Comprehensive overview of autoantibody isotype and subclass distribution
2022; Elsevier BV; Volume: 150; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2022.05.023
ISSN1097-6825
AutoresMikhail Volkov, Mariateresa Coppola, Ruth Huizinga, Filip Eftimov, T. Huizinga, Anneke J. van der Kooi, Liesbeth E.M. Oosten, Joost Raaphorst, Theo Rispens, Rocco Sciarrillo, Maarten J. Titulaer, Luuk Wieske, René E. M. Toes, Maartje G. Huijbers, Karin A. van Schie, Diane van der Woude,
Tópico(s)Autoimmune Bullous Skin Diseases
ResumoThe presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies. The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies. Autoreactive antibodies are the common denominator in many autoimmune diseases. For each specific autoantibody, various isotypes and subclasses can be simultaneously present. The isotypes' and subclasses' constant domains shape most of the antibody effector functions. Thereby, the isotype/subclass profile can potentially influence disease pathophysiology. Five immunoglobulin isotypes are expressed by human B cells: IgM, IgD, IgG, IgA, and IgE. Furthermore, IgG and IgA are subdivided into additional subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.1Petar P. Dubois D. Rabin B.S. Shurin M.R. Chapter 12—Immunoglobulin titers and immunoglobulin subtypes.in: Lotze M.T. Thomson A.W. Measuring immunity. Academic Press, London2005: 158-171Crossref Scopus (0) Google Scholar IgG is the most abundant (∼80%; reference values, 7-15 g/L) of the antibodies present in the serum, followed by IgA (15%; 0.6-4 g/L), IgM (5%; 0.6-3 g/L), IgD (0.25%; 0-0.14 g/L), and IgE (detected in trace amounts, 3-423 kIU/L).2Zegers B.J.M. Stoop J.W. Reerink-Brongers E.E. Sander P.C. Aalberse R.C. Ballieux R.E. Serum immunoglobulins in healthy children and adults levels of the five classes, expressed in international units per millilitre.Clin Chim Acta. 1975; 65: 319-329Crossref PubMed Scopus (39) Google Scholar Secreted IgD has long been an enigmatic antibody with largely unknown functions. Although these have recently become more clear (reviewed elsewhere3Gutzeit C. Chen K. Cerutti A. The enigmatic function of IgD: some answers at last.Eur J Immunol. 2018; 48: 1101-1113Crossref PubMed Scopus (68) Google Scholar), the function of secreted IgD remains poorly understood. Therefore, this review will not focus on IgD. A B-cell response typically starts with the secretion of the pentameric IgM, after which a proportion of B cells undergoes isotype switching and starts producing IgG1-4, IgA1-2, or IgE. The type of switch is regulated by cytokines and costimulatory signals provided by T cells in the germinal center and depends on the location and nature of the antigen.4McHeyzer-Williams L.J. Pelletier N. Mark L. Fazilleau N. McHeyzer-Williams M.G. Follicular helper T cells as cognate regulators of B cell immunity.Curr Opin Immunol. 2009; 21: 266-273Crossref PubMed Scopus (159) Google Scholar Each isotype and subclass exerts a distinct effector function via its fragment crystallizable (Fc) domain, thereby shaping and tuning the immune response to enable efficient clearance of a wide variety of pathogens.5Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front Immunol. 