Chapter Seven - Cellular and molecular bases of refractory celiac disease

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Abstract

Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by a polyclonal expansion of IELs displaying a normal immunophenotype, while RCD II represents a clonal proliferation of immunophenotypically “aberrant” IELs, and is considered a low-grade lymphoproliferative disorder. The pathogenesis of RCD I has not been clarified, but limited studies suggest multifactorial etiology. On the other hand, recent immunologic, molecular and immunophenotypic analyses have proposed lineage-negative innate IELs to be the cell of origin of a proportion of RCD II cases. Furthermore, sequencing studies have identified frequent, recurrent, activating mutations in members of the JAK-STAT pathway in RCD II. This finding, in conjunction with prior in vitro experimental observations, suggests roles of deregulated cytokine signaling in disease pathogenesis. In this review, we describe current understanding of environmental, immune and genetic factors associated with the development of RCD and briefly discuss diagnostic and therapeutic considerations.

Introduction

Celiac disease (CD) is a common (prevalence ~1%) (Singh et al., 2018) chronic immune-mediated disorder, which develops in genetically susceptible individuals in response to gluten ingestion (Green and Cellier, 2007). Although CD patients universally have small bowel mucosal alterations and often present with gastrointestinal (GI) symptoms, studies over the past couple of decades have revealed a high frequency of extra-intestinal manifestations and autoimmune diseases in those afflicted with CD (Hadjivassiliou et al., 2015; Leffler et al., 2015). The diagnosis of CD is based on a constellation of clinical findings, abnormal small bowel histopathology, and detection of circulating celiac-associated autoantibodies. A gluten-free diet (GFD) is effective treatment for the majority of patients, leading to mucosal healing and resolution of symptoms, but a subset (7–30% Leffler et al., 2007; O’Mahony et al., 1996) experience ongoing or recurrent GI symptoms and have villous atrophy, despite adhering to a strict GFD, and are considered to have non-responsive celiac disease (NRCD) (Penny et al., 2020). Slow or incomplete mucosal healing can be attributed to surreptitious gluten ingestion in a significant proportion of individuals with NRCD. However, if gluten ingestion and other CD-associated etiologies for persistent disease symptoms lasting >12 months have been excluded, the patient is deemed to have refractory celiac disease (RCD) (Ludvigsson et al., 2013; Penny et al., 2020).

Ever since its initial description, RCD has been recognized to be biologically and clinically heterogeneous (Ashton-Key et al., 1997; Murray et al., 1995; Wright et al., 1991), with multiple investigators demonstrating clonal expansions of phenotypically abnormal intraepithelial lymphocytes (IELs) in small intestinal biopsies from certain RCD patients (Brousse et al., 1999; Carbonnel et al., 1998; Cellier et al., 1998). Subsequently a clonal relationship between RCD and enteropathy-associated T-cell lymphoma (EATL) was established (Bagdi et al., 1999; Cellier et al., 2000; Daum et al., 2001), affirming that some cases of RCD are precursors to EATL. In 2005, RCD was subclassified into two subtypes, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the IELs (Daum et al., 2005). RCD I is characterized by a polyclonal expansion of immunophenotypically normal IELs, similar to that observed in uncomplicated CD. Conversely, RCD II constitutes a clonal expansion of immunophenotypically “aberrant” IELs, and is considered to represent a low grade lymphoma of intraepithelial T-lymphocytes or “cryptic” EATL (Alfsen et al., 1989; Daum et al., 2005; van Wanrooij et al., 2014; Verbeek et al., 2008a).

Section snippets

Epidemiology

Studies from specialized centers have described the prevalence of RCD to be 1.5–10% among celiacs (Arguelles-Grande et al., 2013; Leffler et al., 2007; O’Mahony et al., 1996; Roshan et al., 2011; Rubio-Tapia et al., 2009) and 8–23% among those with NRCD (Abdulkarim et al., 2002; Dewar et al., 2012; Roshan et al., 2011). However, population based studies report a much lower prevalence of RCD — 0.31–0.38% among celiacs (Biagi et al., 2014; Ilus et al., 2014) and 0.002% in the general population (

Genetic susceptibility

CD has a strong hereditary component, as demonstrated by familial clustering and high concordance in monozygotic twins (Fasano et al., 2003; Kuja-Halkola et al., 2016; Singh et al., 2015). The majority of CD patients carry the HLA-DQ2.5 (DQA1*0501, DQB1*0201) or HLA-DQ8 (DQA1*0301, DQB1*0302) risk alleles (Jabri and Sollid, 2017; Meresse et al., 2012), the remaining harboring either HLA-DQ2.2 (DQA1*0201, DQB1*0201) or HLA-DQ7.5 (DQA1*0505, DQB1*0301) (Karell et al., 2003). These alleles are

Mucosal lymphoid populations in the small intestine

Normal small intestinal mucosa hosts a variety of lymphocytes within the epithelium and lamina propria, including distinct subtypes of lymphocytes and innate lymphoid cells (Calleja et al., 2011; Eberl et al., 2015; Eiras et al., 2000; Jarry et al., 1990; Leon et al., 2003; Schmitz et al., 2016; van Wijk and Cheroutre, 2009). These cells orchestrate myriad functions, including regulation of mucosal immunity and inflammation, antimicrobial defense and maintenance of oral tolerance to dietary

Clinical features

By definition, patients with RCD I and RCD II experience persistent or recurrent gastrointestinal symptoms, including diarrhea, abdominal pain, and weight loss (Ilus et al., 2014; Malamut et al., 2009; Rubio-Tapia et al., 2009), which tend to be more severe in RCD II. Laboratory studies often reveal evidence of malabsorption, including vitamin deficiencies and hypoalbuminemia. Primary refractoriness (lack of response to GFD at diagnosis) is noted in approximately 30% of RCD I and 50% of RCD II

Limitations of the current RCD classification

The current RCD classification does not fully integrate the spectrum of clinical, histopathologic and immunophenotypic features of RCD. Gastrointestinal symptoms are the only RCD clinical criterion. Extra-intestinal manifestations, including neurologic, dermatologic, arthritic, hepatic, and osteologic disorders, are well-documented in CD (Hadjivassiliou et al., 2014; Jericho et al., 2017; Sarrigiannis et al., 2014; Stier et al., 2019) and some RCD patients, including those with RCD II (

Management

Contemporary therapeutic management of RCD patients is discussed in more detail elsewhere (Al-Toma et al., 2019; Baggus et al., 2020; Hujoel and Murray, 2020; Penny et al., 2020), and the principles are briefly summarized here. While RCD patients show persistent symptoms despite adherence to a GFD by definition, compliance with a strict GFD is strongly recommended to dampen mucosal inflammation. There is currently no cure for RCD II and the goals of therapy are to mitigate malnutrition and

Unanswered questions and future directions

Advances in the clinical, pathologic, immunologic and molecular characterization of RCD have furthered our understanding of disease biology, however, many questions remain unanswered. It is unclear whether systematic evaluation of cytokine alterations will resolve biologic subsets of RCD I or II patients that require different therapies. The constellation of non-HLA germline genetic alterations that predispose to RCD I or II are not known, as are microenvironmental factors influencing the

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