RESEARCH ARTICLE
Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy Iago Carballo1, Lucía Alvela1, Luis-Fernando Pérez2, Francisco Gude3, Carmen Vidal4, Manuela Alonso1,3, Bernardo Sopeña1, Arturo Gonzalez-Quintela1* 1 Department of Internal Medicine, Complejo Hospitalario Universitario, Santiago de Compostela, Spain, 2 Department of Clinical Biochemistry, Complejo Hospitalario Universitario, Santiago de Compostela, Spain, 3 Department of Clinical Epidemiology, Complejo Hospitalario Universitario, Santiago de Compostela, Spain, 4 Department of Allergy, Complejo Hospitalario Universitario, Santiago de Compostela, Spain * [email protected]
Abstract OPEN ACCESS Citation: Carballo I, Alvela L, Pérez L-F, Gude F, Vidal C, Alonso M, et al. (2016) Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy. PLoS ONE 11(2): e0149330. doi:10.1371/ journal.pone.0149330 Editor: Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research and Azienda Ospedaliera Ospedali Riuniti di Bergamo, ITALY Received: October 12, 2015
Background and Aim Serum IgG4 concentrations are commonly measured in clinical practice. The aim of this study was to investigate serum IgG4 concentrations in adults and their potential relationship with demographic, lifestyle, metabolic, and allergy-related factors.
Methods Serum IgG4 concentrations were measured with a commercial assay in 413 individuals (median age 55 years, 45% males) who were randomly selected from a general adult population.
Accepted: January 29, 2016 Published: February 24, 2016 Copyright: © 2016 Carballo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The study was supported by grants from the Instituto de Salud Carlos III, Spanish Ministry of Health (PI13/02594 and Red de Investigación en Actividades Preventivas y Promoción de la Salud, redIAPP RD12/0005/0007), Fondo Europeo de Desarrollo Regional (FEDER), and the Consellería de Innovación e Industria, Xunta de Galicia (PGIDIT06PXIB918313). The funders had no role in
Results Median IgG4 concentration was 26.8 mg/dL. Five out of the 413 individuals (1.2%) exhibited IgG4 concentrations >135 mg/dL, and 17 out of 411 (4.1%) exhibited an IgG4/total IgG ratio >8%. Serum IgG4 concentrations were significantly higher in males than in females and decreased with age. After adjusting for age and sex, serum IgG4 concentrations were not significantly influenced by alcohol consumption, smoking or common metabolic abnormalities (obesity and the related metabolic syndrome). Serum IgG4 concentrations were not significantly correlated with serum concentrations of proinflammatory cytokines and inflammation markers. Serum IgG4 concentrations were significantly correlated with IgE concentrations. Serum IgG4 concentrations tended to be higher in atopics (individuals with IgE-mediated sensitization to aeroallergens) than in non-atopics, particularly among atopics without respiratory symptoms. Serum IgG4 concentrations were not significantly correlated with total eosinophil blood count. Cases of IgG4-related disease were neither present at baseline nor detected after a median of 11 years of follow-up.
PLOS ONE | DOI:10.1371/journal.pone.0149330 February 24, 2016
1 / 15
IgG4 in the General Population
study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
Conclusions Studies aimed at defining reference IgG4 values should consider partitioning by age and sex. Further studies are needed to confirm the potential influence of atopy status on serum IgG4 concentrations.
