From genes to environment: A life-course approach to prevent pediatric autoimmune diseases

Table 1 Common autoimmune disorders in children with associated genetic and biomarker risk factors

Autoimmune disorder	Prevalence/incidence (children)	Typical age of onset	Key genetic risk factors	Biomarker risk (preclinical)	Clinical notes
T1DM	Incidence approximately 10-60 per 100000/year (region-dependent)	Peaks 4-7 and 10-14 years	HLA-DR3, HLA-DR4, DR3/DR4; HLA-DQ8; INS, PTPN22, CTLA4	≥ 2 islet autoantibodies (IAA, GAD65, IA-2, ZnT8) → high progression risk	Autoantibodies may precede the onset by years; a strong family history signal
Celiac disease	Prevalence approximately 0.5%-1.5%	After gluten introduction, commonly 1-3 years (but any age)	HLA-DQ2 (especially DQ2.5), HLA-DQ8; IL2/IL21, CTLA4	Anti-tTG IgA, EMA IgA, DGP antibodies	Serology plus histology (or no-biopsy pathway in select pediatric cases)
Autoimmune thyroid disease (Hashimoto’s/Graves’)	Prevalence approximately 1%-2% in adolescents (higher in females)	Late childhood to adolescence (8-18 years)	HLA-DR3/DR5; CTLA4, PTPN22, FOXP3	Anti-TPO, anti-Tg; TRAb in Graves’	Presents with hypo- or hyperthyroidism; consider screening in T1DM/celiac
JIA	Prevalence approximately 30-200 per 100000; incidence 5-20 per 100000/year	< 16 years; peaks 1-3 and 8-12 years (subtype-dependent)	HLA-DRB1 “shared epitope” alleles; PTPN22; STAT4; HLA-B27 (ERA subtype)	ANA (oligoarticular), RF and anti-CCP (polyarticular)	ANA positivity common in oligoarticular JIA; HLA-B27 → enthesitis-related arthritis
Inflammatory bowel disease (Crohn’s, UC)	Prevalence approximately 100-300 per 100000; incidence 5-15 per 100000/year	Peak 10-17 years; can occur earlier	NOD2/CARD15 (Crohn’s), IL23R, ATG16 L1	ASCA (Crohn’s), pANCA (UC)	Biomarkers aid differentiation: PANCA (UC) vs ASCA (Crohn’s); growth failure can be presenting sign
Systemic lupus erythematosus	Prevalence approximately 3-20 per 100000; incidence approximately 0.3-0.9 per 100000/year	Usually 12-16 years; rare < 5 years	HLA-DR2/DR3; IRF5, STAT4; complement (C1q/C4) deficiency	ANA, anti-dsDNA, anti-Sm; low C3/C4	ANA highly sensitive, not specific; anti-dsDNA correlates with activity; multi-organ involvement
Autoimmune hepatitis	Incidence approximately 0.3-1 per 100000/year (rare)	Bimodal; childhood 7-15 years (types 1 and 2)	Corrected: HLA-DRB1*03/04 (type 1), HLA-DRB107/*13 (type 2)	ANA, SMA (type 1); anti-LKM1 (type 2)	Type 1 ANA/SMA; type 2 anti-LKM1; may present with acute hepatitis or insidious transaminitis
Myasthenia gravis (juvenile)	Prevalence approximately 1-5 per 100000; incidence approximately 0.1-0.4 per 100000/year	Peaks in prepubertal (5-10 years, often ocular) and adolescence (10-18 years)	HLA-B8, HLA-DR3	Anti-AChR antibodies; anti-MuSK antibodies (subset)	Fluctuating fatigable weakness; ocular symptoms common initially; thymic abnormalities less frequent than adults
Pediatric-onset multiple sclerosis	Prevalence approximately 1-5 per 100000; incidence approximately 0.1-0.3 per 100000/year	10-17 years (rare < 10)	HLA-DRB1*15:01; IL7R	CSF oligoclonal bands; MOG-IgG in MOGAD phenotype	Usually relapsing-remitting; MRI dissemination in time/space; consider EBV seropositivity context
Juvenile dermatomyositis	Prevalence 2-4 per 100000; incidence 02-0.5 per 100000/year	Peak 4-10 years	HLA-DQA105:01, HLA-DRB103	Myositis-specific antibodies (e.g., anti-Mi-2, anti-TIF1-γ [p155/140])	Symmetric proximal weakness, heliotrope rash, Gottron papules; risk of calcinosis; nailfold capillary changes

