Eric Daugas

Immunoglobulin E plays an immunoregulatory role in lupus

Dema et al. show evidence that deficiency of IgE delays lupuslike disease development and severity, as demonstrated by reduced autoantibody production and amelioration of organ pathologies. Loss of IgE causes a striking decrease in innate immune cell infiltration in secondary lymphoid organs and decreased activation of T cells and basophils.

Renal involvement in Castleman disease

BACKGROUND Castleman disease (CD), or angiofollicular lymph-node hyperplasia, is an atypical lymphoproliferative disorder with heterogeneous clinical manifestations. Renal involvement in CD has been described in only single-case reports, which have included various types of renal diseases. METHODS Nineteen patients with histologically documented CD and renal biopsies available were included. Clinical features and renal histological findings were reviewed, and the available samples were immunolabelled with anti-vascular endothelial growth factor (VEGF) antibody. RESULTS Nineteen CD cases were identified: 89% were multicentric, and 84% were of the plasma-cell or mixed type. Four cases (21%) were associated with human immunodeficiency virus (HIV) infection. Among HIV-negative patients, two main patterns of renal involvement were found: (i) a small-vessel lesions group (SVL) (60%) with endotheliosis and glomerular double contours in all patients and with superimposed glomerular/arteriolar thrombi or mesangiolysis in most; and (ii) AA amyloidosis (20%). Renal histology was more heterogeneous among HIV-positive patients. Decreases in glomerular VEGF were observed only in some patients with SVL, whereas VEGF staining was normal in all other histological groups. Interestingly, glomerular VEGF loss associated with SVL was correlated with plasma C-reactive protein levels, a marker of CD activity. CONCLUSIONS Small-vessel lesions are the most frequent renal involvement in CD, whereas loss of glomerular VEGF is correlated with CD activity and could have a role in SVL pathophysiology.

Presentation of HIV-associated nephropathy and outcome in HAART-treated patients

BACKGROUND Among the numerous renal diseases observed in human immunodeficiency virus (HIV) patients, HIV-associated nephropathy (HIVAN) is a major cause of end-stage renal disease (ESRD). The purpose of our study was to describe the presentation and outcome of HIVAN in the era of highly active antiretroviral therapy (HAART). METHODS We analysed clinical features and outcome of 57 patients with histologically proven HIVAN diagnosed between 2000 and 2009 in four teaching hospitals in Paris, France. RESULTS This series was characterized by median age of 41 years (18-58), frequent African origin (87%), severe renal dysfunction [estimated glomerular filtration rate (eGFR) 20 mL/min/1.73m(2) (1-68)], high-grade proteinuria [4.1 g/day (0.6-16.8)], high proportion of sclerotic glomeruli [31.5% (0-95)], high HIV load [4.5 log copies/mL (0-6.7)] and low CD4+ count [127/mm(3) (3-713)]. Nevertheless, a non-negligible proportion of patients did not present with these typical features. Follow-up data were available for 51 patients. ESRD occurred in 30 patients (58.8%). Median renal survival was 40 months. Baseline characteristics significantly associated with ESRD were as follows: severity of renal dysfunction, percentage of sclerotic glomeruli, time from HIV infection to HIVAN diagnosis longer than 1 year and prior exposure to antiretroviral drugs. There was an insignificant trend towards better renal outcome being associated with viral suppression during follow-up. Use of renin-angiotensin system (RAS) blockers was associated with higher renal survival (P < 0.05). CONCLUSION Despite HAART, HIVAN led to ESRD in more than half of the cases. Early recognition of the disease is crucial to start HAART and RAS blockers before irreversible renal injury.

Acute renal failure associated with immune restoration inflammatory syndrome

Background A 30-year-old HIV-infected woman presented with fever and abdominal pain 4 days after initiation of highly active antiretroviral therapy (HAART), and 1 month after initiation of antimicrobial therapy for Mycobacterium tuberculosis infection. A diagnosis of immune restoration inflammatory syndrome (IRIS) was considered, and corticosteroids were started. Steroid therapy doses were progressively tapered, during which time the patient developed renal failure with enlarged kidneys. A renal biopsy showed acute interstitial nephritis. Extensive investigations failed to detect active infection. The efficacy of HAART was attested by increased CD4+ cell counts and undetectable viral replication.Investigations Physical examination, plasma viral load and CD4+ cell count, abdominal and renal ultrasound, renal and peritoneal biopsies, renal and liver function, chest X-ray, and bronchoalveolar lavage culture.Diagnosis Acute renal failure secondary to IRIS.Management Prednisone therapy.

Brief Report: Childhood-Onset Systemic Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study Group Registry.

To describe the initial features and long‐term outcomes of childhood‐onset small vessel and medium vessel systemic necrotizing vasculitides (SNVs), including antineutrophil cytoplasmic antibody–associated vasculitides (AAVs) and polyarteritis nodosa (PAN).

The Risk of Systemic Lupus Erythematosus Associated With Vaccines: An International Case-Control Study

Studies have suggested that systemic lupus erythematosus (SLE) may be triggered by vaccinations. We undertook this study to investigate the relationship between vaccination and onset of SLE.

