Production Of Pathogenic Autoantibodies Research Articles

The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA fluorescence in situ hybridization and immunofluorescence to profile epigenetic features of the Xi at the single-cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk-cell RNA sequencing datasets, we found that X-linked immunity genes escape XCI in specific healthy human B cell subsets and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female bias in SLE.

CD52 Is Elevated on B cells of SLE Patients and Regulates B Cell Function.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgMlo anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.

T Cell Abnormalities in the Pathogenesis of Systemic Lupus Erythematosus: an Update.

Systemic lupus erythematosus is a complex disease with broad spectrum of clinical manifestations. In addition to abnormal B cell responsive leading to autoantibody production, various T cells also play different roles in promoting systemic autoimmunity and end organ damage. We aim to provide a review on recent developments in how abnormalities in different T cells subsets contribute to systemic lupus erythematosus pathogenesis and how they inform the consideration of new promising therapeutics. Distinct subsets of T cells known as T follicular helper cells enable the production of pathogenic autoantibodies. Detailed understanding of the B cell helping T cell subsets should improve the performance of clinical trials targeting the cognate T:B cell interaction. CD8+ T cells play a role in peripheral tolerance and reversal of its exhausted phenotype could potentially alleviate both systemic autoimmunity and the risk of infection. Research on the abnormal lupus T cell signaling also leads to putative therapeutic targets able to restore interleukin-2 production and suppress the production of the pathogenic IL-17 cytokine. Recently, several studies have focused on dissecting T cell populations located in the damaged organs, aiming to target the pathogenic processes specific to each organ. Numerous T cell subsets play distinct roles in SLE pathogenesis and recent research in understanding abnormal signaling pathways, cellular metabolism, and environmental cues pave the way for the development of novel therapeutics.

Roles of cytokines and T cells in the pathogenesis of myasthenia gravis.

Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti-AChR antibody-positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (Treg ) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of Treg cells have been reported in patients with anti-AChR antibody-positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)-17; a Th17-related cytokine, IL-21 (a Tfh-related cytokine), the B-cell-activating factor (BAFF; a B cell-related cytokine) and a proliferation-inducing ligand (APRIL; a B cell-related cytokine) have been reported to be up-regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future.

Clinical and biological activity of rituximab in the treatment of pemphigus.

B-cells are major effector cells in autoimmunity since they differentiate into plasmocytes that produce pathogenic auto-antibody such as anti-desmoglein antibodies in pemphigus patients. Major advances were obtained using whole B-cell depleting therapies including anti-CD20 antibodies in refractory pemphigus patients that lead to rituximab approval in pemphigus patients in EU and USA. This review summarizes the data supporting the efficacy of rituximab in pemphigus and provides an overview of the reported immunological changes underlying its therapeutic action. Short and long-term remission in pemphigus is explained by the removal of autoreactive B-cells involved in the production of pathogenic IgG auto-antibodies and by enhancement of the appearance of regulatory B-cells that could maintain long term immune tolerance.

Inhibition of Ras GTPases prevents Collagen-Induced Arthritis by Reducing the Generation of Pathogenic CD4+ T Cells and the Hyposialylation of Autoantibodies.

ObjectiveRasGTPases are master regulators of multiple intracellular signaling cascades. Perturbation of this pathway has been implicated in the pathogenesis of rheumatoid arthritis (RA). In this study we aimed to define the therapeutic potential of a novel RasGTPases inhibitor, farnesylthiosalicylate (FTS), in the preclinical mouse model of collagen‐induced arthritis (CIA) and better delineate its immunomodulatory effects both ex vivo and in the mouse.MethodsWe analyzed in vitro the immunomodulatory effects of FTS on various CD4+ T‐cell functions such as activation, proliferation, T‐helper polarization, and production of proinflammatory cytokines. Using the CIA model, we further determined the efficacy of FTS to inhibit clinical, histopathologic, and diverse immunological outcomes of arthritis.ResultsFTS treatment of CD4+ T cells in vitro effectively targeted distinct kinases (extracellular signal‐regulated kinase 1/2, p38, protein kinase B/AKT, and mammalian target of rapamycin), the production of interleukin (IL)‐17A, IL‐22, and granulocyte‐macrophage colony‐stimulating factor, and Th17 polarization. FTS therapy in the mouse CIA model significantly reduced clinical disease severity and joint inflammation/damage by histology. Importantly, FTS suppressed the in vivo induction of splenic IL‐17+IL‐22+ Th17 cells and the secretion of proinflammatory cytokines. The production of pathogenic autoantibodies and their abnormal hyposialylation was significantly attenuated by FTS therapy. Importantly, in vivo generation of collagen type‐II specific effector CD4+ T cells was likewise repressed by FTS therapy.ConclusionThe RasGTPases inhibitor FTS attenuates the production of proinflammatory cytokines by in vitro–activated T cells and is a potent immunomodulatory compound in the CIA model, primarily targeting the generation of autoreactive Th17 cells and the production of autoantibodies and their subsequent pathogenic hyposialylation.

