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Comprehensive Review of Autoantibodies in Patients with Hyper-Igm Syndrome

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Comprehensive Review of Autoantibodies in Patients with Hyper-Igm Syndrome Cellular and Molecular Immunology (2018) 15, 610–617 & 2018 CSI and USTC All rights reserved 2042-0226/18 $32.00 www.nature.com/cmi RESEARCH ARTICLE Comprehensive review of autoantibodies in patients with hyper-IgM syndrome Mohamed-Ridha Barbouche1, Qubo Chen2,3, Marco Carbone4, Imen Ben-Mustapha1, Zakera Shums5, Mehdi Trifa6, Federica Malinverno4, Francesca Bernuzzi4, Haiyan Zhang2,4,7, Nourhen Agrebi1, Gary L Norman5, Christopher Chang8, M Eric Gershwin8 and Pietro Invernizzi2,4 Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand gene. The CD40 ligand has been recently highlighted as playing a key role in the pathogenesis of primary biliary cholangitis. In the present study, we assessed an extensive set of serum autoantibodies in a series of well-defined patients with hyper-immunoglobulin M syndrome. Serum, liver-related and liver-not-related autoantibodies IgG, IgM and IgA were tested by ELISA and standard indirect immunofluorescence in HEp-2 cells in 13 Tunisian patients (8 males and 5 females, aged 1–12 years) with hyper-immunoglobulin M syndrome during 1995–2012 and, as controls, 21 age- and gender-matched blood donors. The level of IgM antibody against MIT3 was significantly higher in patients than in controls (35.8 vs 10.7, P = 0.002). Half of the hyperimmunoglobulin M syndrome patients were found to be anti-MIT3 IgM positive vs none of the controls (Po0.0001). Twenty-three percent of patients were found to be anti-sp100 antibody positive vs only 0.05% of controls. By immunofluorescence, 92.3% of patients were MIT3 IgM positive vs none of the controls. In conclusion, the IgM class of anti-MIT3 antibodies was shown to be present by both ELISA and immunofluorescence in most of the patients with hyper-immunoglobulin M syndrome. The presence of the hallmark of primary biliary cholangitis, a disease where the CD40 ligand is a key player, in an immunodeficiency disease caused by mutations in the CD40 ligand gene is very intriguing and opens new scenarios in understanding the immune pathogenesis of primary biliary cholangitis. Cellular and Molecular Immunology (2018) 15, 610–617; doi:10.1038/cmi.2017.140; published online 5 February 2018 Keywords: immunoglobulin M; autoantibodies; immunodeficiency; hyper-immunoglobulin M syndrome; primary biliary cholangitis INTRODUCTION subsequent development of immune responses against foreign Immunoglobulin M (IgM) is the first antibody to be produced pathogens and self-antigens by accelerating the production of by mature B cells and plasma cells during an immune response high-affinity IgG. The process controlling B-cell maturation after an initial antigen encounter. It is the predominant isotype and immunoglobulin isotype switching is largely regulated by secreted in T-cell-independent immune responses.1 Although the cross-talk between CD40 and CD40L. the existence of IgM has been known for several decades, its Hyper-immunoglobulin M (HIGM) syndrome is a rare form biological significance in immunity and autoimmunity con- of X-linked primary immunodeficiency disease (PIDD) caused tinues to emerge. IgM plays an important regulatory role in the by mutations in the gene that encodes the CD40 ligand 1Laboratory of Immunology, Institute Pasteur de Tunis and Faculty of Medicine, University Tunis El Manar, 1002 Tunis, Tunisia; 2Humanitas Clinical and Research Center, 20089 Rozzano, Italy; 3Clinical Laboratory, Guangdong Provincial Hospital of Chinese medicine, 510000 Guangzhou, China; 4Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza (MB), Italy; 5Department of Research and Development, Inova Diagnostics, 92131 San Diego, CA, USA; 6Department of Anesthesia and Intensive Care, Children Hospital Bechir Hamza, Tunis and Faculty of Medicine, University Tunis El Manar, 1007 Tunis, Tunisia; 7Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State, Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 200001 Shanghai, China and 8Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 95616 Davis, CA, USA Correspondence: Dr Pietro Invernizzi MD PhD, Professor and Chief, Division of Gastroenterology and Hepatology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza (MB), Italy. E-mail: [email protected] Received: 18 October 2017; Accepted: 26 October 2017 Table 1 Clinical features, abnormal biochemistry parameters and serum autoantibodies in patients with HIGM syndrome Serum autoantibodies and abnormal biochemistry Patient Age Gender Gene defect Clinical manifestations parameters p1 8 years M ATM Recurrent ENT and pulmonary infections. His sister with HIGM and coeliac disease died due High IgM level to Hodgkin lymphoma. Later development of ataxia-telangiectasia p2 7 years F ATM Cousin of patient 1. Recurrent pulmonary infections with bronchiectasis, eczema, diarrhea. High IgM /ALP/GGT level, Low IgG, AMA-IgM, sp100- Later