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Primary objective of my MS thesis project is to characterize and develop a B cell ablation model for investigating the pathogenesis of human diseases such as hepatitis and systemic lupus erythematosus (SLE). Conditional and targeted cell ablation is a powerful approach for studying cellular functions in vivo. However, currently available cell ablation models still have some limitations and therefore limit their broader application in biomedical research. For example, two of the most common cell ablation methods currently employed utilize the herpes simplex virus 1 thymidine kinase (HSVtk) or diphtheria toxin (DT) receptor combined with their respective transgenic strategies. The ablation using HSVtk transgenic mice eliminates dividing cells, but does not affect non-dividing cells. In addition, because of its extremely high potency (a single molecule of DT-A, the active cleavage product of DT is sufficient to induce apoptosis), dose dependent responses are difficult to achieve and off-target effects are frequently observed. These facts highlight the unmet need to develop alternative methods of targeted cell ablation, which our model very successfully addresses. Our recently established approach using intermedilysin (ILY)-mediated cell ablation that is specific for human CD59 (hCD59) expressing cells, obviates these problems and provides an excellent and significantly improved alternative approach to the existing cell ablation methodologies. Intermedilysin (ILY), a toxin secreted by Streptococcus intermedius, exclusively binds to the human cell membrane protein CD59 (hCD59) but not to CD59 of any other species. Once bound, ILY rapidly and potently lyses the cells. Using genetic engineering, animal models can be created that express hCD59 in a spatially regulated manner. Administration of ILY will then selectively ablate only those cells in the animals that express hCD59 without any non-specific effect. To expand and facilitate the application of this newly generated model, we recently generated a Cre-inducible floxedSTOP-hCD59 transgenic mouse line (ihCD59), where specific hCD59 expression occurs following Cre-mediated recombination. By crossing ihCD59 mice with specific immune cell (T cells or macrophage) Cre transgenic lines, we obtained double transgenic mice expressing hCD59. ILY administration mediated specific cell ablation in these target cell populations in a dose dependent manner. Based on these results, I wanted to establish a new B cell ablation model for further studying B cell functionality in the pathogenesis of human diseases. CD19-Cre mice expressing the Cre-recombinase in B cell population were crossed with ihCD59 mice to generate the double positive transgenic mice (ihCD59+/-/CD19-Cre+/-). In Aim 1, I have demonstrated that hCD59 is specifically expressed in the B cell populations. In Aim 2, I have documented that 1) ILY has a large pharmacological window, and 2) ILY injection to ihCD59+/-/CD19-Cre+/- mice resulted in a rapid cell ablation of the B cell cells with off-target effect. Further, I have demonstrated that the specific ablation of B cells did not prevent the immune (Con A)-mediated hepatitis. In the future, I will apply this conditional B cell ablation model for investigating the functionality of B cells in the pathogenesis of human disease such as SLE. / Biomedical Sciences

Durante o ciclo menstrual, o endométrio se torna receptivo à chegada do \"futuro embrião\". Estes eventos são regulados pela liberação de progesterona durante a fase secretória do ciclo, que aumenta a secreção do componente C3 do Sistema Complemento (SC). Neste período, também foi observado o aumento fisiológico da expressão de algumas proteínas reguladoras do SC (CRPs) como: C1Inh, C4bp, DAF, CD59 e clusterina, oque sugere uma forte regulação da atividade deste sistema, favorável à implantação e ao desenvolvimento embrionário. Modificações na expressão destas proteínas poderiam resultar em aborto espontâneo recorrente (AER).Neste trabalho estudou-se a expressão endometrial de DAF e CD59 noendométrio de pacientes com AER, durante a fase secretória do ciclo. Adicionalmente, verificou-se a ativação do SC através da presença do neoantígeno de C9 neste mesmo material. A casuística foi composta de nove mulheres férteis normais (Grupo Controle) e doze mulheres com AER (Grupo Aborto), todas analisadas durante a fase secretória do ciclo. A técnica utilizada para detecção destas proteínas foi a imunohistoquímica. O neoantígeno deC9 não foi detectado em nenhum dos grupos, tanto nas glândulas quanto no estroma endometrial. DAF e CD59 foram detectados tanto no Grupo Controle quanto no Grupo Aborto.Houve expressão nitidamente mais acentuada de ambas as CRPs, DAF e CD59, durante a fase secretória intermediária do Grupo Aborto, embora sem diferença estatística. Houve expressão para DAF e CD59 no estroma endometrial de ambos os