Impaired B cell anergy is not sufficient to breach tolerance to nuclear antigen in Vκ8/3H9 lupus-prone mice.

BackgroundSystemic lupus erythematosus (SLE) is a severe autoimmune disease in which immune tolerance defects drive production of pathogenic anti-nuclear autoantibodies. Anergic B cells are considered a potential source of these autoantibodies due to their autoreactivity and overrepresentation in SLE patients. Studies of lupus-prone mice have shown that genetic defects mediating autoimmunity can breach B cell anergy, but how this breach occurs with regards to endogenous nuclear antigen remains unclear. We investigated whether B and T cell defects in congenic mice (c1) derived from the lupus-prone New Zealand Black strain can breach tolerance to nuclear self-antigen in the presence of knock-in genes (Vκ8/3H9; dKI) that generate a ssDNA-reactive, anergic B cell population.MethodsFlow cytometry was used to assess splenic B and T cells from 8-month-old c1 dKI mice and serum autoantibodies were measured by ELISA. dKI B cells stimulated in vitro with anti-IgM were assessed for proliferation and activation by examining CFSE decay and CD86. Cytokine-producing T cells were identified by flow cytometry following culture of dKI splenocytes with PMA and ionomycin. dKI B cells from 6-8-week-old mice were adoptively transferred into 4-month-old wild type recipients and assessed after 7 days via flow cytometry and immunofluorescence microscopy.Resultsc1 dKI mice exhibited B cell proliferation indicative of impaired anergy, but had attenuated autoantibodies and germinal centres compared to wild type littermates. This attenuation appeared to stem from a decrease in PD-1hi T helper cells in the dKI strains, as c1 dKI B cells were recruited to germinal centres when adoptively transferred into c1 wild type mice.ConclusionAnergic, DNA-specific autoreactive B cells only seem to drive profound autoimmunity in the presence of concomitant defects in the T cell subsets that support high-affinity plasma cell production.

Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice.

The autoimmune disease systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. It has been postulated that gut microbial dysbiosis may be one of the mechanisms involved in SLE pathogenesis. Here, we demonstrate that the dysbiotic gut microbiota of triple congenic (TC) lupus-prone mice (B6.Sle1.Sle2.Sle3) stimulated the production of autoantibodies and activated immune cells when transferred into germfree congenic C57BL/6 (B6) mice. Fecal transfer to B6 mice induced autoimmune phenotypes only when the TC donor mice exhibited autoimmunity. Autoimmune pathogenesis was mitigated by horizontal transfer of the gut microbiota between co-housed lupus-prone TC mice and control congenic B6 mice. Metabolomic screening identified an altered distribution of tryptophan metabolites in the feces of TC mice including an increase in kynurenine, which was alleviated after antibiotic treatment. Low dietary tryptophan prevented autoimmune pathology in TC mice, whereas high dietary tryptophan exacerbated disease. Reducing dietary tryptophan altered gut microbial taxa in both lupus-prone TC mice and control B6 mice. Consequently, fecal transfer from TC mice fed a high tryptophan diet, but not a low tryptophan diet, induced autoimmune phenotypes in germfree B6 mice. The interplay of gut microbial dysbiosis, tryptophan metabolism and host genetic susceptibility in lupus-prone mice suggest that aberrant tryptophan metabolism may contribute to autoimmune activation in this disease.

The ISCCA flow protocol for the monitoring of anti-CD20 therapies in autoimmune disorders.

