Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor

Abstract

Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.

Figure 1

In immunohistological comparison of patient (Left) and normal age-matched (Right) thymus sections, hematoxylin and eosin (H&E) staining revealed fibrous septa separating lobules of lymphoid tissue as seen in normal thymus. However, although cortex and medulla are present in the patient thymus, there is a loss of the normally distinct demarcation between the two areas. Immunohistochemical analysis clearly showed lack of expression of CD1 (second row) but normal staining for CD3 (bottom row), while control samples stained strongly for all three markers. bcl-2 expression in the normal thymus is restricted to the medulla, with few positive cells present within the cortex, whereas the patient’s sample displays a uniformly high level of bcl-2 expression (third row). (Figure is printed at 74% of original magnification.)

Figure 2

(A) EBV-transformed patient B lymphocytes (trace i) and normal control B lymphocytes (trace ii) were stained with anti-CD25 and analyzed by flow cytometry, demonstrating the absence of CD25 expression on patient cells (1.1% positive) compared with a normal control (44% positive). Isotype-matched antibody control staining of patient cells (1.8% positive) is shown in trace iii. LFL2, count. (B) Western blot analysis demonstrates the absence of IL-2Rα protein and elevated IL-2Rβ expression in patient peripheral blood lymphocytes compared with normal.

Figure 3

A 4-bp deletion in the patient’s CD25 gene results in a frameshift in protein translation. The sequence around the deletion (base pairs 60–64) is shown (MUT.) and compared with the sequence and reading frame of normal CD25 (WT.).

Figure 4

Light microscopy of hematoxylin and eosin-stained sections of patient lung biopsy (Upper; ×18,250) shows dilatation of airways, partially collapsed lung tissue, and dense infiltration of lymphocytes in the bronchial wall as well as in the lung parenchyma. No fungal elements were identified by specific staining and no viral particles were identified by electron microscopy (not shown). In addition, hepatitis B and C virus, EBV, and cytomegalovirus sequences were not detected by PCR. Light microscopy of liver sections (Lower; ×18,250) shows preserved lobular architecture, with marked infiltration of lymphocytes in the portal tracts. Consistent with the analysis of the lung biopsy, no fungal or viral elements were identified. Similar dense lymphocytic infiltrates were found in stomach and duodenal biopsies (not shown).