grupos. Assim, os resultados deste trabalho apontam para a ausência do neoantígeno de C9 no endométrio humano normal e no endométrio humano de patologias como o AER. As CRPs, DAF e CD59, se mostraram presentes tanto no endométrio humano normal quanto no endométrio humano patológico por AER, com destaque para o aumento da expressão de DAF e CD59 na sub-fase intermediária secretória do ciclo menstrual, período crítico para a implantação, sugerindo que alguma alteração neste período possa resultar na posterior perda gestacional. / In the cycle menstrual, the endometrium becomes ready to the arrived of embryo future. These events are controlled by mechanisms like, liberation of progesterone during the secretory phase of cycle, that increases the secretion of C3 component of Complement System (CS). In this period, it was also observed the physiologic increase of the expressionof some CS regulatory proteins (CRPs) like: C1Inh, C4bp, DAF, CD59 and clusterin, a fact suggesting strong regulation of the activity this system. Changes in this regulation can be harmful to implantation and to embryonary development, causing recurrent spontaneous abortion (RSA). To goal of the present study is to evaluate the endometrial expression of the Membrane Complex Atack (MAC) of CS, representing by neoantígen C9, in the normal and patologic human endometrium with RSA during the secretory phase of the menstrual cycle and of the CRPs, DAF e CD59, in the patologic human endometrium with RSA during the secretory phase, contributing to better understanding of the CS regulation in the endometrium in no physiologic conditions. The study group consisted of twelve endometrial biopsy, during the secretory phase of the menstrual cycle, of women with RSA of no apparent cause, compared to a control group of nine endometrial biopsy, in the same phase, of normal fertile women evaluated to endometrial expression of the neoantígen C9, DAF e CD59 by the immunochemistry technique. Neoantigen C9 was not detected in any group, in the secretory phase of the menstrual cycle in the endometrial glandular epithelium and stromal cells. DAF e CD59 were expressed in both groups during the secretory phase. DAF e CD59 were detected more intensely during the intermediate secretory phase of the Abortion Group when compared to the Control Group. Meanwhile, it not detected any significance difference. There was expression of DAF e CD59 in the stromal cells to the both groups. In summary, we data show that neoantígeno de C9 isn\'t expressed in the normal and patologic human endometrium, and the CRPs, DAF e CD59, are expressed in the normal and patologic human endometrium, predominating in the intermediary secretory phase of the cycle compared to the controls suggesting that some changes in the implantation period can result in the future gestational loss.

Durante o ciclo menstrual, o endométrio se torna receptivo à chegada do \"futuro embrião\". Estes eventos são regulados pela liberação de progesterona durante a fase secretória do ciclo, que aumenta a secreção do componente C3 do Sistema Complemento (SC). Neste período, também foi observado o aumento fisiológico da expressão de algumas proteínas reguladoras do SC (CRPs) como: C1Inh, C4bp, DAF, CD59 e clusterina, oque sugere uma forte regulação da atividade deste sistema, favorável à implantação e ao desenvolvimento embrionário. Modificações na expressão destas proteínas poderiam resultar em aborto espontâneo recorrente (AER).Neste trabalho estudou-se a expressão endometrial de DAF e CD59 noendométrio de pacientes com AER, durante a fase secretória do ciclo. Adicionalmente, verificou-se a ativação do SC através da presença do neoantígeno de C9 neste mesmo material. A casuística foi composta de nove mulheres férteis normais (Grupo Controle) e doze mulheres com AER (Grupo Aborto), todas analisadas durante a fase secretória do ciclo. A técnica utilizada para detecção destas proteínas foi a imunohistoquímica. O neoantígeno deC9 não foi detectado em nenhum dos grupos, tanto nas glândulas quanto no estroma endometrial. DAF e CD59 foram detectados tanto no Grupo Controle quanto no Grupo Aborto.Houve expressão nitidamente mais acentuada de ambas as CRPs, DAF e CD59, durante a fase secretória intermediária do Grupo Aborto, embora sem diferença estatística. Houve expressão para DAF e CD59 no estroma endometrial de ambos os grupos. Assim, os resultados deste trabalho apontam para a ausência do neoantígeno de C9 no endométrio humano normal e no endométrio humano de patologias como o AER. As CRPs, DAF e CD59, se mostraram presentes tanto no endométrio humano normal quanto no endométrio humano patológico por AER, com destaque para o aumento da expressão de DAF e CD59 na sub-fase intermediária secretória do ciclo menstrual, período crítico para a implantação, sugerindo que alguma alteração neste período possa resultar na posterior perda gestacional. / In the cycle menstrual, the endometrium