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.