Celiac disease (CeD) is a common immune-mediated disorder, with a global prevalence of 1–2 % affecting individuals with a genetic HLA-DQ2 or HLA-DQ8 predisposition of all age groups[1]. The disease is characterized by small bowel mucosal damage with villous atrophy and crypt hyperplasia, which develops gradually in response to ingestion of gluten present in wheat, rye and barley. This mucosal damage is driven by a gluten-induced immune response with both adaptive and innate components. Moreover, CeD also encompasses an autoimmune reaction hallmarked by the presence of disease-specific IgA-class transglutaminase 2 (TG2) and endomysial antibodies (EmA) that both target the CeD autoantigen TG2[2], [3]. In addition, the patients may also present with circulating anti-gliadin antibodies (AGA) and anti-deaminated gliadin peptide (DGP) antibodies of both IgA and IgG-class, which however are generally not exploited in clinical practice[4]. Interestingly, TG2 antibodies may be present in the circulation despite normal small intestinal morphology[5]. Some individuals with such a potential CeD (PCeD) presentation may develop overt CeD with small bowel damage upon continuation of gluten consumption[6]. In the vast majority of cases, the removal of gluten from the diet leads to restoration of the small bowel mucosal morphology but in refractory CeD (RCeD), the mucosal damage persists despite a strict gluten-free diet (GFD)[7]. Thus, the immunopathological responses to gluten and its withdrawal from the diet show heterogeneity in the small intestine. Typically, CeD presents with gastrointestinal symptoms such as malabsorption-dominated diarrhea, steatorrhea, failure to thrive, and weight loss. However, the clinical presentation of CeD is highly variable and the symptoms can extend beyond the gastrointestinal tract[8]. A wide range of extraintestinal manifestations affecting skin, the musculoskeletal system, reproductive health and neuronal tissues have been reported in the context of CeD[9]. Thus, the presentation of CeD varies greatly across patients, with varying degree of small bowel damage, treatment response as well as intestinal and extraintestinal manifestations contributing to the heterogeneous disease phenotype. Improving understanding of the immunological nuances behind these varying presentations would allow for the development of more efficient diagnostic and therapeutic strategies [10]. The aim of this review is to summarize the current understanding of the differential immune responses occurring in the context of the heterogeneous clinical presentation of CeD.