Autoimmune enteropathy with a CD8⁺ CD7^-T-cell small bowel intraepithelial lymphocytosis: case report and literature review

Immune enteropathies are heterogeneous group of rare conditions characterized by intractable diarrhea, damage to intestinal epithelia and constituent cells, and villous atrophy. These enteropathies may be associated with primary immune deficiencies (PIDs) such as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, common variable immune deficiency and selective IgA deficiency, or may occur in patients with auto-immune phenomena in the absence of PIDs where it is termed auto-immune enteropathy (AIE) [1].

Typically, the diagnosis of immune mediated enteropathy in the setting of PIDs is clear from the clinical features and a pre-existing diagnosis of PID. In contrast, AIE may be diagnosed in patients with no evidence of PIDs, intractable diarrhea refractory to exclusion diets, and no evidence of celiac disease [1].

Cumulatively, immune enteropathies, including AIE, have an unclear pathogenesis. They are all thought to be mediated by immune phenomena, either through direct damage to gut epithelial cells by auto-reactive cells (IPEX) or auto-antibodies (AIE), or from a propensity for bowel infections (IgA deficiency). However, the exact cell types causing damage and the mechanisms of disease remain unclear in many of these conditions.

Herein, we report a patient with an immune mediated enteropathy distinguished from previously reported cases by an unusual CD8⁺ CD7^- IEL in the absence of a PID. We also review the literature to characterize the histologic and immunophenotyic features of AIE, which our patient's enteropathy most closely resembles.

We report a patient with an enteropathy associated with an aberrant CD8⁺CD7^- T-cell IEL. Clinically, on histology and by flow cytometry, our patient had characteristic features of an immune mediated enteropathy. The abberant T-cell subset in our patient was reproducible, polyclonal, and correlated with the presence of clinical symptoms. Moreover, the symptom resolution and weight gain with steroid therapy correlated with improvement in villous architecture and a decrease in the CD8⁺CD7^- T-cell subset. These facts strongly argue that the T-cell subset was at least partially involved in our patient's enteropathy and was potentially causative, especially considering the failure of dietary exclusion, antibiotics and other therapies in inducing clinical, histologic or immunologic improvement. The salient feature of our case therefore remains the aberrant CD8⁺CD7^- IEL in the absence of abnormalities in CD4⁺ or NK cells as have been previously reported in AIE [5, 13].

CD7 is a member of the immuno-globulin superfamily and is expressed on most thymocytes and early in the ontogeny of T- and NK-cells where it is thought to participate in intracellular signaling [14]. The majority of peripheral T-cells in adults bear CD7, but CD7^- T-cells are a normally circulating minority comprising 9% of all peripheral blood monocytes (PMBC). The majority of CD7^- T-cells are CD4⁺ (8% of PMBC) with CD8⁺CD7^- cells accounting for the remaining 1% of PMBC (CD4⁺/CD8⁺ ratio = 8)[15]. Although the exact function of CD7^- T-cells is uncertain, they appear to be terminally differentiated, activated T-cells. Stimulated CD4⁺CD7^- T-cells produce high levels of interleukin-2 and gamma interferon, and compared with CD7⁺ subsets, have augmented proliferative responses to protein antigens [15]. Furthermore, CD7^- T-cells express higher levels of activation markers including CD45RO and CD25 compared with their CD7⁺ counterparts [15]. CD7^- T-cells may also play a role in autoimmune disease evidenced by the increased CD4⁺CD7^- cell expansion and accumulation reported in rheumatoid arthritis [16] and psoriasis [17]. These data suggest that the CD8⁺CD7^- subset demonstrable in our patient were activated cells that were potentially causative.

The diagnosis of AIE requires the presence of auto-immune phenomena, typically taken to be circulating auto-antibodies to intestinal epithelial cells and/or the presence of auto-immune disease(s) in the absence of celiac disease or PIDs. Our patient had no evidence of anti-epithelial cell antibodies, and in the absence of her diagnosis of AIH, had no other auto-immune conditions. Moreover, her diagnosis of AIH, although based on accepted guidelines, is suspect as she had "auto-antibody negative" AIH, a low pANCA titer, and no liver biopsy [2]. Notably the classical AIE criteria remain controversial, with alternative suggestions to limit the AIE to only those with demonstrable anti-gut epithelial cell antibodies or refine the diagnosis based on histologic immuno-phenotypic characteristics [5]. Regardless of whether our patient meet criteria for AIE, the cumulative evidence suggest our patient had an immune mediated enteropathy. This conclusion is further bolstered by the reduced fraction of CD8⁺CD7^- cells concurrent with clinical improvement on prednisone therapy.

Our review finds that AIE is most often characterized by (a) IgG subclass anti-epithelial cell antibodies, (b) preferential small bowel Involvement, and (c) CD3⁺ αβ TCR⁺ intra-epithelial and lamina propria lympocytosis. A protean set of histologic abnormalities have been reported, including: villous atrophy, absence of goblet and paneth cells [3, 4, 18], IEL and infiltrates into the lamina propria (LP). The clinical features and therapeutic response of those with AIE but without anti-epithelial cell antibodies [4, 10, 19, 20] appears indistinguishable to those with antibodies. While the data suggest AIE is associated with a CD3⁺ T-cell intra-epithelial and lamina propria lymphocytosis, it must be judiciously interpreted due to the paucity of cases that reported immuno-phenotypic findings, and because CD3⁺ cells are the dominant subtypes in these compartments. CD4⁺ T cells are thought to be at least partially responsible for AIE based on (a) the phenotypic similarities between AIE and the IPEX syndrome [21, 22], (b) the role of CD4⁺ T cells in villous atrophy [23] and (c) the aberrant CD4⁺ T cell subsets and CD4⁺ IEL reported in some cases of AIE [5]. Despite these points, our review suggests that, at present, there is insufficient evidence to definitively confirm or refute this hypothesis in adult onset AIE. It also remains possible that AIE is the common phenotypic result of a heterogeneous set of mechanistic abnormalities rather than a single unified condition.

Our patient likely had an auto-immune enteropathy associated with an aberrant CD8+CD7- T-cell IEL. Our review of adult onset AIE suggest that the most common features are the presence of IgG type anti-gut epithelial antibodies and preferential small bowel involvement.

Written informed consent was obtained and the study was approved by the institutional review board of the University of Kentucky Medical Center.