SUMMARY

 

1.  Hyper IgM syndrome (HIGM) is an antibody deficiency syndrome characterized by impaired class-switch recombination (which allows antibody isotype production to change from IgM to IgG, IgA, or IgE).   Both X-linked and autosomal recessive forms of disease have been described.  

 

2.  Three types of autosomal recessive (AR) HIGM syndrome have been identified:  CD40 deficiency, AID deficiency, and UNG deficiency.  A fourth type of AR HIGM (HIGM 4) has been identified but the molecular cause has not been identified.  CD40 deficiency is a combined B cell and T cell immunodeficiency while AID and UNG deficiency are B cell intrinsic immunodeficiencies.  

 

CD40 Deficiency (HIGM 3):  CD40 deficiency causes an AR form of HIGM that is clinically identical to CD40 ligand deficiency.  Patients are at risk for sinopulmonary infections with encapsulated bacteria as well as opportunistic infections (Pneumocystis and Cryptosporidium).   The CD40-CD40L interaction is responsible for inducing antibody class-switching (from IgM to IgG, IgA, and IgE) and generating memory B cells.  As a result, patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses.  The switched memory B cell population is markedly reduced.  The impaired IL-12/IFN- signaling pathway is likely to be responsible for the phenotype of opportunistic infections.   

 

AID Deficiency (HIGM 2):  AID deficiency causes a B cell intrinsic form of AR HIGM that does not result in impaired function of T cells, monocytes, or dendritic cells.  AID is a protein expressed only in activated B cells.  Deamination of cytidine to uracil on single-stranded DNA by AID followed by the removal of uracil residues by UNG leads to the introduction of DNA breaks and initiation of class-switch recombination.  Patients develop recurrent bacterial sinopulmonary infections but do not develop opportunistic infections. Lymphoid hyperplasia and autoimmunity (thrombocytopenia, hemolytic anemia, autoimmune hepatitis) are common clinical findings.  Patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses.  The switched memory B cell (CD27+IgD-IgM-) population is markedly reduced. 

 

UNG Deficiency (HIGM 5):  UNG deficiency causes a B cell intrinsic form of HIGM that does not result in impaired function of T cells, monocytes, or dendritic cells.  UNG removes uracil residues generated by AID to help create DNA breaks that allow for class-switch recombination.  Patients develop recurrent bacterial sinopulmonary infections but do not develop opportunistic infections.  Lymphoid hyperplasia is a common clinical finding.  Patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses.  The switched memory B cell (CD27+IgD-IgM-) population is markedly reduced.

 

3.  Flow cytometry for analysis CD40 expression on the surface of B cells can be useful for diagnosis of CD40 deficiency.  

 

4.  Definitive diagnosis for CD40, AID, and UNG deficiency is made by gene sequencing.

 

5. The mainstay of therapy for all three types of AR HIGM is antibody replacement therapy with IVIG.  

 

6.  Patients with CD40 deficiency additionally require PJP prophylaxis with trimethoprim-sulfamethoxazole.  As with CD40L deficiency, HSCT is a consideration for patients with CD40 deficiency.  However, there is limited data regarding the use of HSCT for treatment of this disease.  A single successful HSCT for a patient with CD40 deficiency has been reported by Mazzolari et al. 

 

7.  HSCT is not indicated for AID or UNG deficiency because these are B cell intrinsic defects and patients are not susceptible to opportunistic infections.    

 

8.  It should be noted that one-half of AR HIGM cases caused by B cell intrinsic defects are not caused by AID or UNG deficiency.  The molecular cause for these AR HIGM patients remains unknown.  

 

 

                                                                                                               

 

OVERVIEW

          

     Three types of autosomal recessive Hyper IgM syndromes have been characterized:  CD40 deficiency, AID deficiency and UNG deficiency.  A fourth type of AR Hyper IgM (HIGM 4) has been identified but the molecular cause has not been identified.  CD40 deficiency is a combined B cell and T cell immunodeficiency while AID and UNG deficiency are B cell intrinsic immunodeficiencies.  

 

CD40 Deficiency (HIGM 3):  
CD40 deficiency causes an AR form of HIGM that is clinically identical to CD40 ligand deficiency.  Patients are at risk for sinopulmonary infections with encapsulated bacterial organisms as well as opportunistic infections (Pneumocystis and Cryptosporidium).  Patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses.  The switched memory B cell population is markedly reduced.  Patients lack CD40 expression on the surface of B cells and monocytes. 

 

AID Deficiency (HIGM 2): 
AID deficiency causes a B cell intrinsic form of AR HIGM that does not result in impaired function of T cells, monocytes, or dendritic cells.  Patients develop recurrent bacterial sinopulmonary infections but do not develop opportunistic infections. Lymphoid hyperplasia is a common clinical finding.  Autoimmunity (thrombocytopenia, hemolytic anemia, autoimmune hepatitis) affects approximately 25% of patients with AID deficiency.  Patients have low IgG and IgA but normal or elevated IgM and poor specific antibody responses.  The switched memory B cell (CD27+IgD-IgM-) population is markedly reduced.

 

UNG Deficiency (HIGM 5):  
UNG deficiency causes a B cell intrinsic form of HIGM that does not result in impaired function of T cells, monocytes, or dendritic cells.  Patients develop recurrent bacterial sinopulmonary infections but do not develop opportunistic infections.  Lymphoid hyperplasia is a common clinical finding.  Patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses.  The switched memory B cell (CD27+IgD-IgM-) population is markedly reduced.

