Celiac disease onset and inflammatory milieu

Table 1 Major inflammatory factors, mechanism, and biomarkers in celiac disease

Environmental factor	Mechanism of inflammatory effect	Key biomarkers
Viral infection (e.g., reovirus, enterovirus)	TLR activation, Th1 skewing, cytokine upregulation	IL-2, IL-6, IFN-γ, CD4+ T-cell activation
Glyphosate exposure	Disruption of tight junctions, oxidative stress	Zonulin, CRP, fecal calprotectin
High-fat diet	Microbial dysbiosis, LPS translocation	LPS, TNF-α, SCFA levels, gut permeability markers
Antibiotic use	Loss of microbial diversity, immune dysregulation	Alpha diversity, Treg/Th17 ratio, fecal SCFA
Chronic psychological stress	Cortisol elevation, HPA axis modulation, IL-6 release	Cortisol, IL-6, neutrophil/Lymphocyte ratio
Air pollution (PM2.5, NOx)	Oxidative stress, epithelial inflammation	CRP, IL-8, 8-isoprostane, oxidized glutathione
Lead/arsenic in water	Heavy metal-induced ROS production, gut barrier damage	8-OHdG, malondialdehyde, IL-1β, CRP
Microplastics	Foreign particle immune activation, mucosal disruption	CRP, IL-1β, gut epithelial stress markers
C-section birth (vs vaginal)	Lack of exposure to maternal microbiome	Delayed colonization profiles, IL-10, TSLP
Ultra-processed foods	Emulsifier-induced permeability, dysbiosis	CRP, TNF-α, calprotectin, dysbiosis indices
Sedentary lifestyle	Reduced gut motility and microbiome diversity	IL-6, reduced SCFA, microbial diversity
Season of birth (winter gluten intro)	Increased infection risk during gluten intro window	Season-correlated cytokine trends, seroconversion timing
Urban vs rural environment	Lower biodiversity, increased allergen burden	IL-6, TLR ligands, LPS burden, biodiversity scores
Early gluten introduction	Possible immunological mistiming	Seroconversion timing, IL-2, immune T cell skew
Lack of breastfeeding	Delayed gut colonization, Treg suppression	Secretory IgA, transforming growth factor-β, Treg deficiency
Sleep deprivation	IL-6 elevation, impaired mucosal recovery	IL-6, TNF-α, cortisol, sleep markers

TLR: Toll-like receptor; Th1: Type 1 helper T cell; IL: Interleukin; CRP: C-reactive protein; LPS: Lipopolysaccharide; TNF-α: Tumor necrosis factor alpha; SCFA: Short-chain fatty acid; Treg: Regulatory T cells; HPA: Hypothalamic-pituitary-adrenal axis; ROS: Reactive oxygen species; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; TSLP: Thymic stromal lymphopoietin; PM2.5: Fine particulate matter; Nox: Nitrogen oxides; IFN-γ: Interferon-γ.

Table 2 Two-signal T-cell immunologic activation

Signal	Component	Normal state	Disease onset
Signal 1	DGP-HLA complex on APC	Present, below threshold	Highly expressed, strongly bound
Signal 2	Co-stimulation, loss of regulation	Tregs dominant, T-cells anergic	Tregs suppressed, cytokines upregulated

DGP: Deamidated gliadin peptides; HLA: Human leukocyte antigens; APC: Antigen-presenting cell; Tregs: Regulatory T cells.