The presence of anticardiolipin antibodies in adults may be influenced by infections in infancy
From the 1Medical Research Council Epidemiology Resource Centre, Southampton, 2Department of Rheumatology, Southampton General Hospital, UK and 3Dipartimento di Medicina Interna e Specialistica, University of Catania, Via Passo Gravina 187, 95125 Catania, Italy
Address Correspondence to Dr C.J. Edwards, Consultant Rheumatologist and Honorary Senior Lecturer, Department of Rheumatology, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. email: cedwards{at}soton.ac.uk
Received 23 August 2007 and in revised form 23 October 2007
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Objectives: There has been limited success defining environmental factors important in the development of antiphospholipid (Hughes) syndrome (APS). Recent work suggests that the perinatal environment may be important in the development of other autoimmune diseases. We measured anticardiolipin antibodies (aCL) in a general population with well-defined early lives to see whether fetal and infant growth and infections were associated with aCL positivity in adult life.
Methods: aCLs were measured using an ELISA in 1384 individuals from the Hertfordshire cohort study. We investigated associations between the presence of aCL and early growth and infectious exposure in infancy in men and women.
Results: ELISA positive aCL (IgM and IgG) was present in 22 (3%) men and 15 (2%) women. Using the highest octile of aCL results, in men higher birth weight (per lb of birth weight: OR 1.18, 95% CI 1.02–1.36, P = 0.02) and diarrhoeal infection in the first year of life (OR 2.55, 95% CI 1.10, 5.92, P = 0.03) were associated with an increased likelihood of being aCL positive. In women, diarrhoeal infection in the first year of life was also associated with an increased likelihood of aCL positivity (OR 2.23, 95% CI 1.01, 4.91, P = 0.05). For IgG titre in men, significant relationships were found with sharing a bedroom (regression coefficient 1.13; 95% CI 1.05, 1.22; P = 0.02) and diarrhoea in the first year (coefficient 1.25; 95% CI 1.00, 1.56; P = 0.05).
Conclusion: A developing immune system when exposed to the infectious environment may influence the likelihood of producing aCL in adult life.
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Introduction |
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Antiphospholipid syndrome (APS) is associated with recurrent thrombosis and the presence of antiphospholipid antibodies (aPL).1 The most common aPLs detected are the anticardiolipin antibodies (aCL) and a positive aCL (IgG or IgM) is a defining characteristic of the international APS diagnostic criteria.2
The development of APS is under the control of both genetic and environmental factors. Animal models have suggested that APS is multi-genic3 and a number of HLA associations have been described.4 The development of aPL antibodies may also occur following viral and bacterial infections, exposure to medication (i.e. phenothiazines), associated with connective tissue diseases, malignancies or spontaneously in the primary antiphospholipid syndrome.5–8 Individuals with SLE have a high prevalence of aPL, as much as 30%.9 Studies have also demonstrated that aPL antibodies can occur in the general population and become more common with increasing age.9 The presence of aPL antibodies in the general population has been studied in a number of centres with the point prevalence varying between 0 and 14%.9
Previous investigation of possible environmental influences on autoimmune disease has concentrated on the time around the onset of disease. However, it now appears that the pathological process that leads to clinical disease onset may begin many years before in autoimmune diseases including RA and SLE.9–11 Recent work has suggested that perinatal characteristics may be important in the development of autoimmune rheumatic diseases such as rheumatoid arthritis (RA).12 In addition, we have shown that exposure to infections in early life may influence the likelihood of developing the autoantibodies rheumatoid factor (RF)13 and antinuclear antibodies (ANA).14
We hypothesised that environmental factors acting in utero or early infancy in the development of RF and ANA may also be important for the development of aPL. To investigate this, we looked for aCLs in a population study of individuals with well-defined early lives to see whether fetal and infant growth or infectious exposure influenced the presence of aCL in later life.
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Study population
The Hertfordshire Cohort Study (HCS) includes 3000 men and women born in the county of Hertfordshire, UK, between 1931 and 1939. The selection procedure for these individuals was as follows: in brief, with the help of the National Health Service Central Registry at Southport, and Hertfordshire Family Health Service Association, we traced men and women who were born during 1931–39 in Hertfordshire, and still lived there during the period 1998–2003. The birth weight and weight at one year of age of each individual had been recorded in a ledger by a team of midwives and health visitors who had attended each birth in Hertfordshire in the 1930s and visited the child's home at intervals during the first year of life. A health visitor in the United Kingdom is a registered nurse with an additional qualification whose main areas of responsibility are health education and the preventative care of families, including mothers and children.
After obtaining written permission from each subject's General Practitioner, we approached individuals by letter, asking them if they would be willing to be contacted by one of our research nurses. If they agreed, a research nurse performed a home visit, where they administered a structured questionnaire. This included information on socioeconomic status, medical history, cigarette smoking, alcohol consumption, dietary calcium intake and reproductive variables in women. Midwife and health visitor records have been preserved for the cohort containing information on birth weight, weight at one year, method of infant feeding, infant infections (including bronchitis/pneumonia, diarrhoeal illness, mumps and rubella) and markers of exposure to childhood infection (sharing a bedroom during childhood, social class [own social class for men and never married women and husbands social class for married women—the social classes used were non-manual (I, II, IIINM) and manual (IIIM, IV, V)] and birth order. Individuals recorded in the ledgers and still living in Hertfordshire were identified from an NHS registry and invited to attend a clinic where serum samples were collected. We included 737 men and 675 women who participated in the first phase of clinics conducted for the Hertfordshire Cohort Study (East Hertfordshire).
