Autoantibodies In Systemic Lupus Erythematosus Research Articles

AID dysregulation in lupus-prone MRL/Faslpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: Modulation by HoxC4

Immunoglobulin gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) play important roles in the generation of autoantibodies in systemic lupus erythematosus. Systemic lupus is characterized by the production of an array of pathogenic high-affinity mutated and class-switched, mainly IgG, antibodies to a variety of self-antigens, including nuclear components, such as dsDNA, histones, and chromatin. We previously found that MRL/Faslpr/lpr mice, which develop a systemic autoimmune syndrome sharing many features with human lupus, display greatly upregulated CSR, particularly to IgG2a, in B cells of the spleen, lymph nodes, and Peyer's patches. In MRL/Faslpr/lpr mice, the significant upregulation of CSR is associated with increased expression of activation-induced cytidine deaminase (AID), which is critical for CSR and SHM. We also found that HoxC4 directly activates the promoter of the AID gene to induce AID expression, CSR and SHM. Here, we show that in both lupus patients and lupus-prone MRL/Faslpr/lpr mice, the expression of HoxC4 and AID is significantly upregulated. To further analyze the role of HoxC4 in lupus, we generated HoxC4− / − MRL/Faslpr/lpr mice. In these mice, HoxC4-deficiency resulted in reduced AID expression, impaired CSR, and decreased serum anti-dsDNA IgG, particularly IgG2a, autoantibodies, which were associated with a reduction in IgG deposition in kidney glomeruli. In addition, consistent with our previous findings in MRL/Faslpr/lpr mice that upregulated AID expression is associated with extensive DNA lesions, comprising deletions and insertions in the IgH locus, we found that c-Myc to IgH (c-Myc/IgH) translocations occur frequently in B cells of MRL/Faslpr/lpr mice. The frequency of such translocations was significantly reduced in HoxC4− / − MRL/Faslpr/lpr mice. These findings suggest that in lupus B cells, upregulation of HoxC4 plays a major role in dysregulation of AID expression, thereby increasing CSR and autoantibody production and promoting c-Myc/IgH translocations.

Contribution of VH replacement products to the generation of autoantibodies in systemic lupus erythematosus (44.19)

Abstract Systemic lupus erythematosus (SLE) is characterized by the over production of high affinity autoantibodies that play important roles in SLE pathogenesis. However, it is not clear how these antibodies are generated and selected during the course of lupus. Our sequence analysis show that VH replacement products are highly enriched in IgH genes derived from different autoimmune diseases, including SLE. To gain insight into the mechanisms responsible for autoantibody generation in SLE, we performed single cell PCR analysis to study the functional antibody repertoires in active SLE patients. Analysis of 102 recombinant antibodies derived from the naive B cells and plasmablasts of the SLE patients show that 4.8% of the antibodies derived from naïve B cells and 26.7% of the antibodies derived from plasmablasts are autoreactive. Detailed sequence analysis reveal that in the plasmablasts of two SLE patients, VH replacement products contribute to more than 30% of IgH genes. These VH replacement products have long CDR3 regions enriched with charged amino acids, and more than 60% of them encode anti-nuclear or poly-reactive autoantibodies. These studies provide the first evidence that VH replacement products directly contribute to the generation of autoantibodies in SLE.

Autoantibodies in systemic lupus erythematosus: comparison of historical and current assessment of seropositivity

Systemic lupus erythematosus (SLE) is characterized by multiple autoantibodies and complement activation. Recent studies have suggested that anti-nuclear antibody (ANA) positivity may disappear over time in some SLE patients. Anti-double-stranded DNA (dsDNA) antibody titers and complement levels may vary with time and immunosuppressive treatment, while the behavior of anti-extractable nuclear antigen (ENA) over time is less well understood. This study sought to determine the correlation between historical autoantibody tests and current testing in patients with SLE. Three hundred and two SLE patients from the ACR Reclassification of SLE (AROSE) database with both historical and current laboratory data were selected for analysis. The historical laboratory data were compared with the current autoantibody tests done at the reference laboratory and tested for agreement using percent agreement and Kappa statistic. Serologic tests included ANA, anti-dsDNA, anti-Smith, anti-ribonucleoprotein (RNP), anti-Ro, anti-La, rheumatoid factor (RF), C3 and C4. Among those historically negative for immunologic markers, a current assessment of the markers by the reference laboratory generally yielded a low percentage of additional positives (3-13%). However, 6/11 (55%) of those historically negative for ANA were positive by the reference laboratory, and the reference laboratory test also identified 20% more patients with anti-RNP and 18% more with RF. Among those historically positive for immunologic markers, the reference laboratory results were generally positive on the same laboratory test (range 57% to 97%). However, among those with a history of low C3 or C4, the current reference laboratory results indicated low C3 or C4 a low percentage of the time (18% and 39%, respectively). ANA positivity remained positive over time, in contrast to previous studies. Anti-Ro, La, RNP, Smith and anti-dsDNA antibodies had substantial agreement over time, while complement had less agreement. This variation could partially be explained by variability of the historical assays, which were done by local laboratories over varying periods of time. Variation in the results for complement, however, is more likely to be explained by response to treatment. These findings deserve consideration in the context of diagnosis and enrolment in clinical trials.

