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REVIEW

CURRENT
OPINION The autoimmune ecology: an update
Juan-Manuel Anaya, Paula Restrepo-Jiménez, and Carolina Ramı´rez-Santana

Purpose of review
The autoimmune ecology refers to the interactions between individuals and their environment leading to a
breakdown in immune tolerance and, therefore, to the development of one or more autoimmune diseases
in such an individual. Herein, an update is offered on four specific factors associated with autoimmune
diseases, namely, vitamin D, smoking, alcohol and coffee consumption from the perspective of exposome
and metabolomics.
Recent findings
Smoking is associated with an increased risk for most of the autoimmune diseases. Carbamylation of
proteins as well as NETosis have emerged as possible new pathophysiological mechanisms for rheumatoid
arthritis. Low-to-moderate alcohol consumption seems to decrease the risk of systemic lupus erythematosus
and rheumatoid arthritis, and studies of vitamin have suggested a beneficial effect on these conditions.
Coffee intake appears to be a risk factor for type 1 diabetes mellitus and rheumatoid arthritis and a
protective factor for multiple sclerosis and primary biliary cholangitis.
Summary
Recent studies support the previously established positive associations between environmental factors and
most of the autoimmune diseases. Nevertheless, further studies from the perspective of metabolomics,
proteomics and genomics will help to clarify the effect of environment on autoimmune diseases.
Keywords
autoimmune diseases, autoimmune ecology, exposome, metabolomics, review

INTRODUCTION explain the molecular mechanisms behind a specific

Ecology was first defined in 1866 as the science that
studies the interaction of plants and animals with
their environment including organic and inorganic
compounds [1,2]. Autoimmune ecology is the study
of the interactions between individuals and their
environment and how the occurrence of an imbal-
ance favors the development of autoimmune dis-
eases [1]. The exposome is the sum of external (i.e.
toxic substances, air pollution, lifestyle, water qual-
ity, tobacco, alcohol) and internal exposures (i.e.
microbiome and genetics) that shapes the immune
system [1,3].
In contrast to conventional hypothesis-driven
bioresearch that routinely focuses on a select num-
ber of biomolecular factors, multiomics research
attempts to evaluate global changes in disease pro-
gression. The integrated analysis of genomic, epige-
netic, transcriptomic, metabolomics, and proteomic
profiling of entire tissue systems can provide useful
insights [4]. Metabolomics is capable of identifying
and quantifying small molecules and their changes
as a function of diet, lifestyle, genetics, or environ-
mental factors [5,6]. The importance of metabolo-
mics in autoimmune diseases lies in its ability to
phenotype of a particular disease [6,7].
A 2016 review assessed autoimmune ecology
with a focus on specific environmental factors that
might contribute to the development of autoim-
mune diseases [1]. In this review, the objective is
to provide an update on four specific factors associ-
ated with autoimmune diseases: vitamin D, smok-
ing, and alcohol and coffee consumption from the
perspective of exposome and metabolomics.
In the text, the most recent evidence regarding
the effect of vitamin D, cigarette smoking, and
alcohol, and coffee consumption on autoimmune
diseases is summarized. The effect of several other
interactions between environment and autoim-
mune diseases is shown in Table 1 [1,2,8–57]. Recent
Center for Autoimmune Diseases Research (CREA), School of Medicine
and Health Sciences, Universidad del Rosario, Bogotá, Colombia
Correspondence to Juan-Manuel Anaya, MD, PhD, Center for Autoim-
mune Diseases Research (CREA), School of Medicine and Health
Sciences, Universidad del Rosario, Carrera 24 No 63-B-69, Bogotá,
Colombia. Tel: +57 3212339828; e-mail: juan.anaya@urosario.edu.co
Curr Opin Rheumatol 2018, 30:000–000
DOI:10.1097/BOR.0000000000000498

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Infections and environmental aspects of autoimmunity

evidence on the four exposures mentioned above

KEY POINTS prior to 2017 is summarized in Table 2 [26,58–67].
 Smoking is associated with increased risk of SLE, Figure 1 shows the effects of these compounds on
multiple sclerosis, rheumatoid arthritis, AITD and PBC. the immune system.

 Low-to-moderate alcohol consumption is a protective

factor for SLE and rheumatoid arthritis.
 Vitamin D appears to lower the risk of most
autoimmune diseases; however, associations are not
strong enough to support supplementation.
 Coffee intake is a protective factor for multiple sclerosis
and PBC and increases the risk of T1DM and
rheumatoid arthritis.
CIGARETTE SMOKING
Cigarette smoke contains several toxic chemicals
that have been associated with immunological dis-
turbances and have been linked to the development
of autoimmune diseases such as multiple sclerosis,
rheumatoid arthritis, autoimmune thyroid disease
(AITD), primary biliary cholangitis (PBC), and sys-
temic lupus erythematous (SLE), among others
&
[1,9 ,55–57,65,68].

Table 1. Environment and autoimmunity

Agent Association Reference
&
Biological Virus [8,9 ]
agents EBV contributes to the development of multiple sclerosis
Parvovirus B19 might contribute to the development of rheumatoid arthritis
Enterovirus might contribute to T1DM development
Bacteria [10]
Association between tick-borne diseases (Borrelia burgdorferi, Coxiella brunetii, Rickettsia ricketsii, Rickettsia
conorii, Borrelia spp.) as possible triggering factors for dermatomyositis, rheumatoid arthritis, polymyalgia
rheumatic, reactive arthritis, uveitis, multiple sclerosis, and AITD have been described, although not confirmed
Parasites [11–15]
High prevalence of antibodies against Toxoplasma gondii have been found among rheumatoid arthritis patients
Helminth infection protects against multiple sclerosis development and severity of disease
Schistosoma mansoni soluble egg antigen protected against T1DM in rats, and changed the phenotype of diffuse
proliferative to membranous nephritis in SLE rats
Microbiome [16–19]
Microbiome disturbances have been associated to multiple sclerosis, T1DM, SSc, and rheumatoid arthritis
Vaccines [1,20]
Hepatitis A has been linked to autoimmune hepatitis whereas hepatitis B has been linked with multiple sclerosis,
SLE flares, and Sjögren’s syndrome
Influenza has been linked to GBS, vasculitis, reactive arthritis, and cryoglobulinemia
Haemophilus influenza type b might be related to T1DM
&&
Diet, foods, and dietary contaminants [1,8,21 ,
Breastfeeding is associated to decreased T1DM, celiac disease, and multiple sclerosis. Time of introduction of 22–27]
certain foods is associated to T1DM
Vitamin D deficiency is associated to the development of multiple sclerosis, and may contribute to the development
of T1DM
Low vitamin D is associated to disease severity in rheumatoid arthritis and SLE
Low-serum vitamin D levels are associated to AITD and SSc
Coffee intake has a positive association with rheumatoid arthritis, T1DM, and SLE, and a negative association with
multiple sclerosis and PBC
Sex hormones [1,2,28–29]
Exogenous hormone use (oral contraceptives and hormone replacement therapy) have been associated to SLE and
SLE flares; however, evidence is conflicting
Progesterone appears to be protective in SLE
Oral contraceptives have a nonsignificant association with reduced risk of rheumatoid arthritis
Use of hormone contraceptives contributes to an increased risk of Crohn’s disease, multiple sclerosis and ulcerative colitis
Not increased, nor decreased risk in hypothyroidism or hyperthyroidism is associated with hormone contraceptives
Lifestyle and Socioeconomic status and education [1,30–32]
social factors Rheumatoid arthritis risk decreases as educational and income level rises
Patients with low socioeconomic status may present with worse disease activity and higher mortality rates
SLE patients with elevated mortality reported greater levels of poverty
SLE has a tendency for earlier onset and worse outcomes in people of Hispanic, Asian, or African ancestry
compared with Caucasians; this may be related to higher incomes, educational level, and better healthcare
among Caucasians
Multiple sclerosis is reported to start at a younger age in African Americans than Caucasians or Hispanics;
Caucasians presented with higher incomes and better healthcare
Relapsing-onset multiple sclerosis shows lower risk of disability in individuals with more than 12 years of education
T1DM is present in higher socioeconomic status families and among individualss with higher educational level
Employment [32–34]
Rheumatoid arthritis patients had higher probability of long-term sickness absence and disability pension
Missing days were more often reported by patients with primary progressive multiple sclerosis
Adults with T1DM are less frequently employed than general population; T1DM population have 12% more sick
leaves per year

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The autoimmune ecology Anaya et al.

Table 1 (Continued)
Agent Association Reference

Physical activity [35–38]

Physical activity is inversely associated to rheumatoid arthritis and decreases disease severity
Multiple sclerosis cases are higher among people with lower physical activity; multiple sclerosis patients tend to
engage less on physical activity than healthy controls
Improvement on fatigue and depression scores in multiple sclerosis are seen after exercise
SLE patients are less fit and have reduced muscle strength; joint symptoms are the most frequent barriers for physical
activity
Hypoglycemia is the most common barrier in T1DM; exercise is associated with lower HbA1c
Inflammatory bowel disease is inversely associated to exercise
Evidence on the impact of exercise in SSc is limited
Evidence on childhood rheumatic diseases indicates that physical activity improves health-related quality of life
Psychological Adults with T1DM scored significantly lower on health-related quality of life [32,48–52]
factors Patients with rheumatoid arthritis show lower health-related quality of life compared with general population
Hope, optimism, and resilience contribute to moderate the perceived social support–fatigue association
Resilience is positively associated with mental health-related quality of life in rheumatoid arthritis
Resilience is associated to maintenance of daily activities and increases in the number of working hours as well as
adherence to therapy in SLE
SSc has psychosocial effects that require a multidisciplinary approach
Physical agents Ionizing radiation contributes to development of Hashimoto thyroiditis and Graves’ disease [1,8,28]
Occupational exposure to ionizing radiation is associated with increased risk of multiple sclerosis
Increased ultraviolet radiation shows an inverse association with risk of developing multiple sclerosis
Sunlight exposure could be a protective factor for T1DM, evidence is insufficient
Prospective studies on sunlight exposure are needed to establish it as risk factor for SLE, ultraviolet radiation may
exacerbate preexisting SLE
Chemical Silica [1,2,8,28,
agents Silica contributes to development of rheumatoid arthritis, SSc, SLE, ANCA-related diseases 43,47]
Silica is associated to ACPA-positive rheumatoid arthritis
Asbestos [1,8,28]
Data indicating that asbestos might contribute to rheumatoid arthritis is limited; occupational exposure has
been associated to rheumatoid arthritis
Asbestos has been associated with ANA development, proteinuria, and rheumatoid arthritis risk; however, further
investigation is warranted
Metals [1,8,28]
There is insufficient evidence on the role of metals on autoimmune diseases; occupational exposure was
associated with a slightly nonsignificant higher risk of SLE
Experimental studies suggest that heavy metals may increase systemic autoimmunity
Pesticides, organic pollutants, and organic solvents [1,8,28,46]
More research is needed on pesticide exposure and risk of SLE and rheumatoid arthritis; however, studies have
reported increased SLE risk with residential and agricultural exposure
Some organic pollutants show a positive association with the risk of developing multiple sclerosis, rheumatoid
arthritis, and SLE
There is a significant association between exposure to organic solvents and autoimmune diseases
Organic solvents show positive associations with SSc risk
Elevated risk of SSc is associated to exposure to toluene, xylene, trichloroethylene, chlorinated solvents, and paint
thinners and removers
A potential association between solvent exposure and increased risk of multiple sclerosis has shown positive results
Hair dyes and cosmetic products [1,8,44,45]
There is insufficient data of the causative association of cosmetic products to autoimmune diseases
Studies have failed to demonstrate a strong association between hair dyes and PBC
Some studies have found a positive association between hair dyes and SLE or PBC
Drugs [2]
Autoimmunity induced by D-penicilamine has been described in rheumatoid arthritis, SSc, myasthenia
gravis, and SLE
Procainamide and hydralazine have been associated with drug-induced SLE
Minocycline, sulfonamides, anticonvulsants, anti-TNF, and IFN have been associated or suggested to induce
autoimmune diseases
& &
Smoking [1,8,9 ,28,42 ,
Cigarette smoking contributes in the risk of developing rheumatoid arthritis; the risk increases in rheumatoid factor- 43,53,55–57]
positive and ACPA-positive rheumatoid arthritis
Smoking is associated with a higher probability of having SLE, Graves’ disease and Hashimoto thyroiditis,
rheumatoid arthritis, PBC, and multiple sclerosis
Smoking has been associated to an increased risk of developing AITD
Cigarette smoke contributes to an increased risk of PBC
Smoking increases the risk of developing multiple sclerosis, especially in HLA-DRB115:01-positive individuals
Smokers with SLE are more likely to have antidsDNA antibodies than nonsmokers; cigarette smoking has been
associated to cardiovascular disease in patients with SLE
The effect of cigarette smoking on Sjögren’s syndrome is still controversial
Current smoking protects against ulcerative colitis and improves its clinical course
Cigarette smoke contributes as a risk factor for Crohn’s disease, increases disease severity and necessity of
medical therapy
&& &
Alcohol [1,39 ,40,41
Low-to-moderate alcohol consumption contributes to lowering the risk of developing SLE and rheumatoid arthritis; ,54]
the protective effect was stronger in ACPA-positive rheumatoid arthritis
No association was found with multiple sclerosis

Data from [1,2,8–57].

ACPA, anticitrullinated protein antibodies; AITD, autoimmune thyroid disease; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies;
dsDNA, double-strand DNA; EBV, Epstein–Barr virus; GBS, Guillain–Barré syndrome; IFN, interferon; PBC, primary biliary cholangitis; SLE, systemic lupus
erythematosus; SSc, systemic sclerosis; T1DM, type 1 diabetes mellitus; TNF, tumor necrosis factor.

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Infections and environmental aspects of autoimmunity

Table 2. Cigarette, coffee, alcohol and vitamin D: recent findings previous to 2017

Autoimmune disease Findings Reference

Multiple sclerosis A meta-analysis showed an OR of 0.71 (95% CI 0.55–0.92) for high-coffee intake compared [26]
with no coffee intake
Important gene–environment interaction between cigarette smoking and specific HLA-alleles [58]
HLA-DRB115:01 confers an increased risk of multiple sclerosis
The risk of multiple sclerosis increases up to 16-fold in smokers who carry the risk allele [59]
DRB115:01 in absence of HLA-A02
Exposure to cigarette smoke results in earlier disease progression. Those with relapsing remitting [60]
multiple sclerosis who smoke should be advised to consider smoking cessation
Cigarette smoke contains compounds that have shown direct toxicity to oligodendroglia and [61]
neurons, or effect on immune function. It is thought that progression is ensuing to protracted
cerebral inflammation and an increasing loss of axons in the central nervous system
Smoking is associated to increased alveolar macrophages in multiple sclerosis patients and [58]
healthy controls. The increase in concentration of alveolar macrophages associated with
smoking is attenuated in HLA-DRB115 carriers. In contrast, DRB101 and DRB103 is
associated with a higher concentration of alveolar macrophages in smokers, compared with
the respective noncarriers. The attenuated macrophage response in HLA-DRB115 carriers
could result in a suboptimal clearance of smoke particles and a subsequently prolonged
smoke-induced inflammatory response, or an altered response towards pathogens in the
airways
Rheumatoid arthritis Cigarette smoking predisposes the HLA-DRB1-positive patients to develop ACPA-positive [62]
rheumatoid arthritis. NETosis induction and a more severe course of arthritis in a murine
model of rheumatoid arthritis provided evidence that nicotine may have an important role in
antigen production
A meta-analysis reported in a recent review showed that the association of rheumatoid arthritis [63]
with a smoking history of 1–10 packs-year and 21–30 packs-year had a relative risk (RR) of
1.26 (95% CI 1.14–1.39) and 1.94 (95% CI 1.65–2.27), respectively
During preclinical and early stages of rheumatoid arthritis, smoking appears to trigger the [64]
immune reactions associated with HLA-DRB1 by initiating inflammation and production of
antibodies and serologic markers, whereas in established rheumatoid arthritis, smoking is
linked to progressive and persistent disease activity. Smoking exerts a down regulatory effect
over IGF1 levels with a concurrent decrease in leptin that leads to an aberrant T-cell formation
during preclinical phases of the disease, poor bone remodeling, joint damage, and increased
cardiovascular mortality in rheumatoid arthritis
An association of smoking with triple autoantibody positivity (ACPA, rheumatoid factor, and [66]
anti-CarP) has been described
SLE A meta-analysis evaluating the association of smoking with SLE showed an odds ratio (OR) of [65]
1.56 (95% CI 1.26–1.95) for current smokers and 1.23 (95% CI 0.93–1.63) for
nonsmokers, suggesting an increased risk of SLE for smokers.
T1DM Genome-wide association studies identified the vitamin D-binding protein (VDBP) as a candidate [67]
autoantigen in T1DM. Higher levels of VDBP antibody–antigen complexes were found in sera
of T1DM patients compared with healthy individuals. An inverse relationship between these
antibodies and serum VD levels was observed during winter

Data from [26,58–67].

ACPA, anticitrullinated protein antibodies; anti-CarP, anticarbamylated proteins; OR, odds ratio; RR, relative risk; SLE, systemic erythematosus lupus; T1DM, type 1
diabetes mellitus; VDBP, vitamin D-binding protein.

In terms of cellular immunity in multiple scle-
rosis, a cohort of smokers and nonsmokers showed a
higher number of circulating immune cells (gran-
ulocytes, monocytes, B cells, CD4þ and CD8þ T
cells, and CD4þCD8þ T cells) among smokers. How-
ever, costimulatory proteins, adhesion molecules,
and chemokine receptors on circulating immune
cells showed no difference between the groups
&
[9 ]. An umbrella review showed an increased risk
of multiple sclerosis with cigarette smoking [69].
Increased risk of developing rheumatoid arthri-
tis with increasing pack-years smoked has been
&&
observed [63,70,71 ]. A twin cohort study on the
association of cigarette smoking with the risk of
developing rheumatoid arthritis showed doubled
rates of the disease after 20 years of smoking regard-
&&
less of sex [71 ].
In addition, carbamylation of vimentin is induc-
ible by smoking and represents an independent
autoantigen in rheumatoid arthritis [72]. Several
carbamylations are formed by the interaction of
isocyanate (HNCO) with amino groups of proteins.
In humans, isocyanate is formed by the decomposi-
tion of urea into ammonia and cyanate, which is

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The autoimmune ecology Anaya et al.

FIGURE 1. Effect of vitamin D, coffee and cigarette smoking on autoimmune diseases. The effects of vitamin D, coffee and
cigarette smoking on the immune system are shown. Coffee downregulates chemotaxis of neutrophils and macrophages,
which play a substantial role in mediating inflammation. Vitamin D induces downregulation of Th1 and Th17 lymphocytes
while upregulates Th2 and T-regulatory lymphocytes. Macrophages and dendritic cells express vitamin D receptors and
participate in the immune regulation process. Cigarrette smoking induces citrullination of proteins that are recognized by
dendritic cells. Activation of autoreactive B cells mediate the production of anti-CarP autoantibodies and ACPA. Nicotine
induces the formation of NETS and further production of autoantibodies and upregulation of Th1 lymphocytes. Cigarette is
associated with an increased risk of developing rheumatoid arthritis, AITD, SLE, CD, PBC and multiple sclerosis and a lower
risk of developing UC. High levels of vitamin D are associated with a lower risk of developing multiple sclerosis whereas low
vitamin D levels confer an increased risk for T1DM, Sjögren’s syndrome, multiple sclerosis, rheumatoid arthritis and SLE.
Coffee intake appears to increase the risk for T1DM and rheumatoid arthritis whereas it is a protective factor for multiple
sclerosis and PBC. ACPA, anticitrullinated protein antibodies; ADs, autoimmune diseases; AITD, autoimmune thyroid disease;
CarP, carbamyllated protein; CD, Crohn’s disease; CVD, cardiovascular disease; DC, dendritic cell; MPO, myeloperoxidase;
multiple sclerosis, multiple sclerosis; NETS, neutrophil extracellular traps; PAD, peptidyl arginine deaminase; PBC, primary
biliary cholangitis; RA, rheumatoid arthritis; SCN-, thiocyanate; SLE, systemic lupus erythematosus; T1DM, type 1 diabetes
mellitus; UC, ulcerative colitis. Convention (þ) indicates risk and () indicates protection.

transformed into isocyanate. A key reactant for iso-
cyanate formation is thiocyanate (SCN), a metab-
olite of cyanide that is present in cigarette smoke
[72]. Thiocyanate increases in urine, serum, and
saliva with increases in the amount of cigarette
smoking [72]. Production of antigens against carba-
mylated proteins (CarP) and high levels of these
were demonstrated in rats after exposure to tobacco
smoke [72]. DNA methylation mediates genotype
and smoking interaction in the development of
anticitrullinated peptide antibody (ACPA)-positive
&
rheumatoid arthritis [73 ].
Moreover, a recent study done of two nurse
cohorts in the United Kingdom, showed that smok-
ing was associated with ACPA positivity only in the
&&
patients who were rheumatoid factor-positive [74 ].
The authors concluded that the rate of ACPA posi-
tivity relied more on the number of copies of the
shared epitope than on the levels of rheumatoid
&&
factor [74 ].
Evidence on the effect of cigarette on Sjögren’s
syndrome is controversial and contradictory.
Although few studies have assessed the effect of
tobacco on Sjögren’s syndrome, a lower prevalence