becomes ready to the arrived of embryo future. These events are controlled by mechanisms like, liberation of progesterone during the secretory phase of cycle, that increases the secretion of C3 component of Complement System (CS). In this period, it was also observed the physiologic increase of the expressionof some CS regulatory proteins (CRPs) like: C1Inh, C4bp, DAF, CD59 and clusterin, a fact suggesting strong regulation of the activity this system. Changes in this regulation can be harmful to implantation and to embryonary development, causing recurrent spontaneous abortion (RSA). To goal of the present study is to evaluate the endometrial expression of the Membrane Complex Atack (MAC) of CS, representing by neoantígen C9, in the normal and patologic human endometrium with RSA during the secretory phase of the menstrual cycle and of the CRPs, DAF e CD59, in the patologic human endometrium with RSA during the secretory phase, contributing to better understanding of the CS regulation in the endometrium in no physiologic conditions. The study group consisted of twelve endometrial biopsy, during the secretory phase of the menstrual cycle, of women with RSA of no apparent cause, compared to a control group of nine endometrial biopsy, in the same phase, of normal fertile women evaluated to endometrial expression of the neoantígen C9, DAF e CD59 by the immunochemistry technique. Neoantigen C9 was not detected in any group, in the secretory phase of the menstrual cycle in the endometrial glandular epithelium and stromal cells. DAF e CD59 were expressed in both groups during the secretory phase. DAF e CD59 were detected more intensely during the intermediate secretory phase of the Abortion Group when compared to the Control Group. Meanwhile, it not detected any significance difference. There was expression of DAF e CD59 in the stromal cells to the both groups. In summary, we data show that neoantígeno de C9 isn\'t expressed in the normal and patologic human endometrium, and the CRPs, DAF e CD59, are expressed in the normal and patologic human endometrium, predominating in the intermediary secretory phase of the cycle compared to the controls suggesting that some changes in the implantation period can result in the future gestational loss.

<p>Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen. Their precise physiological role is not known, although some of their properties assign them to important physiological and patho-physiological functions. In this thesis, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes have been identified. </p><p>Differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) have been characterized. The transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes) has been established. CD59, protein kinases and TF were overexpressed by malignant cell prostasomes. ATPase activity was highest on seminal prostasomes with minimal expression by malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins were phosphorylated by prostasomal protein kinases, <i>viz.</i> complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF was identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes were established. DU145 and PC-3-derived prostasomes exerted a higher clotting effect on whole blood and plasma compared to LNCaP and seminal prostasomes.</p><p>In conclusion, malignant cell prostasomes showed higher ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.</p>

Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen. Their precise physiological role is not known, although some of their properties assign them to important physiological and patho-physiological functions. In this thesis, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes have been identified. Differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) have been characterized. The transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes) has been established. CD59, protein kinases and TF were overexpressed by malignant cell prostasomes. ATPase activity was highest on seminal prostasomes with minimal expression by malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins were phosphorylated by prostasomal protein kinases, viz. complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF was identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes were established. DU145 and PC-3-derived prostasomes exerted a higher clotting effect on whole blood and plasma compared to LNCaP and seminal prostasomes. In conclusion, malignant cell prostasomes showed higher ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

