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Frontiers in Immunology 2019Autoantibodies to cytokines are increasingly being detected in association with immunodeficient, autoimmune and immune dysregulated states. Presence of these... (Review)
Review
Autoantibodies to cytokines are increasingly being detected in association with immunodeficient, autoimmune and immune dysregulated states. Presence of these autoantibodies in an otherwise healthy individual may result in a unique phenotype characterized by predisposition to infection with specific organisms. The ability to detect these autoantibodies is of importance as it may direct treatment toward a combination of anti-microbial agents and immunomodulatory therapies that decrease autoantibody levels, thereby releasing the immune system from autoantibody-mediated inhibition. Ligand binding assays such as ELISA or bead multiplex assays have been used to detect these antibodies. However, not all anti-cytokine autoantibodies have demonstrable function and therefore their clinical significance is unclear. Assays that evaluate the functionality of anti-cytokine autoantibodies can supplement such ligand binding assays and add valuable functional information that, when viewed in the context of the clinical phenotype, may guide the use of adjunctive immunomodulatory therapy. This mini review provides an overview of anti-cytokine autoantibodies identified to date and their clinical associations. It also describes the use of flow cytometry for the functional analysis of anti-IFNγ and anti-GM-CSF autoantibodies.
Topics: Autoantibodies; Cytokines; Flow Cytometry; Humans; Immunomodulation; Interferon-gamma
PubMed: 31354706
DOI: 10.3389/fimmu.2019.01517 -
Neuropharmacology Apr 2018The field of neuronal autoantibody associated diseases of the central nervous system has expanded dramatically in the last few years. The range of identified neuronal... (Review)
Review
The field of neuronal autoantibody associated diseases of the central nervous system has expanded dramatically in the last few years. The range of identified neuronal and glial antibody targets has led to the accurate classification of a number of syndromes which each associate with characteristic clinical features. These diseases are especially important due to their frequent response to immunotherapies. Antibodies against the N-methyl, d-aspartate receptor (NMDAR) and leucine-rich glioma inactivated 1 (LGI1) are the commonest autoantibodies known in patients with autoimmune forms of encephalitis. Patients with NMDAR-antibodies often present with psychiatric symptoms and a movement disorder, whereas patients with LGI1-antibodies have frequent seizures and prominent amnesia. In contrast, aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies are found in patients with inflammation of the spine and optic nerves. The antigenic-specificities appear to determine the associated clinical syndromes, hence the detection of these antibodies informs clinical practice and the biology of these diseases. Indeed, the mechanisms of antibody action are being intensively studied in vitro and in vivo. Overall, these studies confirm the pathogenic potential of the antibodies, and suggest antigen internalisation and complement fixation are the two dominant mechanisms of pathogenicity, and that their relative contributions vary between conditions. In addition to discussing the antigenic targets, the associated clinical features and mechanisms of antibodies, we review the current and future immunotherapy strategies which aim to optimise patient outcomes. This article is part of the Special Issue entitled 'Channelopathies.'
Topics: Animals; Autoantibodies; Autoimmune Diseases of the Nervous System; Central Nervous System Diseases; Channelopathies; Humans
PubMed: 28476644
DOI: 10.1016/j.neuropharm.2017.04.046 -
Blood Reviews Sep 2022Immunodeficiency syndromes represent a diverse group of inherited and acquired disorders, characterized by a spectrum of clinical manifestations, including recurrent... (Review)
Review
Immunodeficiency syndromes represent a diverse group of inherited and acquired disorders, characterized by a spectrum of clinical manifestations, including recurrent infections, autoimmunity, lymphoproliferation and malignancy. Autoantibodies against various self-antigens reflect the immune dysregulation underlying these disorders, and could contribute to certain clinical findings, such as susceptibility to opportunistic infections, cytopenia of different hematopoietic lineages, and organ-specific autoimmune diseases. The mechanism of autoantibody production in the context of immunodeficiency remains largely unknown but is likely shaped by both intrinsic genetic aberrations and extrinsic exposures to possible infectious agents. These autoantibodies if harbor neutralizing activities and reach certain levels in the circulation, could disrupt the biological functions of their targets, resulting in specific clinical manifestations. Herein, we reviewed the prevalence of autoantibodies against cytokines, hematopoietic cells and organ-specific antigens in immunodeficiency syndromes and examined their associations with certain clinical findings. Moreover, the potential mechanism of autoantibody production was also discussed. These may shed light on the development of mechanism-based therapies to reset the dysregulated immune system in immunodeficient patients.
Topics: Autoantibodies; Autoimmune Diseases; Autoimmunity; Cytokines; Humans; Syndrome
PubMed: 35428517
DOI: 10.1016/j.blre.2022.100948 -
Cellular & Molecular Immunology Feb 2021Autoimmune neurological disorders, including neuromyelitis optica spectrum disorder, anti-N-methyl-D-aspartate receptor encephalitis, anti-MOG antibody-associated... (Review)
Review
Autoimmune neurological disorders, including neuromyelitis optica spectrum disorder, anti-N-methyl-D-aspartate receptor encephalitis, anti-MOG antibody-associated disorders, and myasthenia gravis, are clearly defined by the presence of autoantibodies against neurological antigens. Although these autoantibodies have been heavily studied for their biological activities, given the heterogeneity of polyclonal patient samples, the characteristics of a single antibody cannot be definitively assigned. This review details the findings of polyclonal serum and CSF studies and then explores the advances made by single-cell technologies to the field of antibody-mediated neurological disorders. High-resolution single-cell methods have revealed abnormalities in the tolerance mechanisms of several disorders and provided further insight into the B cells responsible for autoantibody production. Ultimately, several factors, including epitope specificity and binding affinity, finely regulate the pathogenic potential of an autoantibody, and a deeper appreciation of these factors may progress the development of targeted immunotherapies for patients.
Topics: Animals; Autoantibodies; Autoimmune Diseases of the Nervous System; B-Lymphocytes; Humans; Single-Cell Analysis
PubMed: 32728203
DOI: 10.1038/s41423-020-0510-z -
Journal of Neuroinflammation Aug 2016Our knowledge of autoantibody-associated diseases of the central (CNS) and peripheral (PNS) nervous systems has expanded greatly over the recent years. A number of... (Review)
Review
BACKGROUND
Our knowledge of autoantibody-associated diseases of the central (CNS) and peripheral (PNS) nervous systems has expanded greatly over the recent years. A number of extracellular and intracellular autoantigens have been identified, and there is no doubt that this field will continue to expand as more autoantigens are discovered as a result of improved clinical awareness and methodological practice. In recent years, interest has shifted to uncover the target epitopes of these autoantibodies.
MAIN BODY
The purpose of this review is to discuss the mapping of the epitope targets of autoantibodies in CNS and PNS antibody-mediated disorders, such as N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), leucine-rich glioma-inactivated protein 1 (Lgi1), contactin-associated protein-like 2 (Caspr2), myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP4), 65 kDa glutamic acid decarboxylase (GAD65), acetylcholine receptor (AChR), muscle-specific kinase (MuSK), voltage-gated calcium channel (VGCC), neurofascin (NF), and contactin. We also address the methods used to analyze these epitopes, the relevance of their determination, and how this knowledge can inform studies on autoantibody pathogenicity. Furthermore, we discuss triggers of autoimmunity, such as molecular mimicry, ectopic antigen expression, epitope spreading, and potential mechanisms for the rising number of double autoantibody-positive patients.
CONCLUSIONS
Molecular insights into specificity and role of autoantibodies will likely improve diagnosis and treatment of CNS and PNS neuroimmune diseases.
Topics: Animals; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Epitope Mapping; Epitopes; Humans; Nervous System Autoimmune Disease, Experimental
PubMed: 27577085
DOI: 10.1186/s12974-016-0678-4 -
Neurobiology of Disease Jan 2021Over the past decades, the identification of autoimmune encephalitis in which patients express autoantibodies directed against neurotransmitter receptors has generated... (Review)
Review
Over the past decades, the identification of autoimmune encephalitis in which patients express autoantibodies directed against neurotransmitter receptors has generated great hope to shed new light on the molecular mechanisms underpinning neurological and psychiatric conditions. Among these autoimmune encephalitides, the discovery of autoantibodies directed against the glutamatergic NMDA receptor (NMDAR-Ab), in the anti-NMDAR encephalitis, has provided some key information on how complex neuropsychiatric symptoms can be caused by a deficit in NMDAR signalling. Yet, NMDAR-Abs have also been detected in several neurological and psychiatric conditions, as well as in healthy individuals. In addition, these various NMDAR-Abs appear to have different molecular properties and pathogenicities onto receptors and synaptic functions. Here, we discuss the current view on the variety of NMDAR-Abs and, in particular, how these autoantibodies can lead to receptor dysfunction in neuronal networks. Since our mechanistic understanding on patients' NMDAR-Abs is still in its infancy, several complementary processes can be proposed and further in-depth molecular and cellular investigations will surely reveal key insights. Autoantibodies represent a great opportunity to gain knowledge on the etiology of neuropsychiatric disorders and pave the way for innovative therapeutic strategies. ONE SENTENCE SUMMARY: Current view on patients' autoantibody against NMDAR.
Topics: Animals; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Autoantigens; Autoimmunity; Humans
PubMed: 33166697
DOI: 10.1016/j.nbd.2020.105161 -
Clinical Reviews in Allergy & Immunology Oct 2022Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by diverse serological autoantibodies. Anti-dsDNA antibodies are involved in multiple... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by diverse serological autoantibodies. Anti-dsDNA antibodies are involved in multiple organ damage, especially the kidney, skin, and central nervous system. Anti-dsDNA antibodies play a pivotal role in SLE, and researchers have developed therapeutic strategies targeting these antibodies. Approaches to reduce anti-dsDNA antibodies via B cell targeted biologics against B cell surface antigens, B cell survival factors, or Bruton's tyrosine kinase have effectively eliminated B cells. However, their non-specific depletion hampers normal immune system functioning and limits the therapeutic benefits. Thus, scientists have attempted anti-dsDNA antibodies or lupus-specific strategies, such as the immature dendritic cell vaccine and immunoadsorption. Recently, synthetic mimic peptides (hCDR1, pCONs, DWEYS, FISLE-412, and ALW) that directly block anti-dsDNA autoantibodies have attracted attention, which could ameliorate lupus, decrease the serological autoantibody titer, reduce the deposition of renal autoantibodies, and improve pathological performance. These potent small peptide molecules are well tolerated, non-toxic, and non-immunogenic, which have demonstrated a benign safety profile and are expected to be hopeful candidates for SLE management. In this review, we clarify the role of anti-dsDNA antibodies in SLE, mainly focus on the current strategies targeting anti-dsDNA antibodies, and discuss their potential clinical value.
Topics: Antibodies, Antinuclear; Autoantibodies; B-Lymphocytes; Humans; Lupus Erythematosus, Systemic; Peptides
PubMed: 34542806
DOI: 10.1007/s12016-021-08898-7 -
Diabetes Care Oct 2022To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children.
OBJECTIVE
To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children.
RESEARCH DESIGN AND METHODS
Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3-12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models.
RESULTS
Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes.
CONCLUSIONS
Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes.
Topics: Autoantibodies; Autoimmunity; Diabetes Mellitus, Type 1; Disease Progression; Female; Finland; Genetic Predisposition to Disease; Genotype; HLA-DR4 Antigen; Humans; Infant, Newborn; Insulin; Islets of Langerhans; Male; Protein Tyrosine Phosphatase, Non-Receptor Type 22
PubMed: 36150053
DOI: 10.2337/dc21-2612 -
Diabetes Care Apr 2020Most individuals with two or more islet autoantibodies progress to clinical type 1 diabetes. However, in some individuals, autoantibodies are subsequently lost. Here,...
OBJECTIVE
Most individuals with two or more islet autoantibodies progress to clinical type 1 diabetes. However, in some individuals, autoantibodies are subsequently lost. Here, our objectives were to determine the frequency of autoantibody loss (reversion) in multiple-autoantibody-positive individuals and to determine the association between reversion and progression to clinical disease.
RESEARCH DESIGN AND METHODS
We analyzed multiple-autoantibody-positive individuals participating in TrialNet's Pathway to Prevention Study for reversion and determined the effect of reversion on progression to clinical disease using a Cox regression analysis.
RESULTS
Of 3,284 multiple-autoantibody-positive subjects, reversion occurred in 134 (4.1%) and was associated with reduced incidence of clinical disease. Reversion occurred more frequently with older age, lower autoantibody titers, and fewer positive autoantibodies.
CONCLUSIONS
Although reversion of multiple-autoantibody positivity is rare, when it occurs, the risk of progressing to clinical disease is reduced. This suggests unknown mechanisms promoting immune remission in some individuals.
Topics: Adolescent; Adult; Autoantibodies; Child; Child, Preschool; Diabetes Mellitus, Type 1; Disease Progression; Female; Humans; Incidence; Infant; Infant, Newborn; Islets of Langerhans; Male; Middle Aged; Remission, Spontaneous; Young Adult
PubMed: 32019856
DOI: 10.2337/dc19-1731 -
PloS One 2022Sarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing....
BACKGROUND
Sarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing. Utilizing samples from the Genomic Research in Alpha-1 anti-trypsin Deficiency and Sarcoidosis (GRADS) study, we examined the prevalence of autoantibodies in sarcoidosis patients with pulmonary-only and extra-pulmonary organ involvement compared to normal controls.
STUDY DESIGN AND METHODS
We analyzed serum samples from sarcoidosis patients who participated in the GRADS study utilizing an autoantigen microarray platform for both IgM and IgG antibodies. The cohort included sarcoidosis patients with pulmonary-only disease (POS, n = 106), sarcoidosis patients with extra-pulmonary disease (EPS, n = 120) and a normal control cohort (NC, n = 101). Organ involvement was assessed following a standardized format across all GRADS participating centers.
RESULTS
Sarcoidosis patients overall had increased levels of IgM and IgG autoantibodies compared to normal controls. In addition, several autoantibodies were elevated in the POS and EPS cohorts compared to the NC cohort. Differences in autoantibody levels were also noted between the POS and the EPS cohorts. When comparing organ involvement with sarcoidosis, bone, spleen and ear, nose and throat involvement had higher IgM expression than other organs.
CONCLUSION
Sarcoidosis patients have elevated IgM and IgG autoantibody levels compared to normal controls. In addition, individuals with pulmonary as well as additional organ involvement had higher IgM expression. Further research is needed focusing on specific organ-autoantibody pairs and role of autoantibodies in disease pathogenesis.
Topics: Humans; Autoantibodies; Sarcoidosis; Immunoglobulin G; Autoantigens; Lung Diseases; Immunoglobulin M
PubMed: 36264970
DOI: 10.1371/journal.pone.0274381