2014; 5: 520Crossref PubMed Scopus (1437) Google Scholar The 2 main antibody effector functions are complement activation (summarized in Table E1 in this article's Online Repository at www.jacionline.org) and FcR binding through which immune cells are activated. An accumulating amount of evidence suggests that the classical and alternative complement pathways play an important role in the pathogenesis of many systemic autoimmune diseases6Chen M. Daha M.R. Kallenberg C.G.M. The complement system in systemic autoimmune disease.J Autoimmunity. 2010; 34: J276-J286Crossref PubMed Scopus (265) Google Scholar and complement inhibitors are being evaluated as potential therapeutic agents.7Thurman J.M. Yapa R. Complement therapeutics in autoimmune disease.Front Immunol. 2019; 10: 672Crossref PubMed Scopus (30) Google Scholar Various Fc receptors (FcRs) have been described for all classes of immunoglobulins: 5 FcγRs and neonatal FcR (FcRn) for IgG, 2 FcεRs for IgE, FcαR for IgA, FcδR for IgD, and FcμR for IgM.8Sun P. Chapter 7—Structural recognition of immunoglobulins by Fcg receptors.in: Ackerman M.E. Nimmerjahn F. Antibody Fc. Academic Press, Boston2014: 131-144Crossref Scopus (8) Google Scholar Engagement of FcRs can affect the antibody serum half-life and induce various proinflammatory, anti-inflammatory, and immune-modulatory effects, which depend on various parameters including the isotype/subclass profile of an antibody. The role of FcRs in autoinflammatory processes has recently been reviewed elsewhere.9Ben Mkaddem S. Benhamou M. Monteiro R.C. Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools.Front Immunol. 2019; 10: 811Crossref PubMed Scopus (124) Google Scholar Autoantibodies play a key role in the diagnostics of autoimmune diseases as highly specific disease biomarkers. A substantial amount of evidence also points to a major role for some autoantibodies in disease pathogenesis. Already in 1957, Witebsky et al's postulates10Witebsky E. Rose N.R. Terplan K. Paine J.R. Egan R.W. Chronic thyroiditis and autoimmunization.J Am Med Assoc. 1957; 164: 1439-1447Crossref PubMed Scopus (270) Google Scholar were formulated, describing which criteria autoantibodies would have to meet to play a causal role in autoimmune diseases. High sensitivity/specificity parameters together with clear pathogenic properties exhibited by some autoantibodies help improve stratification of autoimmune diseases. Although clinical characteristics play a major role in disease classification for most autoimmune conditions, it is debated whether a pathogenesis-driven approach (eg, based on autoantibody presence) could be more insightful.11Suzuki S. Utsugisawa K. Nagane Y. Satoh T. Terayama Y. Suzuki N. et al.Classification of myasthenia gravis based on autoantibody status.Arch Neurol. 2007; 64: 1121Crossref PubMed Scopus (39) Google Scholar,12Lyons P.A. Rayner T.F. Trivedi S. Holle J.U. Watts R.A. Jayne D.R.W. et al.Genetically distinct subsets within ANCA-associated vasculitis.N Engl J Med. 2012; 367: 214-223Crossref PubMed Scopus (712) Google Scholar Particular isotypes/subclasses may play a specific pathophysiological role and determine a phenotype that may require a different treatment strategy. For example, patients with chronic inflammatory demyelinating polyneuropathy with IgG4-predominant autoantibody responses are poorly responsive to intravenous immunoglobulin but may benefit from rituximab.13Iijima M. Treatment of chronic inflammatory demyelinating polyradiculoneuropathy patients with antibodies against paranodal proteins.Clin Exp Neuroimmunol. 