 Your new post is loading...
Your new post is loading...
|
Suggested by
Société Francaise d'Immunologie
March 7, 2019 2:45 PM
|
CD19-targeted chimeric antigen receptor (CAR) T cell therapy is revolutionizing treatment for hematologic malignancies. As CD19 is a marker on all B cells, not just malignant ones, Kansal et al. reasoned that CD19-targeted CAR T cells could possibly be used to deplete autoreactive B cells in lupus.
|
|
Suggested by
Société Francaise d'Immunologie
February 20, 2019 3:32 PM
|
Summary Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infections. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes anti‐viral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen‐presenting cells and CD169+ macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin‐specific peptidase 18 (Usp18), an endogenous type I interferon blocker in CD169+ macrophages, has been identified as a proviral gene, as are B cell activating factor (BAFF) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All these factors modulate splenic architecture and thereby promote the development of CD169+ macrophages. Tumor necrosis factor alpha (TNF‐α) and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling (NF‐κB) have been found to promote the survival of infected CD169+ macrophages, thereby similarly promoting enforced viral replication. Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein–Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus. In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies. Introduction Rapid spread of virus to a susceptible organ causes serious tissue damage, which can lead to fatal disease because of the direct cytopathic effects of the virus. A typically infectious dose of one to a few infectious particles must be replicated several times before it reaches such harmful levels. During this time window, the immune system must be activated so that viral replication can be limited and the spread of virus to the susceptible organ can be avoided. Replication of virus in secondary lymphatic organs accelerates immune activation, and thereby helps to control the virus. Dendritic cells and CD169+ macrophages are important initiators of the anti‐viral immune response The importance of the splenic cellular architecture on viral replication has been recognized for decades 1. Various cell types influence efficient virus replication. In particular, antigen‐presenting cells (APCs), such as specialized macrophages and dendritic cells (DCs), exhibit strong immune‐activating ability. Therefore, viral replication in these cells exerts an important effect on the outcome of an infection. Viral infection leads to antigen presentation on major histocompatibility complex (MHC) class I molecules of DCs, which contributes strongly to the priming of cytotoxic T lymphocytes (CTLs). Even in a situation where viral replication is strongly limited (i.e. infection of mice, which lack the entry receptor of human poliovirus, with human poliovirus) DCs manage to replicate sufficient amounts of virus to induce priming of CD8+ T cells 2. Therefore, it has been suggested that DCs have a special ability to be infected by virus. This ability, as well as the expression of co‐stimulatory molecules would explain the strong immune‐activating ability of DCs during viral infection. However, infectivity of virus may also be dependent on the virus type and the DC subset. Indeed, other studies have indicated that some DC subsets are not susceptible to viral infection 3, 4. The enhanced viral replication in CD169+ macrophages is obviously even more important in those instances where DCs themselves cannot be infected. In such cases, antigen transfer and cross‐presentation by DCs would become important for CD8+ T cell activation 5, 6. Furthermore, we draw attention to the importance of metallophilic macrophages and subcapsular sinus macrophages that express a C‐type lectin, CD169 (Siglec‐1). During virus infection, CD169+ macrophages play an important role in activating the innate and adaptive immune systems by capturing virus and promoting viral replication 7-10. CD169+ macrophages can directly activate CD8+ T cells, but can also transfer antigen to DCs 11. In line with this, CD169+ macrophages can activate CD8+ T cells against non‐replicating antigen 11-13. The absence of CD169+ macrophages leads to a fatal disease outcome because of reduced interferon (IFN) production and limited activation of adaptive immune cells 8, 14, 15. Although we found that the replication ability of these macrophages is an important factor explaining the strong effect of CD169+ macrophages on the anti‐viral immune response, additional mechanisms by which CD169+ macrophages contribute to anti‐viral immune activation must be determined. Mechanisms of splenic architecture maintenance Overview The proper development and function of CD169+ macrophages rely on an intact splenic architecture. Several cytokines and chemokines (i.e. RANK, LXRa), maintain the splenic architecture and thereby influence the development of CD169+ macrophages 16-18. Similarly, the proper development of CD169+ macrophages relies on a balanced B cell function 1, 19. Factors that influence B cell development have a strong effect on viral replication in the spleen of mice. The general absence of B cells or the absence of tumor necrosis factor (TNF)‐α or lymphotoxin (LT) production, which both is linked to the normal function of B cells, influences splenic maintenance and virus replication during lymphocytic choriomeningitis virus (LCMV) infection 20. The promotion of virus replication in CD169+ macrophages relies solely on the presence of B cells rather than on the antibody response 19. In addition, certain members of the TNF superfamily 21, i.e. LTα, LTβ, TNF‐α, B cell‐activating factor (BAFF) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) 22, 23, have been found to be similarly important for the maintenance of splenic architecture because of their influence on B cell development 21-23. Although B cells and members of the TNF superfamily play an important role in the function of macrophages, their impairment of the immune response of DCs is also important. Lymphotoxins are cytokines that consist of LTα and LTβ. Surface‐bound LT expression has been detected on innate lymphoid cells (ILCs), DCs, natural killer (NK) cells and B and T lymphocytes 24. LTs serve several functions in vivo, including organ maintenance, lymphoid organogenesis and immune response regulation 25, 26. Deficiency in LTα, LTβ or lymphotoxin‐beta receptor (LTβR) can manipulate the development of not only Peyer’s patches and lymph nodes, but also of CD169+ macrophages 20. Interestingly, despite a reduction in CD169+ macrophages, LTβ‐deficient mice exhibit reduced viral replication 20. Mice lacking LTβ fail to restrict the replication of vesicular stomatitis virus (VSV) to the marginal zone of the spleen, and this failure leads to fatal outcome of the infection 20. The impact of LTβ deficiency is restricted not only to macrophages, but also to DCs. Mechanistically, LTβ expression influences maturation, activation and the homing ability of lymphocytes. Detailed mechanisms by which LT influences the development of CD169+ macrophages remain to be determined. LT not only influences the development of CD169+ macrophages but also contributes to the generation of splenic conduits, whose function is essential for early virus distribution in the spleen and thereby influences innate immune activation during virus infection 15. Although the absence of LT is clearly linked to impaired organogenesis and reduced numbers of CD169+ macrophages, the role of TNF‐α in the development of CD169+ macrophages is controversial. The impact of TNF‐α on the formation of primary B cells and germinal centers, as well as on follicular DC (FDC) networks, has been studied intensively 27-29, but its role in the maintenance of CD169+ macrophages remains controversial 27-29. On one hand, some reports state that mice deficient in TNF‐α and mice deficient in p55 tumor necrosis factor receptor 1 (TNF‐R1) exhibit severe impairment in marginal zone development 29; on the other hand, some reports hint at the depletion activity of TNF‐α after infection. Excessive production of TNF‐α in mice infected with Leishmania donovani leads to rapid remodeling of splenic structure and loss of marginal zone macrophages (MZMs). In line with this finding, other researchers have found that the pathogenic burden during L. donovani infection can be reversed by TNF depletion 30. In contrast, a recent study found reductions in the numbers of CD169+ cells in the absence of TNF‐α or TNF‐R1. Consequently, reduced production of type I IFN (IFN‐I) can be detected during VSV infection and leads to a severe disease outcome. At the molecular level, the absence of TNF‐α expression impedes RelA translocation into the nuclei of CD169+ macrophages, which is necessary for early IFN‐I expression after viral infection 31. B cell activating factor (BAFF), another TNF superfamily‐related factor, is crucial for B cell development and humoral immunity in mice and humans 32. BAFF binds to B lymphocytes via one of three receptors: B cell maturation antigen (BCMA), transmembrane activator and calcium‐modulating cyclophilin ligand interactor (TACI) or BAFF‐R 33. BAFF specifically co‐stimulates B cell proliferation, promotes splenic B cell survival in vitro and is a key regulator of peripheral B cell populations. BAFF‐R signaling has been found to be crucial for B cell formation. In the absence of BAFF‐R signaling, the development of CD169+ macrophages is hampered. Transfer of BAFF‐R‐competent B cells partially restores the number of CD169+ macrophages 23. Therefore, BAFF‐R contributes to enforced viral replication during viral infection. Limited induction of a functional innate immune response by congenital IFN‐I after viral infection in Baffr−/− mice is due to reduced viral replication. Decreased virus presentation consequently results in greatly reduced anti‐viral adaptive immune responses 23. CEACAM1, in addition to TNF family‐related molecules, is a member of the carcinoembryonic antigen and immunoglobulin families and influences viral replication in a B cell‐dependent manner. CEACAM1 exerts