Adverse reactions to biologic agents and their medical management.

Biologic agents have substantially advanced the treatment of immunological disorders, including chronic inflammatory and autoimmune diseases. However, these drugs are often associated with adverse events (AEs), including allergic, immunological and other unwanted reactions. AEs can affect almost any organ or system in the body and can occur immediately, within minutes to hours, or with a delay of several days or more after initiation of biologic therapy. Although some AEs are a direct consequence of the functional inhibition of biologic-agent-targeted antigens, the pathogenesis of other AEs results from a drug-induced imbalance of the immune system, intermediary factors and cofactors, a complexity that complicates their prediction. Herein, we review the AEs associated with biologic therapy most relevant to rheumatic and immunological diseases, and discuss their underlying pathogenesis. We also include our recommendations for the medical management of such AEs. Increased understanding and improved risk management of AEs induced by biologic agents will enable better use of these versatile immune-response modifiers.

Radioimmunotherapy combined with maintenance anti-CD20 antibody may trigger long-term protective T cell immunity in follicular lymphoma patients.

Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL.

Relevance of death receptors in nervous system: role in the pathogenesis of neurodegenerative diseases and targets for therapy

L���apoptosi ��s un proc��s fisiol��gic que controla el nombre de c��l��lules en organismes superiors. L���apoptosi est�� estrictament regulada i s���ha vist que est�� implicada en la patog��nesi d���algunes malalties del sistema nervi��s. En aquest sentit, un exc��s de mort cel��lular contribueix a les malalties neurodegenerati- ves, mentre que, el seu d��ficit ��s una de les raons del desenvolupament de tumors. El punt principal de regulaci�� del proc��s apopt��tic ��s l���activaci�� de les caspases, ciste��na-proteases que tenen especificitat pels residus asp��rtic. Les caspases es poden activar per dos mecanismes principals: (1) alliberament de citocrom C dels mitocondris alterats al citoplasma i (2) l���activaci�� dels receptors de la membrana anomenats receptors de mort (DR, de l���angl��s death receptor). Aquests receptors s���han caracteritzat extensament en el sistema immunitari, mentre que en el sistema nervi��s les seves funcions s��n encara desconegudes. El present article se centra en el paper dels DR en la patog��nesi de malalties neurodegeneratives i suggereix el seu potencial des del punt de vista terap��utic. Tamb�� es descriuen diverses mol��cules intracel��lulars caracteritzades per la seva habilitat en la modulaci�� dels DR. Entre elles, presentem dues noves prote��nes ��� lifeguard i FAIM ��� que s���expressen espec��ficament al sistema nervi��s.

Flavonoids affect host-microbiota crosstalk through TLR modulation

Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

Flavonoids affect host-microbiota crosstalk through TLR modulation

Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after bone marrow transplantation

Allogeneic bone marrow transplantation (alloBMT) is the only curative therapy for chronic myelogenous leukemia (CML). This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI) producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma), and unstimulated (in vivo) lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR), of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2) on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.

The use of reverse transcription-PCR for the diagnosis of X-linked chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by a defective oxidative burst of phagocytes and subsequent impairment of their microbicidal activity. Mutations in one of the NADPH-oxidase components affect gene expression or function of this system, leading to the phenotype of CGD. Defects in gp91-phox lead to X-linked CGD, responsible for approximately 70% of CGD cases. Investigation of the highly heterogeneous genotype of CGD patients includes mutation analysis, Northern blot or Western blot assays according to the particular case. The aim of the present study was to use reverse transcription (RT)-PCR for the analysis of molecular defects responsible for X-linked CGD in eight Brazilian patients and to assess its potential for broader application to molecular screening in CGD. Total RNA was prepared from Epstein B virus-transformed B-lymphocytes and reverse transcribed using random hexamers. The resulting cDNA was PCR-amplified by specific and overlapping pairs of primers designed to amplify three regions of the gp91-phox gene: exons 1-5, 3-9, and 7-13. This strategy detected defective gp91-phox expression in seven patients. The RT-PCR results matched clinical history, biochemical data (nitroblue tetrazolium or superoxide release assay) and available mutation analysis in four cases. In three additional cases, RT-PCR results matched clinical history and biochemical data. In another case, RT-PCR was normal despite a clinical history compatible with CGD and defective respiratory burst. We conclude that this new application of RT-PCR analysis - a simple, economical and rapid method - was appropriate for screening molecular defects in 7 of 8 X-linked CGD patients.