Measurement of ACA
ACA IgM ± IgG was measured using an enzyme-linked immunoabsorbent assays (ELISA) (ORGENTEC Diagnostika, Mainz, Germany). An aCL positive result was defined from either or both ELISA kits as per the manufacturers’ instructions (IgM > 7 U/ml and IgG > 10 U/ml). aCL results were obtained for 722 (98%) of men and 662 (98%) of women. Known positive and negative samples and kit control samples were included in each assay. The ELISA plates used were coated with purified cardiolipin and then saturated with human beta-2-glycoprotein 1 (β2–GPI). The plates would identify autoantibodies directed against cardiolipin or cardiolipin/β2–GPI complex.
Statistical analysis
We investigated associations between the presence of aCL by ELISA and early growth (birth weight, weight at 1 year and growth rate), infant infectious episodes (bronchitis, pneumonia, diarrhoeal illness, mumps, rubella) and markers of hygiene (breast feeding, sharing a bedroom during childhood, birth order) in infancy, using cross-tabulations and logistic regression models. We also analysed the relationship between these factors and aCL titre. All analyses were conducted for men and women separately, using the Stata statistical software package, release 8.
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ACA prevalence
ELISA results were obtained for 722 men and 662 women. A positive aCL as defined by the manufacturers’ instructions (IgM > 7 U/ml and IgG > 10 U/ml) was present in 22 (3%) men and 15 (2%) women. The low prevalence of aCL positivity using the manufacturers’ instructions limited further analysis. To overcome this, we also used a definition of a positive aCL as the top octile of aCL ELISA results. When using the new cutoff level for aCL as determined by the ‘top octile’ the cutoff point of
3.25 U/ml defined the top eighth for IgG aCL. A cut point of 2.98 U/ml defined the top eighth for IgM aCL. This identified 172 men (24%) and 131 women (20%) as being aCL positive. We believe this to be valid as the cutoff level using the manufacturers’ instructions was designed to demonstrate titres of aCL associated with APS. This study is not designed to look at associations between APS and the early environment.
Early life growth
In men higher birth weight was associated with an increased likelihood of being aCL positive (per lb of birth weight: odds ratio 1.18, 95% CI 1.02–1.36, P = 0.02). This effect remained important in mutually adjusted analysis. In women there was an association between growth in the first year of life and aCL positivity (highest third, OR 1.85, 95% CI 1.15, 3.00, P = 0.01). This relationship remained following mutually adjusted analysis (Tables 1 and 2).
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Early life infections
There were associations between the presence of aCL in men and women and markers of infant hygiene and infant infections. In men diarrhoeal infection in the first year of life was associated with an increased likelihood of aCL positivity (OR 2.55, 95% CI 1.10, 5.92, P = 0.03). In women diarrhoeal infection in the first year of life was also associated with an increased likelihood of aCL positivity (OR 2.23, 95% CI 1.01, 4.91, P = 0.05).
The effect of IgG and IgM titre
Regression analyses were conducted using the natural log of the IgG and IgM titres.
IgG titre
For IgG titre in men significant relationships were found with sharing a bedroom (regression coefficient 1.13; 95% CI 1.05, 1.22; P = 0.02), diarrhoea in the first year (coefficient 1.25; 95% CI 1.00, 1.56; P = 0.05) and having had 3 or more recorded infections between the ages of 1 and 5 (coefficient 1.25; 95% CI 1.04, 1.51; P = 0.02). In mutually adjusted models, sharing a bedroom and having had three or more infections between the ages of 1 and 5 remained significant.
IgM titre
For IgM titre, there was no association with fetal or infant growth or the likelihood of having had diarrhoeal illness.
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Discussion |
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These results show significant associations between growth and environmental factors during infancy and the presence of aCL in adults. They suggest that events at the beginning of life may produce permanent changes in the immune system that influence the production of aPL in adult life. Higher birth weight in men was associated with a significantly increased likelihood of being aCL positive in later life. For women, there was an association between higher growth rate in the first year of life and being aCL positive. There were also associations with early life infections. The presence of recorded diarrhoeal illness during the first year of life was associated with an increased likelihood of being aCL positive as an adult in both men and women. Men with a higher titre of IgG aCL were also most likely to have had recorded diarrhoeal illness during the first year of life and shared a bedroom during childhood.
Up to 14% of a general population may be aCL positive and the prevalence increases with age.9 The levels of aCL positivity in our population is less than would normally be expected. The manufacturers’ kit we used established their normal range using healthy blood donors. A number of aCL ELISA kits have been evaluated in our laboratory and they can vary enormously. In addition, the samples used were not fresh and had been stored frozen at –70°C for up to 3 years and all samples were freeze–thawed once. However, we do not believe that the absolute level measured is the key to this study.