limited influence on the proliferation of B cells but, rather, induces the survival of proliferating B cells via the Bruton’s tyrosine kinase/spleen tyrosine kinase/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (BTK/Syk/NF‐κB) axis. During viral infection, CEACAM1‐deficient mice can barely induce an anti‐viral B cell response. In addition, because of the lack of CD169+ macrophages, CEACAM1‐deficient mice exhibit a reduction in innate immune activation. Therefore, CEACAM1‐deficient mice die after VSV infection 22. Molecules influencing viral replication The influence on viral replication in CD169+ macrophages and DCs is not exclusively restricted to the splenic architecture. Cell‐intrinsic molecules have a large effect on viral replication. Deubiquitinating enzymes are involved in several essential biological processes and pathways, such as transcriptional silencing, growth control and regulation of virus infection 34. The family of ubiquitin‐specific peptidase (USPs) contains more than 100 proteins, all of which share homolog sequences. Ubiquitin‐specific peptidase 18 (Usp18) is a ubiquitin‐specific peptidase that cleaves ISG15 from Isg15ylated proteins 35. In addition to this function, Usp18 binds directly to the Janus kinase (JAK) binding site of the IFN‐α receptor and blocks IFN‐I signaling. At a molecular level, Usp18 represses signal transducer and activator of transcription 1 (STAT‐1) and STAT‐2 heterodimer formation and IFN regulatory factor 9 (IRF9)‐dependent activation of IFN‐stimulated gene (ISG) transcription. CD169+ macrophages and DCs strongly express Usp18 14, 36. Therefore, over‐expression of Usp18 by CD169+ macrophages leads to IFN‐I unresponsiveness and enhanced viral replication within these cells (Fig. 1). The absence of Usp18 in mice leads to rapid death due to defective activation of innate and adaptive immune responses 7. In addition to Usp18, the paracaspase mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important factor in viral replication. MALT1 is widely expressed on various immune cells and plays an important role in immunity, inflammation and cancer by fine‐tuning immune responses 37. After VSV infection, the absence of MALT1 inhibits RelA translocation into nuclei in a TNF‐dependent manner 31. Ablation of MALT1 increases the accumulation of RelB, which regulates RelA signaling by competitive binding to DNA 38. NF‐κB subunit RelA is crucial for regulating early IFN‐β expression after virus infection. Consequently, MALT1 deficiency reduces VSV replication and causes inefficient activation of the innate immune response; this lower immune response leads to a severe outcome of the infection 39. We consider that additional pathways influence viral replication in APCs. Additional screening must be performed so that researchers can identify more players that specifically promote viral replication within APCs in mice and humans. Acute cytopathic infection VSV has a tropism for neuronal tissue. Once VSV reaches the brain, its rapid propagation within the brain tissue usually leads to death. If this lethal outcome is to be avoided, the spread of VSV to the brain must be prevented by the innate and adaptive immune systems 40, 41. The two most important arms of VSV control are IFN‐I and neutralizing antibodies 40. IFN‐I reduces VSV replication in all organs to undetectable levels. Induction of neutralizing immunoglobulin (Ig)G allows complete control of all viral particles, even those that can escape the innate immune response. The absence of IFN‐I leads to overwhelming replication of VSV in several organs, including the liver, spleen, kidney and brain. Therefore, IFN‐I‐deficient mice die quickly after VSV infection 40, 42. In the absence of neutralizing antibodies, some viral particles manage to persist or even exhibit low‐level replication in the presence of IFN‐I 40. From such peripheral niches, virus can spread into the brain and cause death 40. Because of these specific features of VSV, rapid activation of the innate and adaptive immune systems is required for virus control. Viral replication within the lymph nodes and the spleen accelerates the activation of the innate and adaptive immune systems. This activation is mainly explained by increasing concentrations of viral RNA and proteins. Indeed, factors that promote viral replication within the lymphatic system (i.e. Usp18, BAFF, TNF, CEACAM1) accelerate the activation of the innate and adaptive immune systems after VSV infection and thereby promote rapid control of VSV in peripheral niches 14, 22, 23, 39. In this situation, the replication of VSV is beneficial or even essential during infection. VSV is a highly cytopathic virus that responds strongly to IFN‐I. Therefore, early viral replication in the spleen may be especially important. Whether viral replication in the spleen is also important for other virus infections remains to be determined. So far, it is known that several viruses, including murine cytomegalovirus (mCMV), mouse hepatitis virus, LCMV and vaccinia virus, replicate in the spleen, in addition to their typical tissue tropism 42-45. Vaccination Another example of the overall beneficial effect of viral replication occurs during vaccination with live vaccines. In fact, earlier studies indicated that replicating viruses elicit a stronger neutralizing antibody response than do inactivated virus particles 46, 47. In some cases, immunization with a dead virus is inefficient. A number of live attenuated vaccines provide sufficient protection, whereas inactivated vaccines fail to induce a neutralizing antibody response (e.g. rubella, measles, mumps, yellow fever, varicella, chickenpox) 48. Replication of active influenza virus leads to better immune activation than inactive virus does 49, 50. Besides the strength of the immune response, its quality can also be influenced by viral replication. For example, active rubella virus or poliovirus induces the production of IgA in addition to IgG 51-53. Therefore, immunization with active virus is beneficial in disrupting the infection chain, because IgA can neutralize poliovirus in the gut. After exposure to measles virus, prophylactic administration of live attenuated measles, mumps and rubella (MMR) vaccine leads to a beneficial outcome of the infection in some cases if the vaccine is administered within hours or days after exposure 54. In a separate study, we determined whether replication can contribute to anti‐viral immunity during challenge infection with LCMV. Interestingly, virus‐specific antibodies specifically prevent the replication of LCMV in peripheral organs except for the spleen and lymph nodes. The presence of virus‐specific antibodies allows rapid boosting of the existing and new immune components. This boosting results in rapid control of the virus, even in the case of infection with the highly persistent LCMV strain Docile. In this situation, virus control is dependent on CD169+ macrophages and on the priming of new virus‐specific CD8+ T cells 55. Exhaustion and viral replication in APCs During infection with the persistent LCMV strain Docile or clone 13, exhaustion of CD8+ T cells can prevent immunopathology 56. Although this process leads to viral persistence, it can be beneficial for survival. However, partial reduction of exhaustion by depletion of interleukin (IL)‐10, programmed cell death protein 1 (PD‐1) or CEACAM1 can result in virus control with limited adverse effects 57-60. Therefore, exhaustion is a double‐edged sword, with both benefits and disadvantages. Exhaustion is induced by overwhelming amounts of antigen presented together with exhaustive signals 61. IFN‐I strongly influences exhaustion 62. On one hand, IFN‐I reduces viral replication, and this reduction limits the number of antigens and thereby prevents exhaustion 63, 64. On the other hand, IFN‐I induces programmed death ligand 1 (PD‐L1) and thereby promotes exhaustion 62. We found that the absence of CD169+ macrophages or of Usp18 limits the induction of IFN‐I and thereby prevents the expression of PD‐L1 65. This factor also limits the exhaustion of CD8+ T cells; therefore, mice died because of severe immunopathology. Also, timewise‐limited depletion of CD169+ macrophages worsens the outcome of virus infection. Therefore, we conclude that, during infection with an exhaustive virus strain, limitation of replication in the spleen may prevent exhaustion of CD8+ T cells but increases the risk of severe immunopathology. Entry receptor and enforced viral replication To date, researchers have identified several factors that promote replication of virus in APCs. One important question that has not yet been addressed is the role of the entry receptor during the infection of APCs. One important bottleneck in the life cycle of a virus is entry into cells in which the virus can replicate. To enter cells viruses express glycoproteins, which allow cell entry via a specific receptor. Therefore, the specificity of the glycoprotein is a crucial factor determining organ‐specific replication. We used primarily LCMV for our studies. LCMV uses alpha‐dystroglycan as its main entry receptor. Because of the wide expression of alpha‐dystroglycan, LCMV can infect several types of cells in almost all organs 66-68. Because of this feature, LCMV can easily infect APCs. For viruses with a more specific entry receptor, the role of enforced viral replication can be questioned. For example, human poliovirus uses human CD155 as an entry receptor. Wild‐type (WT) mice, which do not express human CD155, can normally not be infected by poliovirus. However, mice expressing human CD155 are susceptible to poliovirus infection 69, 70. Although the role of Usp18 has not been studied during poliovirus infection, Freigang et al. have shown that murine APCs can be infected with poliovirus even in the absence of human CD155 2. This finding suggests that APCs can be infected via a receptor‐independent pathway. Hepatitis C virus (HCV) replicates almost exclusively in hepatocytes. The narrow tropism of HCV can be explained by its requirement for cell entry. The entry of HCV into hepatocytes is synchronized via various receptors: glycosaminoglycans (GAGs), the low‐density lipoprotein receptor (LDL‐R), tetraspanin CD81, the