Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the α3 chain of type IV collagen (α3135-145). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive α3135-145-specific T cells expand in patients with Goodpasture disease and, in α3135-145-immunized HLA-DR15 transgenic mice, α3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135-145 epitope in different binding registers. HLA-DR15-α3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135-145-specific T-cell antigen receptor usage, HLA-DR15-α3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-α3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity.

Patient-reported outcome measures in systemic lupus erythematosus by a web-based application: A randomized, crossover, agreement study.

OBJECTIVES: Patient-reported outcome measures (PROMs) are evaluated in randomized controlled trials (RCTs) in patients with systemic lupus erythematosus (SLE), but not widely used in clinical practice. However, interest in incorporating PROMs into the management of SLE is increasing as PROMs provide a unique insight into the patient's perception of lupus disease activity. The objective was to assess agreement in PROMs answered using a web app versus an outpatient touchscreen among patients with SLE. METHODS: In a crossover RCT, SLE patients answered the following PROMs in a random order using the web app and the outpatient touchscreen: Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) Global Health, SLAQ Symptom, SLAQ Total, SLAQ Worsening, Pain Visual Analog Scale (VAS), Fatigue VAS, Patient Global Health VAS, Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Acceptable Symptom State (PASS), and an Anchoring Question. Equivalence between the two device types was demonstrated if the 95% confidence interval (95% CI) of the difference in PROM scores was within the prespecified equivalence margin. Agreement between the two device types was assessed using mixed linear models. RESULTS: Thirty-four patients with SLE were included. Equivalence was demonstrated between the two device types for SLAQ Global Health with a difference of -0.21 (95% CI: -0.65 to 0.23). Moreover, equivalence was also found for HAQ-DI, Pain VAS, and Fatigue VAS whereas only comparability within the limits of the Minimal Clinically Important Difference (MCID) was demonstrated for VAS Patient Global Health. Statistical comparability was demonstrated for SLAQ Total, SLAQ Worsening, PASS, and Anchoring Question (no predefined MCID/equivalence margins available). However, a statistically significant difference between device types was observed for the SLAQ Symptom of -0.56 (95% CI: -1.10 to -0.01). The difference was, however, very small when considering the scale range of 0-24; thus, it was not judged to be of clinical relevance. Preference for the web app was very high (91.2%). CONCLUSION: For the first time ever, equivalence and comparability between two electronic device types for various PROMs were demonstrated among patients with SLE. Implementation of the device is expected to improve the management of SLE.

High levels of urinary complement proteins are associated with chronic renal damage and proximal tubule dysfunction in immunoglobulin A nephropathy.

AIM: Complement activation is involved in the pathogenesis and progression of immunoglobulin A nephropathy (IgAN); however, the clinical implication of abnormal complement protein levels in serum and urine is not clear. To address this we analyzed the correlation between disease activity and complement proteins in serum and urine from IgAN patients, and compared to patients with other types of chronic kidney disease (CKD) as well as healthy controls. METHODS: We included 85 Chinese patients with IgAN, 23 patients with non-proliferative CKD, and 20 healthy individuals. Patients were divided according to the Oxford classification of M0E0S0T0 (group 1, n = 20), M1E1S0-1 T0-1 (group 2, n = 25), M1E1S0-1 T2 or M0E0S1T1-2 (group 3, n = 40). Complement factor H (CFH), mannose-binding lectin and membrane attack complex in serum and urine were measured by enzyme-linked immunosorbent assay. RESULTS: Urinary CFH, membrane attack complex and serum CFH were increased in both IgAN and CKD patients compared with healthy controls. The urinary excretion of CFH was the highest in IgAN patients with most tubulointerstitial damage (IgAN group 3). Urinary CFH and mannose-binding lectin levels were significantly higher in IgAN patients with crescents formation (C1-2) than in patients without (C0). Urinary complement protein excretion correlated negatively with estimated glomerular filtration rate, and positively with urinary retinol-binding protein and α1-microglobulin excretion indicating proximal tubule dysfunction. CONCLUSION: Increased urinary excretion of complement proteins in IgAN is related to chronic injury and tubular dysfunction. This warrants caution using urinary complement proteins as markers of disease activity.

T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides.