Avec plus de 39 millions de personnes infectées à travers le monde, le virus de l’immunodéficience humaine de type-1 (VIH-1) est un problème majeur de santé publique. Bien que la thérapie antirétrovirale contrôle la réplication virale, améliore la santé et prolongent la vie des personnes vivant avec le VIH-1, elle ne permet pas d’éradiquer complètement le virus. En effet, celui-ci établit des phases de latence en intégrant son génome dans l’ADN cellulaire des cellules cibles, entrainant la formation de ce que l’on appelle le réservoir latent du virus. Ce réservoir se situe principalement dans les lymphocytes T CD4+, bien qu’on le retrouve également dans les cellules myéloïdes, et il constitue le principal obstacle à l’éradication du virus. Il est donc impératif de mieux comprendre les facteurs de l’hôte qui régissent non seulement la susceptibilité de ces cellules à l’infection et qui contribuent également à la persistance du VIH-1. Nous postulons que les micro-ARN (miARN), des petits ARN produits par la cellule et qui régulent l’expression génique, jouent un rôle au cours de l’infection par le VIH-1. Dans un premier temps, nous nous sommes concentrés sur le rôle des miARN dans l’entrée virale. À l’aide d’un séquençage de nouvelle génération des miARN dans les macrophages, nous avons déterminé que le miARN-103, ainsi que son paralogue le miARN-107, ciblent l’ARNm du corécepteur CCR5 utilisé par le VIH-1. Nous montrons que l’induction de l’expression des miARN-103/107 est régulée par le facteur de transcription p53 et rend les macrophages réfractaires à l’entrée du VIH-1. Nous observons que le niveau d’expression des miARN-103/107 est enrichi dans les macrophages résidant dans les tissus intestinaux de donneurs sains et les macrophages alvéolaires des personnes sous thérapie antirétrovirale, ce qui contribue vraisemblablement à leur résistance à l’infection par le VIH-1. Étant donné que les lymphocytes T CD4+ constituent le principal réservoir du VIH-1, nous avons ensuite étendu l’étude du miARN-103 dans ces cellules. Récemment, il a été montré que la latence virale serait la conséquence de l’infection de lymphocytes T CD4+ dans une fenêtre très étroite suite à leur activation. Ces cellules qui 3 transitionnent vers un phénotype mémoire posséderaient des propriétés uniques, comme une augmentation temporaire de l’expression du corécepteur viral CCR5, ainsi qu’une capacité réduite de transcrire l’ADN proviral intégré. Nos résultats montrent que le miARN-103, qui cible également le CCR5 dans les lymphocytes T CD4+, participe à la modulation du CCR5 selon l’état d’activation de la cellule et contribue indirectement à l’établissement de la latence virale dans ces cellules. De plus, nos résultats montrent que les lymphocytes T CD4+ issus d’individus qui contrôlent l’infection par le VIH-1 expriment des niveaux réduits d’ARNm de CCR5 (lorsque comparés à ceux d’individus non-contrôleurs). Cet état étant associé à une tendance à la hausse du miARN-103, suggère que le miARN-103 pourrait participer au contrôle de l’expression de CCR5 in vivo. Dans un deuxième temps, nous avons réalisé un séquençage de nouvelle génération de l’ARN des lymphocytes T CD4+ infectés. À la suite de cette analyse, nous avons déterminé que le miARN-26a participe à la régulation de CD59, une protéine cellulaire incorporée dans les virions jouant un rôle clé dans l’activation du complément en inhibant la formation du complexe d’attaque membranaire. Au cours de l’infection, ce miARN est diminué dans les cellules productivement infectées. Cette diminution est associée à une augmentation de CD59 dans les cellules infectées et à la surface des virions produits par ces cellules, favorisant leur échappement à la lyse médiée par le complément. Nous montrons que l’introduction d’un analogue du miARN-26a dans les cellules rend les virions produits par ces dites cellules plus sensibles à la lyse médiée par le complément. En conclusion, les observations et analyses réalisées dans le cadre de cette thèse nous aident à mieux comprendre le rôle des miARN dans l’infection et la persistance du VIH-1. Ces résultats aident à notre compréhension des facteurs de l’hôte qui régissent la susceptibilité de ces cellules à l’infection ainsi que la persistance virale, et pourraient aider au développement de stratégies thérapeutiques. / With more than 39 million people infected in the world, human immunodeficiency virus type 1 (HIV-1) is a major public health problem. Although antiretroviral therapy controls viral replication, improves the health, and prolongs the lives of people living with HIV-1, it does not completely eradicate the virus. Indeed, the virus has established latency phases by integrating its genome into the cellular DNA of target cells, leading to the formation of what is called the latent reservoir of the virus. This reservoir is located mainly in CD4+ T cells, although it is also found in myeloid cells, and it has become the main obstacle to eradication of the virus. It is therefore imperative to better understand the host factors that not only govern the susceptibility of these cells to infection but also contribute to HIV-1 persistence. We postulate that microRNAs (miRNAs), which are small RNAs produced by the cell involved in regulation of gene expression, have