high‐density lipoprotein receptor scavenger receptor class B type I and two tight junction proteins, claudin‐1 (CLDN1) and occludin (OCLN) 71. The summation of these factors is essential for sufficient entry of HCV into cells and explains the liver specificity. Therefore, it is unthinkable that HCV could replicate in APCs. Nevertheless, HCV infection can induce sufficient immune activation (at least in some people). These facts clearly show that anti‐viral immune activation is possible even in the absence of viral contribution to enforced viral replication. Autoimmune disease and viral replication Autoimmune disease is often associated with infections. This evidence results from three facts: (1) autoimmune phenomena are described during a chronic virus infection 72-74; (2) evidence for a virus infection in patients with autoimmune disease 75, 76; and (3) experimental evidence (cross‐reactive epitopes, mouse models) 77-80. Well‐studied examples are multiple sclerosis and type I diabetes. Viruses can contribute to pathogenesis of autoimmune disease in several ways 77, 81. In type I diabetes, one well‐studied mechanism how viruses can induce diabetes is molecular mimicry 82, 83. In fact, Coxsackie virus, which infection is associated with type I diabetes, carries cross‐reactive antigens with beta islet cells 84. In line with these data, cross‐reactive antigens between a virus and the beta islet cells can be well modeled in the autoimmune diabetes model 85. Beside adaptive immune activation, local and systemic innate immune activation is usually occurring during a virus infection. Obviously, over‐activation of these innate signals can contribute to autoreactivity 86, 87. Especially in the presence of autoreactive CD8+ T cells, a strong induction by pattern recognition receptors (i.e. Toll‐like receptor (TLR)‐3, TLR‐7), which is usually occurring during virus infection, can turn such an autoimmunity into an autoimmune disease 88, 89. Further evidence for the role of innate immune activation in type I diabetes comes from genetic screens showing that a mutation in the genes for MDA5 (IFN‐induced helicase 1, IFIH1), which is one of the most important pattern recognition receptors for viruses, are associated with type I diabetes 90. Further, a rare mutation in IFIH1 can protect from type I diabetes 91, 92. In a recent study we asked whether enforced viral replication, can contribute to autoimmune diabetes. Therefore, we used the rat insulin promoter‐glycoprotein (RIP‐GP) model, which allows the study of virus‐induced diabetes. In this model, induction of diabetes depends on CD8+ T cells and interferons 85, 88, 93. In fact, deletion of Usp18, which limits replication of LCMV in lymphatic tissue, limited the innate immune activation and the induction of autoreactive CD8+ T cells 36. These data were confirmed using a second type I diabetes model, the RIP‐nucleoprotein (NP) model 36. Systemic lupus erythematosus (SLE) is a heterogeneous chronic autoimmune disease affecting diverse organ systems and tissues 94. Uncontrolled inflammatory response results in various clinical manifestations, including skin rash, arthritis, cardiovascular disease, hemolytic anemia and glomerulonephritis 95. While the pathogenesis of SLE is complex and complicated, the pivotal characteristic of SLE disease is an impaired removal of dead cells, with accumulation of apoptotic debris providing the main source for autoantigens 96. Exposition of the nuclear materials derived from apoptotic cells driven by APCs, such as myeloid DCs and macrophages, prime autoreactive T cells 97. Subsequently, activated autoreactive T cells interact with B cells causing production of autoantibodies which form immune complexes. Finally, deposits of immune complexes on tissues activate the complement system, resulting in severe inflammation and tissue damage. Additionally, plasmacytoid DCs triggered by immune complexes up‐regulate the release of type I IFN‐inducing IFN signature as a major pathological indicator of SLE 98. Several environmental factors were suggested to contribute toward the pathogenesis of SLE. Among them, viruses seem to be involved in the establishment of SLE disease in genetically susceptible individuals 99, 100. There is growing evidence suggesting a relationship between infection with Epstein–Barr virus (EBV) and SLE. Recent studies revealed an increase prevalence of EBV infection as well as higher titers of anti‐EBV‐antibodies in SLE patients compared to healthy subjects 101-103. Furthermore, structural similarities between components of EBV protein, in particular Epstein–Barr nuclear antigen 1 (EBNA1) and autoantigens, were described in SLE, suggesting molecular mimicry as a potential mechanism to promote production of cross‐reactive autoantibodies 104, 105. Enhanced expression of type I interferon genes due to viral infection may also mediate IFN signature, allowing the abnormal immune response and as a consequence the onset of SLE. Loss of tolerance to self‐antigens is thought to be additionally responsible for the induction of SLE 106, 107. Fcgr2b contributes to lack of tolerance in SLE 108. Therefore, mice lacking Fcgr2b develop a lupus‐like syndrome 109. In fact, we and others found that during age Fcgr2b knock‐out (KO) mice developed anti‐dsDNA antibodies 110. Almost all mice older than 21 weeks showed elevated anti‐nuclear and anti‐dsDNA autoantibodies. Despite elevated levels of autoantibodies, we did not observe strong disease onset in Fcgr2b KO mice in the absence of further stimuli. However, upon virus infection with LCMV, mice died quickly during infection 110. The death of the mice depended on IFN‐γ and CD8+ T cells. Mechanistically, IFN‐γ derived from virus‐specific CD8+ T cells strongly increased expression of Fcgr1 and Fcgr3 on myeloid cells and thereby made self‐reactive antibodies visible to these immune cells. Together, these data clearly show that activation of virus‐specific CD8+ T cells can also lead to serious harm to the body if they are not cross‐reactive for an autoantigen. Especially in a systemic autoimmune disease, systemic activation of virus‐specific CD8+ T cells will strongly influence myeloid cells, but perhaps also other adaptive immune cells, which then impact on the disease onset. Concluding remarks In some circumstances, replication in immunological niches can be beneficial for the control of virus; however, it carries the risk to induce autoimmune disease. More studies are necessary before final conclusions can be reached. Disclosures The authors declare no competing interests. References Citing Literature Number of times cited according to CrossRef: 1 U. Christen, Pathogen infection and autoimmune disease, Clinical & Experimental Immunology, 195, 1, (10-14), (2018). Wiley Online Library
|
Scooped by
Gilbert C FAURE
February 19, 2019 8:42 AM
|
A*STAR researchers have revealed the mechanism behind the way receptor TLR-9 protects against lupus
Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology,...
Via Krishan Maggon
|
|
Scooped by
Gilbert C FAURE
February 6, 2019 9:04 AM
|
Specialized immune cell subsets are involved in autoimmune disease, cancer immunity, and infectious disease through a diverse range of functions mediated by overlapping pathways and signals. However, subset-specific responses may not be detectable in analyses of whole blood samples, and no efficient approach for profiling cell subsets at high throughput from small samples is available. We present a low-input microfluidic system for sorting immune cells into subsets and profiling their gene expression. We validate the system’s technical performance against standard subset isolation and library construction protocols and demonstrate the importance of subset-specific profiling through in vitro stimulation experiments. We show the ability of this integrated platform to identify subset-specific disease signatures by profiling four immune cell subsets in blood from patients with systemic lupus erythematosus (SLE) and matched control subjects. The platform has the potential to make multiplexed subset-specific analysis routine in many research laboratories and clinical settings.
Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or ELISA assays, the systemic phenotype of SLE patients not taking (MMF–) or taking (MMF+) MMF were studied. MMF+ SLE patients had significant reductions in total numbers of transitional B cells, plasmablasts, and T cells, specifically CD4+ Th17-type and CD4+ Treg-type cells, compared with MMF– patients. Plasma soluble mediators were decreased in MMF+ patients including chemokines (MIG/CXCL9 and SDF-1α/CXCL12) and growth factors (VEGF-A and PDGF-BB). Soluble mediators and cell subsets grouped by functional properties revealed significant modifications associated with STAT3 and B cell pathways. Further, healthy PBMCs treated with IL-6 revealed a reduction in p-STAT3 following the addition of mycophenolic acid (the active metabolite of MMF). In conclusion, the inhibition of STAT3 phosphorylation by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of p-STAT3 are associated with disease pathology.
Via Krishan Maggon
|
|
Scooped by
Gilbert C FAURE
January 29, 2019 1:23 PM
|
Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination. P2X7 stimulation promotes caspase-mediated pyroptosis of Tfh cells and controls the development of pathogenic ICOS+ IFN-γ–secreting cells. Circulating Tfh cells from patients with systemic lupus erythematosus (SLE) but not primary antiphospholipid syndrome (PAPS), a nonlupus systemic autoimmune disease, were hyporesponsive to P2X7 stimulation and resistant to P2X7-mediated inhibition of cytokine-driven expansion. These data point to the P2X7 receptor as a checkpoint regulator of Tfh cells; thus, restoring P2X7 activity in SLE patients could selectively limit the progressive amplification of pathogenic autoantibodies, which deteriorate patients’ conditions.
|
|
Scooped by
Gilbert C FAURE
January 24, 2019 12:23 PM
|
Neuropsychiatric systemic lupus erythematosus (NPSLE) remains highly challenging to diagnose and treat. This Review describes current understanding of its pathogenesis, along with novel therapies and diagnostic tools that could eventually improve the management of NPSLE.
|
|
Scooped by
Gilbert C FAURE
January 10, 2019 4:22 AM
|
Abstract Between 50% and 86% of patients with autoimmune hepatitis (AIH) relapse after immunosuppression withdrawal; long‐term immunosuppression is associated with increased risk of neoplasias and infections. Chloroquine diphosphate (CQ) is an immunomodulatory drug that reduces the risk of flares in rheumatologic diseases. Our aims were to investigate the efficacy and safety of CQ for maintenance of biochemical remission of AIH in a double‐blind randomized trial and to define a subgroup that obtained a greater benefit from its use. A total of 61 patients with AIH in histologic remission (90.1% AIH type 1 [AIH‐1]) were randomized to receive CQ 250 mg/day or placebo for 36 months. Of the 61 patients, 31 received CQ and 30 placebo. At baseline, clinical, laboratory, histologic findings, and human leukocyte antigen (HLA) profile were similar between the two groups. Relapse‐free survival was significantly higher in the CQ group compared to the placebo group (59.3% and 19.9%, respectively P = 0.039). For those patients completing 3‐year treatment, relapse rates were 41.6% and 0% after CQ and placebo withdrawal, respectively. Factors associated with a higher risk of relapse in multiple Cox regression were placebo use (hazard ratio, 2.4; 95% confidence interval [CI], 1.055.5; P = 0.039) and anti‐soluble liver antigen/liver‐pancreas (anti‐SLA/LP) seropositivity (hazard ratio, 5.4; 95% CI, 1.91‐15.3; P = 0.002). Although it was not possible to define a subgroup that obtained a greater benefit from CQ according to anti‐SLA/LP reactivity or HLA profile, 100% of patients who were anti‐SLA/LP‐positive (+) relapsed with placebo compared to 50% with CQ (P = 0.055). In the CQ group, 54.8% had side effects and 19.3% interrupted the drug regimen. Conclusion: CQ safely reduced the risk of relapse of AIH, but it was not possible to define a subgroup that obtained a greater benefit with CQ use, probably because of sample size. Abbreviations – negative + positive AIH autoimmune hepatitis AIH‐1/2 AIH type 1/2 ALT alanine aminotransferase anti‐LKM1 anti‐liver/kidney microsomal antibody type 1 anti‐SLA/LP anti‐soluble liver antigen/liver‐pancreas CI confidence interval CQ chloroquine diphosphate HLA human leukocyte antigen HLA‐DQ human leukocyte antigen isotype DQ HLA‐DR human leukocyte antigen isotype DR IAIHG International Autoimmune Hepatitis Group IgG immunoglobulin G The goal of treatment in autoimmune hepatitis (AIH) is to achieve normalization of aminotransferase and immunoglobulin G (IgG) levels with absent or minimal histologic activity to prevent disease progression. A sustained remission of treatment after its withdrawal is the most desirable endpoint. However, most patients relapse within the first year and need reintroduction of treatment, and only approximately 20% achieve this goal.1-3 Patients who present multiple relapses evolve more frequently for liver cirrhosis, death due to liver disease, and the need for liver transplantation than those who remain in sustained remission.4 A significant advance in the treatment of AIH would be the identification of drugs with a good safety profile and few side effects that would allow the maintenance of AIH remission after withdrawal of the immunosuppressive treatment. Antimalarial drugs have been prescribed for almost 400 years and are used in the treatment of systemic lupus erythematosus with benefits in symptomatic control, general and disease‐free survival, and reduction of severity of disease exacerbations.5, 6 Chloroquine diphosphate (CQ) has multiple mechanisms of action in immune response; this could justify its use in the treatment of AIH. CQ 250 mg/day was used for maintenance of disease remission after immunosuppression withdrawal in a preliminary pilot study with 14 patients in histologic remission; in that study, the CQ‐treated group had a 6.49‐fold lower risk of disease relapse.7 In 2 patients who were anti‐soluble liver antigen/liver‐pancreas (anti‐SLA/LP)(+) and who relapsed after CQ withdrawal, its reintroduction as monotherapy (on request) resulted in normalization of aminotransferases and, in one case, histologic remission. The aims of this study were to evaluate whether CQ is safe and effective in preventing relapse of AIH in patients with histologic remission of the disease after immunosuppression withdrawal and whether there is a specific patient profile in which it could be more beneficial. Participants and Methods Trial Design and Participants This was an interventional, single‐center, randomized, double‐blind, controlled, parallel‐group trial of 36 months of CQ versus placebo in patients with AIH in histologic remission. The authors designed the protocol, monitored patients, acquired and maintained the data, and performed statistical analysis. The protocol was approved by the local ethics committees and registered in the ClinicalTrials.gov database (NCT01980745). All subjects signed a written informed consent before enrollment, and the study was performed according to good clinical practice and the Declaration of Helsinki. Patients 18 to 70 years of age with a probable/definite diagnosis of AIH according to International Autoimmune Hepatitis Group (IAIHG) criteria8 who had biochemical and histologic remission after immunosuppressive therapy were eligible for enrollment in this study. Exclusion criteria were overlapping syndromes with primary biliary cholangitis and primary sclerosing cholangitis, decompensated liver cirrhosis (presence of ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, acute variceal bleeding, or Child‐Turcotte‐Pugh B and C classification), enrollment in a previous study with antimalarial drugs, and pregnancy. Interventions All patients received initial treatment with azathioprine and prednisone, most of them in doses of 50 mg/day and 30 mg/day, respectively. There were monthly reductions in prednisone dose and increases in dose of azathioprine if necessary (up to 2 mg/kg/day if tolerated) in order to maintain the levels of aminotransferases within the normal reference range with the lowest dose possible. Doses of prednisone ranged from 5 to 15 mg/day and azathioprine from 50 to 150 mg/day during maintenance treatment. After normalization of hepatic enzymes with stable doses of the drugs, there were no additional adjustments in the doses (except in the cases of adverse effects that justified some modification) until the liver biopsy was performed to evaluate histologic remission, which never occurred before 18 months of normal aminotransferases and 2 years of treatment. Histologic remission was defined as absence or presence of minimal interface hepatitis (hepatitis activity index <4) according to the IAIHG definition.2 The histologic evaluation was performed by experienced liver pathologists according to the Brazilian Society of Pathology.9 Following confirmation of histologic remission, patients were randomized to receive either a fixed dose of CQ (250 mg/day, drug A) or placebo (drug B). CQ was chosen because it was the only formulation available for dispensing by the public health system. In the first month after enrollment, patients received CQ or placebo in addition to the immunosuppressive regimen that induced histologic remission; this was azathioprine and prednisone in all cases. During the second month, azathioprine was discontinued immediately, with weekly weaning of 2.5 mg of the prednisone maintenance dose. Subsequently, the patients remained on drug A or drug B for up to 36 months, disease relapse, significant side effects, pregnancy, or willing withdrawal from the study. Follow‐up was for at least 1 year after the end of the protocol. Primary Outcomes The primary outcome was the maintenance of biochemical response following immunosuppression withdrawal, which was defined as aminotransferase levels within the normal reference range. Relapse of AIH was defined as elevation of aminotransferase levels above twice the normal upper reference value in at least two different measurements taken within a 15‐day interval during which there was no tendency for liver enzymes to fall or stabilize. Routine blood tests and clinical evaluation were performed monthly during the first 6 months of the study, every 2 months or earlier if necessary until the end of the first year, and every 3 months until the end of the study. Secondary Outcomes Secondary outcomes were to determine whether there was a specific group of patients who would benefit most from the ingestion of CQ and to assess the safety profile of the drug. Autoantibody Testing Anti‐nuclear, anti‐smooth muscle, anti‐liver/kidney microsomal antibody type 1 (anti‐LKM1), anti‐liver cytosol type 1, and anti‐mitochondrial antibodies were detected by indirect immunofluorescence; performed on frozen unfixed rodent substrate that included kidney, liver, and stomach; and were considered positive if the titers were greater than or equal to 1:40 according to IAIHG diagnosis criteria.10 The fluorescent patterns of anti‐nuclear and anti‐microfilament antibodies were detected by indirect immunofluorescence on human epithelial type 2 (HEp2) cells and human fibroblasts. Anti‐SLA/LP antibodies were detected by enzyme‐linked immunosorbent assay using the commercial kits Quanta Lite SLA (Inova Diagnostics Inc., San Diego, CA) and/or anti‐SLA/LP IgG (EUROIMMUN, Luebeck, Germany), according to the manufacturer’s instructions, which consider positive values as ≥25 units and ≥1, respectively. Human Leukocyte Antigen Typing Human leukocyte antigen (HLA) typing was performed with DNA samples previously extracted using the dodecyltrimethylammonium bromide (DTAB)/cetyltrimethylammonium bromide (CTAB) technique and stored at −20°C. For the amplification reaction of the HLA isotype DR (HLA‐DR) and HLA isotype DQ (HLA‐DQ) genes, specific primers were used to test the polymorphism in exon 2. The presence of the allele or allele group was based on the presence or absence of the amplified product. The determination of alleles or groups of class II alleles was performed by polymerase chain reaction (primer‐specific sequence) with Micro SSP HLA DNA typing trays (One Lambda). The reaction was performed following the manufacturer’s instructions. Treatment‐Related Side Effects The relationship between the drug and side effects was defined according to the Naranjo algorithm, which determines the probability that an adverse reaction to the drug is actually due to the drug and not the result of other factors.11 The severity of side effects was classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.12 All patients underwent