Environmental factors account for 75% of the risk of developing multiple sclerosis (MS). Numerous infections have been suspected as environmental disease triggers, but none of them has consistently been incriminated, and it is unclear how so many different infections may play a role. We show that a microbial peptide, common to several major classes of bacteria, can induce MS-like disease in humanized mice by crossreacting with a T cell receptor (TCR) that also recognizes a peptide from myelin basic protein, a candidate MS autoantigen. Structural analysis demonstrates this crossreactivity is due to structural mimicry of a binding hotspot shared by self and microbial antigens, rather than to degenerate TCR recognition. Biophysical studies reveal that the autoreactive TCR binding affinity is markedly lower for the microbial (mimicry) peptide than for the autoantigenic peptide. Thus, these data suggest a possible explanation for the difficulty in incriminating individual infections in the development of MS.

The relation between histopathological classification and renal outcome, ANCA subtype and treatment regimens in ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is associated with an increased risk of death and end stage renal disease (ESRD). The aim of this study was to examine the correlation between a histopathological classification and renal outcome and to describe the interaction with ANCA subtype and initial treatment. METHODS: Eighty-seven patients with AAV from 1999-2010 from two centres in Denmark were included in the study and had a 3 year follow-up. Data was collected retrospectively. The renal biopsies were reclassi ed into one of the following groups: crescentic, sclerotic, focal and mixed. RESULTS: Histopathologic groups were not associated with eGFR at three years. Age and baseline eGFR were independent prognostic for eGFR at three years. More patients in the crescentic group than in the mixed and focal groups developed ESRD (33%, 13% and 5% respectively). Patients reaching ESRD had few- er non-affected glomeruli (14 % vs. 34%, p=0.0014) and lower eGFR at baseline (7 vs. 21.7 ml/min/m(2), p<0.0001). At baseline MPO-ANCA positive patients were older, had more sclerotic glomeruli and had a lower eGFR after three years compared to PR3-ANCA positive patients. PR3-ANCA positive patients receiving plasma exchange (PE) improved eGFR more from baseline to three years than those not receiving PE (36 vs. 20 ml/min/m2, p=0.01). CONCLUSIONS: In our cohort most pa- tients in the crescentic group and fewer in the focal group reached ESRD. Age and baseline eGFR are prognostic of renal function after 3 years, as also in the PR3-ANCA positive subgroup initial treatment with PE.

Early plasma exchange improves outcome in PR3-ANCA-positive renal vasculitis.

OBJECTIVES: Plasma exchange (PE) has been shown to improve renal outcome in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and severe renal failure; however the effect of PE in AAV with moderate renal impairment is controversial. METHODS: A single-centre, retrospective one-year follow-up study, including patients with renal AAV and eGFR <60 ml/min/1.73 m2. Since 2007, all patients with renal AAV and eGFR <60 ml/min/1.73 m2 had PE in addition to induction therapy with cyclophosphamide and prednisolone. Patients admitted from 1999 to 2007 that did not receive PE served as controls. The primary outcome was the combination of death, end-stage renal disease, and relapses after one year. RESULTS: A significant reduction in the primary endpoint was observed following the addition of PE (25% vs. 43%, p=0.04). Furthermore, a greater improvement in renal function after one year was observed among surviving PE treated patients not on dialysis (ΔeGFR 36.1 vs. 19.7 ml/min, p=0.03). There was a significant reduction in serious adverse events in the PE treated group (4% vs. 30%, p=0.02) despite no differences in types and doses of induction immunosuppressive therapy. The advantageous effect of PE was related to the presence of anti-proteinase3 (PR3)-antibodies and also evident among patients with plasma creatinine less than 500 µM. CONCLUSIONS: This study suggests the use of PE in addition to standard induction treatment with cyclophosphamide and glucocorticoids to patients with renal PR3-AAV and an estimated-GFR <60 ml/min/1.73m2.

Functional epistasis on a common MHC haplotype associated with multiple sclerosis.

Genes in the major histocompatibility complex (MHC) encode proteins important in activating antigen-specific immune responses. Alleles at adjacent MHC loci are often in strong linkage disequilibrium; however, little is known about the mechanisms responsible for this linkage disequilibrium. Here we report that the human MHC HLA-DR2 haplotype, which predisposes to multiple sclerosis, shows more extensive linkage disequilibrium than other common caucasian HLA haplotypes in the DR region and thus seems likely to have been maintained through positive selection. Characterization of two multiple-sclerosis-associated HLA-DR alleles at separate loci by a functional assay in humanized mice indicates that the linkage disequilibrium between the two alleles may be due to a functional epistatic interaction, whereby one allele modifies the T-cell response activated by the second allele through activation-induced cell death. This functional epistasis is associated with a milder form of multiple-sclerosis-like disease. Such epistatic interaction might prove to be an important general mechanism for modifying exuberant immune responses that are deleterious to the host and could also help to explain the strong linkage disequilibrium in this and perhaps other HLA haplotypes.

B-cell depletion in the treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients.