Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

Suurmond, Jolien; Diamond, Betty

doi:10.1172/jci78084

Cited by 261 publications

(241 citation statements)

References 113 publications

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“…This in turn results in further downstream activation of signaling pathways and production of proinflammatory cytokines (15,40). In fact, multiple autoimmune disorders are characterized by elevated levels of circulating proinflammatory cytokines and autoantibodies (41)(42)(43). To date, numerous studies and clinical trials have focused on addressing circulating self-RNA and DNA, TLR activation, proinflammatory cytokines and circulating autoantibodies (16).…”

Section: Discussionmentioning

confidence: 99%

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

Holl

Shumansky

Borst

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal’s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

Holl

Shumansky

Borst

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to the prenatal, maternal autoantibodies previously discussed, numerous studies have reported the presence of circulating anti-brain immunoglobulins in patients with ASD, as well as related conditions such as multiple sclerosis (Ryberg, 1982), schizophrenia (Henneberg et al, 1994), and systemic lupus erythematosus (SLE) (Libbey and Fujinami, 2010;Mackay et al, 2015;Suurmond and Diamond, 2015). Singer et al (2006) found that children with autism were more likely than their non-autistic siblings or controls to have serum that tested positive via western blot to fresh human brain samples (caudate, putamen, and prefrontal cortex).…”

Section: Anti-brain Antibodies In Children With Asdmentioning

confidence: 99%

The Role of the Immune System in Autism Spectrum Disorder

Meltzer

Water

2016

Neuropsychopharmacol

387

293

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Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.

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“…George Tsokos and colleagues analyze the central role of T cells in orchestrating autoimmune responses and the characteristics of these cells in a prototypical systemic autoimmune disease (11), while Betty Diamond and Jolien Suurmond address the importance of the mechanisms that drive autoantibody pathogenicity and the mechanisms by which autoantibody production is initiated (12). Autoantibodies appear long before clinical symptoms of autoimmunity, thus representing a marker for potential disease development (13).…”

Section: The Autoimmunity Puzzlementioning

confidence: 99%

Putting together the autoimmunity puzzle

Cava¹

2015

J. Clin. Invest.

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R e v i e w S e R i e S : A u t o i m m u n i t y2highlighting the evidence for a key role of these suppressor cells in the prevention and suppression of autoimmunity, these authors review the experimental support for the existence of functionally and phenotypically distinct suppressor cell subsets and their complementary role in regulating immune responses. By including considerations of Treg stability under changing environments and the recent immunotherapeutic approaches for the restoration of peripheral immune tolerance, these authors ponder the current challenges in achieving remission of autoimmunity without continuous immune suppression (i.e., by maintaining uncompromised overall immune responses). The restoration of immune homeostasis might be accomplished by enhancing suppressive immune responses, to limit the damage caused by T cells or B cells (or by the cytokines that they produce). George Tsokos and colleagues analyze the central role of T cells in orchestrating autoimmune responses and the characteristics of these cells in a prototypical systemic autoimmune disease (11), while Betty Diamond and Jolien Suurmond address the importance of the mechanisms that drive autoantibody pathogenicity and the mechanisms by which autoantibody production is initiated (12). Autoantibodies appear long before clinical symptoms of autoimmunity, thus representing a marker for potential disease development (13). Their predictive value is also reflected by the finding that there is an approximately six-to eight-fold increase in the risk of developing an autoimmune disease when only one autoantibody is present compared with three autoantibodies present (14).Autoantibodies develop because of inefficient removal of autoreactive B cells, which in healthy individuals are eliminated both at central and peripheral levels. In untreated patients with active autoimmune disease, both central and peripheral B cell tolerance checkpoints can be defective (15). Fritz Melchers describes three checkpoints of central tolerance for B cells in the bone marrow and discusses the importance of the microenvironment in the effective removal of the vast majority of B cell clones that express polyreactive antibodies (16). He then discusses the mechanisms of peripheral B cell tolerance, namely checkpoint 4, which removes peripheral autoreactive new emigrant B cells before they enter the mature naive B cell pool (17), and checkpoint 5, which eliminates accidental products of hypermutation that are created during antibody affinity maturation (18). ConclusionsIn summary, this Review series surveys the complex mechanisms of autoimmunity and the potential new therapies that might target critical disease pathways, cells, and molecules. Much has been learned about the pathogenesis of autoimmune disease since the original formulation of the concept of horror autotoxicus that was forged by Paul Ehrlich during his study of the development of hemolytic antibodies in animals injected with blood of unrelated species (19)(20)(21)(22)(23)(24). The failure to deve...

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Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

Cited by 261 publications

References 113 publications

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

The Role of the Immune System in Autism Spectrum Disorder

Putting together the autoimmunity puzzle

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