ophthalmologic evaluation before inclusion in the study and at least one annual evaluation according to protocol thereafter for the detection of retinal antimalarial deposition signals. Sample Size Determination Our main hypothesis to be tested was whether there is a difference in AIH relapse rate between patients who use CQ and patients who use placebo. The rates of AIH relapse were estimated in a pilot study, which resulted in relapse of 23.5% in the CQ group and 72.2% in a historical group without medication.7 Assuming an accrual rate of 7 patients per year, a sample size of 31 patients was defined to allow the study to estimate a minimum detectable difference of 37.2% using a 2‐sided Fisher’s exact test with 80% power at a 5% level of significance. Randomization Eligible patients were randomly assigned to receive CQ or placebo after withdrawal of immunosuppression by simple randomization and were allocated to each group in a 1:1 ratio. A medical assistant unaware of the study generated the random allocation sequence by a draw with 62 numbered papers: 31 named drug A and 31 named drug B. One of the trial investigators enrolled and assigned participants to the proposed interventions after randomization. After patients agreed to participate in the study, the principal investigator checked each patient’s list number and determined which drug was destined for that number. The drugs were formulated at the hospital pharmacy as tablets with an identical external appearance. The research assistant and the patients were all blind to the type of medication used. After the study was completed, the pharmacist revealed the composition of the tablets initially named drugs A and B to the researchers. The secrecy of the formulation was maintained until the end of the study. Statistical Analysis For statistical analysis, all patients undergoing randomization (except those who refused medication immediately after enrollment) were included regardless of the time of follow‐up or withdrawal due to side effects or pregnancy. Relapse‐free survival was defined as the time between a patient’s enrollment and the end of treatment (36 months) or the occurrence of side effects leading to discontinuation of the drug and the subject being censored from the study. Time to relapse was defined as the period between the immunosuppression withdrawal and the biochemical relapse of the disease. Relapse‐free survival curves were estimated using the Kaplan‐Meier method and compared by the log‐rank test. The hazard ratios with their respective 95% confidence intervals (CIs) were estimated using the simple Cox regression. A multivariate regression model was fitted using clinically relevant covariates for AIH relapse defined in previous studies. The interactions between the drug and autoantibody reactivity and HLA profile were evaluated by multivariate Cox regression to investigate whether there would be any subgroup of patients with additional benefits with the use of CQ. The proportional hazard assumption was verified using the Schoenfeld residues.13 Baseline characteristics were compared with Fisher’s exact test for categorical variables and t test or Mann‐Whitney test for quantitative variables. The normality and homoscedasticity hypotheses were evaluated by the Anderson‐Darling14 and Levene15 tests, respectively. All hypothesis tests were 2‐sided and considered P < 0.05 as statistically significant. R, version 3.0.2 (R Core Team, 2013), was used for all calculations. Results Patients were enrolled from May 2002 to October 2011, and the follow‐up ended in 2015. All patients except 1 had a definite diagnosis of AIH before treatment according to IAIHG criteria. One patient who could not undergo a liver biopsy due to the presence of ascites had “probable diagnosis” with a score of 13 points. Clinical, laboratory, and histologic data at diagnosis are shown in Table 1. A total of 62 patients were randomized to receive CQ 250 mg/day (n = 31) or placebo (n = 31) for 36 months. Except for 1 patient in the placebo group who refused treatment immediately after randomization, all patients received their assigned treatment (Fig. 1). The mean follow‐up time was 3,526 ± 1,233 days. The median time of drug intake was 329 days (22‐1,275 days).The median age at diagnosis of AIH was 26.86 years (2.7‐63.4 years), and mean treatment duration time before immunosuppression withdrawal was 5.9 ± 4.08 years (median time, 4.56 years). Approximately 90% had AIH‐1; 23.3% of all patients had anti‐SLA/LP seropositivity. Out of 61 patients, 56 had an initial liver biopsy (91.8%), and hepatic cirrhosis was detected in 52.4%. At baseline, demographic, clinical, laboratory, and histologic data were similar between CQ and placebo groups (Table 2). When the HLA profile was analyzed, HLA‐DR3 (26/61 patients) and HLA‐DR13 (26/61 patients) were the most frequent, followed by HLA‐DR4 (17/61 patients) and HLA‐DR7 (13/61 patients). In the CQ group, there was a lower frequency of HLA‐DR3 (35.5% versus 50%), HLA‐DR4 (19.3% versus 36.7%), and HLA‐DR7 (16.1% versus 26.7%) compared to the placebo group and a higher frequency of DR13 (51.6% versus 33.4%). However, these differences did not reach statistical significance (Table 3). There was no specific HLA‐DR profile significantly related to anti‐SLA/LP seropositivity, although 50% harbored DR3. Data at Diagnosis n (%) Presentation of disease at onset Asymptomatic* 6 (9.8) Acute exacerbation of chronic AIH † 44 (72.2) Insidious onset ‡ 11 (18) Extrahepatic autoimmune diseases 8 (13.1) § AST ‖ (mean ± SD) 26.04 ± 20.1 ALT ‖ (mean ± SD) 22.83 ± 21.2 Alkaline phosphatase ‖ (mean ± SD) 1.73 ± 1.05 Gamma‐glutamyltransferase ‖ (mean ± SD) 4.91 ± 4.1 Albumin g/dL (mean ± SD) 3.37 ± 0.68 Total bilirubin mg/dL (mean ± SD) 9.13 ± 9.08 INR (mean ± SD) 1.5 ± 0.41 Gamma globulin ‖ (mean ± SD) 1.97 ± 1.06 Histologic findings ¶ n (%) Rosettes of hepatocytes 33 (58.9) Plasma cells inflammatory infiltrate 23 (41) Interface hepatitis 52 (92.8) Submassive necrosis 4 (7.14) * Diagnosis due to elevation of liver enzymes or ultrasonographic alterations during follow‐up of extrahepatic diseases (rheumatologic and endocrinologic diseases). † Presentation similar to viral hepatitis, with jaundice, coluria, and fecal acolia with or without signs of portal hypertension. ‡ Nonspecific symptoms of fatigue, general ill health, right upper quadrant pain, lethargy, malaise, anorexia, weight loss, nauseas, pruritus, polyarthargia. § Thyroid disease (n = 2), ulcerative colitis (n = 2), systemic erythematosus lupus (n = 2), Sjögren syndrome (n = 1), idiopathic thrombocytopenic purpura (n = 1). ‖ Values are shown as number of times above the upper normal limits. ¶ Percentage calculated considering 56 patients. Of these patients, 5 patients did not have liver biopsy at diagnosis due to presence of ascites and/or coagulopathy. Liver fibrosis staging according to Brazilian Society of Pathology Classification of chronic hepatitis.9 Abbreviations: AST, aspartate aminotransferase; INR, international normalized ratio. CQ (n = 31) Placebo (n = 30) P Value Female sex (%) 26 (83.9) 26 (86.7) 1 Age at diagnosis of AIH (mean ± SD) 29.4 ± 17.9 30.5 ± 17.1 0.98 Age at study inclusion (mean ± SD) 37.7 ± 16.1 39.1 ± 16.9 0.8 AIH classification (%) 0.27 Type 1 29 (93.5) 26 (86.7) Type 2 1 (3.2) 0 (0) Type 3 (isolated anti‐SLAP/LP) 1 (3.2) 1 (3.3) No serologic markers 0 (0) 3 (10) Anti‐SLA/LP seropositivity (%)* 6 (20) 8 (26.7) 0.76 Antimicrofilament seropositivity (%)† 11 (37.9) 16 (55.2) 0.29 Liver cirrhosis at diagnosis (%)‡ 14 (50) 18 (64.3) 0.42 Advanced fibrosis (F3/F4) at study inclusion (%)§ 18 (58) 16 (53.3) 0.8 Arterial hypertension (%) 3 (9.7) 5 (16.7) 0.47 Diabetes mellitus (%) 4 (12.9) 5 (16.7) 0.73 Normal gamma globulin/IgG levels|| at inclusion (%) 20 (64.5) 23 (76.7) 0.4 Immunosuppression at histologic remission (mg/day) (mean ± SD) Azathioprine 90.7 ± 26.6 97.5 ± 22.1 0.47 Prednisone 8.5 ± 2.8 8.9 ± 2.1 0.8 Treatment time before inclusion at study (years, mean ± SD) 6 ± 4.55 5.8 ± 3.53 0.44 *In 1 patient of the CQ group, it was not possible to assess anti‐SLA/LP seropositivity in initial screening. Regarding differences between patients who were anti‐SLA(+) or (–), patients who were anti‐SLA(+) had lower levels of alkaline phosphatase, gamma‐glutamyltranspeptidase, and bilirubin. There were no differences in histologic findings, IgG levels, albumin, INR, and aminotransferases (data not shown). †Information available in 29 patients in each group. ‡Two patients in each group did not have liver biopsy at diagnosis due to presence of ascites and/or coagulopathy. Liver fibrosis staging according to Brazilian Society of Pathology Classification of chronic hepatitis.9 §Liver biopsy was insufficient to stage liver fibrosis in 1 patient without impairing the degree of inflammatory activity. Classification of liver fibrosis according to METAVIR fibrosis score. ||Gamma globulin and/or IgG levels within the normal range (gamma globulin <1.5 g/dL and IgG <1,538 mg/dL). Abbreviation: INR, international normalized ratio. HLA Profile Chloroquine (n = 31) n (%) Placebo (n = 30) n (%) DR1 4 (12.9) 2 (6.7) DR3 11 (35.5) 15 (50)* DR4 6 (19.3) 11 (36.7)† DR7 5 (16.1) 8 (26.7)‡ DR8 0 (0) 1 (3.3) DR9 2 (6.4) 0 (0) DR10 1 (3.2) 0 (0) DR11 4 (12.9) 2 (6.7) DR13 16 (51.6) 10 (33.4)§ DR14 4 (12.9) 1 (3.3) DR15 3 (9.7) 4 (13.3) DR16 3 (9.7) 2 (6.7) DQ02 14 (45.1) 14 (46.7) DQ04 2 (6.4) 5 (16.7) DQ05 10 (32.2) 5 (16.7) DQ06 16 (51.6) 12 (40)|| DQ07 4 (12.9) 3 (10) DQ08 6 (19.3) 5 (16.7) There were no significant statistical differences in HLA‐DR and HLA‐DQ profiles between the CQ and placebo groups (P > 0.05). *P = 0.3 †P = 0.16 ‡P = 0.36 §P = 0.2 ||P = 0.44 Primary Outcomes Patients in the CQ group completed the study more frequently (38.7% versus 13.3%) and took the medication for a longer period compared to those in the placebo group (616 ± 484.8 versus 386 ± 377.4 days, respectively). The mean alanine aminotransferase (ALT) level at relapse was 271.1 ± 301.5 U/L (reference value <31 U/L). Patients who relapsed restarted immunosuppressive therapy without clinical or laboratory signs of liver dysfunction. Factors associated with higher risk of AIH relapse by univariate Cox regression were anti‐SLA/LP seropositivity, placebo randomization, and HLA‐DR3 profile (Fig. 2; Table 4). In the multivariate analysis, factors associated with AIH relapse were anti‐SLA/LP seropositivity and placebo randomization. Relapse‐free survival was significantly lower in the placebo group compared to the CQ group (CQ group, 59.3% [43.1%‐81.6%] versus placebo group, 19.9% [7.9%‐50.2%]; hazard ratio, 2.4; 95% CI, 1.05‐5.5; P = 0.039) and in patients with anti‐SLA/LP seropositivity (hazard ratio, 5.4; 95% CI, 1.91‐15.3; P = 0.002) (Table 5). After CQ/placebo withdrawal at the end of the study at 3 years, 5 of 12 patients (41.6%) in the CQ group relapsed compared to none of 4 patients in the placebo group. Relapse‐free survival 6 months after the study ended was 60% in the CQ group and 100% in the placebo group (P = 0.03) because no patient in the placebo group who maintained biochemical remission during the 3‐year follow‐up relapsed after the study’s end. Variable Hazard Ratio (95% CI) P Value Droga B (placebo) 2.51 (1.19‐5.25) 0.015 Anti‐SLA/LP seropositivity 2.84 (1.34‐5.98) 0.006 HLA‐DR3 2.04 (1‐4.16) 0.049 HLA‐DQ6 0.53 (0.25‐1.1) 0.089 HLA‐DR13 0.63 (0.3‐1.31) 0.21 HLA‐DR7 0.77 (0.32‐1.89) 0.57 HLA‐DR4 2.02 (0.96‐4.27) 0.066 Antimicrofilament seropositivity 1.24 (0.61‐2.54) 0.55 Classification of AIH* AIH‐2 0 (0‐infinity) 0.99 AIH‐3 0.26 (0.04‐1.93) 0.19 Liver cirrhosis at diagnosis 0.71 (0.34‐1.49) 0.36 Advanced fibrosis at study randomization (F3/F4) 1.09 (0.54‐2.24) 0.8 Normal gamma globulin level at randomization 1.14 (0.51‐2.56) 0.74 Diabetes mellitus 0.38 (0.09‐1.58) 0.18 Age at diagnosis 1 (0.98‐1.02) 0.71 *Considering type 1 AIH as the reference group; (AIH‐3 ‐ anti‐SLA/LP as sole marker). Variable Hazard Ratio (95% CI) P Value Placebo intake 2.4 (1.05‐5.5) 0.039 Anti‐SLA/LP seropositivity 5.4 (1.91‐15.3) 0.002 Age at diagnosis of AIH 1 (0.98‐1.03) 0.99 Normal gamma globulin levels at inclusion 0.54 (0.2‐1.45) 0.22 HLA‐DR3 1.84 (0.73‐4.63) 0.19 HLA‐DR13 0.9 (0.29‐2.79) 0.86 Secondary Outcomes We investigated whether a subgroup showed greater benefit with antimalarial use. Of the 14 patients who had anti‐SLA/LP reactivity, 8 were randomized for placebo and 6 for CQ. Of the 6 patients randomized to receive CQ, 3 relapsed compared to all patients in the placebo group (50% versus 100%, respectively; P = 0.055). The anti‐SLA/LP(+) patients had significantly higher levels of aminotransferases at AIH relapse compared to the anti‐SLA/LP‐negative (–) group (460 ± 429 U/L versus 165 ± 120 U/L; P = 0.048; normal reference value up to 31 U/L). The aminotransferase levels in the relapse of patients with anti‐SLA/LP(+) were higher in the placebo group compared to the CQ group (541 ± 475 U/L versus 243.3 ± 183 U/L), but this difference was not statistically significant (P = 0.33). It was not possible to establish an interaction between the drug and anti‐SLA/LP seropositivity (hazard ratio, 2.17; 95% CI, 0.57‐8.23; P = 0.254) by multivariable Cox analysis. It was also not possible to identify a subgroup achieving the greatest benefit according to HLA profile, AIH type, and antimicrofilament seropositivity (Table 6). Variable Hazard Ratio (95% CI) P Value Antimicrofilament seropositivity 3.82 (0.75‐19.38) 0.10 Anti‐SLA/LP 1.41 (0.28‐7.03) 0.67 HLA‐DR3 0.87 (0.2‐3.86) 0.85 HLA‐DR4 0.98 (0.17‐5.76) 0.98 HLA‐DR7 0.49 (0.07‐3.24) 0.46 HLA‐DR13 0.89 (0.19‐4.13) 0.88 Side Effects In the CQ group, 54.8% of the patients had some side effects compared with 16.7% in the placebo group. The discontinuation due to side effects occurred in 19.3% of patients in the CQ group and 10% in the placebo group. The majority of adverse events in the CQ group were classified as possible according to the Naranjo algorithm; none were classified as definite (Table 7). Adverse Event Chloroquine (n = 31) n (%) Placebo (n = 30) n (%) Any AE 17 (54.8) 5 (16.7) Discontinuation due to AE 6 (19.3) 3 (10) Classification according to Naranjo algorithm Definite (0) Definite (0) Probable (4)* Probable (0) Possible (12)† Possible (3) Doubtful (1)‡ Doubtful (2) Grade 3/4 0 0 Grade 2 Neuropathy 2 (6.4) 0 Dermatologic 6 (19.3) 2 (6.6) Seizure 1 (3.2) 0 Arthralgia 0 1 (3.3) Grade 1 Headache 2 (6.4) 1 (3.3) Worsening renal function 1 (3.2) 0 Dyspepsia 3 (9.7) 0 Myalgia 1 (3.2) 0 Dermatologic 3 (9.7) 0 Retinopathy 1 (3.2) 1 (3.3) *Probable causality between drug and adverse reaction: exfoliative dermatitis (1), neuropathy (1), pruritus (1), impairment of renal function (1). †Possible causality between drug and adverse reaction: headache (2), convulsion (1), nausea (1), cutaneous hyperpigmentation (3), pruritus (4), retinopathy (1), cutaneous papules (1), neuropathy (1), inappetence (1). ‡Doubtful causality between drug and adverse reaction: myalgia (1). Abbreviation: AE, adverse event. There were no grade 3 or 4 side effects. Most side effects in the CQ group were dermatologic and included pruritus (5 patients), skin darkening (3 patients), sporadic pruritic papules (1 patient), and skin lesions similar to pellagra (1 patient). Withdrawal of medications was necessary in only one case; the other symptoms were controlled with antihistamines, skin hydration, and vitamin B3 replacement. The most serious side effects were seizures (1 patient), worsening renal function (1 patient), and peripheral neuropathy (2 patients). Despite drug withdrawal improvement, there was no security that these adverse events were drug related. According to the Naranjo algorithm, none of the side effects were classified as definite in relation to the drug. The seizure was classified as possible (although the patient reported irregular use of anticonvulsants), the impaired renal function as probable (the patient had a further diagnosis of Gitelman’s syndrome), and the two cases of neuropathy as likely and possible (1 patient had the diagnosis of carpal tunnel syndrome). Two patients, 1 in the CQ group (after 19 months) and 1 in the placebo group (after 24 months), had suspicion of CQ deposition in the macula during ophthalmologic evaluations. Although none of these patients had visual loss and the suspicion was not confirmed during follow‐up, the drug was discontinued in both cases. Discussion This was a double‐blind randomized study of 61 patients with AIH in biochemical and histologic remission that demonstrated CQ was safe and effective to significantly reduce the risk of relapse 2.5 times in a period up to 3 years after immunosuppression withdrawal. Antimalarial drugs have immunomodulatory effects and have already been used in other autoimmune diseases. In systemic lupus erythematosus, for which they were better studied, they have beneficial effects on general and disease‐free survival, with a reduction in the risk and delay of quiescent disease reactivation, improvement of the metabolic profile, and protection against occurrence of serious infections.5, 6, 16 Their possible mechanisms of action in the pathophysiology of AIH include inhibition of the processing and presentation of antigens, inhibition of cytokine release (interleukins 1, 2, and 6; tumor necrosis factor α; and interferon‐γ), inhibition of the T helper 17 response (inhibition of the release of interleukins 6, 17, and 22), decreased natural killer cell activity, inhibition of polymorphonuclear chemotaxis, and inhibition of the activity of cytotoxic T lymphocytes and clusters of differentiation (CD)4+ T lymphocytes with autoreactivity.17, 18 In the current study, possible biases that could have interfered with the results were avoided. Patients were blindly randomized, the immunosuppressive treatment was maintained along with CQ for 1 month before withdrawal, and all subjects had at least 18 months of aminotransferase normalization and more than 2 years of immunosuppressive treatment before randomization, as recommended by IAIHG in relation to attempted withdrawal of medication. It appears that duration of treatment may influence relapse rates because patients treated continuously for more than 4 years had more sustained remission rates than those treated for less than 4 years.19 In the current study, the mean duration of treatment before immunosuppressive withdrawal was approximately 6 years. Liver biopsies were performed to confirm histologic remission because approximately 55% of the patients with liver enzymes and normal IgG levels still present interface hepatitis in the biopsy and disease relapse in case of treatment discontinuation.20 However, even normal histology does not completely rule out the possibility of disease relapse because it may occur even in patients with histologic remission.21 The option for the maintenance of immunosuppressive treatment that induced histologic remission during the first month of the study was justified because there is a delay in achieving effective plasma concentrations and stable serum concentrations of CQ are only achieved after 4 to 6 weeks.18 Another reason for this choice was to reduce the risk of confusing possible enzymatic alterations related to immunosuppression withdrawal with hepatotoxicity by the antimalarial, at least in the first month of introduction of a new medication.22 The beneficial effect of CQ on protection against disease relapse may be evidenced by several findings in this study. Patients who used the medication were more apt to complete the study and used the medication for a longer period than those who used the placebo. In addition, after cessation of the drug at the end of the study, relapse in the CQ group was significantly higher than in the placebo group, showing that the antimalarial was actually protecting patients against relapse. The relapse‐free survival was 59.3% in the CQ group and 19.9% in the placebo group during the 3 years of treatment, and this difference was also statistically significant. It can be argued that 59.3% is still a low relapse‐free survival when compared to maintenance of lifelong immunosuppressive therapy, with or without corticosteroids.1-3 These options are associated with the countless side effects of corticosteroids and the increased risk of neoplasias and bacterial and fungal infections secondary to thiopurine drugs, which justifies the search for new therapies.23 The use of immunomodulatory drugs without immunosuppressive properties to maintain AIH remission could add options to this scenario. Another aspect to consider is the adopted definition of disease relapse as the elevation of aminotransferase levels above twice the upper normal limit as proposed by the 1999 IAIHG criteria8 rather than 3 times as proposed by other guidelines.1, 2 This concept certainly increased the rates of relapse diagnosis. Another controversial point is the discontinuation of treatment because of side effects. In several cases, the treatment was interrupted because of the occurrence of clinical manifestations that were not clearly related to CQ. The withdrawal rate due to adverse effects was 19.3% in the CQ group, which may have influenced the final results because these patients did not relapse while taking