SUMMARY

 

1. CTLA-4 deficiency is an autosomal dominant disease characterized by a CVID phenotype and severe autoimmunity with inflammatory bowel disease. Onset of symptoms varies from infancy to adulthood.

 

2. CTLA-4 is an inhibitory T cell receptor that competes with the co-stimulatory protein CD28 for binding to CD80/CD86 on the antigen presenting cell. The inhibitory signal prevents excessive T cell activation and autoinflammation.

 

3. Patients may have reduced IgG, IgA or IgM levels and impaired responses to polysaccharide vaccinations. Patients may also have T and B cell lymphopenia as well as low switched memory B cells. T regulatory cell numbers are normal but their suppressive activity is impaired.

 

4. Patients develop multi-organ autoimmune manifestations including autoimmune cytopenia, inflammatory bowel disease psoriasis, and thyroid disease. Patients also develop splenomegaly, hepatomegaly, bronchiectasis, GLILD, and generalized lymphadenopathy.

 

5. Heterozygous mutations in CTLA-4 typically result in reduced protein expression. Gene sequencing confirms the diagnosis.

 

6. Patients require uninterrupted immunoglobulin replacement therapy for the antibody deficiency component of their disease.

 

7. Abatacept is a CTLA-4-immunoglobulin fusion drug that appears to be quite effective in treating the autoimmune manifestations of this disease.

 

 

OVERVIEW

 

   

     CTLA-4 deficiency is an autosomal dominant disease characterized by a CVID phenotype and severe autoimmunity with inflammatory bowel disease. Onset of symptoms varies from infancy to adulthood.

 

     Clinically patients may have reduced IgG, IgA or IgM levels and impaired responses to polysaccharide vaccinations. Patients may also have T and B cell lymphopenia as well as low switched memory B cells. T regulatory cell numbers are normal but their suppressive activity is impaired.

 

     Patients develop multi-organ autoimmune manifestations including autoimmune cytopenia, inflammatory bowel disease, psoriasis, and thyroid disease.

Patients also develop splenomegaly, hepatomegaly, bronchiectasis, GLILD, and generalized lymphadenopathy.

 

     Of note, CTLA4 mutations have also been found in asymptomatic family members of affected patients, indicating incomplete disease penetrance.

 

 

         

 

PATHOGENESIS

 

     Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T cell receptor that competes with the co-stimulatory protein CD28 for binding to CD80/CD86 on the antigen presenting cell. The inhibitory signal provided by CTLA-4 prevents excessive T cell activation and autoinflammation.

 

     LRBA is an endosomal protein that appears to play a critical role in T cell surface expression of CTLA-4. LRBA may prevent endosomal degradation of CTLA-4, thereby promoting increased cell surface expression of this inhibitory receptor. Not surprisingly, the clinical phenotype of LRBA deficiency patients is similar to CTLA-4 deficiency (CVID phenotype + autoimmunity).

 

 

 

 

 

DIFFERENTIAL DIAGNOSIS

 

      Other conditions that cause a CVID phenotype with autoimmunity include LRBA deficiency, PIK3CD mutations and STAT3 gain of function mutations.

 

 

         

EVALUATION

 

Step 1:  Quantitative and Functional Humoral Evaluation

 

 

- Quantitative immunoglobulins (IgG, IgM, IgA)

- Flow cytometry for B-cell, T-cell, and NK cell numbers

- Antibody titers to vaccine antigens

 

 

- Patients can have have low to normal IgG, IgM, IgA levels. B and T cell numbers may be reduced. Specific vaccine titers to polysaccharide antigens (strep pneumoniae) may be reduced.

 

 

Step 2:  B cell phenotyping

 

- Lymphocyte flow cytometry for B-cell subpopulations (including switched memory B-cell numbers: CD27+ IgD- IgM-).

- Patients typically have low percentage of switched memory B-cells

 

 

Step 3:  Genetic testing

 

- CTLA-4 mutation analysis

- Individual gene sequencing is commercially available. Testing could also be accomplished by whole exome sequencing.

 

 

 

MANAGEMENT

 

     Replacement of serum IgG with monthly IVIG or weekly subcutaneous (SC) Ig is the cornerstone of therapy (400-600 mg/kg per month). Patients who maintain trough IgG levels above 700-900mg/dl have fewer infectious complications. SCIg is ideal for patients who benefit from maintaining steady serum levels of immunoglobulins or who are unable to tolerate IVIG due to adverse side effects (headache, chills, nausea, thrombotic events).

 

     The addition of prophylactic antibiotics can be considered in patients who continue to have infections despite appropriate immunoglobulin replacement.

 

     Abatacept (CTLA-4-immunoglobulin fusion drug) can be very effective in addressing the autoimmune manifestations of this disease.

 

RESOURCES

 

 

Diagnostic Resources    

 

1.Quantitative Immunoglobulin levels and specific antibody responses to vaccines (readily available at many academic centers and commercial laboratories)

 

2. Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell (CD19), and NK cell (CD16/56). A CBC with differential needs to be ordered with each test in order to calculate absolute lymphocyte numbers.

- This test is commonly available at many academic centers as well as commercial laboratories

 

3. Switched Memory B-cells (CD27+IgM-IgD-) by Flow Cytometry

- Children’s Hospital of Philadelphia – Basic Lymphocyte Panel (have pdf of CHOP immunology test requisition and CHOP b cell panel sample requirements)

- Cincinnati Children’s Diagnostic Immunology Laboratory 

 

4.CTLA-4 gene sequencing

- Cincinnati Childrens molecular genetics 

 

Literature Resources

 

1.  Kuehn 2014

     Immune dysregulation in heterozygous CTLA 4 mutations

 

2.  Schubert 2014

      AD immune dysregulation syndrome with CTLA4 mutations

 

3.  Lee 2016

      Abatacept therapy for CTLA4 deficiency patient