SUMMARY

 

1.  MHC class II deficiency is a rare autosomal recessive disease also known as bare lymphocyte syndrome type II.  This immunodeficiency presents with a more severe phenotype than MHC class I deficiency.  Approximately 100 patients with this disease have been reported to date. 

 

2.  Patients typically present in the first year of life with a severe combined immunodeficiency phenotype.  The majority of patients die within the first 10 years of life.  Milder cases of disease have also been described in some patients.

 

3.  Invasive bacterial fungal infections occur with concurrent failure to thrive and diarrhea.  Severe viral infections from CMV, HSV, adenovirus, and enterovirus also occur (fatal infections from live polio virus vaccines have been reported).  Pneumocystis jiroveci pneumonia is common.  

 

4.  Progressive hepatic failure from ascending cholangitis due to Cryptosporidium infection occurs in over one-half of the patients.  

 

5.  Autoimmune cytopenias (hemolytic anemia, neutropenia) have been described in 10% of patients. 

 

6. Laboratory features include normal B cell and CD3 T cell numbers.  However, CD4 lymphopenia is present.  MHC class II surface expression is markedly decreased on antigen presenting cells.  In vitro T cell proliferation to mitogens is normal but proliferation to specific antigens (candida, tetanus) is decreased.  Despite normal B cell numbers, low IgG and poor specific antibody responses are present. 

 

7.  A deficiency of MHC class II expression leads to impaired antigen presentation by dendritic cells, macrophages, and B cells.  This results in a combined immunodeficiency due to defective CD4 T cell development and a lack of T helper cell mediated antibody production by B cells.  

 

8.  Four molecular causes of MHC class II deficiency have been reported:

 

RFXANK, RFXAP, and RFX5 Deficiency - RFXANK, RFXAP, and RFX5 are all subunits of the ubiquitously expressed RFX complex.  This complex binds directly to the promoters of all MHC class II genes and forms part of the MHC enhanceosome.  60% of reported cases have RFXANK deficiency.

 

CIITA Deficiency - CIITA is an inducible factor that controls the expression of MHC class II genes by binding to the RFX complex and triggering transcription. 

 

9.  The diagnosis is made based on the finding of reduced or absent MHC class II (HLA-DR, HLA-DP, HLA-DQ) surface expression on PBMCs by flow cytometry.  The detection of gene mutations can confirm the diagnosis.

 

10.  In addition to the treatment of acute infections, the following immediate management steps must be implemented for patients with a SCID phenotype.
  
-Avoid all live viral vaccines
-Only irradiated, CMV negative blood products should be used (to prevent GVHD and infections)
-Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole 
-IVIG replacement therapy
-HLA typing of the patient and any siblings (for possible HSCT)

 

11.  HSCT is the only curative treatment available and should be strongly considered given the limited life expectancy of patients.  Transplantation is more successful when performed within the first two years of life with HLA-identical donors.  

 

 

 

 

                                                                                                               

OVERVIEW

     

      MHC class II deficiency is a rare autosomal recessive disease also known as bare lymphocyte syndrome type II.  This immunodeficiency presents with a more severe phenotype than MHC class I deficiency.  Approximately 100 patients with this disease have been reported to date. 

 

     Patients present in the first year of life with a severe combined immunodeficiency phenotype.  The majority of patients die within the first 10 years of life.  Milder cases of disease have also been described in some patients.

 

     Invasive bacterial fungal infections occur with concurrent failure to thrive and diarrhea.  Severe viral infections from CMV, HSV, adenovirus, and enterovirus also occur (fatal infections from live polio virus vaccines have been reported).  Pneumocystis jiroveci pneumonia is common.  

 

     Progressive hepatic failure from ascending cholangitis due to Cryptosporidium infection occurs in over half of the patients.  Autoimmune cytopenias (hemolytic anemia, neutropenia) have been described in 10% of patients. 

 

     Laboratory features include normal B cell and CD3 T cell numbers.  However, CD4 lymphopenia is present.  MHC class II surface expression is markedly decreased on antigen presenting cells.  In vitro T cell proliferation to mitogens is normal but proliferation to specific antigens (candida, tetanus) is decreased.  Despite normal B cell numbers, low IgG and poor specific antibody responses are present. 

     ​

 

                                 

PATHOGENESIS

       

    A deficiency of MHC class II expression leads to impaired antigen presentation by dendritic cells, macrophages, and B cells.  This results in a combined immunodeficiency due to defective CD4 T cell development and a lack of T helper cell mediated antibody production by B cells.  

 

    Four molecular causes of MHC class II deficiency have been reported:


RFXANK, RFXAP, and RFX5 Deficiency - RFXANK, RFXAP, and RFX5 are all subunits of the ubiquitously expressed RFX complex.  This complex binds directly to the promoters of all MHC class II genes and forms part of the MHC enhanceosome.  60% of reported cases have RFXANK deficiency.

 

CIITA Deficiency - CIITA is an inducible factor that controls the expression of MHC class II genes by binding to the RFX complex and triggering transcription. 

   

 

 

                                 

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
MHC class II expression by flow cytometry (HLA-DR, HLA-DP, HLA-DQ)
T-cell proliferation to Mitogens (PHA) and Antigens (Candida, Tetanus)
IgG, IgA, IgM, IgE levels 
Specific antibody levels to vaccine antigens (if older than 6 months)

 

The absolute lymphocyte count (ALC) on the CBC with differential may be normal in patients with MHC class II deficiency. 

Patients have normal total T cell (CD3) numbers but CD4 lymphopenia is present (this is in contrast to classic SCID which is characterized by very low T cell numbers).  B cell and NK cell numbers are normal.  

Patients would be expected to have low naïve (CD45RA) CD4+ T cell numbers (MHC class II expression by thymic epithelial cells is necessary for CD4+ positive selection in the thymus). 

In vitro T cell proliferation to mitogens is normal but proliferation to specific antigens (candida, tetanus) is decreased.  Mitogen proliferation is markedly decreased in classic SCID.  

MHC class II surface expression on antigen presenting cells is markedly reduced. 

Low IgG levels are present despite normal B cell numbers. 

Specific antibody responses to vaccine antigens are very low.

 

Step 2:  Gene Sequencing  


Genetic testing for RFXANK, RFXAP, RFX5, and CIITA

Testing for these genes is currently only available through specialized research centers. 

 

 

                                                                    

MANAGEMENT

    

     Pending the completion of an immunologic evaluation for suspected MHC class II deficiency, 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 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)

 

     HSCT is the only curative treatment available and should be strongly considered given the limited life expectancy of patients with MHC class II deficiency.  Transplantation is more successful when performed within the first two years of life with HLA-identical donors.  

 

     The European Registry data indicate that the survival rate for HSCT is lower in patients with MHC class II deficiency than with other primary immunodeficiencies. Patients also have an increased risk of developing GVHD (this appears to be correlated with the presence of active infection before HSCT).  CD4 T cells remain low after HSCT due to continued defective MHC class II expression by thymic epithelial cells.  

     

 

                                                                           

RESOURCES

 

Diagnostic Resources      

 

CHOP Digeorge Panel (MHC class I flow cytometry) - Despite the name, this is not a test to diagnose 22q11.2 deletion.  Rather, it is an advanced lymphocyte flow cytometry panel that evaluates a the following surface markers in addition to  T cell, B cell, and NK cell enumeration:

MHC class II expression (HLA-DR)
MHC class I expression (HLA-A, B, C)
CD45RA and CD45RO (naïve and memory T cells)
CD132 (common gamma chain)

 

 

Literature Resources


1. Picard 2010

    MHC Class II - HSCT and other management strategies (review)