the medication but after antimalarial withdrawal. In addition, this relapse rate occurred over a 3‐year period during which the patients remained without the side effects of corticosteroids and with the possibility of secondary gains in metabolic profile and bone density. With respect to autoantibody reactivity, anti‐SLA/LP and anti‐LKM1 are associated with an increased risk of relapse, and a meta‐analysis suggested never stopping therapy when the former is present.24 In the current study, anti‐SLA/LP(+) patients had higher levels of aminotransferases at disease relapse compared to anti‐SLA/LP(–) patients, and the relapse rates in this subgroup were 100% in the placebo group and 50% in the CQ group. However, when attempting to establish the relationship between anti‐SLA/LP reactivity and the drug used, the difference was not statistically significant; this may be related to sample size and should be confirmed in further studies. A study reporting a 20‐year experience with AIH treatment in childhood25 showed that all anti‐LKM1(+) patients relapsed after treatment discontinuation. In our series, there was one case of AIH‐2 in the CQ group. This patient completed the study without relapse and had biochemical relapse (aspartate aminotransferase, 197 U/L; ALT, 531 U/L [normal value, <31 U/L]) after approximately 90 days of its withdrawal. The HLA profile determines different clinical presentations and different responses to treatment, resulting in an autoimmune response of greater or lesser severity. Caucasian patients with HLA‐DR3 present earlier and more aggressive disease onset with inferior response to corticosteroid treatment compared to patients with HLA‐DR4.2, 26, 27 In Brazil, the susceptibility to AIH‐1 is primarily linked to HLA‐DR13, and there is a secondary association with DR3.28 In the current study, patients with AIH‐1 with HLA‐DR3 or HLA‐DR13 were the most common profiles. A study of AIH‐1 in North America evaluated 26 patients with non‐HLA‐DR3/DR4 and showed that patients in whom the only marker of susceptibility was HLA‐DR13 had lower rates of relapse after treatment withdrawal than those whose sole marker of susceptibility was HLA‐DR3.29 These findings are similar to those found in our study in which the presence of HLA‐DR3 was associated with a higher risk of relapse. Regarding HLA‐DQ, the two serotypes most frequently found in our series were DQ2 and DQ6. This finding is similar to findings in Brazilian and Argentinean patients with AIH‐1 in which susceptibility to the disease with the DR13‐DQ6 haplotype was observed.28, 30 The presence of HLA‐DQ6 resulted in a trend of lower risk of relapse (P = 0.089) with a risk ratio of 0.53, which should be evaluated in studies with a larger sample size. In a Brazilian study of HLA typing, a significant increase in DQ6 was observed in strong linkage disequilibrium with DR13.28 In the present study, 22 of the 28 patients with HLA‐DQ6 had at least one DR13 allele, which was associated with a lower risk of disease relapse compared to HLA‐DR3.29 Therefore, it remains an open question whether this protective effect is actually related to HLA‐DQ6 or to HLA‐DR13. Concerning the safety of antimalarial use, although hydroxychloroquine causes fewer side effects than CQ in patients with rheumatic diseases, CQ is 2‐3 times more potent than hydroxychloroquine.31 This probably influenced the rates of side effects. To minimize the risk of side effects, only patients with cirrhosis with preserved liver function were included because CQ binds moderately (60%) to plasma proteins and undergoes primarily hepatic metabolism by cytochrome P450 enzymes; in addition, impairments in liver function could affect drug metabolism.18, 32 Treatment suspension rates due to side effects were probably overestimated because of the inflexibility adopted in attributing a causal relationship between the symptoms presented during treatment and drug use. In addition, no higher incidence of side effects was observed when compared to published data, and there were no third‐ or fourth‐degree side effects in the current study. The most commonly reported side effects related to the use of CQ, occurring in up to 20% of patients, are dyspeptic and dermatologic symptoms, which were the most frequent in this series. Most of the time, dermatologic findings were reverted in this study with the use of antihistamines and hydration, without impairment of quality of life. The dyspeptic symptoms, which are more common in the first few weeks of treatment, usually improve over time and are minimized by dose reduction or fractionation and postprandial administration18, 33; this was not necessary in any of our patients. Neuromyopathy and seizures are rare events with few reported cases,18, 33, 34 which was also the case in the present study. One of the most feared side effects is retina damage by the antimalarial, which is usually irreversible and dose dependent and time dependent. It is present in less than 1% of patients after 5 years of use but reaches 20% after 20 years. In this series, retinopathy was detected in one case in the CQ group and one in the placebo group, without visual losses. Some risk factors associated with its occurrence are a cumulative total dose of 460 g or daily dose above 250 mg (or >3 mg/kg/day for individuals with low weight), age over 60 years, liver or kidney dysfunction, maculopathy, or retinal preexisting disease.35 In the case of a 50‐year‐old patient in the CQ group, injury suspicion occurred 19 months after starting the medication, the dose by weight was 2.84 mg/kg/day, and there was no renal or hepatic dysfunction. After drug discontinuation, the suspected lesion was completely reversed in less than 6 months of ophthalmologic follow‐up. It is worth remembering that, like antimalarials, long‐term use of corticosteroids is also associated with visual risk, such as glaucoma and cataracts, and a periodic ophthalmologic assessment is also recommended in patients who use long‐term medication. Some criticisms of this study could be made, such as the reduced sample size, the use of CQ instead of hydroxychloroquine, the early withdrawal of antimalarial drugs following the occurrence of some side effects even without a well‐documented causal relationship with the drug, and suspension in pregnancy. Despite the fact that hydroxychloroquine has a better safety profile in rheumatologic diseases, particularly with regard to retinopathy occurrence, a study with 940 patients with several rheumatic disorders revealed that 28% of patients had side effects with CQ compared to 15% with hydroxychloroquine. However, the interruption rate due to side effects was higher with CQ but due to clinical inefficacy was higher with hydroxychloroquine.36 Therefore, in the current study, the use of CQ was probably related to a higher rate of adverse events but maybe with a lower rate of disease relapse. CQ was the only formulation available for dispensing in our Public Health System, but the side effects most frequently reported in our patients were cutaneous and gastrointestinal; these were usually temporary and easy to alleviate. The placebo group also had a high rate of treatment discontinuation, probably reflecting the rigor of investigators in relation to the side effects due to the off‐label use of the drug in the treatment of AIH. On the other hand, the high rates of discontinuation were minimized by the evaluation of relapse‐free survival by the Kaplan‐Meier method because the patient could be observed until its censorship. Although the drug is considered relatively safe during pregnancy and already used in patients with antiphospholipid syndrome, there are no adequate and well‐controlled studies evaluating the safety and efficacy of CQ in pregnancy, justifying its withdrawal in the current study with more decreases in the sample size. The long enrollment period may have added some biases in this study, such as the changes in the AIH criteria for disease remission. The most recent AIH guidelines suggest that biochemical remission should include the normalization of aminotransferases and IgG levels. When the present study was planned and patient recruitment was started, the 1999 IAIHG recommendations, which are still valid, were the reference, and their considerations on complete remission, including histologic remission, were strictly followed. Liver biopsies at the end of the 3‐year CQ administration were not performed because the criteria for AIH relapse after full complete response were based only on biochemical results. However, this long period of time is justified by the low incidence/prevalence of the disease and the fact that the study is unicentric. This in turn also allowed better control of other confounding factors that could influence the results, such as inflammatory activity in liver biopsies before inclusion, standardization of the exams collected, criteria for suspension of the medication, and poststudy follow‐up. In conclusion, CQ safely and significantly reduces the risk of relapsing AIH in remission following discontinuation of immunosuppressive therapy; however, a subgroup with greater benefit from its use has yet to be defined. The side effects presented were mild and more frequently controlled with the use of symptomatic medication without affecting quality of life. The high rates of adverse effects and discontinuation of the drug were a concern in the study but should be interpreted with caution because of the stringent criteria for discontinuation of treatment in the case of side effects resulting from the “off‐label” treatment of AIH with CQ. Possibly the use of hydroxychloroquine instead of CQ could be a safer and better tolerated option to maintain AIH remission, but this should be investigated in further studies. The most outstanding finding of our study is the possibility of using a drug without immunosuppressive effect as part of the treatment of AIH. This creates the expectation that in the long term other drugs with immunomodulatory action can be formulated, allowing an increase of the scarce therapeutic options available for the treatment of the disease. In order to definitely include the drug as a possible therapeutic option, we should consider carrying out multicenter studies, including different countries and populations, to draw more solid conclusions regarding the role of antimalarial drugs in the treatment of AIH. Potential conflict of interest Nothing to report. References
|
|
Scooped by
Gilbert C FAURE
January 6, 2019 11:18 AM
|
Download past episodes or subscribe to future episodes of Rheuminations by Adam J. Brown, MD for free.