Introduction The fourth subclass of immunoglobulin G (IgG4) is the less abundant serum IgG subclass in humans [1]. The half-life of IgG4 is approximately 21 days [2] and, unlike other IgG subclasses, IgG4 does not bind complement [3]. It is also unique among antibodies in that IgG4 molecules can be asymmetric, i.e., a large fraction of plasma IgG4 molecules have two different antigenbinding sites, resulting in bi-specificity [4,5]. Like IgE, regulation of IgG4 production is dependent on Th2 cells [5].The function of IgG4 is not completely understood. It may play a role in allergic disorders by competing for allergen with IgE bound to mast cells, thus blocking their stimulation [5]. The presence of allergen-specific IgG4, either spontaneously or after allergen immunotherapy, indicates that tolerance-inducing mechanisms have been activated [5]. Serum concentrations of IgG4 have been little studied in general populations. In a study of 172 healthy adults, French and Harrison (1984) found that IgG4 concentrations were higher in males than in females [6]. A similar finding was reported by Aucouturier et al. (1984) in a study of 173 adults [7]. No significant effect of age on IgG4 concentrations was reported in these studies, although a trend to increased concentrations in older individuals was reported [7]. To the best of our knowledge, the potential effect of common factors such as metabolic disorders (obesity and related alterations) and lifestyle factors (alcohol consumption and smoking) has been not investigated. Total serum IgG4 concentrations were not influenced by allergy, a common condition in the general population, in one study [7]. In recent decades, the methods for IgG4 measurement have improved and the interest on IgG4 concentrations has increased due to the emerging concept of IgG4-related disease (IgG4-RD), which integrates a wide number of old diseases from a new perspective [8–11]. Inflammation and fibrosis of one or more organs, with a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells is the hallmark of IgG4-RD [8–11]. The role of IgG4 in the pathogenesis of IgG4-RD is unclear. It is not known whether IgG4 antibodies are pathogenic or represent a regulatory response to another primary autoimmune or allergic process [8–15]. While raised IgG4 concentrations alone are not diagnostic of IgG4-RD because both sensitivity and specificity are not optimal [11,16–20], they nevertheless constitute one of the classic diagnostic criteria for IgG4-RD [21] and may also be useful for the monitoring of IgG4-RD [17,18]. Determining the distribution of IgG4 concentrations in the general population is important for the interpretation of reference values in clinical practice. Studies on the general population may serve to explore the potential influence of common factors and/or disorders. Accordingly, the aim of this study was to evaluate serum IgG4 concentrations in a general adult population and their potential relationship with demographic, lifestyle, metabolic, and allergy-related factors.
Methods Study population and design This study forms part of a survey of the general adult population from A-Estrada, a municipality in north-western Spain. Detailed descriptions of methodology and population
PLOS ONE | DOI:10.1371/journal.pone.0149330 February 24, 2016
2 / 15
IgG4 in the General Population
characteristics have been reported elsewhere [22]. Briefly, an age-stratified random sample (n = 720) of the adult population (>18 years) of the municipality was drawn from the Health Care Registry, which covers >95% of the population. A total of 469 individuals were studied across the period January 2000-January 2001 [22]. Frozen serum samples for IgG4 determination were available for 413 of these individuals, median age 55 years (range 18–92 years). All participants were Caucasians. A total of 186 (45.0%) were males. The source study (FIS1306/ 99) was reviewed and approved by the Institutional Review Board of the Complejo Hospitalario Universitario from Santiago de Compostela (Spain). The present study (PGIDIT06PXIB918313) was reviewed and approved by the Clinical Research Ethics Committee from Galicia (Spain). Written informed consent was obtained from each participant in the study, which conformed to the current Helsinki Declaration.
Classification of alcohol consumption and smoking Alcohol consumption was evaluated in standard drinking units [23], by summing the number of glasses of wine (~10g), bottles of beer (~10g), and units of spirits (~10g) regularly consumed per week. Individuals with an habitual alcohol consumption of 1–140 g/week were defined as light drinkers, those with an alcohol consumption of 141–280 g/week were defined as moderate drinkers, and those with an alcohol consumption >280 g/week were defined as heavy drinkers. The remainder, alcohol abstainers or very occasional alcohol drinkers, were included in the same group. Consumers of at least one cigarette per day were considered smokers. Individuals who had quit smoking during the preceding year were still considered smokers, while those who had quit more than one year prior to the study were considered ex-smokers. Individuals with an habitual tobacco consumption of 1–9 cigarettes/day were defined as light smokers, and those with an habitual tobacco consumption of >9 cigarettes/day were defined as heavy smokers.
Definition of metabolic abnormalities Body mass index (BMI) was calculated as weight (in kg) divided by the square of height (in metres). Following standard criteria, individuals were classified as normal-weight (30 kg/m2). Metabolic syndrome was defined according to Adult Treatment Panel III criteria [24], namely: (a) abdominal obesity (waist circumference >102 cm in males or >88 cm in females); (b) hypertriglyceridaemia (fasting serum triglycerides 150 mg/dL); (c) low HDL-cholesterol levels (fasting HDL-cholesterol 40–50
70
28.3 (13.6–43.3)
69
2.6 (1.3–3.7)
>50–60
61
23.7 (11.4–34.9)*
60
2.1 (1.3–3.4)**
>60–70
67
24.5 (11.9–42.5)
67
2.2 (1.1–3.5)*
>70–80
56
26.2 (11.1–42.9)
56
2.2 (1.0–3.3)*
>80
45
20.1 (11.4–37.5)*
45
1.9 (1.1–3.0)**
Alcohol consumption Abstainers (ref.)
