Coeliac disease (CD) is a gluten sensitive chronic enteropathy that affects between 1:100 and 1:300 individuals in the general population of the western world [1]. It is characterised by an increased mortality [2]. Autoimmune disorders such as autoimmune thyroiditis, type 1 diabetes (T1DM), Addison’s disease, autoimmune liver disease, and Sjogren’s syndrome occur much more frequently in patients with CD than in the general population. The clinical relevance of autoimmunity in coeliac disease is threefold: first, it further deteriorates the clinical course of coeliac disease; second, patients might present only with symptoms of secondary autoimmunity and this could favour the diagnosis of minor coeliac disease; and third, gluten withdrawal could improve the control of some associated autoimmune disorders [3]. The associations between CD and T1DM was recognized over 30 years ago, particularly by paediatricians. The prevalence of CD among adults and children with T1DM varies in different geographical populations and is observed to range between 1 and 11 % [4–7]. This close association has been ascribed to the same HLA pattern, namely HLA-DQ2 and/or DQ8, which predisposes individuals to both disorders. Recently, Greco et al. performed a study in the western part of Sicily where they saw that the prevalence of CD among patients with T1DM is 4.5 %. They studied 492 subjects (children and adult patients) with T1DM who had been followed-up regularly at their diabetes unit over a fiveyear period. They found CD in 22 patients [8]. In addition, in accordance with previous studies, they confirmed that CD is more prevalent in female subjects with T1DM than in males [5] and that the age of onset of T1DM is younger in patients with double the disease than in those with diabetes only [6]. None of Greco’s patients presented gastrointestinal symptoms, only two patients presented extraintestinal symptoms (short stature, anaemia and hyposideraemia) and one female patient developed concurrent herpetiformis dermatitis. In fact, one quarter of CD patients with T1DM are totally asymptomatic but the remainder show gastrointestinal symptoms (such as diarrhoea, anorexia, constipation, vomiting, abdominal distension, pain and malnutrition) or extraintestinal symptoms. The most frequent clues in extraintestinal signs are short stature and iron-deficiency anaemia which are present in approximately 50 % of cases; however, fatigue, pubertal delay and vitamin deficiencies are also common, especially in children. Other systemic signs suggesting CD in T1DM patients are a reduced BMI, diminished mass bone, bleeding due to vitamin K deficiency and raised levels of transaminases [9]. CD symptoms (both gastrointestinal and extraintestinal) seem to be much more frequent in children than in adolescents and adults [10]. In the majority of cases (more than 90 %), the diagnosis of T1DM precedes that of CD and Greco et al. confirmed this finding. However, some studies reported that T1DM onset can frequently occur in patients already diagnosed with CD [5]. These data suggest the importance of screening for CD for patients with T1DM at the time of diabetes diagnosis and then annually for several years after diagnosis. In particular, antibody positivity for CD may appear within 6 years from the initial diagnosis of T1DM [4]. Serologial screening for CD consists of endomysial antibodies, antibodies against tissue transglutaminase and deamidated gliadin peptide antibodies. When these antibodies are positive, small intestinal biopsy is mandatory. CD histology is characterized by different degrees of villous A. Marchese E. Lovati F. Biagi (&) G. R. Corazza First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi, 19, 27010 Pavia, PV, Italy e-mail: f.biagi@smatteo.pv.it

HLA-G 14 bp insertion/deletion polymorphism was detected by means of PCR in 118 patients with uncomplicated CD, 19 with complicated CD, 18 with potential CD, and 258 healthy controls. sHLA-G was measured with an ELISA assay in 80 patients with uncomplicated CD while on a gluten-containing diet, 80 with uncomplicated CD while on a gluten-free diet, 25 with complicated CD, 23 with potential CD, and 42 healthy controls. Serum samples from 33 patients with uncomplicated CD were studied before and after the start of a gluten-free diet. Frequency of Ins/Ins genotype was significantly increased in CD patients compared to controls. sHLA-G levels were significantly increased in CD patients by considering them as just one group. However there was no difference among the different groups of CD patients In the patients studied before and after the start of a gluten-free diet, sHLA-G levels were significantly reduced. Interestingly, this reduction (39%) was found only in the patients with a strict gluten-free diet while sHLA-G remained unchanged in patients not on a strict diet. sHLA-G levels are specific for CD and are not due to its activity. Moreover, the reduction of sHLA-G could represent a biological marker of gluten-free diet adherence.

Whipple’s disease (WD) is a very rare chronic systemic condition characterised by a Th2/T regulatory (Treg) dysregulated immune response versus Tropheryma whipplei, a bacterium widely diffuse in the environment. To investigate whether this Th2/Treg polarised response has a genetic background, we investigated the Th1, Th2, Th17 and Treg cytokine genetic profile of 133 patients with WD. Thanks to the European Consortium on WD (QLG1-CT-2002-01049), the polymorphism of 13 cytokine genes was analysed in 111 German and 22 Italian patients using the polymerase chain reaction with sequence-specific primers (PCR-SSP) technique. The frequencies of the genotypes, haplotypes and functional phenotypes were compared with those obtained in 201 German and 140 Italian controls. Clinical heterogeneity was also considered. Functionally, WD patients may be considered as low producers of TGF-β1, having an increased frequency of the genotype TGF-β1+869C/C,+915C/C [12.3 % vs. 3.81 %, odds ratio (OR) = 4.131, p = 0.0002] and high secretors of IL-4, carrying the genotype IL-4-590T/T (5.34 % vs. 1.17 %, OR = 5.09, p = 0.0096). No significant association was found between cytokine polymorphism and clinical variability. Analogously to the recent cellular findings of a Th2/Treg polarised response, we showed that the cytokine genetic profile of WD patients is skewed toward a Th2 and Treg response. This was similar in both German and Italian populations. However, the significant deviations versus the controls are poorer than that expected on the basis of these recent cellular findings.