SUMMARY

 

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

 

2. LRBA is expressed by almost all cell types but has higher expression in immune cells. It is a cytosolic protein located in the ER, golgi apparatus and vesicle and is a homolog of the LYST protein (which is mutated in Chediak Higashi Syndrome).

 

3. LRBA appears to play a critical role in the surface expression of CTLA-4, an inhibitory T cell receptor that is critical for maintaining immune tolerance.

 

4. Patients may have reduced IgG, IgA or IgM levels and impaired responses to protein or polysaccharide vaccinations. Patients may also have T and B cell lymphopenia as well as low switched memory B cells.

 

5. 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.

 

6. CTLA-4 surface expression is reduced. Sequencing of the LRBA gene confirms the diagnosis.

 

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

 

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

   

 

 

                                                                                                               

OVERVIEW      

     

     LPS responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID phenotype and severe autoimmune disease. Inflammatory bowel disease is a prominent clinical feature. 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.

 

     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.

 

 

 

PATHOGENESIS

 

     LRBA is expressed by almost all cell types but has higher expression in immune cells. It is a cytosolic protein located in the ER, golgi apparatus and vesicle and is a homolog of the LYST protein (which is mutated in Chediak Higashi Syndrome).

 

     LRBA appears to play a critical role in the surface expression of CTLA-4, 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 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 quite similar to those with CTLA-4 deficiency (CVID phenotype + autoimmunity).

 

                         

DIFFERENTIAL DIAGNOSIS

 

Other conditions that cause a CVID phenotype with autoimmunity include CTLA-4 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 protein (tetanus, diphtheria) and 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 Sequencing

 

- LRBA 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. LRBA gene sequencing

- Cincinnati Childrens molecular genetics

 

 

 

Literature Resources

 

1.   Lopez-Herrera 2012  

      Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
      
      

2.   Lo 2015

      Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy