-GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune-suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof-of-principle of a low-dose-combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Autoimunidade/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/genética , Neoplasias/patologia , Uso Off-Label , Estudo de Prova de Conceito , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
15.
Isr Med Assoc J ; 21(7): 454-459, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507120

RESUMO

BACKGROUND: Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.


Assuntos
Artrite Reumatoide/imunologia , Plaquetas/imunologia , Sinovite/imunologia , Artrite Reumatoide/patologia , Autoimunidade/imunologia , Fibroblastos/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia , Linfócitos T/imunologia
16.
Isr Med Assoc J ; 21(7): 480-486, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507125

RESUMO

BACKGROUND: Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for SjÓ§gren's syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.


Assuntos
Hepatite B/imunologia , Hepatite C/imunologia , Fator Reumatoide/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Crioglobulinemia/imunologia , Humanos , Transtornos Linfoproliferativos/imunologia , Neoplasias/imunologia , Fator Reumatoide/sangue
17.
Int J Mol Sci ; 20(18)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31540175

RESUMO

The oral cavity is suggested as the reservoir of bacterial infection, and the oral and pharyngeal biofilms formed by oral bacterial flora, which is comprised of over 700 microbial species, have been found to be associated with systemic conditions. Almost all oral microorganisms are non-pathogenic opportunistic commensals to maintain oral health condition and defend against pathogenic microorganisms. However, oral Streptococci, the first microorganisms to colonize oral surfaces and the dominant microorganisms in the human mouth, has recently gained attention as the pathogens of various systemic diseases, such as infective endocarditis, purulent infections, brain hemorrhage, intestinal inflammation, and autoimmune diseases, as well as bacteremia. As pathogenic factors from oral Streptococci, extracellular polymeric substances, toxins, proteins and nucleic acids as well as vesicles, which secrete these components outside of bacterial cells in biofilm, have been reported. Therefore, it is necessary to consider that the relevance of these pathogenic factors to systemic diseases and also vaccine candidates to protect infectious diseases caused by Streptococci. This review article focuses on the mechanistic links among pathogenic factors from oral Streptococci, inflammation, and systemic diseases to provide the current understanding of oral biofilm infections based on biofilm and widespread systemic diseases.


Assuntos
Estomatite/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus/fisiologia , Idoso , Doenças Autoimunes/etiologia , Autoimunidade , Aderência Bacteriana , Biofilmes , Biomarcadores , Proteínas de Ligação a DNA/metabolismo , Humanos , Masculino , Estomatite/diagnóstico , Infecções Estreptocócicas/diagnóstico , Virulência , Fatores de Virulência
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