Regulatory and pathogenetic mechanisms of autoantibodies in SLE

In the 53 years since the discovery of anti-DNA autoantibodies in lupus , recalcitrant questions have been pondered and possible answers have been debated. The discovery of anti-DNA autoantibodies presented many puzzles: How is immunological tolerance to native B-form DNA broken? What elicits characteristic systemic lupus erythematosus (SLE) autoantibodies? Which of the diverse anti-nuclear reactivities are pathogenic? What is the role of autoantibodies in the clinical presentation of disease? How do genetic predisposition and environmental triggers contribute to SLE? These questions were brought into focus by Professor David Stollar in an introductory presentation to an intense, three-day meeting set among the rugged and inspiring scenery of the Norwegian arctic coastline (the Scientific Program is included as supplemental File 1). Other participants presented and discussed topics directed to understanding the origin and clinico-pathological impact of autoantibodies to chromatin and phospholipid antigens. In the following, several aspects of the workshop are discussed.

Hydroxyl Radical Modification of Immunoglobulin G Generated Cross-Reactive Antibodies: Its Potential Role in Systemic Lupus Erythematosus

Objective:Role of reactive oxygen species (ROS) modified human Immunoglobulin G (IgG) in systemic lupus erythematosus (SLE) has been investigated.Methods:Human IgG was modified by hydroxyl-radicals. Immunogenicity of native and modified human IgG was probed by inducing polyclonal antibodies in rabbits. Cross-reactions of induced antibodies with nucleic acid, chromatin, different blood proteins and their ROS modified conformers were determined by competitive inhibition ELISA. The binding characteristics of circulating autoantibodies in SLE patients (n = 72) against native and modified IgG were screened by direct binding and competition ELISA and the results were compared with healthy age-matched controls (n = 39).Results:Induced antibodies against ROS-modified human IgG exhibited diverse antigen binding characteristics. Native DNA, native chromatin and their ROS-modified conformers were found to be effective inhibitors of induced antibody-immunogen interaction. Induced antibodies against native human IgG showed negligible binding to the above mentioned nucleic acid antigens. SLE sera (48.6%) showed strong binding to ROS-human IgG in comparison with its native analogue (P < 0.01). Normal human sera (NHS) showed negligible binding with either antigen (P > 0.05).Conclusion:ROS-induced modifications in human IgG present neo-epitopes, and make it a potential immunogen. The induced antibodies against ROS-modified human IgG resembled the diverse antigen-binding characteristics of naturally occurring SLE anti-DNA autoantibodies. ROS-modified IgG may be one of the factors for the induction of circulating SLE autoantibodies.

Spontaneous immunogenicity of ribosomal P0 protein in patients with benign and malignant breast lesions and delay of mammary tumor growth in P0‐vaccinated mice

