What are the factors that contribute to the development of celiac disease?

How Celiac Disease Develops

Celiac disease develops through a complex interplay of three essential factors: genetic predisposition (primarily HLA-DQ2 or HLA-DQ8 genes), gluten exposure from wheat/rye/barley, and environmental triggers that break down immune tolerance—all three must be present for the disease to manifest. 1

Genetic Foundation

The genetic component is mandatory but not sufficient alone:

• HLA genes account for 40% of genetic risk, with approximately 90% of celiac patients carrying HLA-DQ2.5 (encoded by DQA105:01 and DQB102:01 genes on the DR3 haplotype), while most remaining patients express HLA-DQ8 (DR4, DQ8 haplotype) 1
• Nearly 100% of individuals with celiac disease exhibit HLA-DQ2 and/or HLA-DQ8, making the absence of these genes highly effective at ruling out the condition 1
• 39 additional non-HLA genetic loci contribute only 14% of genetic variance, with each gene contributing minimally to overall risk—most relate to B-cell and T-cell immune functions 1
• First-degree relatives have approximately 10% prevalence (compared to 1% in general population), and monozygotic twins show 75% concordance, demonstrating strong heritability 1

Environmental Trigger: Gluten Exposure

Gluten ingestion is an absolute prerequisite for disease development:

• Gluten proteins from wheat, rye, and barley are incompletely digested due to their high proline and glutamine content and lack of human prolyl endopeptidases, resulting in large peptides (10-50 amino acids) that persist in the small intestine 1
• Tissue transglutaminase (tTG) deamidates glutamine residues in these peptides, converting them to negatively charged glutamic acid, which creates peptides with specific proline-glutamic acid spacing 1
• These modified peptides uniquely bind to HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells, triggering activation of pathogenic CD4+ T cells in the intestinal mucosa 1

Breakdown of Immune Tolerance

The factors causing loss of gluten tolerance remain incompletely understood, but several triggers have been identified:

• Gastrointestinal infections may compromise epithelial barrier function and initiate intestinal inflammation that breaks tolerance 1
• Surgery, interferon-α therapy, and certain drugs have been implicated as potential trigger factors 1
• Local pro-inflammatory changes are paramount in the breakdown of tolerance, though the precise initiating mechanisms remain unknown 1
• Early cereal introduction before 3 months of age may increase childhood celiac disease risk, though delaying beyond 3-6 months shows no protective benefit 1
• Breastfeeding at and beyond gluten introduction may lower risk of developing childhood celiac disease, though research is inconsistent 1
• Large amounts of gluten exposure or gluten introduction without ongoing breastfeeding may increase future celiac disease risk 1

The Immunological Cascade

Once tolerance breaks down, a dual immune response develops:

• The humoral response targets both exogenous gluten antigens and the autoantigen tTG, leading to production of anti-tissue transglutaminase antibodies (TG2Ab) and anti-endomysial antibodies 1
• Gliadin peptides presented to T cells trigger pro-inflammatory cytokine production, lymphocyte infiltration, and subsequent tissue injury 1
• This cascade results in characteristic histological changes: increased intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy 1

Critical Clinical Pitfall

The disease will not develop without all three components present: Even individuals with high genetic risk (HLA-DQ2/DQ8 positive) will never develop celiac disease if they never consume gluten, and gluten exposure alone cannot cause the disease without the genetic predisposition 1. This explains why approximately 30-40% of the general population carries HLA-DQ2 or DQ8, yet only 1% develop celiac disease 1.