193
27.7 (14.3–45.2)
193
2.5 (1.4–3.9)
Light drinkers
131
23.8 (12.4–41.0)
129
2.2 (1.2–3.6)
Moderate drinkers
52
26.3 (12.1–42.1)
52
2.5 (1.3–3.9)
Heavy drinkers
37
32.4 (16.0–48.3)
37
2.9 (1.4–4.3)
Smoking Never smokers (ref.)
260
24.4 (12.2–40.3)
259
2.1 (1.2–3.3)
Ex-smokers
63
26.2 (14.0–46.1)
63
2.5 (1.3–3.9)
Light smokers
20
29.6 (13.4–44.3)
20
2.8 (1.1–4.0)
Heavy smokers
70
33.2 (20.1–51.7)**
69
3.2 (2.0–4.7)***
Body mass index Normal weight (ref.)
112
29.0 (15.7–44.0)
112
2.8 (1.6–4.1)
Overweight
179
25.6 (12.8–45.1)
177
2.4 (1.3–3.9)
Obese
121
25.3 (13.1–42.5)
121
2.2 (1.3–3.7)
No (ref.)
313
26.9 (13.3–45.4)
311
2.5 (1.3–4.0)
Yes
100
25.0 (13.1–39.8)
100
2.2 (1.3–3.5)
Negative (ref.)
308
24.9 (12.7–42.0)
306
2.3 (1.2–3.7)
Positive
105
33.2 (17.3–47.2)*
105
2.8 (1.5–4.3)*
Metabolic syndrome
Specific IgE
Skin prick tests Negative (ref.)
302
26.2 (12.9–41.7)
300
2.4 (1.2–3.8)
Positive
111
28.5 (16.2–46.7)
111
2.6 (1.5–4.4)
Data are expressed as medians and interquartile (25th-75th percentile) ranges (within parentheses). *P
Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy Iago Carballo1, Lucía Alvela1, Luis-Fernando Pérez2, Francisco Gude3, Carmen Vidal4, Manuela Alonso1,3, Bernardo Sopeña1, Arturo Gonzalez-Quintela1* 1 Department of Internal Medicine, Complejo Hospitalario Universitario, Santiago de Compostela, Spain, 2 Department of Clinical Biochemistry, Complejo Hospitalario Universitario, Santiago de Compostela, Spain, 3 Department of Clinical Epidemiology, Complejo Hospitalario Universitario, Santiago de Compostela, Spain, 4 Department of Allergy, Complejo Hospitalario Universitario, Santiago de Compostela, Spain * [email protected]
Abstract OPEN ACCESS Citation: Carballo I, Alvela L, Pérez L-F, Gude F, Vidal C, Alonso M, et al. (2016) Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy. PLoS ONE 11(2): e0149330. doi:10.1371/ journal.pone.0149330 Editor: Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research and Azienda Ospedaliera Ospedali Riuniti di Bergamo, ITALY Received: October 12, 2015
Background and Aim Serum IgG4 concentrations are commonly measured in clinical practice. The aim of this study was to investigate serum IgG4 concentrations in adults and their potential relationship with demographic, lifestyle, metabolic, and allergy-related factors.
Methods Serum IgG4 concentrations were measured with a commercial assay in 413 individuals (median age 55 years, 45% males) who were randomly selected from a general adult population.