A common carboxyl-terminal epitope (C-22 P0) of the ribosomal P proteins (P0, P1 and P2) was shown to elicit autoantibodies in systemic lupus erythematosus (SLE) and in head and neck cancer patients. In this report we provide evidence for the in vivo immunogenicity of the P0 protein in breast cancer patients. Using recombinant P proteins, we demonstrated that sera from breast carcinoma patients (8/75) displayed significant reactivity to P0 protein when compared with healthy donor sera (0/45). Four out of the eight sera showed simultaneous reactivity to all P proteins. Breast benign tumor (3/17) and mammary hyperplasia (3/17) patient sera also showed significant reactivity to P proteins, thus suggesting that the occurrence of P protein autoantibodies might reveal mammary cell cycle dysregulation. Patient sera reacting with all P proteins recognized C-22 P0. Anti-P0 autoantibodies did not correlate with prognostic parameters of breast carcinomas. High level expression of C-22 P0 was found in mammary carcinomas compared with normal adjacent epithelium and benign lesions. To determine the antitumor activity of P0 as an immunogen, BALB-neuT transgenic mice displaying age-related breast cancer progression were vaccinated using xenogeneic P0 at the stage of mammary atypical hyperplasia. P0 vaccination significantly delayed the onset of mouse mammary tumors that overexpressed C-22 P0. Sera from P0 vaccinated mice recognized C-22 P0. Evidence for immunity to the P0 protein, its overexpression in carcinomas and its peculiar surface localization on cancer cells, along with its antitumor activity as an immunogen might be relevant for the use of P0 protein in monitoring cancer progression and in planning immunotherapeutic strategies.

Peroxynitrite-induced modification of H2A histone presents epitopes which are strongly bound by human anti-DNA autoantibodies: Role of peroxynitrite-modified-H2A in SLE induction and progression

Peroxynitrite is a potent oxidant and nitrating agent and has in vivo existence. It is a powerful proinflammatory substance and may increase vascular permeability in inflamed tissues. Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease of unknown etiology. Since its discovery, numerous self- and non-self, nuclear, and cytoplasmic antigens have been suggested as stimuli for SLE initiation, but the exact trigger is yet to be identified. In this study, an attempt has been made to investigate the binding characteristics of SLE anti-DNA autoantibodies to native DNA and native and peroxynitrite-modified H2A histone to explore the possible role of modified protein antigen(s) in SLE initiation and progression. The nuclear protein (H2A histone) was modified by peroxynitrite synthesized in our laboratory. The peroxynitrite-modified H2A revealed generation of nitrotyrosine, dityrosine, and carbonyls when subjected to investigation by physicochemical methods. Binding characteristics and specificity of SLE anti-DNA antibodies were analyzed by direct binding and inhibition enzyme-linked immunosorbent assay. The data show preferential binding of SLE autoantibodies to peroxynitrite-modified H2A histone in comparison with native H2A histone or native DNA. A band shift assay further substantiated the enhanced recognition of peroxynitirite-modified H2A histone by anti-DNA autoantibodies. The results suggest that peroxynitrite modification of self-antigen(s) can generate neoepitopes capable of inducing SLE characteristic autoantibodies. The preferential binding of peroxynitrite-modified H2A histone by SLE anti-DNA antibodies points out the likely role of oxidatively modified and nitrated H2A histone in the initiation/progression of SLE. Moreover, oxidatively modified and nitrated nuclear protein antigen, rather than nucleic acid antigens, appear to be more suitable as a trigger for SLE.

Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that can mediate tissue damage in multiple organs. The underlying aetiology of SLE autoantibodies remains unknown, and treatments aimed at eliminating B cells, or limiting their function, have demonstrated limited therapeutic benefit. Thus, the current therapies for SLE are based on the concept of nonspecific immunosuppression and consist of nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, anti-malarials and cytotoxic drugs, all of which have serious adverse side effects including organ damage. The major auto-specificity in SLE is double-stranded (ds) DNA. Many anti-dsDNA antibodies cross-react with non-DNA antigens that may be the direct targets for their pathogenic activity. Studying anti-dsDNA antibodies present in SLE patients and in animal models of lupus, we have identified a subset of anti-dsDNA antibodies which is pathogenic in the brain as well as in the kidney. We have recently demonstrated that specific peptides, or small molecules, can protect target organs from antibody-mediated damage. Thus, it might be possible to treat the aspects of autoimmune disease without inducing major immunosuppression and ensuing infectious complications.

The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus?