2020; 11: 94-100Crossref Scopus (2) Google Scholar In the last decades, a vast body of literature on autoantibodies has been published. Several publications have aimed to summarize the existing data with a specific focus on a disease group or a specific isotype/subclass14Outschoorn I. Rowley M.J. Cook A.D. Mackay I.R. Subclasses of immunoglobulins and autoantibodies in autoimmune diseases.Clin Immunol Immunopathol. 1993; 66: 59-66Crossref PubMed Scopus (25) Google Scholar, 15Huijbers M.G. Plomp J.J. Van Der Maarel S.M. Verschuuren J.J. IgG4-mediated autoimmune diseases: a niche of antibody-mediated disorders.Ann N Y Acad Sci. 2018; 1413: 92-103Crossref PubMed Scopus (42) Google Scholar, 16Koneczny I. Update on IgG4-mediated autoimmune diseases: new insights and new family members.Autoimmun Rev. 2020; 19102646Crossref Scopus (34) Google Scholar; however, a broad overview summarizing the existing data on the presence and role of autoantibody isotypes and subclasses across different diseases is lacking. We hypothesize that knowing the isotype/subclass profiles of various autoantibodies may yield valuable insights regarding the pathophysiology and potential interrelatedness of different autoimmune disorders usually scattered across the medical and academic areas. Grouping diseases by dominance or absence of particular isotypes/subclasses could help identify common effector mechanisms that drive the disease pathogenesis and thus could be used for targeted therapy. Examples of this could be complement components, specific FcRs or cytokines known to stimulate production of specific isotypes/subclasses.5Vidarsson G. Dekkers G. Rispens T. IgG subclasses and allotypes: from structure to effector functions.Front Immunol. 2014; 5: 520Crossref PubMed Scopus (1437) Google Scholar,17Kawano Y. Noma T. Kou K. Yoshizawa I. Yata J. Regulation of human IgG subclass production by cytokines: human IgG subclass production enhanced differentially by interleukin-6.Immunology. 1995; 84: 278-284PubMed Google Scholar Isotype/subclass profile can also be pathophysiologically linked with the breach of tolerance and the antigen(s) playing a role in this process4McHeyzer-Williams L.J. Pelletier N. Mark L. Fazilleau N. McHeyzer-Williams M.G. Follicular helper T cells as cognate regulators of B cell immunity.Curr Opin Immunol. 2009; 21: 266-273Crossref PubMed Scopus (159) Google Scholar; thus, investigation of autoantibody isotype/subclass profiles may also help understand the mechanisms of autoimmunity induction and thus make a step toward prevention of autoimmunity. Moreover, a broad overview of this topic may identify knowledge gaps, which can simply direct future research and allow more detailed stratification of patients based on their isotype/subclass profiles. Therefore, we here give a comprehensive survey of the literature, covering a large variety of autoimmune diseases and autoantibodies with a specific focus on the autoantibodies that have been shown to play a direct pathogenic role. To focus this review on autoantibodies that are clinically relevant, possibly important for disease pathogenesis, and relatively well investigated, we used 5 criteria: (1) the targeted antigen should be defined on a molecular level (eg, a specific protein); (2) a prevalence of the autoantibody in more than 10% of a specific patient group for mutually