The table summarizes the major autoimmune disorders encountered in childhood, highlighting their epidemiology, age of onset, key genetic susceptibility markers, and preclinical biomarker profiles. Genetic risk factors primarily include human leukocyte antigen class I and II alleles and non-human leukocyte antigen immunoregulatory loci. Biomarkers represent serological or cerebrospinal fluid indicators that may precede clinical disease and assist in risk stratification, early detection, or phenotypic differentiation. Estimates for prevalence and incidence vary substantially by geography, ethnicity, and diagnostic criteria. The presence of genetic or biomarker abnormalities reflects increased susceptibility but is not diagnostic. Autoantibodies may emerge months to years before clinical disease. Data are synthesized from epidemiologic, immunogenetic, and pediatric autoimmune disease cohorts. The table was adapted from multiple studies on the epidemiology and immunogenetics of pediatric autoimmune diseases. T1DM: Type 1 diabetes mellitus; HLA: Human leukocyte antigen; INS: Insulin gene; PTPN22: Protein tyrosine phosphatase non-receptor type 22; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; IAA: Insulin autoantibody; GAD: Glutamic acid decarboxylase 65; IA-2: Insulinoma-associated antigen 2; ZnTB: Zinc transporter; IL: Interleukin; tTG: Tissue transglutaminase; Ig: Immunoglobulin; EMA: Endomysial antibodies; DGP: Deamidated gliadin peptide antibodies; FOXP3: Forkhead box P3; TPO: Thyroid peroxidase antibodies; Tg: Thyroglobulin; TRAb: Thyroid-stimulating hormone receptor antibodies; JIA: Juvenile idiopathic arthritis; STAT4: Signal transducer and activator of transcription 4; ERA: Enthesitis-related arthritis; ANA: Antinuclear antibodies; RF: Rheumatoid factor; CCP: Anti-cyclic citrullinated peptide; UC: Ulcerative colitis; NOD2: Nucleotide-binding oligomerization domain 2; CARD15: Caspase recruitment domain family member 15; ATG16 L1: Autophagy-related 16-like 1; ASCA: Anti-saccharomyces cerevisiae antibodies; pANCA: Perinuclear anti-neutrophil cytoplasmic antibodies; IRF: Interferon regulatory factor; dsDNA: Double-stranded DNA; SMA: Smooth muscle antibodies; LKM1: Liver kidney microsomal type 1 antibodies; AChR: Acetylcholine receptor; MuSK: Muscle-specific kinase; CSF: Cerebrospinal fluid; MOG-IgG: Myelin oligodendrocyte glycoprotein immunoglobulin G; MOGAD: Myelin-oligodendrocyte glycoprotein antibody-associated disease; MRI: Magnetic resonance imaging; EBV: Epstein-Barr virus; TIF1-γ: Transcription intermediary factor 1-gamma.

Table 2 Environmental triggers of autoimmune disorders and preventive strategies

Environmental trigger	Associated autoimmune risk	Proposed mechanism	Prevention strategy
Tobacco smoke	JIA, T1DM, multiple sclerosis, rheumatoid arthritis, SLE	Induces oxidative stress, promotes pro-inflammatory cytokines, impairs T-cell function, and alters epigenetic markers	Complete avoidance of prenatal and second-hand smoke exposure
Endocrine disruptors (e.g., BPA, phthalates, pesticides)	Increased autoantibody production, immune dysregulation	Mimic or block hormones critical for immune regulation; can alter gut microbiome and promote inflammation	Use glass/stainless steel containers, avoid microwaving in plastic, buy organic produce, and use non-toxic household products
Infections (viruses and bacteria)	T1DM (enteroviruses), lupus (EBV), myocarditis (coxsackievirus)	Molecular mimicry (pathogen antigens resemble self-antigens), bystander activation (inflammation damages tissues and releases self-antigens)	Adhere to vaccination schedules for preventable diseases
Nutrient deficiencies (vitamin D)	T1DM, SLE, multiple sclerosis, rheumatoid arthritis	Impairs regulatory T-cell function and promotes pro-inflammatory Th1 and Th17 pathways	Ensure adequate vitamin D intake through sunlight exposure, fortified foods, or supplementation as recommended by a physician
Diet (high sugar/fat, low fiber)	IBD, T1DM, rheumatoid arthritis	Promotes gut dysbiosis, “leaky gut” (increased intestinal permeability), and systemic inflammation	Emphasize a diet rich in fiber, fruits, vegetables, and whole grains; limit processed foods, sugar, and unhealthy fats
Stress (physical/psychological)	IBD, psoriasis, rheumatoid arthritis, SLE	Activates the hypothalamic-pituitary-adrenal axis, leading to the release of stress hormones (e.g., cortisol) and pro-inflammatory cytokines that can exacerbate autoimmunity	Promote stress-reduction techniques such as mindfulness, adequate sleep, and physical activity
Overly sterile environment	Impaired immune tolerance (hygiene hypothesis)	Lack of exposure to diverse microbes and parasites in early life impairs the maturation of regulatory T-cells and other immune-modulating pathways	Encourage balanced microbial exposure through outdoor play, pets, and safe interaction with natural environments