Anti-CD20 monoclonals (MoAbs) are used in a variety of autoimmune disorders. The aim is to eliminate memory B cells sustaining the tissue damage and the production of pathogenic autoantibodies, while preserving naïve cells. The disappearance of memory B cells and the repopulation by naïve cells correlate with good clinical response, while the reappearance of memory B cells and plasmablasts correlates with relapse or resistance to therapy. Anti-CD20 induce extremely low B cell levels, requiring high-resolution techniques. The immune monitoring protocol developed by ISCCA is described and validated, to provide a standardized method for the clinical decision-making process during anti-CD20 therapies in autoimmune diseases. A 10-marker, 8-color staining panel (CD20-V450, CD45-V500c, CD4-FITC + sIgM-FITC, CD38-PE, CD3-PerCP Cy5.5, CD19-PE-Cy7, CD27-APC, CD8-APC H7 + sIgG-APC-H7) is used to identify B cells, plasma cells/blasts, naïve and memory B cells, sIgM+ and sIgG-switched memory B cells, T and NK cells, with high-sensitivity analysis (>106 CD45+ cells). After an anti-CD20 dose, the B cell level is about zero in most patients. If B cells remain virtually absent (<0.1/μl), subsetting is not reliable nor meaningful. If B cells raise >0.3-0.5/μl, subsetting is possible and informative, acquiring >1.0-1.5 × 106 CD45+ events. Further testings can follow the quality of B cell repopulation. If B cells become detectable (>1/μl), the prevalence of memory B cells indicates non-responsiveness or a possible relapse. The ISCCA Protocol is proposed for a standardized prospective monitoring of patients with autoimmune disorders, to assist the safe and rational usage of anti-CD20 therapies.

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology.

Myasthenia gravis (MG) is a prototypical autoantibody mediated disease. The autoantibodies in MG target structures within the neuromuscular junction (NMJ), thus affecting neuromuscular transmission. The major disease subtypes of autoimmune MG are defined by their antigenic target. The most common target of pathogenic autoantibodies in MG is the nicotinic acetylcholine receptor (AChR), followed by muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4). MG patients present with similar symptoms independent of the underlying subtype of disease, while the immunopathology is remarkably distinct. Here we highlight these distinct immune mechanisms that describe both the B cell- and autoantibody-mediated pathogenesis by comparing AChR and MuSK MG subtypes. In our discussion of the AChR subtype, we focus on the role of long-lived plasma cells in the production of pathogenic autoantibodies, the IgG1 subclass mediated pathology, and contributions of complement. The similarities underlying the immunopathology of AChR MG and neuromyelitis optica (NMO) are highlighted. In contrast, MuSK MG is caused by autoantibody production by short-lived plasmablasts. MuSK MG autoantibodies are mainly of the IgG4 subclass which can undergo Fab-arm exchange (FAE), a process unique to this subclass. In FAE IgG4, molecules can dissociate into two halves and recombine with other half IgG4 molecules resulting in bispecific antibodies. Similarities between MuSK MG and other IgG4-mediated autoimmune diseases, including pemphigus vulgaris (PV) and chronic inflammatory demyelinating polyneuropathy (CIDP), are highlighted. Finally, the immunological distinctions are emphasized through presentation of biological therapeutics that provide clinical benefit depending on the MG disease subtype.

TLR7/8 agonist accelerates lupus development with heart disease in lupus-prone mice

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by loss of self-tolerance to nuclear antigens leading to the production of pathogenic autoantibodies, immune complex deposition and multi-organ damage. Although the prevalence of heart disease is higher than 50% in SLE patients, its etiology remains unclear but both genetic and environment factors are likely involved. Here, we compared the effect of TLR7/8 agonist Resiquimod (R848) on lupus and cardiac lesion development in lupus-prone B6.Sle1.Sle2.Sle3 (TC) and congenic normal mice B6 mice. Two weeks of R848 treatment increased the production of antinuclear antibodies and induced antiphospholipid autoantibodies lined to vascular pathology in TC mice. Correspondently, R848 expanded the frequency of Tfh cells and plasma cells in TC mice as compared to R848 treated B6 mice. More importantly, unlike the near normal appearance in hearts of R848-treated B6 mice, R848 induced severe cardiac pathology in TC mice with infiltration of CD45+ cells, edema, hemorrhage, enlarged endothelial cells and myocyte damage. Our results indicate that heart disease develops by combining genetic predisposition to lupus together with TLR7/8 activation. This novel model may lead to the identification of autoimmune mechanisms responsible for lupus-associated heart disease.

