New Clues in Celiac Disease Epidemiology, Pathogenesis, Clinical Manifestations, and Treatment

Figures & data

FIGURE 1  The celiac iceberg model.

FIGURE 2  Prevalence of celiac disease in the US during the last decades [22].

FIGURE 3  A simplified scheme of the adaptive immune response to gluten in celiac disease from gluten ingestion to intestinal damage. (1) Gluten peptides reach the lamina propria via either an increased epithelial tight junctional permeability or epithelial transcytosis. (2) Deamidation of gluten peptides by tissue transglutaminase creates potent immunostimulatory epitopes that (3) bind to HLA-DQ2 or HLA-DQ8 on antigen-presenting cells and (4) activate CD4+ T cells. (5) Activated CD4+ T cells secrete mainly Th1 cytokines, such as IFN-γ, which induces the release and activation of metalloproteases by myofibroblasts, (6) finally resulting in mucosal remodeling and villus atrophy. (7) CD4+ T cells also increase cytotoxicity of intraepithelial lymphocytes or natural killer (NK) T cells, thus leading to enterocyte apoptotic death. (8) Through the production of Th2 cytokines, activated CD4+ T cells also drive the activation and clonal expansion of B cells, which differentiate into plasma cells and produce antibodies to gluten and transglutaminase, contributing to the intestinal damage.

Table 1  Clinical manifestations of celiac disease (CD).

Typical CD	Atypical CD	Associated autoimmune diseases	Associated genetic diseases
Chronic diarrhea	Anemia (iron, vitamin B12, folic acid deficiency)	Type 1 diabetes	Down syndrome
Failure to thrive	Short stature	Autoimmune thyroiditis	Turner syndrome
Abdominal distension	Osteopenia/osteoporosis	Autoimmune hepatitis	Williams syndrome
Muscle wasting	Hypertransaminasemia	Myasthenia gravis	IgA deficiency
Anorexia	Dermatitis herpetiformis	Primary biliary cirrhosis
Behavioral changes	Dental enamel hypoplasia	Primary sclerosing cholangitis
	Recurrent aphtous stomatitis	Psoriasis
	Recurrent abdominal pain	Sjögren disease
	Vomiting
	Constipation
	Headache
	Polyneuropathy
	White matter lesions
	Cerebellar ataxia
	Epilepsy
	Pubertal delay
	Recurrent abortions
	Infertility

Table 2  Potential novel therapies for celiac disease.

Objective	Therapeutic agent
Decrease gluten exposure	Wheat variants with low immunogenicity [67–69]
	Transamidation of gliadin [70]
	Pre-treatment with probiotics [71]
	Prolyl endopeptidases from Aspergillus niger or Sphingomonas capsulata + barley endoprotease [72–74]
	Polymeric gliadin binders [75]
Inhibit intestinal permeability	Zonulin receptor antagonist [76]
Modulate the immune response	Tissue transglutaminase inhibitors [77, 78]
	HLA-DQ2/DQ8 blocker [79–82]
	Gluten vaccination [83]
	Anti-interleukin 15 [84]
	Anti-interferon-γ [85]
	Anti-tumor necrosis factor-α [86]
	Anti-CD52 [87]
	Interleukin 10 [88]

Catassi C, Kryszak D, Bhatti B, Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010;42:530–538.

 PubMed Web of Science ®Google Scholar

Gianfrani C, Siciliano RA, Facchiano AM, Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology. 2007;133:780–789.

 PubMed Web of Science ®Google Scholar

Di Cagno R, De Angelis M, Auricchio S, Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appl Environ Microbiol. 2004;70:1088–1096.

 PubMed Web of Science ®Google Scholar

Pinier M, Verdu EF, Nasser-Eddine M, Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. 2009;136:288–298.

 PubMed Web of Science ®Google Scholar

Kelly CP, Green PH, Murray JA, Intestinal permeability of larazotide acetate in celiac disease: results of a phase IIB 6-week gluten-challenge clinical trial [abstract]. Gastroenterology. 2009;136(Suppl 1):A474.

 Google Scholar

Keech CL, Dromey J, Chen Z, Immune tolerance induced by peptide immunotherapy in an HLA-DQ2-dependent mouse model of gluten immunity. Gastroenterology. 2009;136:A355.

 Web of Science ®Google Scholar

Baslund B, Tvede N, Danneskiold-Samsoe B, Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 2005;52:2686–2692.

 PubMed Web of Science ®Google Scholar

Hommes DW, Mikhajlova TL, Stoinov S, Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut. 2006;55(8):1131–1137.

 PubMed Web of Science ®Google Scholar

Costantino G, della Torre A, Lo Presti MA, Treatment of life-threatening type I refractory coeliac disease with long-term infliximab. Dig Liver Dis. 2008;40:74–77.

 PubMedGoogle Scholar

Vivas S, Ruiz de Morales JM, Ramos F, Alemtuzumab for refractory celiac disease in a patient at risk for enteropathy-associated T-cell lymphoma. N Engl J Med. 2006;354:2514–2515.

 PubMed Web of Science ®Google Scholar

Salvati VM, Mazzarella G, Gianfrani C, Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa. Gut. 2005;54:46–53.

 PubMed Web of Science ®Google Scholar