1. Celiac Disease
Celiac disease (CeD) is defined as a life-long intolerance to dietary gluten that results in small intestinal inflammation, villous atrophy, crypt hyperplasia, and often malabsorption. The ingestion of gluten containing cereal grains, mainly wheat, rye, and barley, drives this T cell driven auto-destructive process within the small intestinal mucosa which usually recovers when these cereals and gluten are rigorously withdrawn from the diet [1
At least 50% of CeD is diagnosed in adulthood, and in the majority of adolescents and adults clinical features at diagnosis are subtle, with mild abdominal discomfort, fatigue, low bone mineralisation and hypocalcaemia, and only rarely manifest anemia, weight loss, infertility, or recurrent aphtous stomatitis. However, up to one third of adults suffer from one or more CeD-associated autoimmune diseases, prominently with autoimmune thyroid disease (AITD) and type 1 diabetes mellitus (T1D), but also rheumatoid diseases including systemic lupus erythematodes, Sjoegren’s syndrome, autoimmune liver diseases, and others [5
]. Severe complications, like refractory CeD type 2, a premalignant condition, and overt enteropathy-associated T-cell lymphoma, occur in patients with longstanding undetected and untreated CeD, but remain rare [6
]. Iron, zinc, vitamin D, vitamin B12, or folic acid deficiency, iron deficiency or overt anemia are the most common laboratory finding. Frequent episodes of hypoglycemia, a reduction of insulin requirements and brittle diabetes may indicate the presence of CeD in patients with T1D [8
]. CeD is considered sufficiently prevalent and the benefits of diagnosis and treatment by gluten withdrawal are such that it is advocated to screen all patients with T1D (and autoimmune thyroid disease) for this disorder.
Both endoscopic-histological diagnosis and the presence of circulating IgA antibodies (Ab) to tissue transglutaminase (TG2) confirm the diagnosis. As shown in Table 1
, anti-transglutaminase antibodies may be of IgG isotype in the presence, but also in the absence of a selective IgA deficiency. This suggests that the gluten-triggered autoantibody response shows mucosal IgA as its main component, while systemic IgG may represent a long-term reaction probably related to the occurrence of extra-intestinal manifestations. Consistently, it has been reported previously that the prevalence of CeD in T1D increases dramatically when the detection of both IgA and IgG autoantibodies is used in the screening. After a gluten-free diet the IgA-TG2-Ab disappear in most patients with CeD, usually with a half-life between 30 and 60 days.
Genetic factors greatly determine susceptibility to CeD. All CeD patients carry HLA DR3/DQ2 (mainly DQA1*0501-DQB1*0201; 85–95%), or HLA DR4/DQ8 (DQA1*0301-DQB1*0302; 5–15%), or both haplotypes [1
]. Exceptions are certain Native American populations that mainly carry DQ8 [9
]. Since, e.g., the prevalence of HLA DQ2 in most populations is between 25 and 50%, only a minority with this necessary but insufficient genetic predisposition will ever develop CeD. This implies the involvement of additional, non-HLA linked genes, as well as environmental factors in CeD manifestation, as discussed below.
The ubiquitous enzyme TG2, the CeD autoantigen, is central to the pathogenesis of CeD, since it can deamidate specific glutamine residues in certain gluten peptides that remain undigested and reach the subepithelial small intestinal lamina propria. This deamidation of the gluten peptides and their haptenization by binding to TG2 itself (autocatalysis) thereby increases their affinity to DQ2 or DQ8 on professional antigen presenting cells like macrophages, dendritic, and B cells, favoring the subsequent gluten specific destructive T cell response [1
3. The Role of a Gluten Free Diet in Preventing Celiac Disease and Glandular Autoimmunity
A large prospective study demonstrated that in infants at genetic risk for CeD and T1D (i.e., from families with at least one affected parent and the DR3/DQ2
risk genes) a careful early introduction of 100 mg gluten per day in the diet from month 5–6 did not prevent celiac autoimmunity compared to placebo [45
]. Moreover, the introduction of gluten at 12 instead of 6 months of age only delayed the onset of CeD, with similar prevalences at age 5 years [46
]. However, a retrospective study indicated that patients on a long-term gluten free diet developed 50% fewer autoimmune diseases in up to 15 years of follow up [47
]. The (retrospective) studies that examined the effect of a gluten free versus gluten containing diet on the development and severity of T1D and AITD remain controversial (Table 3
and Table 4
). Interestingly, T1D appears to precede the development of CeD, as determined by IgA-TG2 Ab positivity, which would assign a less important role to the gluten free diet in the prevention of glandular autoimmunity [19
Several mainly retrospective and correlative studies, often based on registries, have tried to address the question, how far an early diagnosis of CeD and/or a gluten free diet may protect from AITD or T1D. As shown in tables 3 and 4, in these studies early diagnosis of CeD did not appear to protect from the development of T1D [42
]; whereas some studies suggested such protection in AITD [42
]. In comparison, a gluten free diet (GFD) may positively impact the occurrence of T1D rather than of AITD. These somewhat conflicting data need validation in large, prospective studies with well-defined diagnosis and markers of CeD, T1D, and AITD. Such studies are currently performed in children with an increased risk for the three diseases (being offspring of affected parents and carrying the DQ2
genes. However, a beneficial effect of a gluten free diet may be expected, since in general, in children as well as in adults, intestinal inflammation and the associated dysbiosis, with or without underlying CeD, are known to promote extra intestinal autoimmune diseases [60
]. Therefore, any measure that would dampen gut inflammation in CeD patients will likely positively impact the evolution and perhaps the manifestation of glandular autoimmunity.