Viral infections in celiac disease: what should be considered for better management

Abstract

Following a gluten-free diet (GFD) is known as the main effective therapy available for celiac disease (CD) patients, which in some cases is not enough to heal all patients presentations completely. Accordingly, emerging researchers have focused on finding novel therapeutic/preventive strategies for this disorder. Moreover, previous studies have shown that celiac patients, especially untreated subjects, are at increased risk of developing viral and bacterial infections, which can become a challenge for the clinician. Viruses, such as Rotavirus, Reovirus, Adenovirus, Enterovirus, Rhinovirus, Astrovirus, Hepatitis virus, COVID-19, Norovirus, and Herpesvirus, have been related to CD pathogenesis. Therefore, clinicians need to pay more attention to evaluate CD patients' viral infection history (especially nonresponders to the GFD), to look for effective preventive strategies and educate patients about important risk factors. In addition, there are still viruses whose role in CD pathogenesis has not been fully studied. In this review, current information on the association between CD and various viral infections was gathered to improve knowledge in this subject area and draw researchers'/clinicians' attention to unstudied/less studied viruses in CD pathogenesis, which might guide future prevention approaches.

Keywords: Autoimmune; Celiac disease; Gluten-free diet; Management; Viral infections.

Fig. 1

Comparative Overview of Oral Tolerance and Intestinal Immune Responses during Viral Infection. Left panel: 1) Antigens that are ingested make their way to the small intestine, where they are captured by CD103-expressing dendritic cells. At the same time, CXC3R1 + macrophages extend their dendrites through the intestinal epithelium to sample antigens from the lumen and transfer these antigens to CD103 + cells for transportation to the mesenteric lymph nodes (MLN). Particulate antigens are taken up by M cells positioned above Peyer’s patches [19, 20]. 2) Dendritic cells loaded with antigens then migrate to the mesenteric lymph nodes, where they present the antigens to naïve CD4⁺ T cells. During this process, DCs secrete transforming growth factor-beta (TGF-β) and retinoic acid (RA), which stimulate the expression of the Treg master transcription factor Foxp3 and equip newly differentiated Tregs with gut-homing receptors CCR9 and α4β7, they may secrete IL-6 to induce the expression of the Tfh master transcription factor BCL6. Subsequently, antigen-specific Tregs and Tfh cells return to the lamina propria of the small intestine. 3a) At this stage, Tregs can produce anti-inflammatory cytokines such as IL-10 and 3b) Tfh cells can activate B cells, converting them into plasma cells that produce IgA [21, 22]. 4) IgA can bind to and neutralize food allergens, thereby enabling oral tolerance to food [23]. Right panel: 1) The early detection of viruses by innate immune cells is facilitated by pattern recognition receptors, including intracellular sensors for DNA and RNA, 1`) which triggers an interferon and cytokine response that alerts neighboring cells and recruits leukocytes. 2) Dendritic cells in the lamina propria migrate to the mesenteric lymph nodes, where they present viral antigens to virus-specific T cells. 3a) Once activated, T cells travel to the intestinal tissue to promote antiviral immunity by secreting cytokines or through exerting cytotoxic effects. 3b) Cytotoxic CD 4 + T cells can lead to the destruction of infected cells by releasing perforin and granzyme B. 3c) B cells activated in Peyer’s patches undergo class switching to IgA and differentiate into plasma cells, supported by follicular T helper cells. 4) The intestinal plasma cells then produce secretory IgA, which serves to neutralize viruses present in the mucosal environment [24, 25].

Fig. 2

A Proposed Model for the Induction of Celiac Disease by Viruses. 1a) Upon entry, gluten antigens are captured by dendritic cells (DCs). 1b) Viruses, such as the T1L reovirus strain T1L, manipulate antiviral responses to establish persistent infections, leading to 2a) the release of type 1 interferons and other mediators that 2b) enhance the expression of interferon regulatory factor-1 (IRF-1) in dendritic cells within the lamina propria. 2c) Both DCs that have taken up gluten and those that have captured viral antigens migrate into the lymphatic vessels. 3) In this cytokine-rich inflammatory environment, antigen-laden dendritic cells travel to the mesenteric lymph nodes. 4) By promoting IRF-1 expression, virus-activated DCs secrete increased levels of IL-12. 5) The presence of IL-12 in the mesenteric lymph nodes activates gluten-specific inflammatory T cells (Th1). 6a These T cells, in turn, secrete IFN-γ, which damages enterocytes. 6b) Additionally, the type 1 interferons induced during T1L infection suppress regulatory T cells, promoting the expansion of Th1 immunity to gluten, a critical element in the pathogenesis of celiac disease [26]