SUMMARY

 

1. IL-2 receptor alpha chain (CD25) deficiency is an autosomal recessive form of SCID characterized by the following features:

- Combined immunodeficiency

- Lymphoproliferation

- Autoimmune disorders

 

2. While this disease has many clinical similarities to IPEX syndrome with regard to autoimmune manifestations, CD25 deficiency patients also have combined immunodeficiency which results in extensive infectious complications.

 

3. Patients typically present with invasive viral (CMV), bacterial and fungal infections typical of SCID. Lymphoproliferation manifests as lymphadenopathy and hepatosplenomegaly. Autoimmune features include severe autoimmune enteropathy with FTT, type I diabetes, autoimmune hemolytic anemia, and autoimmune neutropenia.

 

4. Laboratory studies reveal normal or reduced CD3 T cell numbers. CD25 surface expression is absent on resting and activated T cells. In vitro lymphocyte proliferation to mitogens is poor. Normal or elevated immunoglobulin levels are present. A variety of serum autoantibodies may be detected.

 

5. Small bowel biopsy reveals chronic inflammation and villous atrophy (similar to IPEX syndrome).

 

6. CD25 deficiency should be suspected in patients presenting with a SCID phenotype and severe autoimmune disease. CD25 surface expression on activated T cells will be absent. Sequencing of the IL2RA gene can confirm the diagnosis.

 

7. The differential diagnosis includes other types of SCID, Omenn syndrome, SCID with maternal engraftment, Wiskott-Aldrich syndrome, and IPEX syndrome.

 

8. Aggressive treatment of invasive infections is the mainstay of therapy. Standard precautions for SCID should be implemented including the following:

- Avoid all live viral vaccines

- Only irradiated, CMV negative blood products should be used (to prevent GVHD and infections)

- Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole

- IVIG replacement therapy

 

9. Immunosuppressive therapies are required for treatment of autoimmune manifestations such as enteropathy. Supportive treatment with TPN may be required for patients with FTT secondary to enteropathy. HSCT is the only known curative therapy for patients.

 

 

 

                                                                                                                   

OVERVIEW

 

          IL-2 receptor alpha chain (CD25) deficiency is an autosomal recessive form of SCID characterized by the following features:

- Combined immunodeficiency

- Lymphoproliferation

- Autoimmune disorders

 

          CD25 is necessary for proper T cell proliferation in response to IL-2. It is also required for normal function of FOXP3+ T regulatory cells. While this disease has many clinical similarities to IPEX syndrome with regard to autoimmune manifestations, CD25 deficiency patients also have com

 

          Patients present with invasive viral (CMV), bacterial and fungal infections typical of SCID. Lymphoproliferation manifests as lymphadenopathy and hepatosplenomegaly. Autoimmune features include severe autoimmune enteropathy with FTT, type I diabetes, autoimmune hemolytic anemia, and autoimmune neutropenia.

 

          Laboratory studies reveal normal or reduced CD3 T cell numbers. CD25 surface expression is absent on resting and activated T cells. In vitro lymphocyte proliferation to mitogens is poor. Normal or elevated immunoglobulin levels are present. A variety of serum autoantibodies may be detected.

 

Small bowel biopsy reveals chronic inflammation and villous atrophy (similar to IPEX syndrome).

 

 

 

PATHOGENESIS

 

         The high affinity IL-2 receptor is composed of an alpha, beta, and gamma subunit (the beta and gamma chains together can form a low affinity IL-2 receptor). The beta and gamma chains are constitutively expressed on T cells but alpha chain expression is restricted to early T cell differentiation and activated mature T cells. The high affinity IL-2 receptor is necessary for proper T cell proliferation in response to IL-2 following stimulation of the T cell receptor.

 

          CD25 is also highly expressed on CD4+FOXP3+ T regulatory cells. These cells function to maintain peripheral tolerance by suppressing autoreactive T cells. CD25 is required for the proper function of T regulatory cells; this explains the increased incidence of autoimmunity found in patients with CD25 deficiency.

 

 

 

                                   

EVALUATION

 

CD25 deficiency should be suspected in patients presenting with a SCID phenotype and severe autoimmune disease. The differential diagnosis includes other forms of SCID, Omenn syndrome, SCID with maternal engraftment, Wiskott-Aldrich syndrome, and IPEX syndrome.

 

 

Step 1: Immune Evaluation

         

                      - CBC with Differential

- Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)

- Naive (CD45RA) and memory (CD45RO) T cell enumeration by flow cytometry

- T-cell proliferation to Mitogens (PHA)

- IgG, IgA, IgM levels

- Specific Antibody levels (if older than 6 months)

 

-The absolute lymphocyte count may be normal or reduced

 

-CD3 T cell numbers may be normal or reduced. B cell numbers and NK cell numbers are normal.

 

-CD45RA T cell numbers may be decreased. Markedly elevated CD45RO T cells should raise suspicion for oligoclonal T cell expansion (Omenn, maternal engraftment).

 

-In vitro T cell proliferation in response to mitogens is reduced.

 

-Unlike typical SCID, IgG levels are normal or elevated.

 

 

Step 2:  Additional Testing

 

- CD25 expression

 

- Presence of CD25 on activated T cells should be determined by flow cytometry. Patients will have markedly reduced or absent CD25 expression.

 

 

Step 3: Genetic Testing

 

- IL2RA gene sequencing

 

-This test can confirm the diagnosis of CD25 deficiency and is commercially available (Seattle Children's)

 

 

                                                                   

MANAGEMENT

 

          In addition to aggressive management of acute infections, standard precautions taken for SCID should be initiated:

 

1. Avoid all live viral vaccines (rotavirus, varicella, MMR, BCG)

          -Severe vaccine strain disease can occur if SCID patients receive these vaccines.

 

2. Only irradiated, CMV negative blood products should be used

          -Leukocytes from non-irradiated blood can cause graft versus host disease and CMV can cause life-threatening infections.

 

3. Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole

          -4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week

 

4. IVIG replacement therapy

          -Immunosuppressive therapies (cyclosporine, rapamycin, prednisone, etc) are required for treatment of autoimmune manifestations such as enteropathy. Supportive treatment with TPN may be required for patients with FTT secondary to enteropathy. HSCT is the only known curative therapy for patients.

 

 

                                                                           

RESOURCES

 

Diagnostic Resources    (LAB ORDER FORMS)

 

1. SPECIFIC CD25 Deficiency Testing: Lymphocyte activation markers (including CD25)

2. The following tests resources are accessible on the SCID overview diagostic resources page:

1. Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell (CD19), and NK cell (CD16/56).

2. Naïve (CD45 RA) and Memory (CD45 RO) T cells by Flow Cytometry

3. T-cell proliferation to Mitogens and Specific Antigens (candida, tetanus)

4. TREC (T-cell receptor excision circle) Analysis

5. T-cell Recepror Gene Rearrangement (TCR Spectratyping) 

 

 

Literature Resources

 

1.  Caudy 2007

     CD25 deficiency patient report