exclusive antibodies (ie, autoantibodies exclusively found in patients with a specific phenotype, such as antimyeloperoxidase and anti–proteinase 3 antibodies, hardly ever present in the same ANCA-associated vasculitis patients) and more than 50% for concomitantly present antibodies (eg, in systemic lupus erythematosus, where various autoantibodies can be detected in the same patient18Sui M. Lin Q. Xu Z. Han X. Xie R. Jia X. et al.Simultaneous positivity for anti-DNA, anti-nucleosome and anti-histone antibodies is a marker for more severe lupus nephritis.J Clin Immunol. 2013; 33: 378-387Crossref PubMed Scopus (42) Google Scholar), not specific for a particular ethnicity or geographical region, based on published prevalence studies; (3) a relative consensus in the field regarding autoantibody pathogenicity (reproducible and repeatedly published evidence shown in animal models, in vitro assays, and/or newborns from seropositive mothers, supported by the opinion of a respective disease expert from Target2B); (4) presence of published isotype-specific data; and (5) lack of a direct causal association with a different preceding disease or use of a pharmaceutical agent for most patients with the autoantibody response. When fulfilling all of these inclusion criteria, autoantibodies were included in Fig 1 and Tables I and II. Nonincluded autoantibodies/diseases are summarized in Table E2 in this article's Online Repository at www.jacionline.org.Fig 1Prevalence of autoantibodies isotypes and subclasses in different diseases. Percentage of patients with a particular autoantibody isotype/subclass present in serum is shown, unless indicated otherwise. BP, bullous pemphigoid antigen; PLA2R, phospholipase A2 receptor; PR3, proteinase 3; MPO, myeloperoxidase; SSA/SSB, Sjögren syndrome antigen A/B; AChR, acetylcholine receptor; GD1b, ganglioside; GD1bGM1, ganglioside GM1; AQP4, aquaporin 4; MOG, myelin oligodendrocyte glycoprotein; NMDAR, N-methyl D-aspartate receptor; LGI1, leucine-rich glioma inactivated 1; β2GPI, beta 2 glycoprotein I; ADAMTS13, ADAM metallopeptidase with thrombospondin type 1 motif 13; GP, glycoprotein; TSAb, thyrotropin receptor stimulating antibody; CSF, cerebrospinal fluid; EGPA, eosinophilic granulomatosis with polyangiitis; FS, Fogo Selvagem; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; NMDAR, N-methyl d-aspartate receptor; PA, platelet-associated. The reference list for the figure is separate and it can be found in this article's Online Repository at www.jacionline.org. ∗Diagnosis of anti-NMDAR encephalitis is based on presence of IgG antibodies in CSF; anti-NMDAR IgA and IgM levels were measured in patients with anti-NMDAR IgG positivity in CSF. †These patient subsets are defined by the presence of this antibody.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table IClinically relevant effects of various autoantibodiesDiseaseAutoantibodyCorrelation with disease activityPrediction of relapseAssociation with a clinical phenotypePresence in healthy controlsOther effectsPresentAbsentPresentAbsentBlistering diseasesPemphigus vulgarisAnti-Dsg3IgGE151-E156;IgG4E1,E5,E157;IgEE5IgG, IgG1E157IgGE158——IgG 0%E159,E160IgG associates with HLA-DRB1*04:02 or DQB1*05:03E161Anti-Dsg1IgGE152-E156,E162——IgGE158IgG: cutaneous phenotypeE154,E162IgG ∼0%E159,E160;IgG1E163—Pemphigus foliaceusAnti-Dsg1IgGE153;IgG4E164—————Bullous