Serum Interleukin (IL)-15 as a Biomarker of Alzheimer's Disease

Bishnoi, Ram J.; Palmer, Raymond F.; Royall, Donald R.

doi:10.1371/journal.pone.0117282

Cited by 45 publications

(24 citation statements)

References 79 publications

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“…IL‐15 is a cytokine that induces the proliferation of NK cells and is up‐regulated in the presence of a viral infection. It is also known to reduce disease activity in celiac disease and has been implicated as a potential biomarker for Alzheimer's disease . Serum levels of IL‐15 in SLE patients have been examined previously , but the sample sizes of those studies were too limited for findings to be considered conclusive.…”

Section: Discussionmentioning

confidence: 99%

Identification of Low‐Abundance Urinary Biomarkers in Lupus Nephritis Using Electrochemiluminescence Immunoassays

Stanley

Mok

Vanarsa

et al. 2019

Arthritis & Rheumatology

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Objective. To investigate the utility of a sensitive platform using electrochemiluminescence (ECL) for the identification of low-abundance urinary protein biomarkers in lupus nephritis (LN).Methods. Forty-eight urine samples were obtained from subjects in 2 independent cohorts, each consisting of 3 groups (matched for age, sex, and race) of 8 patients with active LN (renal Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] >0), 8 patients with inactive SLE (renal SLEDAI 0), and 8 healthy controls. Samples were tested using a preexisting 40-plex ECL panel. A custom 5-plex ECL panel was then developed for further validation studies and used to test 140 urine samples (from 44 patients with active LN, 41 patients with inactive SLE, 28 healthy controls, and 27 patients with other kidney diseases).Results. Levels of 17 urinary proteins were elevated (P < 0.05 by 2-tailed Mann-Whitney U test) in samples from patients with active LN compared to samples from patients with inactive SLE and healthy controls in cohort 1, while 9 were similarly elevated in cohort 2. Of these, interleukin-7 (IL-7), IL-12p40, IL-15, interferonγ-inducible protein 10 (IP-10), and thymus and activation-regulated chemokine (TARC) were chosen for further validation. These 5 proteins were undetectable by enzyme-linked immunosorbent assay (ELISA). Hence, a custom 5-plex ECL panel was developed and used to validate the results from the initial 40-plex screening panel. Urinary IL-7, IL-12p40, IL-15, IP-10, and TARC levels were again significantly elevated in patients with active LN compared to those with inactive SLE and healthy controls, and correlated well with the renal SLEDAI and physician's global assessment of disease activity (R > 0.67, P < 0.05). All 5 urinary proteins were more frequently elevated in LN compared to controls with other chronic kidney diseases, although overall group differences attained significance only for urinary IL-7 and IL-15.Conclusion. Urinary levels of IL-7, IL-12p40, IL-15, IP-10, and TARC are potentially useful diagnostic tools in LN. The use of ECL assays may allow detection of urinary biomarkers that are below ELISA detection limits. ECL ASSAYS FOR LOW-ABUNDANCE BIOMARKERS IN LUPUS NEPHRITIS| 745 and others (6) are revolutionizing biomarker discovery, allowing researchers to screen for new biomarkers in an unbiased manner. These new technologies vary in sensitivity and cannot handle the high-volume sample throughput needed for subsequent biomarker validation studies or routine clinical diagnostics.Newer technologies have attempted to reduce the levels of background noise seen in a traditional enzyme-linked immunosorbent assay (ELISA) or antibody-based arrays by replacing an enzymatic-based detection signal with an alternative signal. One of the most promising techniques is the use of an electrode-coupled immunoassay with an electrochemiluminescent (ECL) signal. In this arrangement, the capture antibody is coupled to an electrode, and the detection antibody is labeled with a tag that emits a chemiluminescent...

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Section: Discussionmentioning

confidence: 99%

Identification of Low‐Abundance Urinary Biomarkers in Lupus Nephritis Using Electrochemiluminescence Immunoassays

Stanley

Mok

Vanarsa

et al. 2019

Arthritis & Rheumatology

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“…Systemic infection in AD was also associated with a reduction in several pro-inflammatory cytokines, mainly associated with the adaptive immune system. The few studies that have examined their role in AD have found: (i) elevated serum IL7 in early to mild AD [ 20 ]; (ii) elevated IL12p40 levels in the cerebrospinal fluid (CSF) of Alzheimer’s patients [ 68 ]; (iii) administration of IL12p40 subunit blocker enhanced microglial phagocytosis and reduced inflammation in Aβ transgenic mice [ 68 ]; (iv) raised IL15 levels in the CSF and serum of Alzheimer’s patients correlated with severity of cognitive dysfunction [ 6 , 58 ]; (v) increased peripheral IL16 in AD [ 19 ]; and overexpression of IL17A decreased soluble Aβ levels without exacerbating neuroinflammation in a mouse model of Aβ accumulation [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