Patients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease (CVD). Traditional risk factors fail to fully explain all of this increased risk. As atherosclerosis is recognized as a chronic inflammatory disease, it has been advocated that persistent inflammatory activity in patients with SLE is the principal mechanism that promotes accelerated atherogenesis. Autoantibodies in SLE might contribute to the pathogenesis of atherosclerosis by causing injury to the endothelium and altering the metabolism of lipoproteins involved in atherogenesis. Circulating immune complexes and anti-endothelial cell antibodies can induce expression of a proinflammatory and proadhesive endothelial cell phenotype. Similarly, antiphospholipid antibodies (aPL) may directly activate the endothelium or, via cross-reactivity with other antigens, interfere with lipoprotein metabolism. Antibodies to oxidized low-density lipoprotein (anti-oxLDL) rise with anti-double-stranded DNA antibody titres, complement activation and disease activity scores in patients with SLE. Both clinical and in vitro studies, however, have yielded conflicting results regarding the role of anti-oxLDL and aPL antibodies in CVD. Elevated levels of antibodies to high-density lipoprotein (HDL) and apolipoprotein A1 (the principal protein fraction of HDL) are found in patients with coronary ischaemia. Titres of these antibodies are significantly higher in SLE patients with persistent inflammatory disease and correlate inversely with activity of paraoxonase, a key enzyme that gives HDL its anti-oxidant properties. This review summarizes the evidence that autoantibodies in SLE might contribute to the pathogenesis of atherosclerosis by causing injury to the endothelium and altering the metabolism of lipoproteins involved in atherogenesis.

A/H1N1 influenza vaccination in patients with systemic lupus erythematosus: Safety and immunity

Objectives To determine the safety of and immunogenicity induced by A/H1N1 influenza vaccination in patients with systemic lupus erythematosus (SLE). Research design and methods The study population comprised 21 SLE patients and 15 healthy control subjects who underwent split-virion, inactivated monovalent A/H1N1 vaccination between December 2009 and January 2010. Sera were obtained before, three weeks after, and six months after vaccination. SLE disease activity index (SLEDAI) scores and autoantibodies were measured at every visit in SLE patients. Haemagglutination inhibition and the serum immunoglobulin G (IgG) level were calculated using the World Health Organization (WHO) procedure to evaluate the antibody responses. We also recorded current medications and past seasonal influenza vaccinations to analyse the interactions between vaccinations and the autoimmunity of SLE patients. Results The mean age of the enrolled population was 34.3 years for SLE patients and 39.4 years for control subjects. The average SLEDAI score for SLE patients was 4.1 at vaccination, 4.5 at three weeks, and 4.3 at six months. The seroprotection rate at three weeks was 76.2% in SLE patients and 80.0% in healthy control subjects; by six months, the seroprotection rate was 66.7% in SLE patients and 60% in healthy control subjects. The seroconversion rate was 76.2% in SLE patients and 80% in healthy controls at three weeks; by six months, the seroconversion rate was 52.4% in SLE patients and 53.3% in healthy controls. The response in SLE patients met the criteria of the European Committee for Proprietary Medicinal Products guidelines at three weeks, while the percentage of seroprotection did not at six months. The clinical disease activity and SLEDAI scores did not differ significantly from before to after vaccination in SLE patients, although the level of anticardiolipin IgG increased at three weeks after vaccination, but with no apparent clinical manifestations. Conclusions The A/H1N1 influenza vaccine is safe and effective in SLE patients and has no obvious adverse clinical effects. Treatment with a single immunosuppressive agent or combination therapy also leads to effective humoral immunity in these patients.

Glycoprotein specificity of cold-reactive IgM antilymphocyte autoantibodies in systemic lupus erythematosus

Sera from patients with systemic lupus erythematosus frequently contain IgM antibodies to glycoproteins of Mr 46,000 and approximately 200,000 isolated from nonionic detergent lysates of mature T cells by affinity chromatography with solid-phase wheat germ agglutinin. Autoantibodies of this specificity correlate strongly with the presence of IgM anti-T cell autoantibodies, as determined by independent indirect immunofluorescence and complement-dependent microcytotoxicity assays, and are specifically absorbed by incubation of patient serum with viable T cells. Collectively, the data suggest that gp46 and, to a lesser extent, gp approximately 200 represent major targets of IgM antilymphocyte autoantibodies in systemic lupus erythematosus.

Apoptosis-induced histone H3 methylation is targeted by autoantibodies in systemic lupus erythematosus

ObjectivesIn systemic lupus erythematosus (SLE) apoptotic chromatin is present extracellularly, which is most likely the result of disturbed apoptosis and/or insufficient removal. Released chromatin, modified during apoptosis, activates the immune...