a role during HIV-1 infection. First, we focused on the role of miRNAs in viral entry. Using next generation miRNA sequencing in macrophages, we determined that miRNA-103, as well as its paralogue miRNA-107, target the mRNA of CCR5, the HIV-1 coreceptor. We show that the induction of miRNA-103/107 expression is regulated by the transcription factor p53 and makes macrophages more resistant to HIV-1 entry. We observe that the expression level of miRNAs-103/107 is enriched in resident macrophages in intestinal tissues of healthy donors and alveolar macrophages of people on antiretroviral therapy, which likely contributes to their resistance to infection by HIV-1. Given that CD4+ T cells constitute the main reservoir of HIV-1, we then extended the study of miRNA-103 in these cells. Recently, it has been shown that viral latency is the consequence of the infection of CD4+ T cells within a very narrow window following their activation. These transitioning to memory T cells are thought to possess unique properties, such as a temporary increase in the expression of the viral coreceptor CCR5, as well as a reduced capacity to transcribe integrated proviral DNA. Our results show that miRNA-103, which also targets CCR5 in CD4+ T cells, participates in the modulation of CCR5 depending on the activation state of the cell 5 and indirectly contributes to the establishment of viral latency in these cells. Furthermore, our results show that CD4+ T cells from individuals who control HIV-1 infection express reduced levels of CCR5 mRNA (when compared to those from non- controller individuals), this being associated to a upward trend in miRNA-103 expression, suggesting that miRNA-103 may participate in the control of CCR5 expression in vivo. Secondly, we carried out next generation RNA sequencing of HIV-1 infected CD4+ T cells. Their resulting analyses determined that miRNA-26a participates in the regulation of CD59, a cellular protein that is incorporated into virions and has a key role in complement activation by inhibiting the formation of the membrane attack complex. During infection, this miRNA is decreased in productively infected cells. This decrease is associated with an increase in CD59 in infected cells, as well as on the surface of virions produced by these cells, favoring their escape from complement- mediated lysis. We show that introduction of miRNA-26a mimics in cells makes the virions produced by these cells more sensitive to complement-mediated lysis. In conclusion, the observations and analyses developed in this thesis will help us better understand the role of miRNAs in HIV-1 infection and persistence. These results help in the understanding of host factors that govern the susceptibility of these cells to infection as well as viral persistence and could help in the development of therapeutic strategies.

A Artrite Reumatóide (AR) é uma doença autoimune associada a poliartropatia inflamatória que acomete principalmente as articulações periféricas. Cerca de 1% da população mundial é afetada, sendo duas a três vezes mais prevalente em mulheres. Apresenta uma patogênese complexa e multifatorial. A sinóvia das articulações afetadas é infiltrada por linfócitos T e B, macrófagos e granulócitos. A sinóvia reumatóide adquire características proliferativas, formando o pannus, e invade a cartilagem articular e o osso, levando à destruição da arquitetura normal da articulação e perda de função. Em vários modelos de doenças autoimunes, a ausência ou diminuição da expressão de proteínas reguladoras do complemento tem sido observada, associada com o agravamento dos sintomas clínicos, sendo que, muitos destes casos, a superativação do sistema complemento pode ser a causa da exacerbação da doença. O presente artigo tem por objetivo revisar os principais aspectos relacionados à regulação do sistema complemento na artrite reumatóide, a fim de propiciar uma melhor compreensão do potencial papel desse sistema na fisiopatologia da doença. / Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis that affects mainly the peripheral joints. About 1% of the world population is affected, and it is two to three times more prevalent in women. RA has a complex and multifactorial pathogenesis. The rheumatoid synovium acquires proliferative characteristics, forming the pannus, and invades cartilage and bone, leading to the destruction of normal architecture and loss of function. In several models of autoimmune diseases, the absence or decreased expression of complement regulatory proteins has been observed, associated with worsening of the clinical symptoms, and many of these cases the over-activation of the complement system is the cause of disease exacerbation. This article aims to review the main aspects related to regulation of the complement system in rheumatoid arthritis in order to provide a better understanding of the potential role of this system in the pathophysiology of the disease.