pemphigoidAnti-BP180IgGE15,E18,E165-E167;IgG1, IgG4E166,E168,E169;IgEE17,E18,E20,E24IgEE170IgG1, IgG4 (high levels)E166; IgG (high titer)E171—IgG: erosions and blistersE24IgG 0%-4%E159,E172-E174;IgE 4%-7%E20,E22,E173,E175—Nephrological diseasesAnti-GBM diseaseAnti-α3 NC1IgGE25;IgG1, IgG3E26———IgG4: predominant lung involvementE176——Idiopathic membranous nephropathyAnti-PLA2RIgGE27,E29,E177;IgG4E30,E31,E178—IgGE179-E183——IgG 0%E184High IgG4 titer associates with low chance of spontaneous remissionE28Nephrological/rheumatological diseasesANCA-associated vasculitisAnti-PR3IgGE185-E187;IgA, sIgAE33IgGE188IgGE189-E201; IgG3E192IgGE188,E195,E202-E204;IgG1, IgG3, IgG4E204—IgG 3%E205IgG associates with stronger prediction of relapse in patients with specific clinical phenotypesE193,E206Anti-MPOIgE207;IgGE187,E208,E209IgGE185IgGE190,E193-E197,E208,E210IgGE195,E203,E204;IgG1, IgG3, IgG4E204IgM: pulmonary hemorrhageE39IgG ∼0%E205IgG associates with stronger prediction of relapse in patients with specific clinical phenotypesE193,E206Systemic lupus erythematosusAnti–ds-DNAIgGE46,E211-E213;IgEE47,E214—IgGE212,E215,E216;IgG1E216;IgE217—IgG: lupus nephritisE218IgG 0%-2%E43,E44,E219,0% (≥65 y/o)E220,E221;IgM 0%-3%E43,E44,E221,0%-2% (≥65 y/o)E220,E221;IgA 0%-3%E43,E44, 7% (≥65 y/o)E220—Rheumatological diseasesPrimary Sjögren syndromeAnti-SSA/RoAnti-SSB/LaIgGE53,E54IgGE53,E54——————IgG: extraglandular manifestationsE53,E222,E223IgG: extraglandular manifestationsE53,E226IgG 1%-3%E54,E219;Ig 0%-1%E224IgG 0%-3%E54,E219;Ig 0%-5%E224IgE associates with fetal lossE225—Neurological diseasesImmune-mediated necrotizing myopathyAnti-SRPIgGE59————IgG 0%E227IgG associates with HLA-DRB1*08:03E228, HLA-DRB1*14:0E229, poor response to steroid monotherapyE58,E230Myasthenia gravisAnti-AChRIgG1E60,E62IgGE60,E231;IgG2, IgG3, IgG4E62IgGE232——IgG 0%E61Ig associates with HLA-B8 and HLA-DR3 haplotypesE233MuSK-myasthenia gravisAnti-MuSKIgG4E60,E234————IgG: 0%-2%E61,E63IgG4: 0%E64,E235IgG4: HLA haplotype associationsE236-E238Multifocal motor neuropathyAnti-GM1IgME73———IgM: disability, axon lossE73IgM 0%-9%E72,E239,E240;—Guillain-Barré syndromeAnti-GM1IgG1E88;IgE81———IgG: motor phenotypeE79,E241,E242;IgG, IgM, IgA: axonal phenotypeE242;IgG1: slow recoveryE88,E89;IgG3: rapid recoveryE88IgG 0%-2%E72,E239,E240IgA with preceding diarrhea, anti–C jejuni antibodiesE92;IgG1 with preceding gastrointestinal infection, anti–C jejuni antibodiesE88,E89;IgG3 with preceding upper respiratory tract infectionE88Miller Fisher syndromeAnti-GQ1bIgGE93———IgG: (acute) ophthalmoplegiaE91,E243,E244 and ataxiaE91,E244IgM 0%E239,E240;IgG ∼0%E239,E240—Neuromyelitis optica spectrum disordersAnti-AQP4IgGE101,E104,E106IgGE100,E245,E246;IgG1, IgG2E100—IgGE245IgG at onset: optic neuritisE246IgG 0%E247—MOG antibody diseaseAnti-MOG——IgGE248; IgE249,E250; IgG1E251IgE252—IgG 0%E253IgG, IgG1 with preceding infection or vaccinationE251High IgG with bilateral optic neuritisE254Autoantibody-positive autoimmune encephalitisAnti-NMDARIgGE116,E255,E256IgAE111——IgAE111 and high IgG titersE256: tumors; high IgG titers: poor outcomeE256IgG 0%-1%E257-E259;IgM 0%-4%E257,E259;IgA 0%-4%E257,E259,E260IgG in CSF correlates better with disease activity than IgG in serumE256Anti-LGI1IgG1E120;IgG4 in CSFE119———IgG1 with cognitive impairment, IgG4 with FBDSE120Intrathecal synthesis of IgG with worse outcomeE119Ig 0%E257IgG levels are higher in serum