The table outlines key environmental triggers implicated in the development of pediatric autoimmune disorders and summarizes the proposed biological mechanisms linking these exposures to immune dysregulation. The table also provides practical, evidence-informed prevention strategies to reduce risk during critical developmental windows. Environmental triggers include tobacco smoke, endocrine-disrupting chemicals, infectious agents, nutritional deficiencies, dietary patterns, psychosocial stress, and reduced early-life microbial exposure. These factors can influence immune maturation through oxidative stress, hormonal disruption, microbiome alterations, molecular mimicry, impaired gut barrier function, and dysregulation of both innate and adaptive immunity. Preventive recommendations emphasize modifiable behaviors and early-life interventions that may lower autoimmune susceptibility in genetically predisposed children. T1DM: Type 1 diabetes mellitus; JIA: Juvenile idiopathic arthritis; SLE: Systemic lupus erythematosus; BPA: Bisphenol A; EBV: Epstein-Barr virus; IBD: Inflammatory bowel disease.

Table 3 Periodic antibody screening for early detection of autoimmune diseases in high-risk children

Autoimmune disease	High-risk population	Key antibodies for screening	Interpretation	Potential early intervention
Established standard
T1DM	Children with a first-degree relative with T1DM or high-risk HLA genotypes	GAD65, IA-2, insulin autoantibodies, ZnT8	High evidence quality: ≥ 2 positive antibodies = high risk of progression to diabetes	Close monitoring, enrollment in prevention trials (e.g., teplizumab for stage 2), lifestyle/dietary counseling
Celiac disease	Children with a first-degree relative with celiac disease, or high-risk HLA (DQ2/DQ8)	Anti-tTG (IgA), EMA, deamidated gliadin peptide antibodies	High evidence quality: Positive serology suggests a high likelihood of disease and villous atrophy even in asymptomatic children	Early dietary intervention (gluten-free diet) to prevent growth failure and nutritional deficiencies
Autoimmune thyroid disease	Children with a family history of thyroid disease, or other autoimmune disorders (e.g., T1DM, down syndrome, turner syndrome)	Anti-thyroid peroxidase, anti-thyroglobulin	Moderate-high evidence quality: Antibody positivity often precedes clinical hypothyroidism/thyroiditis	Monitoring thyroid function, early initiation of hormone therapy if indicated
Emerging/research
SLE (research/experimental use)	Offspring of mothers with SLE or anti-Ro/SSA positivity	ANA, anti-dsDNA, anti-Ro/SSA. Antibodies may appear before clinical disease	Lower specificity: ANA is highly sensitive but lacks specificity for prediction in asymptomatic children	Serial monitoring; counseling on sun protection and infection triggers; hydroxychloroquine in specific research cohorts
JIA	Children with a strong family history of JIA or early-onset uveitis	ANA, RF, anti-CCP, HLA-B27	Lower evidence quality: ANA is primarily a marker for uveitis risk; RF/anti-CCP are predictive of severe polyarticular course but not disease onset	Baseline ophthalmologic exam for uveitis; prompt referral upon subtle musculoskeletal symptoms

