Immunodeficiency Search

CD3 COMPLEX DEFICIENCIES

SUMMARY

1. Deficiencies of the CD3 subunits (delta, gamma, epsilon, or zeta) can cause an autosomal recessive form of SCID with a T-B+NK+ phenotype. Patients with CD3 delta, epsilon, and zeta deficiency have a typical SCID phenotype. Patients with CD3 gamma deficiency can have a SCID phenotype or a milder, non-fatal form of disease.

2. The T cell receptor complex consists of the TCR heterodimer (alpha/beta or gamma/delta chain) associated with four CD3 subunits (delta, gamma, epsilon, zeta). The CD3 transmembrane proteins play a key role in T cell signaling as well as signaling through the pre-TCR which is required for proper T cell development.

-CD3 Delta Deficiency has been described in six patients and results in a T-B+NK+ SCID phenotype with presentation early in infancy.

-CD3 Gamma Deficiency has been reported in three patients with a SCID phenotype. Two other patients however, have had a relatively benign course with survival into the teenage years.

-CD3 Epsilon Deficiency has been associated with T-B+NK+ SCID in three patients.

-CD3 Zeta Deficiency has been described in two patients with T-B+NK+ SCID.

3. Patients typically present in infancy with lymphopenia and decreased T cell numbers. B cell and NK cell numbers are normal. T cell proliferation in response to mitogens and specific antigens is reduced. Specific antibody responses are typically decreased (although they may be preserved in patients who have a milder form of disease).

4. HSCT is indicated for patients who have a severe T-B+NK+ SCID phenotype.

OVERVIEW

The CD3 complex consists of four transmembrane subunits (delta, gamma, epsilon, or zeta) that associate with the T cell receptor (alpha/beta or gamma/delta chain) to transduce signals required for T cell activation. The CD3 complex is also associated with the pre-T cell receptor and is required for signaling that initiates progression to the double positive stage and TCR gene rearrangement. Mutations in each of the four CD3 complex subunits have been described to cause autosomal recessive T-B+NK+ SCID. Patients with CD3 delta, epsilon, and zeta deficiency have a typical SCID phenotype in infancy (FTT, diarrhea, opportunistic infections). Patients with CD3 gamma deficiency can have a SCID phenotype or a milder, non-fatal form of disease.

CD3 Delta Deficiency has been described in six patients from three unrelated families. Patients had a T-B+NK+ SCID phenotype and presented early in infancy with opportunistic infections.

-CD3 Gamma Deficiency has been reported in three patients with a SCID phenotype presenting early in life. However two other patients (one patient is the brother of a SCID patient) have reached their teenage years without any history of life-threatening infections.

-CD3 Epsilon Deficiency has been associated with T-B+NK+ SCID in three patients with complete absence of the protein. All three patients died from severe opportunistic infections during infancy.

-CD3 Zeta Deficiency has been described in two patients with T-B+NK+ SCID.

Patients with CD3 deficiencies typically present in infancy with lymphopenia and decreased T cell numbers. B cell and NK cell numbers are normal. T cell proliferation in response to mitogens and specific antigens is reduced. Specific antibody responses are typically decreased (although they may be preserved in patients who do not have a SCID phenotype).

CD3 deficiencies resulting in SCID should be treated with a HSCT. For patients with milder forms of immunodeficiency due to CD3 gamma deficiency, supportive measures alone (IVIG, prophylactic antibiotics) may be adequate.

EVALUATION

STEP 1: Immune Evaluation

-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-Naïve (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 (ALC) should be calculated from the CBC (WBC multiplied by the lymphocyte percentage). As with other types of SCID, lymphopenia (ALC < 3000) is common.

-Low T cell numbers are typically seen but the B cell numbers can be normal. The NK cell numbers are variable.

-Very low naïve (CD45RA) T cell numbers can be a useful clue for lack of thymic output.

-Extremely low T-cell proliferation to mitogens can be seen (<10% of control). However, in milder cases, mitogen proliferation can be normal.

-Immunoglobulin levels and specific antibody responses can be normal in milder cases.

STEP 2: Additional Immune Evaluation
The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations but not necessarily required.

-TREC Analysis
-TCR Gene Rearrangement PCR (TCR Spectratyping)
-Maternal Engraftment Study

-TRECs (T-cell receptor excision circles) are loops of DNA excised during TCR rearrangement in the thymus. Because TRECs are not replicated with cell division, they are gradually diluted as T-cells become activated and expand. Thus, naïve T-cells that are recent thymic emigrants have high TREC numbers. SCID patients typically have very low TREC numbers.

-TCR gene rearrangement is useful for identifying oligoclonally expanded T-cells. This can be seen in maternal engraftment as well as Omenn syndrome.

-Maternal T cells can occasionally undergo clonal expansion in patients with SCID. Maternal T cells typically are CD45RO+ and proliferate poorly to mitogen stimulation. Assessing for the presence of maternal cells in circulation (maternal engraftment) is useful because it can affect the selection of a stem cell donor and it may necessitate immunosuppression prior to transplantation.

STEP 3: Genetic Testing

Genetic testing for CD3 delta and CD3 epsilon mutations is commercially available through Correlagen diagnostics (see resource section).

MANAGEMENT

Pending the completion of an immunologic evaluation for suspected CD3 complex deficiency SCID, it is critical to initiate certain measures to prevent life-threatening complications for patients. The following precautions should be implemented immediately:

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 severe 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

5. High resolution HLA-typing for the patient and any siblings
For possible Hematopoietic Stem Cell Transplantation (HSCT)

RESOURCES

Diagnostic Resources (LAB ORDER FORMS)

SPECIFIC RESOURCES FOR CD3 DEFICIENCY

1. Genetic Testing for CD3 delta and CD3 epsilon deficiency (Correlagen)

The following tests resources are accessible on the SCID overview diagnostic 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