development of Ataxia-telangiectasia IgM, AMA (1:640), nuclear dots (1:320) p3 3 years M Bronchopneumopathies, hepatosplenomegaly, adenopathies, skin rash High IgM level, Low IgG, AMA-IgM, sp100-IgM, AMA (1:1280), nuclear dots (1:40) p4 6 years M AID/ /AID-C ter def Recurrent ENT and pulmonary infections, cervical adenophlegmon AMA (1:40), MPO-IgG p5 12 years M AID /AID-C ter def Brother of patient 4, recurrent pulmonary and ENT infections, cervical adenophlegmon, Low IgG, AMA-IgM, sp100-IgM, AMA (1:1280), nuclear bilateral mastoiditis, lambliasis and coeliac disease dots (1:640), Centromere p6 5 years F Oral candidiasis, adenophlegmon, uveitis, deafness AMA (1:160), p7 1 years M Oral thrush, bronchopneumopathies, ENT infections, diarrhea Low IgG, AMA (1:80), p8 M CD40 ligand Chronic diarrhea, lambliasis with villous atrophy, ulcéronecrotic cutaneous lesions, recurrent High IgM level, Low IgG, AMA-IgM, sp100-IgM, gp210- pneumopathies IgM, AMA/nuclear dots/rim (1:160), ANA, GPA p9 12 years F AID /AID-C ter def Multiple adenopathies, arthralgia with unidentified etiology, nephrotic syndrom due to a High IgM level, Low IgG, AMA-IgM, sp100-IgM, AMA /AID-C ter def membranoproliferative glomerulonephritis at biopsy and type II cryoglobulinemia (1:2560), nuclear dots/Rim (1:640), p10 6 years M AID /AID-C ter def Bronchopneumopathies and ENT infections High IgM level, Low IgG, AMA-IgM, AMA (1:160), p11 3 years F AID /AID-C ter def Recurrent otitis and pneumonia High IgM/ALT level, Low IgG, AMA-IgM, AMA (1:320), p12 4 years M Recurrent otitis, adenopathies, gingival hypertrophy, molluscum contagiosum lesions High IgM level, Low IgG, AMA-IgM, sp100-IgM, AMA M-R Barbouche Serum autoantibodies in hyper-IgM syndrome (1:1280), nuclear dots (1:640) p13 3 years F Diarrhea, oral candidiadis, pneumopathy, cervical skin rash, hepatosplenomegaly, erythe- Low IgG, AMA-IgM, sp100-IgM, AMA (1:2560), nuclear matous and necrotic lesions of the anal margin dots (1:640), Rim (1:160) et al Abbreviations: AID, activation-induced cytidine deaminase; ATM, the gene responsible for Ataxia-telangiectasia, located on chromosome 11q22-23; ENT, ear, nose and throat; F, female; HIGM, hyper-immunoglobulin M; IgM, immunoglobulin M; M, male. Cellular and Molecular Immunology 611 Serum autoantibodies in hyper-IgM syndrome M-R Barbouche et al 612 (CD40L) in which defective immunoglobulin (Ig) class-switch Although the first description of HIGM syndrome cases recombination (CSR) leads to deficiencies in IgG, IgA and IgE dates to the 1960s, there has been no systematic evaluation of with preserved or elevated levels of IgM. Six main forms of either the prevalence or spectrum of antibodies to common HIGM are known. They can generally be divided into those autoantigens in this disorder. In the present study, we that result from mutations in the genes encoding CD40L and/ performed an extensive assessment of serum autoantibodies fi or CD40 and those resulting from defects in genes encoding in a series of well-de ned patients with HIGM syndrome. intrinsic factors involved in immunoglobulin CSR and somatic MATERIALS AND METHODS hypermutation (SHM) in B cells. HIGM caused by genetic Patient population and study design defects of CD40L or CD40 presents with features of cellular Thirteen patients with HIGM who were referred to the and humoral immunodeficiencies, while that caused by intrin- Children’s Medical Center in Tunis, Tunisia during 1995– sic B-cell defects shows pure humoral immunodeficiencies.2 2012 were enrolled in this study. The criteria for the diagnosis The major defect shared by all forms of HIGM syndromes is a of HIGM were low serum IgG and IgA levels ≤ 2s.d.below failure in the ability of B lymphocytes to switch from IgM to normal values for age, normal or elevated IgM, and recurrent 3 the other immunoglobulin isotypes. HIGM is characterized by or severe infections. Informed consent was obtained from all increased susceptibility to infections and low serum levels of patients and their parents, and blood was collected under IgG, IgA and IgE but normal or elevated levels of IgM and institutional guidelines. The clinical features of the enrolled normal numbers of circulating B cells, with or without defects patients are summarized in Table 1. Eight of the 13 patients of SHM.4 underwent genetic testing for HIGM. At the same time, 21 age- Autoimmunity has been described in all forms of HIGM and gender-matched blood donors served as controls (Table 2). syndrome, with variable presentation and immunological and These control individuals had undergone minor surgery for clinical phenotype.5 In a somewhat paradoxical manner, the orthopedic, non-infectious conditions. The sera were analyzed susceptibility to opportunistic and bacterial infections seen in for basic chemistry and liver panels, including AST, ALT, ALP, HIGM patients is accompanied by a vulnerability to develop GGT, total and direct bilirubin, and baseline IgG, IgA and IgM autoimmune diseases such as immune thrombocytopenia, levels.
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