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Infections and environmental aspects of autoimmunity
of cigarette smoking among Sjögren’s syndrome
&
patients has been reported [75 ]. Case–control stud-
ies have shown a lower OR of current smokers being
classified as having Sjögren’s syndrome compared
& &
with nonsmokers [42 ,75 ]. In a case–control study,
a lower risk for the presence of antiRo/SSA and a
salivary gland biopsy with a focus score greater than
1 was found for current smokers compared with
&
nonsmokers [75 ]. There are studies demonstrating
persistence of high risk of autoimmune diseases after
smoking cessation [68]. Because of the negative
effects of tobacco on cardiovascular and pulmonary
status, Sjögren’s syndrome patients are encouraged
&
to avoid smoking [75 ].
ALCOHOL CONSUMPTION
Some components of alcohol are known to regulate
systemic inflammation by decreasing the secretion
of pro-inflammatory molecules, such as TNF, IL-6,
&&
and IL-8 [39 ,76] and increasing the production of
IL-10. These effects have been shown to produce a
dose-dependent behavior [77].
A protective effect on the risk of developing SLE
associated with the consumption of 5 g per day or
&&
more of alcohol has been reported [39 ]. Interest-
ingly, hard alcohol consumption showed no benefit
in lowering the risk. Low concentrations of inflam-
matory biomarkers have been observed in individu-
als with moderate alcohol consumption (5–9 g/day
alcohol) who, in addition, also had a lower risk of
developing rheumatoid arthritis than nondrinkers
&&
[39 ]. The effect seems to be stronger for ACPA-
&
positive individuals [40,41 ].
VITAMIN D
Vitamin D deficiency has been associated with type
1 diabetes mellitus (T1DM), Sjögren’s syndrome,
multiple sclerosis, SLE, and rheumatoid arthritis
& &
along with other autoimmune diseases [78 ,79 ].
A European population of rheumatoid arthritis
patients had significantly lower serum concentra-
tions of 1.25-dihydroxyvitamin D when compared
with healthy individuals. Low vitamin D levels were
&
associated with increased disease activity [80 ]. A
&
case–control study showed similar results [81 ]. A
negative association between 25-hydroxy vitamin D
levels, cytokines, and nitric oxide resulting in redox
balance disturbances and exacerbation of pro-
inflammatory cytokine formation was found in
& &
rheumatoid arthritis patients [81 ].
A randomized controlled trial of vitamin D versus
placebo with standard rheumatoid arthritis therapy
showed a higher improvement in global health for
&
the vitamin D group [82 ]. A meta-analysis evaluating
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the effect of vitamin D supplementation in rheuma-
toid arthritis showed nonsignificant positive results
in disease flares and disease activity measured with
&
DAS-28 [83 ].
A meta-analysis including three studies on vita-
min D and SLE showed significantly lower rates of
anti-dsDNA positivity in patients with supplemen-
tation compared with controls (risk differ-
ence ¼ 1.10, 95% CI 0.18 to 0.03; P ¼ 0.005)
&
[83 ]. Low vitamin D levels have been associated
with higher levels of antinuclear antibodies (ANA).
Elevated anti-dsDNA and ANA serum levels suggest
that a vitamin D deficiency may be a possible trigger
of autoantibody production and a possible predictor
&
of SLE flares [83 ]. Vitamin D serum concentration
showed significant differences between inactive,
slightly active, or severely active disease in a study
&&
including 199 SLE patients [84 ]. The proportion of
patients with vitamin D insufficiency or deficiency
&&
was higher in the severe activity group [84 ].
A meta-analysis evaluating the risk of pediatric-
onset multiple sclerosis found a significant differ-
ence in HLA-DRB115:01 status between cases and
&&
controls [21 ]. Vitamin D was associated with a
decreased risk of multiple sclerosis (P ¼ 0.002),
although no association of vitamin D with HLA-
DRB115:01 status was observed [21 ]. Genetic
&&
studies in multiple sclerosis patients have demon-
strated a positive association between specific
CYP2R1 variants and risk of vitamin D insufficiency,
and whenever tested as a risk factor for developing
multiple sclerosis, a positive association was sug-
&
gested [78 ]. Evaluation of cytokine production
showed higher levels of IFNg and no differences
in IL-17, TNF-a, or IL-10 between multiple sclerosis
patients with low vitamin D compared with patients
&
with normal levels [85 ]. Seasonal variations in vita-
min D concentration showed a negative relation-
&
ship with multiple sclerosis relapse rates [86 ].
A positive association between vitamin D levels
and IL-8, and a negative association between vita-
min D and leptin were observed in two cohorts of
&
T1DM children [87 ]. No associations between vita-
min D and 16 other peripheral immune mediators
&
were found [87 ]. Leptin is thought to activate leu-
kocytes and mediate inflammation. However, the
effect of vitamin D supplementation on leptin levels
&
is still to be determined [87 ].
Evidence regarding low vitamin D levels and
Sjögren’s syndrome is controversial. A recent review
summarized the evidence of a possible correlation
between vitamin D and Sjögren’s syndrome [79 ].
Vitamin D deficiency has been linked to an
increased risk for Sjögren’s syndrome in patients
with rickets or osteomalacia. Vitamin D deficiency
has been hypothesized to be secondary to immune
