R. Goulabchand

Impact of autoantibody glycosylation in autoimmune diseases

OBJECTIVE Recent outcomes enhanced the critical role of glycosylation pattern of autoantibodies in the pathophysiology of antibody-mediated autoimmune diseases. In this review, we discuss the critical role of immunoglobulin (Ig) glycosylation on skewing immune response towards a pro- or anti-inflammatory pathway. METHODS A comprehensive search of Pubmed references was completed by hand searching of selected articles. RESULTS We first described the impact of glycosylation on Ig immune effector functions: antibody-dependent cell-mediated cytotoxicity, complement activation, dendritic cell, macrophage or B-cell activation and maturation, neoantigen formation, or Ig-receptor binding. We then reviewed autoimmune diseases with abnormal Ig glycosylation, trying to understand its role in the pathogenic process. We then discussed the usefulness of monitoring Ig glycosylation as a biomarker of disease activity, as demonstrated in proteinase-3 anti-neutrophil cytoplasmic autoantibodies associated vasculitis. After reporting environmental and immune factors known to affect Ig glycosylation process, we finally evoked therapeutic strategies currently being developed in order to modulate Ig glycosylation pattern and autoimmune disease evolution. CONCLUSION This overview on Ig glycosylation mechanisms and impact on immune system modulation is necessary to face new therapeutic approaches of autoimmune diseases.

Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis.

Background: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). Objectives: to confirm these findings. Methods: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. Results: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. Conclusions: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

Emerging clinical phenotypes associated with anti-cytokine autoantibodies

Anti-cytokine autoantibodies (AAbs) are frequent and involve a very large panel of cytokines both in healthy subjects and in patients with various pathological conditions. In healthy individuals, anti-cytokine AAbs are described as a part of the natural AAb repertoire and are thought to contribute to the fine regulation of cytokine homeostasis. In some patients, neutralizing AAbs targeting cytokines required for the immune protection against specific microbes may induce acquired immunodeficiency leading to very specific infectious phenotypes. For instance, anti-IFNγ AAbs may induce disseminated non-tuberculous mycobacterial infections; anti-IL-17 AAbs are associated with the development of chronic mucosal candidiasis, and anti-IL-6 AAbs with severe staphylococcal or streptococcal infections. In patients with autoimmune diseases, AAbs directed against pathogenic cytokines are able to influence the course of the diseases. In lupus patients, neutralizing anti-IFNα and anti-TNFα AAbs are associated with a decreased bioactivity of the corresponding cytokine and a lower disease severity. Similarly, anti-IL-1α AAbs are associated with nondestructive forms of chronic polyarthritis. More surprisingly, neutralizing anti-BAFF AAbs are observed in the serum of lupus patients with elevated IFNα signature and higher disease activity. In this review, we summarize the current literature describing the different phenotypes and the main mechanisms associated with the occurrence of anti-cytokine AAbs.

Glycosylation des autoanticorps au cours des maladies auto-immunes

Protein glycosylation is one of the most common post-translational modifications, involved in the well described protein biosynthesis process. Protein glycosylation seems to play a major role in the pathogenesis of auto-immune diseases. Herein are described the main alterations of autoantibody glycosylation associated with autoimmunes diseases such as rheumatoid arthritis, IgA glomerulonephritis, Schoenlein-Henoch purpura, Sjögrens syndrome, systemic scleroderma, systemic lupus erythematosus, myasthenia gravis and granulomatosis with polyangiitis (Wegener). Molecular identification of altered immunoglobulin glycosylation could lead to a better understanding of the pathogenesis of those diseases, might allow an evaluation of their biological activity and could even be a new therapeutic target.

