Naturally occurring auto-antibodies in homeostasis and disease

Lutz, Hans; Binder, Christoph J.; Kaveri, Srini V.

doi:10.1016/j.it.2008.10.002

Cited by 166 publications

(177 citation statements)

References 79 publications

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“…S2 A and B). These antibody titers are also consistent with peptide array-based measurements of IgGs reactive to A␤ and myelin proteins in patients with multiple sclerosis (31) and support the concept of a circulating pool of self-reactive IgG antibodies in the general population (32,33 Relative antibody reactivity (DFU) or the average reactivities against A␤1-40 and A␤1-42 ( Fig. 1J).…”

Section: Plasma A␤ Igg Antibodies Are Abundant and Directed Preferentsupporting

confidence: 79%

“…Without getting too much into the complexity of natural autoantibodies (32,33) there are 2 main possibilities: the specific antigen triggers the expansion of antibodies, or crossreactive epitopes, endogenous or foreign, provide the antigenic stimulus. In favor of the first possibility, no A␤-specific antibodies could be detected in wild-type mice (22,38), but they are present in human mutant amyloid precursor protein (APP) transgenic mice where A␤ antibody titers correlated inversely with plaque pathology (41).…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Britschgi¹,

Olin²,

Johns³

et al. 2009

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

168

163

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A number of distinct ␤-amyloid (A␤) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A␤-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A␤ and amyloidogenic non-A␤ species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A␤ and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A␤1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A␤, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A␤ toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A␤ the monkeys developed high titers not only against A␤ peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A␤ antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. A lzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 5.3 million individuals in the United States alone. Deposits of ␤-amyloid peptide (A␤) in extracellular plaques characterize the AD brain, but soluble oligomeric A␤ species appear to be more neurotoxic than plaques and interfere with synaptic function (reviewed in ref. 1). Notably, most A␤ peptides isolated from AD brains are posttranslationally modified and truncated (2-6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A␤ assemblies, interfere with proteolytic degradation, and increase A␤ toxicity in vitro (7,8,10).One line of defense against toxic A␤ species could be neutralizing antibodies. Stimulating the production of A␤ antibodies by active immunization with synthetic A␤ (11) or administering monoclonal A␤ antibodies (12, 13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14). In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A␤ antibodies correlated with attenuated cognitive decline (16). It has also been suggested that antibodies recognizing different domains (12,13,17) or conformations (18, 19) of A␤ may have different efficacy in humans.Interestingly, antibodies agai...

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Section: Plasma A␤ Igg Antibodies Are Abundant and Directed Preferentsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Britschgi¹,

Olin²,

Johns³

et al. 2009

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

168

163

View full text Add to dashboard Cite

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“…Germ-line-type IgMs, also termed "natural antibodies," are part of the innate immune system and are the most evolutionarily conserved antibody isotype (16)(17)(18). As the earliest isotype to be expressed during immune development, IgMs are thought to have been selected during the evolution of immunity for their contribution to critical immunoregulatory and housekeeping functions, which include clearance of apoptotic cells to prevent inflammation and autoimmunity (19,20). Intriguingly,…”

mentioning

confidence: 99%

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Frescas

Roux

Aygun‐Sunar

et al. 2017

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

113

103

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Studying the phenomenon of cellular senescence has been hindered by the lack of senescence-specific markers. As such, detection of proteins informally associated with senescence accompanies the use of senescence-associated β-galactosidase as a collection of semiselective markers to monitor the presence of senescent cells. To identify novel biomarkers of senescence, we immunized BALB/c mice with senescent mouse lung fibroblasts and screened for antibodies that recognized senescence-associated cell-surface antigens by FACS analysis and a newly developed cell-based ELISA. The majority of antibodies that we isolated, cloned, and sequenced belonged to the IgM isotype of the innate immune system. In-depth characterization of one of these monoclonal, polyreactive natural antibodies, the IgM clone 9H4, revealed its ability to recognize the intermediate filament vimentin. By using 9H4, we observed that senescent primary human fibroblasts express vimentin on their cell surface, and MS analysis revealed a posttranslational modification on cysteine 328 (C328) by the oxidative adduct malondialdehyde (MDA). Moreover, elevated levels of secreted MDA-modified vimentin were detected in the plasma of aged senescence-accelerated mouse prone 8 mice, which are known to have deregulated reactive oxygen species metabolism and accelerated aging. Based on these findings, we hypothesize that humoral innate immunity may recognize senescent cells by the presence of membrane-bound MDA-vimentin, presumably as part of a senescence eradication mechanism that may become impaired with age and result in senescent cell accumulation.aging | oxidative posttranslational modifications | biomarker | SAMP8 | malondialdehyde

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“…Natural antibodies are responsible for direct neutralization of pathogens, complement-mediated lysis and prevention of bacterial and viral spreading , and are mostly directed against non-self-antigens (Lutz et al 2009). Natural antibodies can also be present after (immune) stress of the host and be directed against self-antigens .…”

Section: Natural Antibodiesmentioning

confidence: 99%

“…Therefore, additional biomarkers are needed to improve the prediction of the overall health and longevity of a cow. Since antibodies are highly related to disease resistance both with respect to infections and metabolic disorders Lutz and Miescher 2008;Lutz et al, 2009) and consequently to longevity, antibody levels and antibody isotypes could be good measurable traits to predict the longevity potential of a cow. Antibodies were suggested as an indicator for the metabolic state of a cow which is very important in maintaining a healthy energy balance.…”

Section: Introductionmentioning

confidence: 99%

Antibodies and longevity of dairy cattle : genetic analysis

Klerk¹

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De . Antibodies and longevity of dairy cattle: genetic analysis. PhD thesis, Wageningen University, the Netherlands In dairy cattle longevity is an important trait. Longevity is strongly related to disease resistance, since a more healthy cow is expected to realize a longer productive life (longevity). Information on longevity records, however, can only be measured after an animal has been culled. Therefore, predictors of longevity traits are needed in order to breed for improved longevity. This thesis aimed to gain more knowledge and genetic background on (natural) antibodies as predictors for longevity. Both natural antibody-and specific antibody levels were studied. Antibody binding the naive antigen KLH was assumed to be natural antibody. Antibodies binding bacteria-derived antigens LTA, LPS and PGN were assumed to be specific antibodies. It was shown that natural antibody levels measured in milk and blood are genetically high correlated (± 0.80) for the two studied isotypes (IgG and IgM). On the other hand, phenotypically, natural antibodies (from both IgG and IgM isotype) measured in milk cannot be interpreted as the same trait (phenotypic correlation = ± 0.40). Antibodies (both natural-and specific antibodies) showed a negative relation with longevity: first lactation cows with low IgM or IgG levels were found to have a longer productive life. When using estimated breeding values for longevity, only a significant relation was found between natural antibody level (IgM binding KLH) and longevity. Lastly, this thesis reports on a genome-wideassociation study (GWAS), to detect genes contributing to genetic variation in natural antibody level. For natural antibody isotype IgG, genomic regions with a significant association were found on chromosome 21 (BTA). These regions included genes that play an important role in isotype class switching (from IgM to IgG). The gained knowledge on relations between antibodies and longevity and the gained insight on genes responsible for natural antibodies level make antibodies potential predictors for longevity.

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Naturally occurring auto-antibodies in homeostasis and disease

Cited by 166 publications

References 79 publications

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Antibodies and longevity of dairy cattle : genetic analysis

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