Celiac Disease and Endocrine Autoimmune Disorders in Children

An Update

Antonella Diamanti; Teresa Capriati; Carla Bizzarri; Fabio Panetta; Francesca Ferretti; Monica Ancinelli; Francesca Romano; Mattia Locatelli

Disclosures

Expert Rev Clin Immunol. 2013;9(12):1289-1301. 

In This Article

Environmental Factors

Gluten is the main environmental factor responsible for CD signs and symptoms; however, gluten exposure does not fully explain the manifestation of CD and AI.

Early feeding practices (e.g., breast milk vs formula, duration of breastfeeding, pattern/timing of gluten introduction in infant feeding), infections and alterations in the intestinal microbiota composition might, indeed, play a role in CD and AI development.

Gluten & Pattern of Infant Nutrition

Gluten represents the main environmental factor that triggers CD. The high proline content makes gluten proteins resistant to complete proteolytic digestion, leading to the accumulation of relatively large peptide fragments with a high proline and glutamine content in the small intestine triggering abnormal immune response in susceptible individuals.

The exposure of an immature immune system to gliadin, a gluten protein component, in susceptible individuals seem to be a prominent cofactor in modifying the immunological response earlier in life, thus predisposing such individuals not only to overt CD, but also to AI.[5,9]

The pattern of infant nutrition may play a critical role on the development of CD and other AI. A longitudinal follow-up study of a cohort of children with dietary gluten exposure before 3 months of age highlighted a significantly increased risk of developing CD-associated autoantibodies compared with the exposure at 4–6 months of age or later.[19] Furthermore, breastfeeding is thought to delay or reduce the risk of developing CD.[20,21] This protective effect seems to be due to the different pattern of intestinal microbiota in breastfed infants (see below).

In both European and US infant populations, it is not recommended to introduce the complementary feeding containing gluten too early (<4 months) or too late (≥7 months) and to start gluten while the infant is still breastfed.[22–25]

Intestinal Microbiota

The composition of the intestinal microbiota has also been recently related to the development of CD. The first associations were established in CD patients, untreated and treated by GFD.[26–28]

The microbiota pattern of CD patients seems to be characterized by increased numbers of Bacteroides spp. and a reduced presence of Bifidobacterium spp. and B. longum, which were not completely normalized by GFD.[26–28]Escherichia coli and Staphylococcus numbers also resulted higher in feces and biopsies of untreated CD patients than in those of controls, but this difference recovered after gluten withdrawal.[27] The milk-feeding patterns and HLA-DQ genotype could have a possible effect on microbiota early in life and, consequently, on later development of CD.[29,30] Some studies have reported a protective effect of breastfeeding on CD onset, probably partly related to the ability of human milk to modulate the intestinal microbiota differences related to genotype HLA-DQ.[21,31]

Human studies have shown a relationship between the changes in the composition of the intestinal microbiota and T1D development.[32] This hypothesis seems to be confirmed by the data taken from studies on animal models as biobreeding.[33] LEW1.WR1 rat models of virus-induced T1D[34] and the nonobese diabetic mouse.[35–37] In particular, there are evidences that the cross-talk between the gut microbiota and the innate immune system may be involved in the destruction of the islet. Although the causal link between gut microbiota and T1D is evident, the identity of the bacteria involved and the mechanism by which they promote the disease remains unclear.

There are only a few studies that have evaluated the link between the gut and Hashimoto's thyroiditis.[38]

Literature reports several evidences that Hashimoto's thyroiditis also involves ultrastructural changes of enterocytes associated with functional alterations of the intestinal barrier similar to those observed in nonceliac patients with T1D. Although these data need further confirmation, they suggest that the endocrine autoimmune diseases have similar autoimmune pathogenetic mechanisms of cell damage and impaired intestinal morphology and function.[39]

Infectious Diseases

It is known that infectious agents are potential AI triggers. It has also been suggested that in patients with CD, exposure to viruses or bacteria might contribute to a reduction of tolerance to gluten, being the cause of tissue damage and inflammation.[40] Infections can also influence the host immune tolerance through three main mechanisms: polyclonal activation of lymphocytes, increased immunogenicity of the organ of self-antigens secondary to infection and inflammation mediated by antigen molecular mimicry (autoimmune response related to cross-reactivity between epitopes of the host man and immunologically similar epitopes of the infectious microorganism).[41]

There are several studies linking the onset of CD (in susceptible patients) with different infectious agents and several hypotheses have been made about the possible pathogenic mechanisms of these associations.[42]

The adenovirus Type 12 was one of the first infectious agents associated with CD,[43] although further studies have not confirmed this association. Hepatitis C virus (HCV) has an epidemiologic association with the onset of CD: in fact, CD prevalence in patients with chronic liver disease is higher (15-times) than in the general population.[44] CD is also present in 5% of patients with autoimmune liver disease.[45] Several other studies have not shown an increased prevalence of CD in patients with HCV infection,[46] thus concluding that the association between CD and HCV can also be random.[47]

On the basis of these studies, it has been suggested that gastrointestinal infections may trigger or facilitate the onset of CD by amplifying the immune response to gliadin or increasing intestinal permeability.[48]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....