The table summarizes recommended periodic antibody screening for the early detection of autoimmune diseases in children with elevated genetic, familial, or clinical risk. Early serologic positivity - often emerging months to years before overt disease - provides a window for close monitoring, anticipatory guidance, and, in selected cases, preventive intervention. The table outlines high-risk populations, key disease-specific autoantibodies used for screening, typical interpretation thresholds, and corresponding early actions. Note the disparity in evidence quality: Strategies for type 1 diabetes mellitus and celiac disease are supported by standardized international guidelines and highly specific biomarkers. In contrast, screening for systemic lupus erythematosus and juvenile idiopathic arthritis remains less standardized and primarily exploratory, as markers like antinuclear antibodies lack the specificity to predict disease onset in asymptomatic pediatric cohorts without high-risk familial contexts. These recommendations support proactive surveillance while acknowledging that clinical implementation for emerging protocols should be personalized and cautious. T1DM: Type 1 diabetes mellitus; HLA: Human leukocyte antigen; GAD: Glutamic acid decarboxylase 65; IA-2: Insulinoma-associated antigen 2; ZnT8: Zinc transporter 8; tTG: Tissue transglutaminase; Ig: Immunoglobulin; EMA: Endomysial antibodies; SLE: Systemic lupus erythematosus; Ro/SSA: Ro/Sjögren syndrome-related antigen A; ANA: Antinuclear antibodies; dsDNA: Double-stranded DNA; RF: Rheumatoid factor; CCP: Anti-cyclic citrullinated peptide.

Table 4 Candidate next-generation probiotics and their potential role in autoimmune disease prevention

Candidate NGP	Key mechanism(s)	Relevance to autoimmune diseases
Akkermansia muciniphila	Enhances gut barrier integrity, increases mucin production, modulates Treg/Th17 balance	Associated with reduced inflammation; protective role in type 1 diabetes and multiple sclerosis models
Faecalibacterium prausnitzii	Produces butyrate (short-chain fatty acid), exerts anti-inflammatory effects via IL-10 induction and NF-κB inhibition	Lower abundance linked with IBD and rheumatoid arthritis; supplementation may restore tolerance
Bacteroides fragilis (polysaccharide A strain)	Promotes Treg differentiation and reduces pro-inflammatory cytokines	Shown to prevent colitis and experimental autoimmune encephalomyelitis in animal models
Roseburia species	Butyrate production strengthens the epithelial barrier and suppresses pro-inflammatory pathways	Reduced levels observed in IBD and type 1 diabetes; potential for restoring immune tolerance
Clostridium clusters IV and XIVa	Induce colonic Treg expansion, short-chain fatty acids production	Protective in colitis and systemic autoimmune models; contributes to mucosal immune balance
Prevotella histicola	Modulates dendritic cells and T cell responses, decreasing pro-inflammatory Th1/Th17 cells	Demonstrated efficacy in reducing MS-like symptoms in experimental models
Escherichia coli Nissle 1917 (engineered forms)	Enhances epithelial barrier, modulates innate immunity, and can be engineered for anti-inflammatory metabolite production	Shown protective effects in IBD; engineered strains under study for systemic autoimmunity

The table presents emerging next-generation probiotics with potential roles in the prevention or modulation of autoimmune diseases. These candidate microbes - identified through human and preclinical studies - exert immunoregulatory effects through mechanisms such as strengthening epithelial barrier integrity, producing short-chain fatty acids, inducing regulatory T cells, and suppressing pro-inflammatory pathways including nuclear factor kappa-light-chain-enhancer of activated B cells, Th1, and T helper 17 cell signaling. Alterations in the abundance of these organisms have been associated with autoimmune conditions such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. The table highlights key mechanisms of action and summarizes evidence supporting their relevance in restoring immune tolerance and reducing chronic inflammation. These next-generation probiotics represent promising therapeutic and preventive strategies, although most remain in early stages of investigation and require validation in pediatric populations. Treg: Regulatory T cell; Th17: T helper 17 cell; IL-10: Interleukin-10; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; IBD: Inflammatory bowel disease; MS: Multiple sclerosis.

Table 5 Licensed and candidate vaccines: Direction of effect on autoimmune disease risk, rare signals, and evidence type