A Artrite Reumatóide (AR) é uma doença autoimune associada a poliartropatia inflamatória que acomete principalmente as articulações periféricas. Cerca de 1% da população mundial é afetada, sendo duas a três vezes mais prevalente em mulheres. Apresenta uma patogênese complexa e multifatorial. A sinóvia das articulações afetadas é infiltrada por linfócitos T e B, macrófagos e granulócitos. A sinóvia reumatóide adquire características proliferativas, formando o pannus, e invade a cartilagem articular e o osso, levando à destruição da arquitetura normal da articulação e perda de função. Em vários modelos de doenças autoimunes, a ausência ou diminuição da expressão de proteínas reguladoras do complemento tem sido observada, associada com o agravamento dos sintomas clínicos, sendo que, muitos destes casos, a superativação do sistema complemento pode ser a causa da exacerbação da doença. O presente artigo tem por objetivo revisar os principais aspectos relacionados à regulação do sistema complemento na artrite reumatóide, a fim de propiciar uma melhor compreensão do potencial papel desse sistema na fisiopatologia da doença. / Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis that affects mainly the peripheral joints. About 1% of the world population is affected, and it is two to three times more prevalent in women. RA has a complex and multifactorial pathogenesis. The rheumatoid synovium acquires proliferative characteristics, forming the pannus, and invades cartilage and bone, leading to the destruction of normal architecture and loss of function. In several models of autoimmune diseases, the absence or decreased expression of complement regulatory proteins has been observed, associated with worsening of the clinical symptoms, and many of these cases the over-activation of the complement system is the cause of disease exacerbation. This article aims to review the main aspects related to regulation of the complement system in rheumatoid arthritis in order to provide a better understanding of the potential role of this system in the pathophysiology of the disease.

A Artrite Reumatóide (AR) é uma doença autoimune associada a poliartropatia inflamatória que acomete principalmente as articulações periféricas. Cerca de 1% da população mundial é afetada, sendo duas a três vezes mais prevalente em mulheres. Apresenta uma patogênese complexa e multifatorial. A sinóvia das articulações afetadas é infiltrada por linfócitos T e B, macrófagos e granulócitos. A sinóvia reumatóide adquire características proliferativas, formando o pannus, e invade a cartilagem articular e o osso, levando à destruição da arquitetura normal da articulação e perda de função. Em vários modelos de doenças autoimunes, a ausência ou diminuição da expressão de proteínas reguladoras do complemento tem sido observada, associada com o agravamento dos sintomas clínicos, sendo que, muitos destes casos, a superativação do sistema complemento pode ser a causa da exacerbação da doença. O presente artigo tem por objetivo revisar os principais aspectos relacionados à regulação do sistema complemento na artrite reumatóide, a fim de propiciar uma melhor compreensão do potencial papel desse sistema na fisiopatologia da doença. / Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis that affects mainly the peripheral joints. About 1% of the world population is affected, and it is two to three times more prevalent in women. RA has a complex and multifactorial pathogenesis. The rheumatoid synovium acquires proliferative characteristics, forming the pannus, and invades cartilage and bone, leading to the destruction of normal architecture and loss of function. In several models of autoimmune diseases, the absence or decreased expression of complement regulatory proteins has been observed, associated with worsening of the clinical symptoms, and many of these cases the over-activation of the complement system is the cause of disease exacerbation. This article aims to review the main aspects related to regulation of the complement system in rheumatoid arthritis in order to provide a better understanding of the potential role of this system in the pathophysiology of the disease.