Serum-Mediated Oxidative Stress from Systemic Sclerosis Patients Affects Mesenchymal Stem Cell Function

Objectives Properties of mesenchymal stromal/stem cells (MSCs) from systemic sclerosis (SSc) patients have been reported to be altered. MSC-based therapy may therefore rely on the use of allogeneic MSCs from healthy subjects. Here, we investigated whether heterologous MSCs could exhibit altered properties following exposure to oxidative environment of SSc sera. Methods Human bone marrow-derived MSCs were cultured in the presence of various sera: control human serum AB (SAB), SAB with HOCl-induced AOPPs at 400 or 1,000 µmol/L (SAB400 or SAB1000, respectively), or H2O2-induced AOPPs or SSc patient serum (PS). Proliferation, apoptosis, and senescence rates of MSCs were evaluated after 3, 6, and 10 days in culture. Reactive oxygen species and nitric oxide production were quantified at 24 h. Trilineage potential of differentiation was tested after 21 days in specific culture conditions and immunosuppressive function measured in a T lymphocyte proliferative assay. Results In the presence of oxidative environment of PS, MSCs retained their proliferative potential and survived for at least the first 3 days of exposure, while the number of senescent MSCs increased at day 6 and apoptosis rate at day 10. Exposure to PS enhanced the antioxidant capacity of MSCs, notably the expression of SOD2 antioxidant gene. By contrast, the osteoblastic/adipogenic potential of MSCs was increased, whereas their immunosuppressive function was slightly reduced. Discussion Although some functional properties of MSCs were affected upon culture with PS, evidence from preclinical studies and the present one suggested that MSCs can adapt to the oxidative environment and exert their therapeutic effect.

Acute and regressive scleroderma concomitant to an acute CMV primary infection

OBJECTIVES To describe the pathophysiological mechanisms involving cytomegalovirus (CMV) primary infection and natural killer (NK) cell expansion in the development of localized scleroderma. RESULTS A 43-year-old woman presented acute erythematous discoloration and skin thickening concerning face, neck, trunk, abdomen, and the four limbs, predominantly in proximal areas. Our case did not respond to systemic sclerosis criteria diagnosis. However, skin and muscle biopsy revealed early scleroderma associated with capillary thrombi, and tissue infiltration with NK cells (CD56+/Granzyme B). Scleroderma was attributed to CMV primary infection responsible for cytolytic hepatitis (7-fold over the limit) and circulating NK cell excess. After 6 months of prednisone and a 2-year follow-up, a complete resolution of symptoms was observed. CONCLUSION Our observation suggests a potential triggering role of CMV primary infection in the development of scleroderma. Histological features from our observation addresses the role of CMV and NK cells in the development of endothelial damage and fibrotic process.

Comment on the article entitled “Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome” ( Autoimmunity Reviews 16 ( 2017 ) 1036–1043 )

Please cite this article as: Radjiv Goulabchand, Julien Delicques, Mathieu Gallo, Alain Le Quellec, Philippe Guilpain , Comment on the article entitled “Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome” (Autoimmunity Reviews 16 (2017) 1036–1043). The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Autrev(2018), https://doi.org/10.1016/j.autrev.2017.12.003

Anti-NXP2 antibody-associated extensive subcutaneous calcinosis in adult-onset myositis

A 68-year-old woman was followed since 1988 for DM. A combined therapy of corticosteroids and MTX controlled muscle involvement. In 1993, multiple subcutaneous nodules of calcinosis appeared on the limbs, chest and abdomen. In 2013, extensive calcinosis severely impaired the patient’s quality of life while myositis was under control (Fig 1). In 2016, a blood sample was collected in which circulating anti-NXP2 antibodies were detected. Anti-NXP2 antibodies were first identified in 1997. Today, 25% of patients with juvenile DM demonstrate these autoantibodies in their blood samples, indicating a poor prognosis [1]. Anti-NXP2 antibodies are detected in only 1% of cases of adult patients with myositis, and are likely linked to the occurrence of neoplasms [2]. Therefore, although typical in paediatric patients, an extensive form of calcinosis in an adult case of anti-NXP2 antibody-associated myositis is extremely rare. In our case, the evolution of calcinosis is independent from muscle involvement. Furthermore, MTX, corticosteroids and IVIGs were inefficient in preventing the spreading of calcinosis. Currently, a topical sodium thiosulphate treatment is being trialled. Thus, an early detection of anti-NXP2 antibodies could help identify a subset of adult patients at risk of developing calcinosis during the early stages of DM.