     

 

 

PATHOGENESIS

         

CD40 Deficiency (HIGM 3):  
CD40 is the receptor for CD40 ligand and is expressed on the surface of B cells.  CD40-CD40L signaling plays a critical role in B cell proliferation and differentiation.  The interaction is responsible for inducing antibody class-switching (from IgM to IgG, IgA, and IgE) and generation of memory B cells.  CD40 is also expressed on the surface of monocytes and dendritic cells.  Defective CD40-CD40L signaling leads to impaired IL-12 secretion from dendritic cells, which results in decreased IFN- secretion from T cells and impaired macrophage activation.  This likely explains the susceptibility of patients to key opportunistic pathogens such as Pneumocystis jiroveci and Cryptosporidium.  

 

AID Deficiency (HIGM 2):  
Activation induced cytidine deaminase (AID) is an enzyme expressed only in activated B cells.  It is involved in initiation of class-switch recombination by catalyzing the deamination cytidine to uracil on single stranded DNA.  The uracil is then removed by the action of UNG and this leads to the creation of DNA breaks.  Class-switch recombination of the constant region alone (without affecting the variable region) allows for generation of a different antibody isotype (IgG, IgA, IgE) with the exact same antigen specificity.   

 

UNG Deficiency (HIGM 5): 
Uracil N-glycosylase (UNG) catalyzes the removal of uracil residues that have been created by AID on single-stranded DNA.  The resulting abasic site is cleaved by apyrimidinic (AP) endonuclease allowing for class-switch recombination to occur.  

 

 

 

DIFFERENTIAL DIAGNOSIS

 

 

1.  X-linked or AR agammaglobulinemia
2.  X-linked Hyper IgM syndrome
3.  CVID
4.  WHIM syndrome
5.  X-linked Lymphoproliferative Syndrome (XLP)
6.  Transient Hypogammaglobulinemia of Infancy
7.  NEMO deficiency

 

 

                                   

EVALUATION

 

Step 1:  Quantitative and Functional Humoral Evaluation

 

-Quantitative immunoglobulins (IgG, IgM, IgA) 
-Antibody titers to vaccine antigens   
-Flow cytometry for B, T, and NK cell numbers 

 

-Classically patients present with low IgG and IgA but elevated IgM.  However, many patients have normal IgM at initial presentation.  
-Protein and polysaccharide vaccine antibody (IgG) responses should be evaluated (ex.  Tetanus, Diphtheria, and Pneumococcus).  These will typically be very low.  
-Absolute B, T, and NK cell numbers are normal.    

 

Step 2:  Additional Immune Evaluation

 

-Lymphocyte flow cytometry for B-cell subpopulations (including switched  memory B-cell numbers: CD27+ IgD- IgM-).  
-T cell proliferation to mitogens
-CD40 surface expression (on B cells or monocytes)

 

-Patients with AR HIGM have a markedly decreased switched memory B cell population  
          (CD27+IgD-IgM-)
-T cell proliferation to mitogens is normal for CD40 deficiency.  This is a useful evaluation to consider for patients with suspected CD40 deficiency because opportunistic infections can be seen in SCID and other combined immune deficiencies.   
-Flow cytometry to assess surface expression of CD40 on the surface of B cells or monocytes can be useful for diagnosis of CD40 deficiency.  

 

Step 3:  Gene Sequencing


-CD40, AICDA, UNG  gene sequencing 

 

-The detection of mutations in CD40, AICDA, or UNG genes provides a definitive diagnosis.  These tests are commercially available through correlagen diagnostics (see resources section).    

 

 

 

                                                                   

MANAGEMENT

 

1. Immunoglobulin (IVIG) therapy 
    Replacement of serum IgG with monthly IVIG or weekly subcutaneous (SC) Ig is the cornerstone of  
    therapy.  Typical replacement is started with 400-600mg/kg of IVIG every 4 weeks.

 

2. Prophylactic Antibiotics
    The addition of prophylactic antibiotics can be considered in patients who continue to have infections 
    despite appropriate immunoglobulin replacement.  Two sample prophylaxis regimens are outlined below:

Amoxicillin 20mg/kg divided twice daily.  Maximum of 500mg twice daily.
Azithromycin 10mg/kg once weekly.  Maximum of 1 gram once weekly.

 

3.Pneumocystis jiroveci pneumonia prophylaxis (CD40 deficiency only)
    Trimethoprim-sulfamethoxazol 4-6 mg/kg (TMP component) divided twice daily 3 days a week.  

    Maximum one double strength tablet (sulfamethoxazole 800 mg; trimethoprim 160 mg) once daily 3 days a week.

 

                                                                           

 

 

RESOURCES

 

Diagnostic Resources     

 

1. B cell panel - CHOP & Cincinnati

 

2. CD40, AID, UNG gene sequencing - Correlagen Diagnostics

 

 

Literature Resources

 

1.  Davies 2010
     Hyper IgM Syndromes Review
 

2.  Notarangelo 2006
     Defects of class-switch recombination
    

3.  Jesus 2008
     Autoimmunity in Hyper IgM Syndromes
     

4.  Ferrari 2001
     AR Hyper IgM from CD40 deficiency
     

5.  Kutukculer 2003
     Disseminated Cryptosporidium in an infant with CD40 deficiency
     

6.  Kutukculer 2003
     HSCT for a patient with CD40 deficienc


7.  Mazzolari 2007 
     First report of successful HSCT for CD40 deficiency
     

8.  Quartier 2004 
     Features of 29 patients with AID deficiency  
    

9.  Imai 2003 
     Human UNG deficiency  
     

10.  Imai 2003 
     HIGM Type 4 in 15 patients