Proteomic inventory of myocardial proteins from patients with chronic Chagas' cardiomyopathy

Chronic Chagas' disease cardiomyopathy (CCC) is an often fatal outcome of Trypanosoma cruzi infection, with a poorer prognosis than other cardiomyopathies. CCC is refractory to heart failure treatments, and is the major indication of heart transplantation in Latin America. A diffuse myocarditis, plus intense myocardial hypertrophy, damage and fibrosis, in the presence of very few T. cruzi forms, are the histopathological hallmarks of CCC. To gain a better understanding of the pathophysiology of CCC, we analyzed the protein profile in the affected CCC myocardium. Homogenates from left ventricular myocardial samples of end-stage CCC hearts explanted during heart transplantation were subjected to two-dimensional electrophoresis with Coomassie blue staining; protein identification was performed by MALDI-ToF mass spectrometry and peptide mass fingerprinting. The identification of selected proteins was confirmed by immunoblotting. We demonstrated that 246 proteins matched in gels from two CCC patients. They corresponded to 112 distinct proteins. Along with structural/contractile and metabolism proteins, we also identified proteins involved in apoptosis (caspase 8, caspase 2), immune system (T cell receptor �� chain, granzyme A, HLA class I) and stress processes (heat shock proteins, superoxide dismutases, and other oxidative stress proteins). Proteins involved in cell signaling and transcriptional factors were also identified. The identification of caspases and oxidative stress proteins suggests the occurrence of active apoptosis and significant oxidative stress in CCC myocardium. These results generated an inventory of myocardial proteins in CCC that should contribute to the generation of hypothesis-driven experiments designed on the basis of the classes of proteins identified here.

Evasion of immune responses by Trypanosoma cruzi, the etiological agent of Chagas disease

Infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects millions of people in Latin America. Infection with T. cruzi cannot be eliminated by the immune system. A better understanding of immune evasion mechanisms is required in order to develop more effective vaccines. During the acute phase, parasites replicate extensively and release immunomodulatory molecules that delay parasite-specific responses mediated by T cells. This immune evasion allows the parasite to spread in the host. In the chronic phase, parasite evasion relies on its replication strategy of hijacking the TGF-β signaling pathway involved in inflammation and tissue regeneration. In this article, the mechanisms of immune evasion described for T. cruzi are reviewed.

Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

Players of Th-cell differentiation and immune dysregulation ��� focus on GIMAP family genes

The balance of T helper (Th) cell differentiation is the fundamental process that ensures that the immune system functions correctly and effectively. The differentiation is a fine tuned event, the outcome of which is driven by activation of the T-cell in response to recognition of the specific antigen presented. The co-stimulatory signals from the surrounding cytokine milieu help to determine the outcome. An impairment in the differentiation processes may lead to an imbalance in immune responses and lead to immune-mediated pathologies. An over-representation of Th1 type cytokine producing cells leads to tissue-specific inflammation and autoimmunity, and excessive Th2 response is causative for atopy, asthma and allergy. The major factors of Th-cell differentiation and in the related disease mechanisms have been extensively studied, but the fine tuning of these processes by the other factors cannot be discarded. In the work presented in this thesis, the association of T-cell receptor costimulatory molecules CTLA4 and ICOS with autoimmune diabetes were studied. The underlying aspect of the study was to explore the polymorphism in these genes with the different disease rates observed in two geographically close populations. The main focus of this thesis was set on a GTPase of the immunity associated protein (GIMAP) family of small GTPases. GIMAP genes and proteins are differentially regulated during human Th-cell differentiation and have been linked to immune-mediated disorders. GIMAP4 is believed to contribute to the immunological balance via its role in T-cell survival. To elucidate the function of GIMAP4 and GIMAP5 and their role in human immunity, a study combining genetic association in different immunological diseases and complementing functional analyses was conducted. The study revealed interesting connections with the high susceptibility risk genes. In addition, the role of GIMAP4 during Th1-cell differentiation was investigated. A novel function of GIMAP4 in relation to cytokine secretion was discovered. Further assessment of GIMAP4 and GIMAP5 effect for the transcriptomic profile of differentiating Th1-cells revealed new insights for GIMAP4 and GIMAP5 function.