than in CSFE261Hematological diseasesPrimary antiphospholipid syndromeAnti-β2GPIIgGE262-E266;IgAE267;IgME264———IgG: thrombosisE268,E269 and heart valve diseaseE270;IgA: thrombosisE268;IgG, IgA: livedo reticularisE270IgG 0%-2%E224,E271;IgA 0%E224;IgM 0%-1%E224—Idiopathic thrombotic thrombocytopenic purpuraAnti–ADAMTS13IgG1, IgG3, IgAE272IgG, IgA, IgME129;IgG, IgM, IgG2, IgG4E272IgGE272;IgG4E127IgGE129,E273;IgM, IgAE129—IgG 4%-5%E136,E274IgG associates with mortalityE275, need for plasmapheresisE272Idiopathic immune thrombocytopenic purpuraAnti–GP IIb/IIIa—PA IgGE276PA IgGE277PA IgGE276—PA IgG 0%E139,E141,E278Double-positive for PA IgG anti–GP IIb/IIIa and anti–GP Ib/IX associates with severe bleeding manifestations and poor response to therapyE276; amount of targeted GPs associates with severityE279Anti–GP Ib/IX—PA IgGE276PA IgGE277PA IgGE276PA IgG: severe bleeding manifestationsE280 and poor response to treatmentE280,E281PA IgG 0%E278Endocrinological diseasesGraves' diseaseTSAbIgGE149,E282,E283IgGE284IgGE285,E286IgGE287IgG: Graves' ophthalmopathyE283,E284,E288,E289IgG 0%E149,E290—The reference list for the table is separate, and it can be found in this article's Online Repository at www.jacionline.org.AChr, Acetylcholine receptor; ADAMTS13, ADAM metallopeptidase with thrombospondin type 1 motif 13; ANCA, antineutrophil cytoplasmic antibody; AQP4, aquaporin 4; BP, bullous pemphigoid antigen; β2GPI, beta 2 glycoprotein I; CSF, cerebrospinal fluid; ds-DNA, double-stranded DNA; FBDS, faciobrachial dystonic seizures; GBM, glomerular basement membrane; GM1, ganglioside GM1; GP, glycoprotein; GQ1b, ganglioside GQ1b; Ig, immunoglobulin; PA, platelet-associated; LGI1, leucine-rich glioma inactivated 1; MOG, myelin oligodendrocyte glycoprotein; MPO, myeloperoxidase; NC1, NC1 domain of collagen 4 network; NMDAR, N-methyl d-aspartate receptor; PA, platelet-associated; PLA2R, phospholipase A2 receptor; PR3, proteinase 3; sIgA, secretory IgA; SRP, signal recognition particle; TSAb, thyrotropin receptor stimulating antibody. Open table in a new tab Table IIPathogenic features of antibodiesDiseaseAutoantibodyEvidence of pathogenicity in animal modelsPathogenic in vitro effectPathogenicity in newbornsPresentAbsentPresentAbsentPresentAbsentBlistering diseasesPemphigus vulgarisAnti-Dsg3Passive: IgGE91,IgG1E292,E293, IgG4E293Passive: IgG1E292IgGE291,E294-E298;IgG1E292,E293;IgG4E293IgGE291IgGE299,E300—Anti-Dsg1Passive: IgGE291—IgGE291,E301IgGE291,E301——Pemphigus foliaceusAnti-Dsg1Passive: IgGE302,E303—IgGE295,E303-E305;IgG1E306IgGE303IgGE299,E307,E308FS: IgGE309BullouspemphigoidAnti-BP180Passive: IgGE310—IgG1, IgG4E311—IgGE299—Nephrological diseasesAnti-GBM diseaseAnti-α3 NC1Active: IgE312,E313;Passive: IgE314; rabbit IgGE315—IgGE316——IgGE317Idiopathic membranous nephropathyAnti-PLA2RPassive: IgGE318—IgE319;IgG4E320——IgGE321;IgG4E322Nephrological/rheumatological diseasesANCA-associated vasculitisAnti-PR3Active: IgE323;Passive: IgGE324—IgG1, IgG3, IgG4E325,E326IgGE326—IgGE327,E328Anti-MPOActive: IgE329-E333; Passive: IgGE334—IgGE335IgGE326IgGE327IgGE327Systemic lupus erythematosusAnti–ds-DNAActive: IgE336-E338;Passive: IgGE339-E342—IgGE342-E346;IgEE214———Rheumatological diseasesPrimary Sjögren syndromeAnti-SSA/RoPassive: IgGE347—IgGE348,E349—IgGE350—Anti-SSB/LaPassive: IgGE347—IgGE348,E349—IgGE350—Neurological diseasesImmune-mediated necrotizing myopathyAnti-SRPActive: IgE351;Passive: IgGE351,E352—IgG, FabE353;IgGE352———Myasthenia gravisAnti-AChRActive: IgE354,E355; Passive: IgGE356,E357, rat IgGE358,E359Passive: IgG4E360;Protective effect: IgG4E361IgG, IgG1E357—IgGE362-E364IgGE365,E366MuSK-myasthenia gravisAnti-MuSKPassive: IgG4E66,E367,E368Active: IgG4E66,E367,E369IgG1,IgG2,IgG3E369IgG4E367IgGE368—IgGE370,E371—Multifocal motor neuropathyAnti-GM1Passive: SerumE372-E374Passive: IgME375IgE374;IgME376-E378—IgGE379—Guillain-Barré syndromeAnti-GM1Active: IgE380-E383;Passive: IgGE384Passive: IgGE375IgE377; Mouse: IgG2bE385Mouse: IgG2bE377——Miller Fisher syndromeAnti-GQ1bPassive: mouse IgME386—IgE387-E389; IgGE389-E394; IgG1 + IgG2E389; IgG3E389;Mouse: IgME388,E395;IgG2bE396IgME390——Neuromyelitis optica spectrum disordersAnti-AQP4Passive: IgE397,IgG1E398Passive: IgE397IgG1E96; IgGE399,E400IgG, F(ab')2E401;——IgGE402MOG antibody diseaseAnti-MOGActiveE403,E404Passive: IgGE405-E408—IgGE405,E408———Autoantibody-positive autoimmune encephalitisAnti-NMDARActive: IgE409-E411;Passive:IgGE412-E418, IgE419Active: IgE409IgE373;IgGE259,E419-E421;IgAE260IgA, IgME259IgGE422-E424—Anti-LGI1Natural development: feline IgE425;Passive: IgGE426,IgG4E261—IgG1E120;IgG4E120,E261;IgGE261,E426,E427;Fab'E261——Hematological diseasesPrimary antiphospholipid syndromeAnti-β2GPIActive: IgE428-E430;Passive: IgGE347,E431,E432,Fab'E433—IgGE434-E437;IgME435—IgGE438-E440—Idiopathic thrombotic thrombocytopenic purpuraAnti-ADAMTS13Passive: IgGE441,E442—IgGE443,E444——IgGE445Idiopathic immune thrombocytopenic purpuraAnti–GP IIb/IIIaActive: IgE446;Passive: IgGE447-E449—IgGE450,E451;IgME452—IgGE453—Anti–GP Ib/IXActive: IgE446;Passive: IgGE447,E448—IgGE450-E452,E454,E455———Endocrinological diseasesGraves diseaseTSAbActive: IgE456-E458;Passive: IgGE459, mouse IgGE460—IgGE461; IgG1E462; Mouse IgG, Fab'E458,E460—IgGE463—The reference list for the table is separate, and it can be found in this article's Online Repository at www.jacionline.org.AChr, Acetylcholine receptor; ADAMTS13, ADAM metallopeptidase with thrombospondin type 1 motif 13; ANCA, antineutrophil cytoplasmic antibody; AQP4, aquaporin 4; BP, bullous pemphigoid antigen; β2GPI, beta 2 glycoprotein I; ds-DNA, double-stranded DNA; FS, Fogo Selvagem; GBM, glomerular basement membrane; GM1, ganglioside GM1; GQ1b, ganglioside GQ1b; Ig, immunoglobulin; LGI1, leucine-rich glioma inactivated 1; MOG, myelin oligodendrocyte glycoprotein; MPO, myeloperoxidase; NC1, NC1 domain of collagen 4 network; NMDAR, N-methyl d-aspartate receptor; PLA2R, phospholipase A2 receptor; PR3, proteinase 3; SRP, signal recognition particle; TSAb, thyrotropin receptor stimulating antibody. Open table in a new tab The reference list for the table is separate, and it can be found in this article's Online Repository at www.jacionline.org. AChr, Acetylcholine receptor; ADAMTS13, ADAM metallopeptidase with thrombospondin type 1 motif 13; ANCA, antineutrophil cytoplasmic antibody; AQP4, aquaporin 4; BP, bullous pemphigoid antigen; β2GPI, beta 2 glycoprotein I; CSF, cerebrospinal fluid; ds-DNA, double-stranded DNA; FBDS, faciobrachial dystonic seizures; GBM, glomerular basement membrane; GM1, ganglioside GM1; GP, glycoprotein; GQ1b, ganglioside GQ1b; Ig, immunoglobulin; PA, platelet-associated; LGI1, leucine-rich glioma inactivated 1; MOG, myelin oligodendrocyte glycoprotein; MPO, myeloperoxidase; NC1, NC1 domain of collagen 