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dysregulation or a result of chronic inflammation or
&
decreased sun exposure [79 ]. There are studies that
have not succeeded in demonstrating an association
&
between vitamin D and Sjögren’s syndrome [79 ].
The exact effect of vitamin D on Sjögren’s syndrome
&
has yet to be fully established [79 ].
Low vitamin D levels have been associated with
AITD [88] and AITD patients have a higher proba-
bility of having low vitamin D levels, especially
those with Graves’ disease [43,44]. A recent study
showed no differences between vitamin D levels and
&
titers of Graves’ disease antibodies [89 ]. High levels
of vitamin D were associated with lower recurrence
of Graves’ disease whenever medication was sus-
& &&
pended [89 ].
A retrospective study of patients with systemic
sclerosis (SSc) found serum vitamin D deficiency in
more than 50% of patients and a high rate of sea-
& &&
sonal fluctuations [24 ]. No significant associations
between vitamin D levels and autoantibody speci-
ficity, inflammatory biomarkers, and parameters of
&
disease severity or activity were found [24 ].
COFFEE
In addition to caffeine, the most frequently ingested
psychoactive molecule, coffee also contains lipidic
molecules such as cafestol and kahweol, and anti-
oxidant substances such as polyphenols. In addi-
&&
tion, coffee includes many antimutagens [25 ,90].
Caffeine has a long history of consumption as a part
of the human diet. It is a natural component of a lot
of food and beverages as well as of dietary supple-
ments [91]. Authoritative bodies and independent
research groups have concluded that a moderate
daily caffeine intake of up to 400 mg/day is not
associated with adverse health effects in adults
[91]. Many of the effects of coffee on the immune
system are attributed to the ability of caffeine to
inhibit cyclic adenosine monophosphate (cAMP)
phosphodiesterase (PDE) leading to elevated levels
of intracellular cAMP that cause activation of pro-
tein kinase A (PKA) [92,93].
Although coffee consumption seems to be cor-
related with a reduced risk of multiple sclerosis or
ulcerative colitis, the effects of coffee consumption
on rheumatoid arthritis and SLE diseases seem unfa-
vorable [93]. A recent review described the evidence
of an effect of coffee consumption on some autoim-
&&
mune diseases [25 ]. For rheumatoid arthritis, the
authors described a meta-analysis that found a sig-
nificant association between rheumatoid arthritis
and intake of more than four cups of coffee per
&&
day [25 ]. They presented the results from a study
showing that consumption of decaffeinated coffee
showed a higher association with rheumatoid
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The autoimmune ecology Anaya et al.
arthritis than noncoffee consumption and that caf-
feinated coffee consumption had no association
with rheumatoid arthritis. However, according to
them, there are no other studies replicating these
&&
results [25 ]. The review includes two studies that
have reported controversial results on the possible
effect of coffee intake on the outcomes of patients
&&
treated with methotrexate [25 ].
&&
Results from the review by Sharif et al. [25 ]
include studies suggesting an increased risk of T1DM
with a coffee intake more than two cups per day.
They report a study that found an increase in hypo-
glycemic episodes during the day and another one
that found reduced hypoglycemic events during the
night [25 ]. Finally, some studies have found coffee
intake to decrease peripheral tissue sensitivity to
&&
insulin [25 ].
Concerning multiple sclerosis and PBC, Sharif
et al. [25 ] concluded that coffee plays a protective
role with respect to the risk of developing these
diseases whereas they found no associations
between coffee intake and the risk of SLE, PBC,
AITD, inflammatory bowel disease (IBD), and celiac
&&
disease in the studies evaluated [25 ].
A metabolic urinary profile study found negative
associations between urine metabolites (alanine, gly-
cine, N-N-dimethylglycine, lactic acid) and serum T4
levels whereas a positive association was found for
trigonelline, an alkaloid present in coffee [94]. Higher
levels of trigonelline showed an OR of 1.38 (95% CI
1.14 to 1.67; P < 0.01) for hypothyroidism [94].
A recent in-vitro study done in peripheral blood
mononuclear cells (PBMC) from healthy individuals
showed significant downregulation at the mRNA
levels of key inflammatory genes including STAT1,
TNF, and PPARG at a dose-dependent concentration
&&
of caffeine [95 ]. The doses tested corresponded to
the serum concentration of caffeine after adminis-
tration of one cup of coffee. The authors suggest that
these findings indicate the potential downregula-
tory effects of caffeine on key inflammatory genes
&&
and cytokines involved in autoimmunity [95 ].
A metanalysis evaluating tea and coffee con-
sumption in relation to DNA methylation showed
no association between coffee consumption and
DNA methylation in men or women even when
the analysis combined both sexes [96]. A significant
relationship was found for tea intake. The authors
suggest the effect of coffee on DNA could vary
depending on individual factors, preparation tech-
niques, and sample utilized [96].
METABOLOMICS
Environmental health research focuses on how an
individual chemical influences a specific health
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Infections and environmental aspects of autoimmunity