The immune pathology that results in autoimmune diseases such as RA and SLE begins many years before the clinical expressions of disease with ANA and RF present up to 10 years before clinically apparent disease.10, 11 In the same way individuals can be positive for aPL many years before clinically apparent APS becomes evident. This makes aCL a potential early marker of the pathogenic process in APS. Thus, these results may suggest that early growth and infectious exposure may influence the likelihood of developing APS in adult life. However, this study was not designed to look at APS directly. Fetal and infant growth has been shown previously to have effects on a number of adult phenotypic characteristics and diseases. These include hypertension, ischaemic heart disease, osteoporosis, glucose metabolism and the hypothalamic-pituitary adrenal axis.15–18 Low infant growth occurring due to malnutrition is associated with a number of changes to immune function.19, 20 However, these are generally short lived.21
It seems likely that the majority of episodes of diarrhoea described in the HCS will have been infective. aCLs are well known to arise following infectious episodes. The most common causes of infant diarrhoea are viruses including Rotavirus, Picornavirus, Small-round viruses, Corona-like viruses and Adenovirus.22 A number of viruses and bacteria have been shown to lead to the production of aPL.5 These include organisms that may also cause diarrhoeal illness including Adenovirus and Salmonella. In addition, a number of other infections in children are associated with the production of aPL.23–26 However, production of aPL associated with infectious events have been assumed to be short term. The level of infectious exposure in early life has also been used to demonstrate the importance of infections in the aetiology of autoimmune diseases, including type I diabetes, and allergies.27–33 Previous work by our group has shown that greater infectious exposure during early childhood decreases the likelihood of being RF positive.13 In addition, greater infectious exposure, in particular mumps and rubella, increases the likelihood of being ANA positive in adult life.14 A record of diarrhoeal illness in the first year of life was also associated with an increased likelihood of being ANA positive in adult life. The differences between RF, ANA and now aCL suggest that the effect of early life infectious exposure may not be the same for all autoantibodies. This suggests that infection may produce distinct effects on different autoantibody systems and perhaps different autoimmune diseases. In addition, different infectious organisms that effect different organ systems may also have different effects. In particular, diarrhoeal illness may have a particular role in the development of autoantibodies.
The HCS population has been extensively studied and is representative of the population of England as determined by comparing the HCS with the national Health Survey for England.34 However, this study has a number of limitations. In particular, our observation shows how early life factors influence the presence of an autoantibody rather than a disease state. There are also potential problems with the diagnosis of specific childhood infections. The history of diarrhoea was based on pragmatic diagnoses made by healthcare workers on the basis of clinical findings alone. The exact cause of the diarrhoea (infectious or otherwise) cannot be elucidated from our records. However, the precise cause of diarrhoea may be less important than the effect of diarrhoeal illness on the immune function and integrity of the gut wall as a barrier to entry of antigen. The gut contains its own lymphoid tissues ‘gut-associated lymphoid tissue’ (GALT). In recent years, the processes involved in this oral tolerance have been extensively explored.35 They include tolerogenic antigen-presenting cells and regulatory T cells. Oral administration of antigens normally results in tolerance and disruption of this tissue secondary to infection may alter the likelihood of tolerance induction.
Infections occurring during clinically active CTDs also have effects on disease activity. Infections may trigger a flare of SLE or worsening of the current disease activity.36 Infections may also be the trigger for thrombotic events in individuals with APS. This is particularly dramatic when catastrophic antiphospholipid syndrome occurs. Ultimately, the timing of any infectious exposure may be key to its effect. In the rodent models of RA described animals were reared in a germ-free environment from birth. However, the SLE animal model relied on later infectious exposure of rodents.
The developing immune system may be particularly vulnerable to manipulation by external factors at certain critical periods. The effects of these environmental characteristics may occur very early in life as a result of occult exposure to microorganisms rather than clinically apparent infectious episodes.37 In humans, intra-uterine growth restriction (IUGR) results in enduring effects on immunity including a diminished response to recall antigens.38 In addition, low birth weight has been associated with a poor response to typhoid vaccination in adults.39 Work from The Gambia showed that adults born during low food availability were 10 times more likely to die from infectious diseases than those born during periods of high food availability.40 Subsequent work in the same population showed seasonal effects on thymic size and T cell function.41
Our results suggest that a developing immune system exposed to a particular growth environment and infectious burden is more likely to produce aCL and perhaps begin the pathological process that leads to APS. Contrasting effects may be seen between different autoimmune and allergic diseases whereby infections at critical periods of development produce permanent, and potentially damaging, changes in immune functioning. These, in conjunction with specific genetic backgrounds and other environmental factors may lead to disease. This suggests that the human immune system can be programmed during early life to produce particular autoantibodies. It is intriguing to consider that an infectious episode can have long-lasting effects on the production of an autoantibody such as aCL.
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We acknowledge with thanks the assistance of the Hertfordshire Cohort Study and volunteers.
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