Enhanced reactivity to malondialdehyde-modified proteins by systemic lupus erythematosus autoantibodies

Objective: Evaluation of the reactivity of autoantibodies of systemic lupus erythematosus (SLE) patients directed against malondialdehyde (MDA)-modified catalase, superoxide dismutase (SOD), and different Hep2 protein fractions (hydrophobic, hydrophilic, and nuclear).Method: Thiol groups and MDA–protein adducts were first assessed among 65 SLE patients and 60 healthy controls. Then, the reactivities of SLE immunoglobulin (Ig)G autoantibodies towards MDA-modified and unmodified proteins were compared using a standard enzyme-linked immunosorbent assay (ELISA).Results: An increase in the levels of MDA-modified proteins and a decrease in the concentration of thiol groups among SLE patients (p < 0.05) were observed. IgG circulating autoantibodies in the sera of SLE patients exhibited a significant enhanced reactivity (p < 0.05) against catalase and SOD-modified proteins. The same data were observed in the different protein fractions extracted from cultured cells (p < 0.05).Conclusion: These data reinforce the role of oxidative stress and especially lipid peroxidation products in the progression of SLE disease.

Are anti-C1q antibodies different from other SLE autoantibodies?

Anti-C1q antibodies were first identified as low-molecular weight C1q precipitins in the sera of patients with systemic lupus erythematosus (SLE) over 30 years ago. Anti-C1q antibodies are strongly associated with the development of proliferative lupus nephritis, so much so that active renal inflammation in SLE patients is very unlikely if these antibodies are not present. These antibodies seem to develop through mechanisms that are similar to those of other SLE autoantibodies.

Anticyclic citrullinated peptide autoantibodies in systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease with protean manifestation. Arthritis is one of the most common manifestations seen in SLE. Anti-CCP Ab is a recently described autoantibody that has been claimed as a most sensitive and specific marker for the diagnosis of RA. Study was performed to see whether anti-CCP2 Ab is positive in lupus arthritis or not. Anti-CCP Ab, ANA, ds DNA, and APLA were estimated by ELISA. Anti-CCP2 Ab was positive in 22 cases (37.93%) of SLE. Mean value of anti-CCP (18.08±16.95 U/ml) was statistically significant (P<0.001) when compared to control (5.07±U/ml). A total of 44 (75.86%) patients with SLE had arthritis. In 29 (50.00%) cases, arthritis resembled RA along with classical features of SLE, while 15 cases (25.86%) had nonspecific lupus arthritis. In 13 cases (44.82%) of RA type lupus arthritis, anti-CCP2 Ab was positive, while only three (20%) nonspecific lupus arthritis cases had elevated anti-CCP. In 14 (24.13) patients with SLE, there was no arthritis, but in this group also (6/14) 42.85% cases had elevated anti-CCP. A total of 11 (50%) patients with duration less than 1 year had more anti-CCP 2 positivity when compared to disease duration between 1 and 3 years (27.27%) and disease duration more than 3 years (22.72%), but specifically, it was not significant. Our study concludes that anti-CCP2 is not a specific antibody for RA, but it is present in autoimmune diseases.

B-CELL ACTIVATING FACTOR OF THE TNF FAMILY IS UPREGULATED IN NEUROMYELITIS OPTICA

Neuromyelitis optica (NMO) is characterized by optic neuritis and longitudinally extensive transverse myelitis, and serum NMO-IgG antibody against aquaporin-4 (AQP4) has been implicated in the pathogenesis.1 It has been reported that NMO patients are often complicated by either serum non-organ-specific autoantibodies and autoimmune diseases such as systemic lupus erythematosus (SLE) or Sjogren syndrome (SS).1 Efficacy of interferon (IFN)-β for the prevention of NMO relapses is not supported in contrast to that for multiple sclerosis (MS).2 These findings suggest that humoral immunity plays a pivotal role in the pathogenesis of NMO. B-cell activating factor of the tumor necrosis factor family (BAFF) is a key molecule involved in the differentiation and survival of B cells, and this molecule also promotes immunoglobulin production.3 Previous studies have shown that serum level of BAFF is increased and correlates with disease activity and titers of pathogenic autoantibodies in SLE and SS.3 BAFF is implicated in the establishment and maintenance of autoantibody-associated autoimmune diseases. Since it has been speculated that more intense humoral immune responses are involved in the pathogenesis of NMO than MS, we investigated whether BAFF in serum and CSF is increased in NMO. ### Methods. Serum and CSF were collected from patients with relapsing-remitting MS (RRMS) and patients with NMO during the acute relapse phase. Patients with NMO included 7 women and 3 …

Decreased frequency and activated phenotype of blood CD27 IgD IgM B lymphocytes is a permanent abnormality in systemic lupus erythematosus patients