Resistivity Index (RI): A Fast and Reliable Indicator of Lupus Nephritis Severity

Abstract Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of pathogenic autoantibodies against nuclear structures. Lupus nephritis (LN) affects up to 60% of patients with SLE who develop immune complex-mediated renal injury and its squeal. Color Coded Doppler Ultrasound (CCDUS) allows non-invasive method for investigating renal hemodynamics. Renal resistive index (RI) measured using CCDUS reflects intrarenal vascular resistance. RI is an essential parameter in renal Doppler US and integrates arterial compliance, pulsatility and peripheral resistance. Aim of Study: Evaluate the role of Color-Coded Doppler Ultrasound in the assessment of nephritis in SLE patients and correlation between resistivity index (RI) and lupus nephritis pathological classes. Such assessment will help reaching diagnosis, guide the choice of management and monitor the follow-up. Patients and Methods: This study was conducted on ninety six SLE patients with renal affection, diagnosed clinically and laboratory first, then each patient included in the study was subjected to Ultrasound Doppler renal examination and renal biopsy. Twenty subjects with normal renal laboratory, ultrasound and Doppler findings were recruited as a control group. B-Mode ultrasound and Color-coded Doppler exami-nation were performed using GE Logiq p5 Ultrasound machine by (3.5-5MHz) transducer. Doppler parameters were adjusted before Doppler examination scan. First general renal vascu-larity was checked then RI was calculated in different segments of intra renal arteries at upper, mild and lower poles. RI=(peak systolic velocity-end diastolic velocity)/peak systolic velocity. The normal value is » 0.60 with 0.70 being around the upper limits of normal. Finally, radiological findings were correlated with clinical findings and correlated with biopsy results. Results: The study included 96 SLE patients, their ages ranged from (13-45) mean 28.19±8.026. Males represented 12.5% (12 patients) and females represented 87.5% (84 patients). Renal biopsy showed 70 patients (73%) with LN and 26 patients (27%) with no renal affection.The parenchymal echogenicity was increased in all LN seventy patients except one (1.5%). 15 patients (21.5%) scored grade I echogenicity while 16 patients (22.9%) scored grade II and 38 patients (54.1%) scored grade III. There was a significant increase in renal RI in lupus nephritis LN patients, p-value 0.022. Distribution of renal pathologic classes within the LN group. Class II (7 patients) represented 10%, class III (27 patients) represented 38.5%, class IV (22 patients) represented 31,5% and class, V (11 patients) represented 15.7% and class IV (3 patients) repre-sented 4.3 % of LN patients according to biopsy results. There was positive correlation between RI and renal biopsy classi-fication with high significance, p-value 0.001 with r=0.794. Conclusion: There is a significant correlation between pathologic RI and lupus nephritis histological classes suggest-ing a role for RI as a severity marker.

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.

The Progress of Investigating the CD137-CD137L Axis as a Potential Target for Systemic Lupus Erythematosus.

Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory molecules is crucial in driving proinflammatory responses from the stage of autoantigen presentation to the subsequent process of pathogenic autoantibody production. While the physiology of the costimulatory systems including OX40-OX40L, CD28/CTLA-4-CD80/86, ICOS-B7RP1 and CD70-CD27 has been relatively well studied in SLE, recent data on the immunopathology of the CD137-CD137 ligand (CD137L) system in murine lupus models and patients with SLE highlight the critical role of this costimulatory system in initiating and perpetuating the diverse clinical and serological phenotypes of SLE. CD137, a membrane-bound receptor which belongs to the tumour necrosis factor receptor superfamily, is mainly expressed on activated T cells. Activation of the CD137 receptor via its interaction with CD137L which is expressed on antigen present cells (APC) including B cells, triggers bi-directional signalling; that is, signalling through CD137 as well as signalling through CD137L (reverse signalling), which further activates T cells and polarizes them to the Th1/Tc1 pathway. Further, via reverse CD137L signalling it enhances differentiation and maturation of the APC, particularly of dendritic cells, which subsequently drive proinflammatory cytokine production. In this review, recent data including our experience in the manipulation of CD137L signalling pertaining to the pathophysiology of SLE will be critically reviewed. More in-depth understanding of the biology of the CD137-CD137L co-stimulation system opens an opportunity to identify new prognostic biomarkers and the design of novel therapeutic approaches for advancing the management of SLE.

Transitional B cells in quiescent SLE: An early checkpoint imprinted by IFN

Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our work was to determine whether transitional B cells, as the most immature naïve B cell subset upstream of pathogenic B cells, display specific features compared to healthy non SLE subjects. Through extensive analysis of transitional B cells from untreated or low treated, mostly Caucasian, SLE patients, we demonstrated that transitional (T1 and T2) B cell frequencies were increased in SLE and positively correlated with disease activity. SLE transitional B cells displayed defects in two closely inter-related molecules (i.e. TLR9 defective responses and CD19 downregulation). RNA sequencing of sorted transitional B cells from untreated patients revealed a predominant overexpression of interferon stimulated genes (ISGs) even out of flares. In addition, early transitional B cells from the bone marrow displayed the highest interferon score, reflecting a B cell interferon burden of central origin. Hence, the IFN signature in transitional B cells is not confined to African American SLE patients and exists in quiescent disease since the medullary stage. These results suggest that in SLE these 3 factors (i.e. IFN imprintment, CD19 downregulation and TLR9 responses impairment) could take part at the early transitional B cell stage in B cell tolerance by-pass, ultimately leading in periphery to the expansion of autoantibodies-secreting cells.