|
|
Scooped by
Gilbert C FAURE
December 31, 2018 12:51 PM
|
The initial events predisposing to loss of tolerance in patients with systemic lupus erythematosus (SLE) are largely unknown, as are the events that precipitate the transition from preclinical to overt disease. We hypothesized that induction of murine SLE would require tipping the balance between tolerance and immunity in two ways: 1) an immunogen that could take advantage of apoptotic cells as a scaffold for epitope spread, and 2) an immune activator that would generate a strong and persistent T cell response to the inciting immunogen. We show that immunization of C57BL/6 and BALB/c mice with human β2-glycoprotein I, an apoptotic cell-binding protein, in the presence of LPS induces a long-lived, potent response to β2-glycoprotein I that results in epitope spread to multiple SLE autoantigens. SLE-specific autoantibodies emerged in a sequential manner that recapitulated the order seen in human SLE. Moreover, immunized mice developed overt glomerulonephritis closely resembling human lupus nephritis.
Mediators of Inflammation is a peer-reviewed, Open Access journal that publishes original research and review articles on all types of inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, leukotrienes, PAF, biological response modifiers and the family of cell...
Via Krishan Maggon
Background: Systemic Lupus Erythematosus (SLE) is characterised by increased mortality
secondary to Cardiovascular Diseases (CVD). Despite being common in ...
Via Krishan Maggon
|
|
|
Scooped by
Gilbert C FAURE
February 20, 2019 3:39 PM
|
Previous studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials.
|
|
Scooped by
Gilbert C FAURE
February 19, 2019 2:33 PM
|
The disease systemic lupus erythematosus (SLE)—marked by the attack on joints, skin, and kidneys by the body's immune system—is linked to an abnormal mix of bacteria in the gut. This is according to a new study led by scientists at NYU School of Medicine.
Objectives The generation of systemic lupus erythematosus (SLE)-related autoantibodies have been shown to be T cell dependent and antigen driven with HLA-DR restriction. In this study, the initiating antigen(s) and the mechanism of autoantibody diversification were investigated.
Via Krishan Maggon
|
|
Scooped by
Gilbert C FAURE
February 11, 2019 7:35 AM
|
|
|
Scooped by
Gilbert C FAURE
February 5, 2019 1:41 PM
|
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder whose pathology involves multiple immune cell types, including B and T lymphocytes as well as myeloid cells. While it is clear that autoantibody producing B cells as well as CD4+ T cell help are key contributors to disease, little is known regarding the role of innate lymphoid cells such as Natural Killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multicolor flow cytometry in a large cohort of SLE patients. While the overall percentage of NK cells was similar or slightly decreased compared to healthy controls, a subset of patients displayed a high frequency of NK cells expressing the proliferation marker, Ki‐67, which was not found in healthy donors. Although expression of Ki67 on NK cells correlated with Ki67 on other immune cell subsets, the frequency of Ki67 on NK cells was considerably higher. Increased frequencies of Ki67+ NK cells correlated strongly with clinical severity and active nephritis and was also related to low NK cell numbers but not overall leukopenia. Proteomic and functional data indicate that the cytokine IL‐15 promotes the induction of Ki67 on NK cells. These results suggest a role for NK cells in regulating the immune‐mediated pathology of SLE as well as reveal a possible target for therapeutic intervention. This article is protected by copyright. All rights reserved.
|
|
Scooped by
Gilbert C FAURE
January 31, 2019 6:26 AM
|
Systemic lupus erythematosus (SLE) is clinically and
immunologically heterogeneous with variable organ involvement,
severity and therapeutic responses.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the presence of pathogenic autoantibodies associated with polyclonal B cell hyperreactivity. Previous study reported that autophagy-related gene Leucine-rich repeat kinase 2 (LRRK2) was likely a susceptible gene for SLE. However, the pathogenic function of LRRK2 in SLE is undefined. Using quantitative PCR, we compared the expression levels of LRRK2 in B cells between SLE patients and healthy controls. The expression levels of LRRK2 in in vitro induced CD19hi B cells and naïve B cells were compared as well based on RNA-seq assay. A pristane-induced lupus-like mouse model was used to explore the effects of LRRK2 on the development of SLE. IgG level, B cell subsets in the spleens and bone marrows and pathological features in the kidneys were compared between wildtype (WT) and Lrrk2−/− littermates. It was obvious that LRRK2 expression was dramatically up-regulated in primary B cells from SLE patients compared to those from healthy controls, as well as in activated CD19hi B cells. More significantly, LRRK2 expression in B cells was positively correlated with system lupus erythematosus disease activity index (SLEDAI), an indicator for disease severity, and serum IgG levels in SLE patients. Negative correlations were observed between LRRK2 expression and serum C3 or C4 levels, two clinical features associated with SLE-related nephritis. LRRK2 deficiency reduced the death rate of pristane treated mice. Decreased levels of total IgG and autoantibody were detected in the serum with less deposition of immune complexes and attenuated pathological symptoms in the kidneys of Lrrk2−/− mice. Consistent with the reduction in IgG production, the percentages of germinal center B cells and plasma cells decreased significantly as well with LRRK2 deficiency. Our study demonstrates that LRRK2 expression is upregulated in B cells from SLE patients with strong correlations to disease severity. LRRK2 deficiency largely attenuates the pathogenic progress of lupus-like features in pristane-induced mice. This is probably achieved through affecting B cell terminal differentiation and subsequent immunoglobulin production.
Via Krishan Maggon
|
|
Scooped by
Gilbert C FAURE
January 22, 2019 4:55 AM
|
French experts call for new assessment tools and better use of available treatments...
|
|
Scooped by
Gilbert C FAURE
January 6, 2019 12:00 PM
|
The role of ICOS and its ligand (ICOSL) have both been shown to be essential for proper humoral responses as well as autoimmune Ab development in mouse models of lupus. In this paper, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse...
|
|
Scooped by
Gilbert C FAURE
January 2, 2019 8:54 AM
|
J Med Biochem. 2018 Apr 1;37(2):163-171. doi: 10.1515/jomb-2017-0048. eCollection 2018 Apr.
Background Autoreactive IgE antibodies have been implicated in the pathogenesis systemic lupus erythematosus (SLE). We hypothesized that omalizumab, a monoclonal antibody (mAb) binding IgE, may improve SLE activity by reducing type I IFN production by hampering plasmacytoid dendritic cells and basophil activation. This study assessed the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. Methods Fifteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) of > 4 and elevated autoreactive IgE antibodies were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16‐week open label treatment and 4‐week washout period. SLEDAI 2K, British Isles Lupus Assessment Group index (BILAG 2004) and Physician Global Assessment (PGA) were recorded at each visit. Type I interferon (IFN) induced gene signature was determined using quantitative PCR. Results Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to placebo treatment. SLEDAI 2K scores improved in the omalizumab group at week 16 (p=0.038), as well as during the open label phase in subjects initially receiving placebo (p=0.020). No worsening in BILAG scores or PGA were detected. Omalizumab led to a trend towards reduction in IFN gene signature in subjects treated with omalizumab (p=0.11), especially in subjects with high baseline IFN signature (p=0.052). Conclusion Omalizumab is well tolerated in SLE and associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess efficacy of omalizumab in patients with SLE. This article is protected by copyright. All rights reserved.
Via Krishan Maggon
|
|
Scooped by
Gilbert C FAURE
December 26, 2018 1:38 PM
|
Lupus. 2018 Dec 6:961203318816820. doi: 10.1177/0961203318816820.[Epub ahead of print]...
|
Scoop.it!
