Celiac disease (CD) is a specific enteropatic response to gluten, a protein found in wheat, barley, and rye. In the people affected by the CD, eating gluten causes an immune response leading to serious changes of small intestine tissue architecture and as a consequence to malabsorption 1,2 . CD is an inflammatory disorder characterized by the leukocyte infiltration that develops in genetically susceptible individuals as the result of an inappropriate immune response to gluten proteins. CD4 (+) T cells that recognize deaminated gluten peptides bound to predisposing HLA-DQ molecules (DQ2.5, DQ2.2, and DQ8) play a key pathogenetic role in CD 3 . Interestingly, the deamidation of the gluten peptides is catalyzed by the enzyme type 2 transglutaminase (TG2) to which antibodies are produced representing the hallmark of the disease 4,5 . In addition to autoimmunity, TG2 has been implicated in all major human pathological conditions, including neurodegenerative and metabolic disorders, fibrosis, and cancer. TG2 is a peculiar member of the transglutaminase family since it catalyzes, in addition to the canonical Ca2+-dependent transamidating activity, several other enzymatic activities (GTPase/ATPase, protein disulfide isomerase, protein kinase) as well as nonenzymatic functions based on its non-covalent scaffold interactions with many cellular proteins. Due to its multifunctionality, TG2 has been reported to have a complex biology playing a role in a variety of cellular processes, such as differentiation, survival, apoptosis, autophagy, and cell adhesion 6,7 . The identification of autoantibodies against TG2 in CD was first reported by Dieterich et al. in 1997 8 . Since then, the detection of the IgA anti-TG2 Ab has become the most widely used test both for the diagnosis and initial screening for CD because of its very high sensitivity and specificity 9 . Despite the accepted evidence of the involvement of TG2 in the CD, there are still many open questions about its role in the disease's pathogenesis.Recently, in addition to the T cells, a role for B cells in the CD pathogenesis is receiving increased attention from the scientific community. A recent study appeared in Journal Experimental Medicine 10 from the Sollid's group has elucidated the function of B cells in the CD pathogenesis. To address this problem the authors developed an Ig knock-in mouse based on the CD-derived B cell receptor (BCR) able to react with both human and mouse TG2. This mouse was then crossed with Tgm2 knock out mice producing a new elegant model to study the functional behavior of B cells in the presence and in the absence of the autoantigen. Surprisingly the data obtained by this new animal model showed that there is not clonal deletion and/or anergy development to TG2. Instead, breaking B cell tolerance to the presence of the TG2 autoantigen required the help provided by the T cells. In the J. Exp. Med. paper, the authors demonstrated that nontolerized TG2-specific B cells can produce autoantibodies once gluten-specific T cells provide help. In...