Accepted: January 29, 2016 Published: February 24, 2016 Copyright: © 2016 Carballo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The study was supported by grants from the Instituto de Salud Carlos III, Spanish Ministry of Health (PI13/02594 and Red de Investigación en Actividades Preventivas y Promoción de la Salud, redIAPP RD12/0005/0007), Fondo Europeo de Desarrollo Regional (FEDER), and the Consellería de Innovación e Industria, Xunta de Galicia (PGIDIT06PXIB918313). The funders had no role in
Results Median IgG4 concentration was 26.8 mg/dL. Five out of the 413 individuals (1.2%) exhibited IgG4 concentrations >135 mg/dL, and 17 out of 411 (4.1%) exhibited an IgG4/total IgG ratio >8%. Serum IgG4 concentrations were significantly higher in males than in females and decreased with age. After adjusting for age and sex, serum IgG4 concentrations were not significantly influenced by alcohol consumption, smoking or common metabolic abnormalities (obesity and the related metabolic syndrome). Serum IgG4 concentrations were not significantly correlated with serum concentrations of proinflammatory cytokines and inflammation markers. Serum IgG4 concentrations were significantly correlated with IgE concentrations. Serum IgG4 concentrations tended to be higher in atopics (individuals with IgE-mediated sensitization to aeroallergens) than in non-atopics, particularly among atopics without respiratory symptoms. Serum IgG4 concentrations were not significantly correlated with total eosinophil blood count. Cases of IgG4-related disease were neither present at baseline nor detected after a median of 11 years of follow-up.
PLOS ONE | DOI:10.1371/journal.pone.0149330 February 24, 2016
1 / 15
IgG4 in the General Population
study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
Conclusions Studies aimed at defining reference IgG4 values should consider partitioning by age and sex. Further studies are needed to confirm the potential influence of atopy status on serum IgG4 concentrations.
Introduction The fourth subclass of immunoglobulin G (IgG4) is the less abundant serum IgG subclass in humans [1]. The half-life of IgG4 is approximately 21 days [2] and, unlike other IgG subclasses, IgG4 does not bind complement [3]. It is also unique among antibodies in that IgG4 molecules can be asymmetric, i.e., a large fraction of plasma IgG4 molecules have two different antigenbinding sites, resulting in bi-specificity [4,5]. Like IgE, regulation of IgG4 production is dependent on Th2 cells [5].The function of IgG4 is not completely understood. It may play a role in allergic disorders by competing for allergen with IgE bound to mast cells, thus blocking their stimulation [5]. The presence of allergen-specific IgG4, either spontaneously or after allergen immunotherapy, indicates that tolerance-inducing mechanisms have been activated [5]. Serum concentrations of IgG4 have been little studied in general populations. In a study of 172 healthy adults, French and Harrison (1984) found that IgG4 concentrations were higher in males than in females [6]. A similar finding was reported by Aucouturier et al. (1984) in a study of 173 adults [7]. No significant effect of age on IgG4 concentrations was reported in these studies, although a trend to increased concentrations in older individuals was reported [7]. To the best of our knowledge, the potential effect of common factors such as metabolic disorders (obesity and related alterations) and lifestyle factors (alcohol consumption and smoking) has been not investigated. Total serum IgG4 concentrations were not influenced by allergy, a common condition in the general population, in one study [7]. In recent decades, the methods for IgG4 measurement have improved and the interest on IgG4 concentrations has increased due to the emerging concept of IgG4-related disease (IgG4-RD), which integrates a wide number of old diseases from a new perspective [8–11]. Inflammation and fibrosis of one or more organs, with a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells is the hallmark of IgG4-RD [8–11]. The role of IgG4 in the pathogenesis of IgG4-RD is unclear. It is not known whether IgG4 antibodies are pathogenic or represent a regulatory response to another primary autoimmune or allergic process [8–15]. While raised IgG4 concentrations alone are not diagnostic of IgG4-RD because both sensitivity and specificity are not optimal [11,16–20], they nevertheless constitute one of the classic diagnostic criteria for IgG4-RD [21] and may also be useful for the monitoring of IgG4-RD [17,18]. Determining the distribution of IgG4 concentrations in the general population is important for the interpretation of reference values in clinical practice. Studies on the general population may serve to explore the potential influence of common factors and/or disorders. Accordingly, the aim of this study was to evaluate serum IgG4 concentrations in a general adult population and their potential relationship with demographic, lifestyle, metabolic, and allergy-related factors.
Methods Study population and design This study forms part of a survey of the general adult population from A-Estrada, a municipality in north-western Spain. Detailed descriptions of methodology and population
PLOS ONE | DOI:10.1371/journal.pone.0149330 February 24, 2016
2 / 15
IgG4 in the General Population
characteristics have been reported elsewhere [22]. Briefly, an age-stratified random sample (n = 720) of the adult population (>18 years) of the municipality was drawn from the Health Care Registry, which covers >95% of the population. A total of 469 individuals were studied across the period January 2000-January 2001 [22]. Frozen serum samples for IgG4 determination were available for 413 of these individuals, median age 55 years (range 18–92 years). All participants were Caucasians. A total of 186 (45.0%) were males. The source study (FIS1306/ 99) was reviewed and approved by the Institutional Review Board of the Complejo Hospitalario Universitario from Santiago de Compostela (Spain). The present study (PGIDIT06PXIB918313) was reviewed and approved by the Clinical Research Ethics Committee from Galicia (Spain). Written informed consent was obtained from each participant in the study, which conformed to the current Helsinki Declaration.