CLEVER-1 as an immune suppressive molecule

The immune response and immune suppression are equally essential for the immune system to protect the host against an infection and to protect self-molecules in different pathophysiological conditions. Pregnancy is one of the conditions where the maternal immune system remains resistant against microbes and yet attains tolerance to protect the fetus, whose genetic material differs partially from the mother���s. However, if the balance of immune suppression is not precise in the host it can favor conditions which lead to diseases, such as cancer and autoimmune disorders. This study was initiated to investigate the expression and functions of CLEVER-1/Stabilin-1, a multifunctional protein expressed on subsets of endothelial cells and type II macrophages, as an immune suppressive molecule. Firstly, the expression of CLEVER-1/stabilin-1 and its function in human placental macrophages were examined. Secondly, the expression profile and functional significance of stabilin-1 on healthy human monocytes was investigated. The results clarified the expression of CLEVER-1/stabilin-1 on placental macrophages, and verified that CLEVER-1/stabilin-1 functions as an adhesion and scavenging molecule on these cells. The data from normal monocytes revealed that the monocytes with low stabilin-1 expression carried a pro-inflammatory gene signature, and that stabilin-1 can directly or indirectly regulate pro-inflammatory genes in monocytes. Finally, it was shown that monocyte CLEVER-1/stabilin-1 dampens IFN��� production by T cells. To conclude, CLEVER-1/stabilin-1 is defined as an immune suppressive molecule on monocytes and macrophages. Strikingly, anti-stabilin-1 antibodies may have the potential to promote the Th1 dependent inflammatory response and counteract the tumor induced immune suppression.

Chronic mild social stress increases neurogenesis in adolescent male rats

Once thought to occur only during specific periods of development, it is now clear that neurogenesis occurs in the rat hippocampus into adulthood. It is wellestablished that stress during adulthood decreases the rate of neurogenesis, but during adolescence, the effects of stress are much less understood. I investigated the effect of short-term or chronic stress during adolescence (daily lhr isolation and change of cage partner from postnatal day (PND) 30-32 or 30-45) on hippocampal neurogenesis. In experiment 1, rats were administered Bromodeoxyuridine (BrdU) daily on PND 30-32, or 46-48, to mark neurogenesis at the beginning of the stressor or after the stressor had ceased, respectively. Neither short-term nor chronic stress had an effect on proliferation or survival (evidenced by BrdU and Doublecortin (Dcx) immunohistochemistry respectively) of cells born at the beginning of the stress procedure. Compared to controls, BrdU-labeling showed chronic stress significantly increased proliferation of cells generated after the stressor had ceased, but survival of new neurons was not supported (Dcx-Iabeling). However, it may be that BrdU injections are inherently stressful. In experiment 2, the stressor (described above) was applied in the absence of BrdU injections. Ki67 (a marker of proliferation) showed that stress transiently increased cell proliferation. Dcx-Iabeling showed that stress also increased neuron survival into adulthood. Labeling with OX.,.42 (a marker of macro phages) suggested that the immune system plays a role in neurogenesis, as stress transiently decreased the number of activated microglia in the hippocampus. It can be concluded that in the adolescent male rat, chronic mild stress increases neurogenesis.