Vaccine	Target infection(s)	Direction of effect on autoimmune risk (population level)	Notable autoimmune-type adverse events (rare)	Evidence type/key findings
Rotavirus	Rotavirus gastroenteritis	Possible decrease in T1DM incidence in some large cohorts, while others report a neutral effect	No consistent autoimmune signal has been demonstrated	Large administrative and time-series cohort studies have yielded mixed results; some show a modest (approximately 33%) reduction in T1DM risk following a complete vaccine series in specific cohorts
MMR	Measles, mumps, rubella	Neutral. No proven increase in the risk of chronic autoimmune diseases	Immune thrombocytopenic purpura has a very rare association (approximately 1 per 40000 doses), which is typically self-limited. The risk of neurological complications from measles infection is far higher	Decades of evidence from large case-control studies, active surveillance systems, and analyses by advisory committees (e.g., ACIP)
Hepatitis B	Hepatitis B virus	Neutral. No increase in the incidence of multiple sclerosis or other autoimmune diseases	No consistently demonstrated autoimmune-type adverse events	Large nested case-control studies and cohort studies, including a landmark study published in the New England Journal of Medicine, have shown no association with MS
Meningococcal conjugate	Neisseria meningitidis	Neutral. No increased risk of autoimmune diseases	No causal link to GBS has been found in large cohort studies, despite initial post-licensure signals	Extensive pharmacoepidemiology and record-validated cohort studies have provided a reassuring safety profile
Pneumococcal (PCV13, PPSV23)	Streptococcus pneumoniae	Neutral. No increased risk of autoimmune diseases	None consistently demonstrated	Large-scale safety studies and post-licensure surveillance have found no association with autoimmune conditions
Varicella (chickenpox)	Varicella-zoster virus	Neutral. No increased risk of autoimmune diseases	Very rare cases of vasculitis or arthritis have been reported, but a causal link has not been established. The risk of these conditions from natural infection is higher	Extensive safety data from clinical trials and post-licensure surveillance systems
HPV	Human papillomavirus	Neutral. No increase in autoimmune diseases, including MS, IBD, and SLE, has been found	Very rare cases of GBS have been observed in some post-licensure analyses, but overall rates are not elevated compared to the background population	Extensive multinational cohort studies, case-control studies, and national surveillance registries have consistently shown a reassuring safety profile with no causal link
Influenza (seasonal)	Influenza A and B viruses	Neutral. Prevention of influenza infection significantly reduces the risk of post-infectious autoimmune complications	GBS is a very rare adverse event, with an estimated risk of approximately 1-2 cases per million doses, which is lower than the risk of GBS from influenza infection itself	Evidence from meta-analyses of randomized trials, large-scale surveillance data (e.g., from the CDC), and national cohorts
COVID-19 mRNA	SARS-CoV-2	Neutral. No signal for chronic autoimmune disease; preventing infection reduces post-infectious autoimmunity	Myocarditis/pericarditis is a rare, typically mild adverse event, with the highest risk observed in adolescent and young adult males, particularly after the second dose. The risk of these conditions from COVID-19 infection itself is significantly higher	National surveillance (CDC’s V-safe and VAERS), international cohorts, and analyses published in reputable journals like JAMA have characterized these rare events
(Future) EBV vaccine	EBV	Potential decrease (hypothesized). Strong potential to reduce the incidence of MS and other EBV-linked autoimmune diseases	N/A; no licensed product available yet	Evidence is based on strong epidemiological and mechanistic links between EBV infection and autoimmune diseases; multiple vaccine platforms are currently in development
(Future) T1DM vaccine	N/A (Immunomodulatory)	Potential decrease (hypothesized). Aims to induce immune tolerance to prevent the autoimmune attack on the pancreas	N/A; no licensed product available yet	Multiple clinical trials are underway for both oral and parenteral immunomodulatory vaccines; early results for oral insulin and other agents have shown promise in delaying disease progression

The table summarizes currently licensed vaccines and selected candidate vaccines, outlining their population-level impact on autoimmune disease risk, the risk of rare autoimmune-type adverse events, and the strength and type of supporting evidence. Across extensive epidemiologic, clinical trial, and post-licensure surveillance data, the overwhelming evidence demonstrates that routine childhood vaccines have a neutral or protective effect on autoimmune risk. In contrast, natural infections - many of which these vaccines prevent - carry substantially higher autoimmune complications, including Guillain-Barre syndrome, myocarditis, thrombocytopenia, vasculitis, and post-infectious autoimmunity. Rare autoimmune-type events following vaccination are typically mild, self-limited, and far less frequent than those triggered by infection. Candidate vaccines targeting Epstein-Barr virus and type 1 diabetes mellitus have the potential to reduce autoimmune disease incidence by interrupting key causal pathways. Evidence is synthesized from multinational cohort studies, ecological analyses, randomized trials, national vaccine safety systems, and expert advisory committee reviews.

T1DM: Type 1 diabetes mellitus; MMR: Measles-mumps-rubella; ACIP: Advisory committee on immunization practices; MS: Multiple sclerosis; GBS: Guillain-Barre syndrome; PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-Valent pneumococcal polysaccharide vaccine; IBD: Inflammatory bowel disease; SLE: Systemic lupus erythematosus; CDC: Centers for disease control and prevention; VAERS: Vaccine adverse event reporting system; HPV: Human papillomavirus; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; EBV: Epstein-Barr virus; N/A: Not applicable.