4 network; NMDAR, N-methyl d-aspartate receptor; PA, platelet-associated; PLA2R, phospholipase A2 receptor; PR3, proteinase 3; sIgA, secretory IgA; SRP, signal recognition particle; TSAb, thyrotropin receptor stimulating antibody. The reference list for the table is separate, and it can be found in this article's Online Repository at www.jacionline.org. AChr, Acetylcholine receptor; ADAMTS13, ADAM metallopeptidase with thrombospondin type 1 motif 13; ANCA, antineutrophil cytoplasmic antibody; AQP4, aquaporin 4; BP, bullous pemphigoid antigen; β2GPI, beta 2 glycoprotein I; ds-DNA, double-stranded DNA; FS, Fogo Selvagem; GBM, glomerular basement membrane; GM1, ganglioside GM1; GQ1b, ganglioside GQ1b; Ig, immunoglobulin; LGI1, leucine-rich glioma inactivated 1; MOG, myelin oligodendrocyte glycoprotein; MPO, myeloperoxidase; NC1, NC1 domain of collagen 4 network; NMDAR, N-methyl d-aspartate receptor; PLA2R, phospholipase A2 receptor; PR3, proteinase 3; SRP, signal recognition particle; TSAb, thyrotropin receptor stimulating antibody. Of the 5 existing isotypes, we reviewed IgM, IgG, IgA, and IgE but not IgD, because of the scarce amount of literature on its secreted form. Moreover, because the vast majority of the data investigating IgA did not distinguish between IgA1 and IgA2 subclasses, we only included studies on total IgA. The information on specific isotypes was presented in tables summarizing the existing data on 3 main aspects: (1) presence of specific autoantibody isotypes in patients, (2) relationship between autoantibody isotypes and various clinical parameters, and (3) signs of in vitro or in vivo pathogenicity. Articles were identified by a manual search of the literature listed in PubMed, Web of Science, and Google Scholar. Additional articles were found by reviewing reference lists of the already included articles. In view of the large number of disorders and autoantibodies checked for possible inclusion (27 disorders and more than 72 autoantibodies), the full methodology of systematic review was not used to make the project feasible to perform by a small team. The studies were selected on the basis of presence of data related to this review: assessment of positivity for specific isotypes/subclasses, correlation of antibody levels with clinical parameters, and evidence of in vitro or in vivo pathogenicity. Eligibility was determined by reviewing the title, the abstract, and then the data presented in the full article. Fig 1 and Table I include only those studies that assessed autoantibodies in at least 10 patients. Only those studies that distinguished seropositive and seronegative individuals were incorporated in Fig 1. In Fig 1 and Tables I and II, 26 autoantibodies occurring in 21 different diseases were included. Data on autoantibody isotype/subclass prevalence in the respective diseases are summarized in Fig 1. The percentage of positivity for each particular isotype/subclass was included: if more than 1 cohort or 1 study was used, the percentage range was given. Because of the scarcity of the data available for isotypes besides IgG, it was not possible to retrieve data regarding positivity for all isotypes of all antibodies. Data regarding IgM positivity were retrieved for 19 of 26 autoantibodies (73.1%), 17 of 24 (69.2%) for IgA, and only 5 of 24 (19.2%) for IgE. Dat
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