T-Cell Depletion in the Colonic Mucosa of Patients With Idiopathic CD4⁺Lymphopenia

Abstract

Idiopathic CD4(+) lymphopenia (ICL) is a rare syndrome characterized by low peripheral CD4(+) T-cell counts that can lead to serious opportunistic infections. The pathogenesis of ICL remains unclear, and whether effector sites are also lymphopenic is unknown. In this study, rectosigmoid mucosal biopsy specimens from patients with ICL and healthy controls were evaluated. Significant T-cell lymphopenia was observed in the mucosal tissue of patients with ICL by flow cytometry and immunohistochemistry, compared with healthy controls. Functional capacity of T cells, assessed by production of interferon γ and interleukin 17, was preserved in the mucosa of patients with ICL. In contrast to T lymphocytes, the frequency of myeloid cells (neutrophils and macrophages) was elevated in the colonic mucosa of patients with ICL. Despite the observed mucosal abnormalities, plasma levels of intestinal fatty acid binding protein, a marker of enterocyte turnover and other inflammatory biomarkers, including interleukin 6, C-reactive protein, and tumor necrosis factor, were not elevated in patients with ICL, compared with healthy controls, whereas soluble CD14 levels were minimally elevated. These data suggest that patients with ICL, despite gut mucosal lymphopenia and local tissue inflammation, have preserved enterocyte turnover and T-helper type 17 cells with minimal systemic inflammation. These observations highlight differences from patients with human immunodeficiency virus infection, with or without AIDS, and may partially explain their distinct clinical prognosis.

Humanized mouse models reveal an immunologic classification of idiopathic CD4 lymphocytopenia subtypes

“…Similar to blood, the spleen, lymph nodes (LNs), bone marrow, and liver from ICL hPBMC mice showed much lower percentages of CD3 + T cells than HC hPBMC mice ( Figure 4B). Therefore, and similar to our previous findings in patients with ICL (38), the lymphopenia observed in ICL hPBMC mice was not caused by increased migration and/ or retention of ICL CD3 + T cells into lymphoid or nonlymphoid tissues. The numbers of CD4 + , CD8 + , γδ T cells, and B cells in the spleen corroborated the generalized lymphopenia observed in ICL mice relative to HC mice ( Figure 4C).…”

<p>Idiopathic CD4 Lymphocytopenia: Current Insights</p>

“…In rectosigmoid endoscopies of 12 patients with ICL, reduced CD4 lymphocytes with normal functional indicators of enterocyte turnover (intestinal fatty acid-binding protein and inflammatory biomarkers) were observed. 20 In this study, patients with ICL had a higher percentage of DN T cells when compared to controls, but T H 1 and T H 17 cell subsets were normal. This suggested tissue depletion of CD4 + and not entrapment of CD4 + cells in the mucosa.…”

“…This suggested tissue depletion of CD4 + and not entrapment of CD4 + cells in the mucosa. 20 This contrasted with the observation by Griffiths et al 42 In three cases of erythroderma, one each due to cutaneous T cell lymphoma, atopic dermatitis, and psoriasis, they found CD4 + counts were markedly increased in the skin with high CD4:CD8 ratios and simultaneous peripheral blood CD4 lymphocytopenia. 42 In these patients, resolution of the erythroderma resulted in normalization of CD4 counts.…”

“…19 In a study by Kovacs et al, patients with ICL had a lower percentage of naïve cells in the rectosigmoid mucosa compared to effector and central memory cells. 20 A higher proportion of Tregs (CD25 + FoxP3 + CD4 + ) is also seen in ICL. 18 Enhanced CD45RO expression with reduced CD45RA expression (lower naïve T cell) and increase in γδ-TCR cells was reported in a 9-year old boy with ICL and was suggestive of a maturation defect.…”

Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia

“…18 After observing increases in T cells in the peripheral blood following rhIL-7 treatment, we wanted to assess whether T cells were also increased in the tissues. As we found previously, immunohistochemical analysis of Figure 7A-B Figure 2A-B).…”