Association of celiac disease and hereditary angioedema due to C1-inhibitor deficiency. Screening patients with hereditary angioedema for celiac disease: is it worth the effort?

OBJECTIVE: Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases. METHODS: One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up. RESULTS: Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema. CONCLUSION: Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet.

Detection of complement activation on antigen microarrays generates functional antibody profiles and helps characterization of disease-associated changes of the antibody repertoire.

Humoral immune responses are traditionally characterized by determining the presence and quality of Abs specific for certain Ags. Arraying of large numbers of Ags allows the parallel measurement of Abs, generating patterns called Ab profiles. Functional characterization of these Abs could help draw an even more informative map of an immune response. To generate functional Ab profiles we simultaneously tested not only IgM, IgG, and IgA binding to, but also complement activation by, a panel of endogenous and exogenous Ags printed as microarrays, using normal and autoimmune human sera. We show that complement activation by a particular Ag in a given individual cannot be predicted by the measurement of Ag-specific Abs, despite a general correlation between the amount of Ag-bound Ab and the deposited C3 fragments. This is due to both differences in the isotypes that dominate in the recognition of an Ag and individual variations for a given isotype, resulting in altered complement activation potential. Thus, Ag-specific C3 deposition can be used as an additional parameter in immune response monitoring. This is exemplified by comparing the coordinates of Ags, used for the diagnosis of systemic lupus erythematosus, of normal and autoimmune serum samples in a two-dimensional space derived from C3 deposition and Ab binding. Since cleavage fragments of C3 mediate important immunological processes, we propose that measurement of their deposition on Ag microarrays, in addition to Ab profiling, can provide useful functional signature about the tested serum.

[Methods of screening for adult celiac disease in patients attending ambulatory care service in immunology]. / A felnóttkori coeliakia felismerésének lehetósége szúróvizsgálatok alkalmazásával immunológiai szakambulancián jelentkezó betegekben.

INTRODUCTION: Coeliac disease (gluten sensitive enteropathy) is a very frequent disease appearing in variegated clinical form. In the last decade--concerning the immunogenetic and immunopathological aspects of the disease many of new recognition came to alight. AIM: As the disease can lay hidden in its non classical manifesting form for a very long time, authors wished to study the efficacy of screening, which may be introduced for patients attending immunological outpatient care service. PATIENTS, METHODS AND RESULTS: In the frame of nation-wide patient care, out of the 200 potential patients sent for immunological check up, various form of coeliac disease was diagnosed in 20 cases. Among these cases there are two--presented for the first time--which are connected to bone marrow transplantation. Based on the immunogenetics and autoantibody serology as well as on small intestine biopsies the following conclusions were made. CONCLUSION: 1. Coeliac disease in Hungary is very frequent. Hidden disease should be considered first of all in cases of malabsorption symptoms. 2. Demonstration of autoantibodies on wide-scale palette helps to state the diagnosis based on the systematic auto-immune disease connection. 3. Study of Human Leukocyte Antigen allotype (HLA-DQA1*0501/DQBI*02) applied as marker can considerably support the suspicion of disease. 4. Histology test of the small intestine cannot be omitted.

High normal serum levels of C3 and C1 inhibitor, two acute-phase proteins belonging to the complement system, occur more frequently in patients with Crohn's disease than ulcerative colitis.

Few data are available on measurements of serum concentrations of complement proteins in inflammatory bowel disease (IBD). Therefore we measured serum levels of C3, C4, and C1-esterase inhibitor (C1-INH) as well as C-reactive protein (CRP) in 167 patients with Crohn's disease (CD) and 111 patients with ulcerative colitis (UC). Median serum concentrations of C3 and C1-INH were significantly higher in CD than in UC. According to multiple logistic regression analysis adjusted to age, sex, activity of disease, and presence of extraintestinal manifestations, IBD patients with high-normal (> or = 128%, > or = 75th percentile ) C1-INH concentrations had significantly (0.0275) higher odds ratio to have a diagnosis of CD than UC. Patients with high-normal C3 (> or = 1.40 g/liter) and high (> or =20 mg/liter) CRP concentrations had an even higher odds ratio of a CD diagnosis (P = 0.0132). Our findings indicate that measurement of C3, C1-INH, and CRP can be used as an additional marker to pANCA/ASCA for distinguishing patients with CD and UC.

Impaired humoral immune response against mycobacterial 65-kDa heat shock protein (HSP65) in patients with inflammatory bowel disease.

Since only scarce data are available on the immune response against heat shock proteins (HSP) in inflammatory bowel disease (IBD), we have measured with an ELISA method serum levels of IgG, IgA, and IgM antibodies to mycobacterial HSP65 and human HSP60 in 66 patients with Crohn's disease (CD), 42 patients with ulceratiVe colitis (UC), and 126 age-and gender-matched healthy controls. Serum concentration [median (25th-75th percentiles) of IgG anti-HSP65 antibodies was substantially lower in patients with either CD (P < 0.01) or UC (P < 0.001) than in healthy controls, while no difference was found in the levels of anti-HSP60 antibodies. Low anti-HSP65 antibody levels were measured in patients with active CD and in both active and inactive UC, and only in IBD patients with no extraintestinal manifestations. In conclusion, our present findings indicate that an abnormal immune response to bacterial HSP65 or some epitopes of the protein may contribute to the dysregulation of host defenses against certain intestinal bacteria.