Pulmonary Complications of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by the production of pathogenic autoantibodies and immune complexes and is responsible for significant morbidity and mortality through a wide range of clinical manifestations which can affect almost any organ. Pulmonary involvement is prevalent and seen in 50 to 70% of SLE patients and may even be the presenting feature in 4 to 5% of patients. By 10 years postdiagnosis, 12% will have accumulated an element of permanent lung damage. Pulmonary complications are broad and include pleural disease, interstitial lung disease (ILD), vasculitis, pulmonary embolism, pulmonary hypertension, large airway disease, shrinking lung syndrome, and infection. Conditions can range mostly from asymptomatic, for example, in mild cases of pleural effusion or obstructive airway disease, to life-threatening disease, for example, in acute lupus pneumonitis or diffuse alveolar hemorrhage. ILD and pulmonary hypertension are both frequently seen in other autoimmune rheumatic diseases such as systemic sclerosis; however, in SLE, they tend to be milder and have a comparatively favorable prognosis. Although collectively pulmonary involvement in SLE is common, the heterogeneity of SLE and rareness of individual complications make clinical trials difficult and treatment is usually based on case series reports and anecdotal experience with various immunosuppressive agents. Some of these immunosuppressive agents such as azathioprine, methotrexate, and cyclophosphamide have also been linked with drug-induced lung injury.

Apoptotic cell-mimicking gold nanocages loaded with LXR agonist for attenuating the progression of murine systemic lupus erythematosus

Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

Targeted Therapies for Autoimmune Bullous Diseases: Current Status.

Autoimmune bullous skin disorders are rare but meaningful chronic inflammatory diseases, many of which had a poor or devastating prognosis prior to the advent of immunosuppressive drugs such as systemic corticosteroids, which down-regulate the immune pathogenesis in these disorders. Glucocorticoids and adjuvant immunosuppressive drugs have been of major benefit for the fast control of most of these disorders, but their long-term use is limited by major side effects such as blood cytopenia, osteoporosis, diabetes mellitus, hypertension, and gastrointestinal ulcers. In recent years, major efforts were made to identify key elements in the pathogenesis of autoimmune bullous disorders, leading to the identification of their autoantigens, which are mainly located in desmosomes (pemphigus) and the basement membrane zone (pemphigoids). In the majority of cases, immunoglobulin G, and to a lesser extent, immunoglobulin A autoantibodies directed against distinct cutaneous adhesion molecules are directly responsible for the loss of cell-cell and cell-basement membrane adhesion, which is clinically related to the formation of blisters and/or erosions of the skin and mucous membranes. We describe and discuss novel therapeutic strategies that directly interfere with the production and regulation of pathogenic autoantibodies (rituximab), their catabolism (intravenous immunoglobulins), and their presence in the circulation and extravascular tissues such as the skin (immunoadsorption), leading to a significant amelioration of disease. Moreover, we show that these novel therapies have pleiotropic effects on various proinflammatory cells and cytokines. Recent studies in bullous pemphigoid suggest that targeting of immunoglobulin E autoantibodies (omalizumab) may be also beneficial. In summary, the introduction of targeted therapies in pemphigus and pemphigoid holds major promise because of the high efficacy and fewer side effects compared with conventional global immunosuppressive therapy.

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis.

The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism.

T Follicular Helper Cells in Autoimmune Disorders.

T follicular helper (Tfh) cells are a distinct subset of CD4+ T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity. Indeed, deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. In the present review, we briefly introduce the molecular factors involved in Tfh cell formation in the context of a normal immune response, as well as markers associated with their identification (transcription factor, surface marker expression, and cytokine production). We then consider in detail the role of Tfh cells in the pathogenesis of a broad range of autoimmune diseases, with a special focus on systemic lupus erythematosus and rheumatoid arthritis, as well as on the other autoimmune/inflammatory disorders. We summarize the observed alterations in Tfh numbers, activation state, and circulating subset distribution during autoimmune and some other inflammatory disorders. In addition, central role of interleukin-21, major cytokine produced by Tfh cells, is discussed, as well as the involvement of follicular regulatory T cells, which share characteristics with both Tfh and regulatory T cells.