Table 3. Metabolomics in autoinmune diseases

Autoimmune disease Findings Reference

SLE A urinary metabolomic profiling in SLE patients detected 81 metabolites, of which 70 were [100]
identified as amino acids, organic acids, nucleotides, amines, and fatty acids
High levels of intermediaries in the tricarboxylic acid support abnormalities in energy metabolism
seen in SLE as well as increased levels of metabolites involved in processes of oxidative stress
and high levels of uracil and xanthine suggest imbalances in the oxidant/antioxidant
mechanisms and disturbances in nucleotide metabolism
A similar metabolic profile between three different SLE phenotypes was observed in a study [101]
constituting 30 SLE patients. The primary component analysis was able to differentiate the
metabolic profile of SLE from SSc, Sjögren’s syndrome, and healthy controls
Sjögren’s syndrome The salivary metabolites of Sjögren’s syndrome patients show reduced diversity compared with [102]
healthy controls. Decreased levels of glycine, tyrosine, uric acid, and fructose were the major
contributors to the difference with healthy controls and the primary component analysis showed
that history of major salivary glanditis affected the metabolic profile in Sjögren’s syndrome
patients
APS Serum metabolomics from APS patients show higher levels of choline, betaine, 2-hydroxybutyrate, [103]
acetoacetate, arginine and glutamate, and lower levels of glutamine and valine compared with
healthy controls. Women show lower levels of valine, suggesting it could be a biomarker for
monitoring APS in women
T1DM Salivary metabolic profile in T1DM shows slightly less protein and succinic acid levels. Higher [104]
salivary glucose is observed among T1DM patients with HbA1c levels above 8.5. Higher lactate,
acetate, n-acetyl-sugar, and sucrose levels are responsible for the distinction between T1DM
patients and healthy controls. The identified metabolites are related to pyruvate metabolism
Distinct molecular lipid patterns in cord blood have been described in T1DM patients. Studies have
found a reduction in phosphatidylcholines, sphingomyelin,s and ether phosphatidylcholines [6]
before seroconversion with increased levels of lysophosphatidylcholine.
Choline-containing phospholipids have been established as predictors of T1DM
Multiple sclerosis Metabolomic profiling of multiple sclerosis patients shows higher levels of 2-hydroxybutyrate, [105]
acetone, formate and pyroglutamate, and lower levels of citrate compared with healthy controls.
Different disease states (relapse-remission) show no large differences in the metabolic profile with
the primary component analysis. In the univariate analysis, higher levels of 2-hydroxybutyrate,
acetone and formate, and lower levels of acetate and glucose were described in relapse and
remission multiple sclerosis
The urinary metabolomics profile showed that creatinine, 3-hydroxyisovalerate, and oxaloacetate [106]
differentiate between multiple sclerosis patients and healthy controls
The metabolic disturbances observed in multiple sclerosis suggest altered pathways of energy [105,106]
metabolism, fatty acid biosynthesis, and gut microflora

Date from [6,100–106].

APS, antiphospholipid syndrome; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; T1DM, type 1 diabetes mellitus.

outcome [97]. This single exposure-disease approach
does not represent the complexity of exposures
encountered throughout life. There is a significant
need to link external exposures to internal body
burden and internal body burden to biological
responses and disease outcomes [97].
Exposome studies help to identify causal pathways
that link environmental exposures to disease end-
points by combining a range of technologies that
probe external and internal exposures and concomi-
tant responses. Beyond implementing exposome stud-
ies, the objective is to describe the metabolome, a
phenotypical measure that encodes a wealth of infor-
mation relating to genes, environmental exposure,
and their various interactions [98]. Subsequently,
high-resolution platforms such as ultraperformance
liquid chromatography-mass spectrometry (UPLC-
MS) and 1H nuclear magnetic resonance (NMR)
spectroscopy for generating metabolic phenotypical
data are now commonly included in molecular epide-
miological studies of chronic diseases.
A recent article discusses the possible bias in the
results obtained from studies assessing the concen-
tration of vitamin D with regards to the existence of
different bioavailable forms of vitamin D (25-
hydroxivitamin D, 1.25-dihydroxivitamin D), the
effect of sunlight exposure, and the possible effect
of other vitamin D metabolites on various autoim-
mune diseases. The authors suggest that metabolo-
mics, alone or supported by proteomics and other -
omics, could give an appropriate response to the
doubts about vitamin D studies as well as studies
&&
involving other environmental interactions [99 ].
Recent evidence regarding the use of metabolo-
mics applied to the study of some autoimmune
diseases is summarized in Table 3 [6,100–106].

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BOR 300407
CONCLUSION
Knowledge about the effect of autoimmune ecology
has gained serious attention from the medical com-
munity. Metabolomics, as well as other -omic sci-
ences such as proteomics or genomics, make further
understanding of the exposome as well as how its
interaction with the individual’s immune system
confers protective or risk factors for the develop-
ment of autoimmune diseases possible. Study of all
these complex interactions from the perspective of -
omics is of critical importance to confirm the exist-
ing associations and to establish new ones that
would help provide personalized medicine for
autoimmune diseases.
Acknowledgements
The authors are grateful to the members of the Center for
Autoimmune Disease Research (CREA) for fruitful dis-
cussions.
Financial support and sponsorship
This work was supported by the Universidad del Rosario
(ABN011), Bogotá, Colombia.
Conflicts of interest
There are no conflicts of interest.
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