International and multidisciplinary expert recommendations for the use of biologics in systemic lupus erythematosus

BACKGROUND/PURPOSE Despite conventional immunosuppressants, active and steroid-dependent systemic lupus erythematosus (SLE) represents a therapeutic challenge. Only one biologic, belimumab, has been approved, but other biologics are sometimes used off-label. Given the lack of evidence-based data in some clinical situations encountered in real life, we developed expert recommendations for the use of biologics for SLE. METHODS The recommendations were developed by a formal consensus method. This method aims to formalize the degree of agreement among experts by identifying, through iterative ratings with feedback, the points on which experts agree, disagree or are undecided. Hence, the recommendations are based on the agreed-upon points. We gathered the opinion of 59 French-speaking SLE experts from 3 clinical networks dedicated to systemic autoimmune diseases (FLEUR, IMIDIATE, FAI2R) from Algeria, Belgium, France, Italy, Morocco, Switzerland and Tunisia. Represented medical specialities were internal medicine (49%), rheumatology (34%), nephrology (7%), dermatology (5%), pediatrics (3%) and cardiology (2%). Two methodologists and 3 strictly independent SLE expert groups contributed to developing these recommendations: a steering group (SG) (n=9), an evaluation group (EG) (n=28) and a reading group (RG) (n=22). Preliminary recommendations were drafted by the SG, then proposed to the EG. Each EG member rated the degree of agreement from 1 to 9 (1: lowest; 9: strongest) for each recommendation. After 2 rating rounds, the SG submitted a new version of the recommendations to the RG. With comments from the RG, the SG finalised the recommendations. RESULTS A total of 17 final recommendations were formulated by the SG, considering all agreement scores and comments by the EG and RG members and the two methodologists. These recommendations define the subset of patients who require a biologic; the type of biologics to use (belimumab, rituximab, etc.) depending on the organ involvement and associated co-treatments; what information should be given to patients; and how to evaluate treatment efficacy and when to consider discontinuation. CONCLUSION Overall, 17 recommendations for the good use of biologics in SLE were formulated by a large panel of SLE experts to provide guidance for clinicians in daily practice. These recommendations will be regularly updated according to the results of new randomized trials and increasing real life experience.

Basophils contribute to pristane-induced Lupus-like nephritis model

Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn−/− mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production. In order to study the basophil-specific mechanisms by which these cells contribute to LN development, we needed to validate their involvement in a genetically independent SLE-like mouse model. Pristane, when injected to non-lupus-prone mouse strains, induces a LN-like disease. In this inducible model, basophils were activated and accumulated in SLOs to promote autoantibody production. Basophil depletion by two distinct approaches dampened LN-like disease, demonstrating their contribution to the pristane-induced LN model. These results enable further studies to decipher molecular mechanisms by which basophils contribute to lupus progression.

Autoantibodies against podocytic UCHL1 are associated with idiopathic nephrotic syndrome relapses and induce proteinuria in mice

Idiopathic steroid sensitive nephrotic syndrome (INS), the most frequent childhood nephropathy, is thought to be mediated by a circulating soluble factor that reversibly affects the renal protein sieving. The efficiency of rituximab therapy recently highlighted the involvement of B cells. Here we studied the involvement of a specific immunoglobulin G (IgG) in the disease. After plasma fractionation by size exclusion chromatography, a detachment of cultured podocyte was observed with one IgG-containing fraction from 47% patients in relapse, 9% of patients in remission and 0% of controls. Podocyte protein lysates were immunoprecipitated by IgG from those plasma fractions identifying a list of 41 podocyte proteins after proteomic analysis. Five podocyte targets were selected on statistical and biological criteria. Specific antibodies were tested and only anti-Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) IgG led to podocyte detachment. UCHL1 was mainly found inside the podocyte but also weakly expressed on podocyte cell surface. Incubation of either anti-UCHL1 IgG or plasma fractions with recombinant UCHL1 prevented podocyte detachment. Plasma levels of anti-UCHL1 IgG were significantly increased in relapsing INS patients compared to patients in remission and controls. Proteinuria correlated with anti-UCHL1 IgG level at various stages of the disease. Purified patient anti-UCHL1 antibodies induced proteinuria and podocyte foot effacement in mice. Altogether, these results identified UCHL1 as a target podocyte protein of autoantibodies in a set of relapsing patients and support a causative role of anti-UCHL1 autoantibodies in the development of INS.

Prostaglandin D 2 amplifies lupus disease through basophil accumulation in lymphoid organs

In systemic lupus erythematosus (SLE), autoantibody production can lead to kidney damage and failure, known as lupus nephritis. Basophils amplify the synthesis of autoantibodies by accumulating in secondary lymphoid organs. Here, we show a role for prostaglandin D2 (PGD2) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD2 receptors (PTGDR) on blood basophils and increased concentration of PGD2 metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD2 induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD2 can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD2/PTGDR axis as a ready-to-use therapeutic modality in SLE.In a lupus environment, basophils accumulate in secondary lymphoid organs where they affect pathogenesis by stimulating autoantibody production. Here the authors show this accumulation is driven by PGD2-induced CXCR4 surface expression and trafficking of basophils.