IntroductionSystemic lupus erythematosus (SLE) is characterized by B cell hyper-activation and auto-reactivity resulting in pathogenic auto-antibody generation. The phenotypic analysis of blood B cell subsets can be used to understand these alterations.MethodsThe combined detection of CD19, CD27 and IgD (or IgM) by flow cytometry (FC) analysis delineates five well-defined blood B cell-subsets: naive, switched (S) memory, double negative (DN) memory and CD27 IgD IgM (non-switched memory) B lymphocytes, and plasma cells (PCs). This phenotypic study was performed in 69 consecutive SLE patients and 31 healthy controls.ResultsSLE patients exhibited several abnormalities in the distribution of these B cell subsets, including elevated levels of DN memory B cells and PCs, and decreased CD27 IgD IgM B cells. Active SLE patients also showed decreased presence of S memory B cells and increased proportions of naive B lymphocytes. Nevertheless, when the patients in remission who did not require treatment were studied separately, the only remaining abnormality was a reduction of the CD27 IgD IgM B cell-subset detectable in most of these patients. The level of reduction of CD27 IgD IgM B cells was associated with elevated values of serum SLE auto-antibodies. Further analysis of this latter B cell-subset specifically showed increased expression of CD80, CD86, CD95, 9G4 idiotype and functional CXCR3 and CXCR4.ConclusionsThe presence of a reduced blood CD27 IgD IgM B cell-subset, exhibiting an activated state and enriched for auto-reactivity, is a consistent B cell abnormality in SLE. These findings suggest that CD27 IgD IgM B lymphocytes play a role in the pathogenesis of this disease.

Do we need new autoantibodies in lupus?

Systemic lupus erythematosus (SLE) is a clinically and serologically complex disease that demonstrates clinical, epidemiological and genetic differences among racial and ethnic groups. Some autoantibodies are useful for diagnosis of the illness. Others are clinically important because of associations with a particular manifestation of SLE. Antibodies to RNA helicase A (anti-RHA) comprise a newly described class of SLE autoantibodies. These antibodies have so far been found only in SLE patients and differ substantially in prevalence and nature between Mexican and white American SLE patients. Study of anti-RHA may provide insights into the origin of population differences in SLE.

B-cell anergy is maintained in anti-DNA transgenic NZB/NZW mice

Clonal anergy has been well recognized as an important mechanism of B cell immunologic tolerance. However, the properties of anergic B cells and especially their role in the development of autoimmune disease in susceptible animals have been controversial. Here we show that low-affinity anti-DNA anergic B cells populate the mature B-cell compartment in the mouse spleen in excessive numbers and display paradoxical behavior in response to a combined B-cell receptor/TLR9 activation. Surprisingly, B-cell anergy was maintained in aged NZB/NZW F1 mice that develop a systemic lupus erythematosus (SLE)-like autoimmune disease. In several parameters of anergy, such as calcium mobilization and antibody secretion, the lupus-prone mice appeared more anergic than their non-autoimmune counterparts. We conclude that low-affinity anergic B cells are unlikely to serve as precursors for the high-affinity autoreactive B cells that give rise to pathogenic anti-DNA auto-antibodies in SLE.

Innate immunity and inflammation in systemic sclerosis

Recent advances in our understanding of innate immunity and inflammation have direct bearing on how we understand autoimmunity, fibrosis and how innate immune sensors might stimulate both of these key features of systemic sclerosis (SSc) Nucleic acid containing immune complexes activate toll-like receptors (TLRs) and induce expression of interferon responsive genes (IRGs) and autoantibodies in systemic lupus erythematosus (SLE). Recent studies indicate that increased SSc expression of IRGs may also be mediated by nucleic acid containing immune complexes. An expanding array of non-TLR innate immune pathways has recently been discovered. In particular, nalp3 mediated inflammasome activation of caspase-1 and conversion of pro-IL-1 to IL-1 play a key role in silica-mediated and bleomycin-mediated pulmonary fibrosis. TLR activation stimulates other inflammatory mediators, such as IL-1, IL-6 and TNFa in macrophages and dendritic cells. Activation of these and other inflammatory mediators, through TLR and non-TLR sensors, may cooperate to upregulate fibrotic mediators such as TGFbeta and IL-13. These observations provide a new paradigm for understanding the relationship between immunity/inflammation and fibrosis. New therapeutics, including TLR agonists and antagonists, and IFN inhibitors are currently under investigation. Further understandings of inflammasome-mediated fibrosis may provide further insights into SSc pathogenesis.