R��gulation de l'hepcidine et le r��le de la lipocaline 2 dans l'hom��ostasie du fer / Novel insights into the regulation of hepcidin and the role of lipocalin 2 in iron homeostasis

Le fer, un m��tal de transition, est requis pour la survie de presque tout les organismes vivant �� cause de son habilit�� �� accepter ou donner un ��lectron et donc �� catalyser plusieurs r��actions biochimique fondamentales. Cependant, la m��me propri��t�� permet aussi au fer ionique d���acc��l��rer la formation de radicaux libres et donc le fer peut potentiellement avoir des effets n��fastes. Cons��quemment, l���hom��ostasie du fer doit ��tre ��troitement r��gul��, tant au niveau cellulaire que syst��mique. Notre ��tude met l���emphase sur deux mol��cules importante pour r��gulation du m��tabolisme du fer : la lipocaline 2 (Lcn2) et l���hepcidine. Lcn2, une prot��ine de phase aigu��, est impliqu��e dans le transport du fer par les sid��rophores. Lcn2 est un candidat potentiel comme transporteur du fer qui pourrait ��tre responsable de l���accumulation excessive du fer non li�� �� la transferrine dans le foie des patients atteints d���h��mochromatose h��r��ditaire (HH). Nous avons g��n��r�� des souris double-d��ficiente HfeLcn2 pour ��valuer l���importance de Lcn2 dans la pathogen��se de surcharge en fer h��patique dans les souris knock-out Hfe (Hfe -/-). Notre ��tude r��v��le que la d��l��tion de Lcn2 dans les souris Hfe-/- n���influence pas leur accumulation de fer h��patique ou leur r��ponse �� une surcharge en fer. Le ph��notype des souries HfeLcn2-/- demeure indiscernable de celui des souris Hfe-/-. Nos donn��es impliquent que Lcn2 n���est pas essentiel pour la livraison du fer aux h��patocytes dans l���HH. L���hepcidine, un r��gulateur cl�� du m��tabolisme du fer, est un petit peptide antimicrobien produit par le foie et qui r��gule l���absorption intestinale du fer et son recyclage par les macrophages. L���expression de l���hepcidine est induite par la surcharge en fer et l���inflammation, tandis que, �� l'inverse, elle est inhib��e par l'an��mie et l'hypoxie. Dans certaine situations pathologique, l���hepcidine est r��gul��e dans des directions oppos��es par plus d���un r��gulateur. Nous avons, en outre, analys�� comment les diff��rents facteurs influencent l���expression de l���hepcidine in vivo en utilisant un mod��le de souris avec un m��tabolisme du fer alt��r��. Nous avons examin�� la r��gulation de l���hepcidine en pr��sence de stimuli oppos��s, ainsi que la contribution des m��diateurs et des voix de signalisation en aval de l���expression de l���hepcidine. Nous avons d��montr�� que l'��rythropo����se, lorsque stimul�� par l�����rythropo����tine, mais pas par l���hypoxie, diminue l���expression de l���hepcidine d���une fa��on d��pendante de la dose, m��me en pr��sence de lipopolysaccharides ou de surcharge de fer alimentaire, qui peuvent agir de mani��re additive. De plus, l���entra��nement ��rythropo����tique inhibe tant la voix inflammatoire que celle de d��tection du fer, du moins en partie, par la suppression du signal IL-6/STAT3 et BMP/SMAD4 in vivo. Au total, nos donn��es sugg��rent que le niveau d���expression de l���hepcidine en pr��sence de signaux oppos��s est d��termin�� par la force du stimulus individuel plut��t que par une hi��rarchie absolue. Ces d��couvertes sont pertinentes pour le traitement de l���an��mie des maladies chronique et les d��sordres de surcharge en fer.

Recognition of hepatitis C virus RNA by toll like receptors 7 and 8 : implications for the initiation of innate immune response