Classification of alcohol consumption and smoking Alcohol consumption was evaluated in standard drinking units [23], by summing the number of glasses of wine (~10g), bottles of beer (~10g), and units of spirits (~10g) regularly consumed per week. Individuals with an habitual alcohol consumption of 1–140 g/week were defined as light drinkers, those with an alcohol consumption of 141–280 g/week were defined as moderate drinkers, and those with an alcohol consumption >280 g/week were defined as heavy drinkers. The remainder, alcohol abstainers or very occasional alcohol drinkers, were included in the same group. Consumers of at least one cigarette per day were considered smokers. Individuals who had quit smoking during the preceding year were still considered smokers, while those who had quit more than one year prior to the study were considered ex-smokers. Individuals with an habitual tobacco consumption of 1–9 cigarettes/day were defined as light smokers, and those with an habitual tobacco consumption of >9 cigarettes/day were defined as heavy smokers.
Definition of metabolic abnormalities Body mass index (BMI) was calculated as weight (in kg) divided by the square of height (in metres). Following standard criteria, individuals were classified as normal-weight (30 kg/m2). Metabolic syndrome was defined according to Adult Treatment Panel III criteria [24], namely: (a) abdominal obesity (waist circumference >102 cm in males or >88 cm in females); (b) hypertriglyceridaemia (fasting serum triglycerides 150 mg/dL); (c) low HDL-cholesterol levels (fasting HDL-cholesterol 40–50
70
28.3 (13.6–43.3)
69
2.6 (1.3–3.7)
>50–60
61
23.7 (11.4–34.9)*
60
2.1 (1.3–3.4)**
>60–70
67
24.5 (11.9–42.5)
67
2.2 (1.1–3.5)*
>70–80
56
26.2 (11.1–42.9)
56
2.2 (1.0–3.3)*
>80
45
20.1 (11.4–37.5)*
45
1.9 (1.1–3.0)**
Alcohol consumption Abstainers (ref.)
193
27.7 (14.3–45.2)
193
2.5 (1.4–3.9)
Light drinkers
131
23.8 (12.4–41.0)
129
2.2 (1.2–3.6)
Moderate drinkers
52
26.3 (12.1–42.1)
52
2.5 (1.3–3.9)
Heavy drinkers
37
32.4 (16.0–48.3)
37
2.9 (1.4–4.3)
Smoking Never smokers (ref.)
260
24.4 (12.2–40.3)
259
2.1 (1.2–3.3)
Ex-smokers
63
26.2 (14.0–46.1)
63
2.5 (1.3–3.9)
Light smokers
20
29.6 (13.4–44.3)
20
2.8 (1.1–4.0)
Heavy smokers
70
33.2 (20.1–51.7)**
69
3.2 (2.0–4.7)***
Body mass index Normal weight (ref.)
112
29.0 (15.7–44.0)
112
2.8 (1.6–4.1)
Overweight
179
25.6 (12.8–45.1)
177
2.4 (1.3–3.9)
Obese
121
25.3 (13.1–42.5)
121
2.2 (1.3–3.7)
No (ref.)
313
26.9 (13.3–45.4)
311
2.5 (1.3–4.0)
Yes
100
25.0 (13.1–39.8)
100
2.2 (1.3–3.5)
Negative (ref.)
308
24.9 (12.7–42.0)
306
2.3 (1.2–3.7)
Positive
105
33.2 (17.3–47.2)*
105
2.8 (1.5–4.3)*
Metabolic syndrome
Specific IgE
Skin prick tests Negative (ref.)
302
26.2 (12.9–41.7)
300
2.4 (1.2–3.8)
Positive
111
28.5 (16.2–46.7)
111
2.6 (1.5–4.4)
Data are expressed as medians and interquartile (25th-75th percentile) ranges (within parentheses). *P