Rakić

Hung

Smith

et al. 2018

acta neuropathol commun

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Clinical studies indicate that systemic infections accelerate cognitive decline in Alzheimer’s disease. Animal models suggest that this may be due to enhanced pro-inflammatory changes in the brain. We have performed a post-mortem human study to determine whether systemic infection modifies the neuropathology and in particular, neuroinflammation, in the late-stage of the disease.Sections of cerebral cortex and underlying white matter from controls and Alzheimer's patients who died with or without a terminal systemic infection were immunolabelled and quantified for: (i) Αβ and phosphorylated-tau; (ii) the inflammation-related proteins Iba1, CD68, HLA-DR, FcγRs (CD64, CD32a, CD32b, CD16), CHIL3L1, IL4R and CCR2; and (iii) T-cell marker CD3. In Alzheimer's disease, the synaptic proteins synaptophysin and PSD-95 were quantified by ELISA, and the inflammatory proteins and mRNAs by MesoScale Discovery Multiplex Assays and qPCR, respectively.Systemic infection in Alzheimer's disease was associated with decreased CD16 (p = 0.027, grey matter) and CD68 (p = 0.015, white matter); increased CD64 (p = 0.017, white matter) as well as increased protein expression of IL6 (p = 0.047) and decreased IL5 (p = 0.007), IL7 (p = 0.002), IL12/IL23p40 (p = 0.001), IL15 (p = 0.008), IL16 (p < 0.001) and IL17A (p < 0.001). Increased expression of anti-inflammatory genes CHI3L1 (p = 0.012) and IL4R (p = 0.004) were detected in this group. T-cell recruitment to the brain was reduced when systemic infection was present. However, exposure to systemic infection did not modify the pathology. In Alzheimer's disease, CD68 (p = 0.026), CD64 (p = 0.002), CHI3L1 (p = 0.016), IL4R (p = 0.005) and CCR2 (p = 0.010) were increased independently of systemic infection.Our findings suggest that systemic infections modify neuroinflammatory processes in Alzheimer's disease. However, rather than promoting pro-inflammatory changes, as observed in experimental models, they seem to promote an anti-inflammatory, potentially immunosuppressive, environment in the human brain.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0592-3) contains supplementary material, which is available to authorized users.

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“…The TARCC's model, constrained across random 50% splits, had acceptable fit (chi square 5 1264. 6 [295], P , .001; CFI 5 0.95; RMSEA 5 0.031) ( Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Blood‐based protein predictors of dementia severity as measured by δ: Replication across biofluids and cohorts

Bishnoi

Pavlik

Massman

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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Introduction Dementia severity can be empirically described by the latent dementia phenotype “δ” and its various composite “homologs”. We have explored δ's blood‐based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we recently engineered a δ homolog from observed cognitive performance measures common to both projects (i.e., “dT2A”). Methods We used nine rationally chosen peripheral blood‐based protein biomarkers as indicators of a latent variable “INFLAMMATION”. We then associated that construct with dT2A in structural equation models adjusted for age, gender, depressive symptoms, and apolipoprotein E (APOE) ε4 allelic burden. Significant factor loadings and INFLAMMATION's association with dT2A were confirmed in random splits of TARCC's relatively large sample, and across biofluids in the ADNI. Results Nine proteins measured in serum (TARCC) or plasma (ADNI) explained ≅10% of dT2A's variance in both samples, independently of age, APOE, education, and gender. All loaded significantly on INFLAMMATION, and positively or negatively, depending on their known roles are PRO‐ or ANTI‐inflammatory proteins, respectively. The parameters of interest were confirmed across random 50% splits of the TARCC's sample, and replicated across biofluids in the ADNI. Discussion These results suggest that SEM can be used to replicate biomarker findings across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood‐based protein levels.

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Serum Interleukin (IL)-15 as a Biomarker of Alzheimer's Disease

Cited by 45 publications

References 79 publications

Identification of Low‐Abundance Urinary Biomarkers in Lupus Nephritis Using Electrochemiluminescence Immunoassays

Identification of Low‐Abundance Urinary Biomarkers in Lupus Nephritis Using Electrochemiluminescence Immunoassays

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

Blood‐based protein predictors of dementia severity as measured by δ: Replication across biofluids and cohorts

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