Le virus de l���h��patite C (VHC) est un virus �� ARN simple brin positif (ssARN) qui se replique dans le foie. Deux cents millions de personnes sont infect��es par le virus dans le monde et environ 80% d���entre elles progresseront vers un stade chronique de l���infection. Les th��rapies anti-virales actuelles comme l���interf��ron (IFN) ou la ribavirin sont de plus en plus utilis��es mais ne sont efficaces que dans la moiti�� des individus trait��s et sont souvent accompagn��es d���une toxicit�� ou d���effets secondaires ind��sirables. Le syst��me immunitaire inn�� est essentiel au contr��le des infections virales. Les r��ponses immunitaires inn��es sont activ��es suite �� la reconnaissance par les Pathogen Recognition Receptors (PRRs), de motifs macromol��culaires d��riv��s du virus appel��s Pathogen-Associated Molecular Patterns (PAMPs). Bien que l'activation du syst��me immunitaire par l'ARN ou les prot��ines du VHC ait ��t�� largement ��tudi��e, tr��s peu de choses sont actuellement connues concernant la d��tection du virus par le syst��me immunitaire inn��. Et m��me si l���on peut tr��s rapidement d��celer des r��ponses immunes in vivo apr��s infection par le VHC, l���augmentation progressive et continue de la charge virale met en ��vidence une incapacit�� du syst��me immunitaire �� contr��ler l���infection virale. Une meilleure compr��hension des m��canismes d���activation du syst��me immunitaire par le VHC semble, par cons��quent, essentielle au d��veloppement de strat��gies antivirales plus efficaces. Dans le pr��sent travail nous montrons, dans un mod��le de cellule primaire, que le g��nome ARN du VHC contient des s��quences riches en GU capables de stimuler sp��cifiquement les r��cepteurs de type Toll (TLR) 7 et 8. Cette stimulation a pour cons��quence la maturation des cellules dendritiques plasmacyto��des (pDCs), le production d���interf��ron de type I (IFN) ainsi que l���induction de ch��mokines et cytokines inflammatoires par les diff��rentes types de cellules pr��sentatrices d���antig��nes (APCs). Les cytokines produites apr��s stimulation de monocytes ou de pDCs par ces s��quences ssARN virales, inhibent la production du virus de fa��on d��pendante de l���IFN. En revanche, les cytokines produites apr��s stimulation de cellules dendritiques my��lo��des (mDCs) ou de macrophages par ces m��mes s��quences n���ont pas d���effet inhibiteur sur la production virale car les s��quences ssARN virales n���induisent pas la production d���IFN par ces cellules. Les cytokines produites apr��s stimulation des TLR 7/8 ont ��galement pour effet de diminuer, de fa��on ind��pendante de l���IFN, l���expression du r��cepteur au VHC (CD81) sur la lign��e cellulaire Huh7.5, ce qui pourrait avoir pour cons��quence de restreindre l���infection par le VHC. Quoiqu���il en soit, m��me si les r��cepteurs au VHC comme le CD81 sont largement exprim��s �� la surface de diff��rentes sous populations lymphocytaires, les DCs et les monocytes ne r��pondent pas aux VHC, Nos r��sultats indiquent que seuls les macrophages sont capables de reconna��tre le VHC et de produire des cytokines inflammatoires en r��ponse �� ce dernier. La reconnaissance du VHC par les macrophages est li��e �� l���expression membranaire de DC-SIGN et l���engagement des TLR 7/8 qui en r��sulte. Comme d���autres agonistes du TLR 7/8, le VHC stimule la production de cytokines inflammatoires (TNF-��, IL-8, IL-6 et IL-1b) mais n���induit pas la production d���interf��ron-beta par les macrophages. De mani��re attendue, la production de cytokines par des macrophages stimul��s par les ligands du TLR 7/8 ou les s��quences ssARN virales n���inhibent pas la r��plication virale. Nos r��sultats mettent en ��vidence la capacit�� des s��quences ssARN d��riv��es du VHC �� stimuler les TLR 7/8 dans diff��rentes populations de DC et �� initier une r��ponse immunitaire inn��e qui aboutit �� la suppression de la r��plication virale de fa��on d��pendante de l���IFN. Quoiqu���il en soit, le VHC est capable d�����chapper �� sa reconnaissance par les monocytes et les DCs qui ont le potentiel pour produire de l���IFN et inhiber la r��plication virale apr��s engagement des TLR 7/8. Les macrophages poss��dent quant �� eux la capacit�� de reconna��tre le VHC gr��ce en partie �� l���expression de DC-SIGN �� leur surface, mais n���inhibent pas la r��plication du virus car ils ne produisent pas d���IFN. L�����chappement du VHC aux d��fenses antivirales pourrait ainsi expliquer l�����chec du syst��me immunitaire inn�� �� contr��ler l���infection par le VHC. De plus, la production de cytokines inflammatoires observ��e apr��s stimulation in vitro des macrophages par le VHC sugg��re leur potentielle contribution dans l���inflammation que l���on retrouve chez les individus infect��s par le VHC.