Antinuclear antibodies in healthy aging people: a prospective study

doi:10.1016/0047-6374(94)01532-Q

Mechanisms of Ageing and Development

Volume 78, Issue 2, 1 March 1995, Pages 145-154

https://doi.org/10.1016/0047-6374(94)01532-Q Get rights and content

Abstract

In order to evaluate the expression of antinuclear antibodies (ANA) in normal elderly individuals over time and clinical significance, a cross-sectional ANA testing in healthy Japanese was performed, followed by annual evaluations of ANA positive aged (≥ 65 years) and a control group. ANA was more prevalent in the aged (11.4% vs. 3.8%) and most were persistent after 4 years. Anti-ssDNA and anti-histone antibodies were increased in aged ANA positive as compared to ANA negative controls. Except for a history of spontaneous abortion, there was no differences in clinical findings. HLA DRB1^∗0901 and the DQB1^∗0602 + 0302 + 0303 set of alleles were increased in ANA positive. Therefore, ANA in the aged were persistent, apparently directed toward chromatin elements, and shared MHC associations with autoimmune diseases. Longer follow-up may be necessary to improve the evaluation of clinical significance of ANA in the aged.

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Our study makes an important contribution to understanding the intersection of sex-specific aging, ANA and morbidity. Some studies have reported a linear, dose-response relationship between age and ANA over the lifecourse (Satoh et al., 2012; Xavier et al., 1995), and others have reported no association between age and ANA in older individuals (Manoussakis et al., 1987). However, understanding patterns of ANA prevalence by sex at older ages is limited by a lack of research in healthy older adults and the absence of reporting of ANA prevalence by age and sex in the few studies that have been conducted.
Antinuclear antibodies (ANA), a marker of self-reactivity to DNA and other nuclear antigens, are present in several autoimmune diseases and have been observed in healthy persons in the absence of autoimmune disease. ANA prevalence is higher in women and older adults, but the health implications of ANA in middle- to older-aged adults are unknown. Immune system differences by sex may further result in sex-specific susceptibility to morbidity. In a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging, we examined the sex-specific relationship between age and ANA as well as the associations (odds ratios and 95% confidence intervals) between ANA and type-2 diabetes and multimorbidity (2 or more chronic diseases), stratified by sex and controlling for age and race. ANA was measured in a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Overall ANA seroprevalence was 12% (15.1% in women, 8.8% in men). We observed a non-linear relationship between age and ANA that varied by sex (interaction p-value < 0.05), with a clear sex differences in younger participants (ages 48–59), which converged in the oldest (age 80+). ANA positive women had higher odds of type 2 diabetes (OR: 2.06, 95% confidence interval: 1.04, 4.07) and multimorbidity (OR: 2.47, 95% confidence interval 1.11, 5.50) than women who were ANA negative. No statistically significant associations were observed in men. Insight into differences in age-related ANA positivity and ANA associations with chronic diseases by sex is important for understanding the impact of immune dysregulation in aging individuals.
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They are also seen in the general population in the absence of an autoimmune diagnosis. In the absence of autoimmune disease, prevalence of ANA generally increases with age [1,2]. In the US, ANA prevalence has been estimated to be 15% in men and 22% in women over age 70, nearly twice the prevalence in those aged 12–19 [1].
Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes.
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This may be due to the existence of circulating antigens that are not routinely tested for, such as those resulting from infectious stimuli, from multifactorial synthesis or those naturally produced by CD5+ cells [14]. For this reason, clinicians should pay close attention to the titers in which the ANAs are reported, taking into account that in healthy individuals, antibodies should be negative or can be present in low titers, and that intermediate titers may be present in non-affected relatives of patients with autoimmune diseases or in elders with chronic infections or neoplasms [8,11,12,15]. In Mexico, ANA prevalence has been studied in healthy individuals and consensus has been reached as to consider positive a gross mottled pattern in dilutions over 1:160, while homogeneous, centromeric, peripheral or centriolar patterns should be considered positive even in dilutions as low as 1:40 [16].
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Of note, both schizophrenia and autoimmune disorders are associated with olfactory impairment, which may map in proximity to the HLA genetic locus on chromosome 6 (Ortega-Hernandez et al., 2009). Age is also an important potential factor, as spontaneous production of antibodies, including ANA and thyroid peroxidase, increases with increasing age (Chen et al., 2010; Xavier et al., 1995). Previous studies have found associations between age and ANA (Ganguli et al., 1992a), anti-histone (Chengappa et al., 1992a), and alpha-7 nicotinic receptor antibodies (Chandley et al., 2009).
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We identified articles by searching PubMed, PsychInfo, and ISI, and the reference lists of identified studies.
Eighty-one of 111 studies identified met the inclusion criteria. There was a significant increased prevalence of positive titers for 20 different autoantibodies in patients with schizophrenia compared to controls. The prevalence of positive anti-cardiolipin IgG and NMDA receptor titers was also significantly increased in subjects with first-episode psychosis versus controls (p < 0.01). Absolute titers for anti-cardiolipin IgG and IgM, and nerve growth factor were significantly increased in patients with schizophrenia compared to controls (p < 0.02 for each).
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Antinuclear antibodies in healthy aging people: a prospective study

Abstract

Mech. Ageing Dev.

Lancet

Mech. Ageing Dev.

Lancet

Immunol. Today

Mech. Ageing Dev.

Mech. Ageing Dev.

Lancet

Significance of antinuclear factors in older persons

Ann. Rheum. Dis.

Age-related antinuclear factors: immunologic characteristics and associated clinical aspects

Arthritis Rheum.

Autoimmunity in a rural community

Clin. Exp. Immunol.

Lymphocyte phytohemagglutinin responsiveness, immunoglobulins and autoantibodies in ageing humans

J. Immunol.

Studies of human lymphocytes in the newborn and the aged

Am. J. Med.

Circulating immune complexes in old people and in diabetics: correlation with autoantibodies

Clin. Exp. Immunol.

Immunological responses of a healthy elderly population

Clin. Exp. Immunol.

High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population

Clin. Exp. Immunol.