Hyper IgM syndromes (HIGM)

Immunobiology

People with HIGM have an inability to switch from the production of IgM antibodies to antibodies of the IgG, IgA, or IgE types. As a result, individuals with this disorder have absent or decreased levels of IgG, IgA, and IgE but normal or elevated levels of IgM in their blood. B cells, the cells that make antibodies, can produce IgM antibodies on their own, but they require interactive help from T cells to switch from IgM to IgG, IgA, or IgE. HIGM syndromes result from a variety of genetic variants that affect this interaction between T cells and B cells, as well as cell signaling events that occur within B cells that are necessary for antibody switching.

The most common form of HIGM results from a deficiency or non-functional version of a protein found on the surface of activated T cells. The affected protein is called CD40 ligand because it binds (ligates) to a protein on B cells called CD40. The interaction between CD40 and CD40 ligand signals the B cell to switch from the production of IgM to other types of antibodies like IgG or IgA.

CD40 ligand is encoded by a gene on the X chromosome. Therefore, this form of PI is inherited as an X-linked recessive trait. X-linked recessive trait means that mothers can be carriers, and boys are affected if they inherit the affected X chromosome from their mothers. CD40 ligand is also important for other functions carried out by T cells, so individuals with XHIGM have issues with cellular immunity and are also susceptible to opportunistic infections and some types of cancer.

Some individuals with HIGM due to CD40 ligand deficiency have normal IgA levels, and the mechanism for this is not clear. It appears to occur via a CD40 ligand-independent pathway. 

Other forms of HIGM are inherited as autosomal recessive traits and have been observed in both girls and boys. One of these forms results from a variant in CD40 and is clinically identical to XHIGM (the disorder caused by non-functioning CD40 ligand). Other autosomal recessive forms of HIGM result from variants in proteins that are involved in antibody class switching through the CD40 signaling pathway. These are known as uracil-DNA glycosylase (UNG) deficiency and activation-induced cytidine deaminase (AID) deficiency. Autosomal recessive inherited genetic variants in two other proteins involved in antibody class switching, INO80 and MSH6, have also been seen in individuals with clinical HIGM.

The function of these genes is limited to antibody switching (after the B cell has received the signal to switch from the interaction of CD40 and CD40 ligand). The other T cell functions of CD40 ligand are not affected, and these patients are less likely to have opportunistic infections or cancer. Unlike individuals with variants in CD40 or CD40 ligand whose B cells cannot receive the signal to switch due to faulty communication with the T cells, B cells from individuals with variants in AID or UNG do receive an activating signal, and this may lead to the development of enlarged lymph nodes (where B cells and T cells are found). Individuals with AID or UNG variants may be more susceptible to developing autoimmune diseases.

Finally, since switching antibody types in B cells involves breaks and subsequent repair of DNA, variants in genes that are important for DNA repair may also present with HIGM. The main features of these disorders are related to the inability to repair DNA, but some individuals have immunoglobulin levels similar to HIGM. These disorders include ataxia-telangiectasia, Nijmegen breakage syndrome, and PMS2 deficiency.

Treatment

Since individuals with all forms of HIGM have a severe IgG deficiency, they require immunoglobulin (Ig) replacement therapy. The Ig replaces the missing IgG and often results in a reduction or normalization of the serum IgM level if it is elevated. Ig replacement therapy can be given intravenously (IVIG) or subcutaneously (SCIG).

Since individuals with XHIGM or CD40 deficiency also have a marked susceptibility to Pneumocystis jiroveci pneumonia, they should be started on prophylactic treatment with the antibiotic trimethoprim-sulfamethoxazole (orally) as soon as the diagnosis is made. Other drugs for prophylaxis are available if the individual is allergic to sulfa drugs.

When present, neutropenia may also improve during Ig replacement therapy. Individuals with persistent neutropenia may also require granulocyte colony-stimulating factor (G-CSF) therapy, especially if they have infections, mouth sores, or other complications associated with the neutropenia. G-CSF treatment, however, is only necessary for select individuals, and long-term treatment with G-CSF is usually not recommended.

Individuals with XHIGM or CD40 deficiency should not receive live vaccines since there is a remote possibility that the vaccine strain may cause disease. Bottled water should be used to avoid exposure to Cryptosporidium if using well water or water outside the U.S.

Individuals with XHIGM or CD40 deficiency have defects in T cell function in addition to their antibody deficiency, and treatment with Ig replacement therapy may not fully protect them against all infections and does not protect them from some opportunistic infections or cancer. Hematopoietic stem cell transplantation (bone marrow, peripheral blood stem cells, or cord blood stem cells) has been performed successfully in individuals with XHIGM. While a permanent resolution of the PI is anticipated after successful stem cell transplantation, the long-term prognosis for these individuals is not yet known. Earlier transplant is associated with improved survival.

Since individuals with autosomal recessive HIGM caused by variants in AID or UNG only have defects of antibody production with no defect in T cell function, stem cell transplantation is not recommended at this time.

While gene therapy has been effective in treating some severe forms of PI, there are a number of issues that make it difficult for HIGM:

• The genetic variant in HIGM does not affect the development of T cells or B cells, and thus gene therapy will have to be very efficient to correct a sufficient percentage of stem cells. 
• CD40 ligand is expressed only transiently on activated T cells, and thus gene therapy will have to mimic the normal expression of CD40 ligand, which remains a difficult task. 
• Dysregulated expression of CD40 ligand is associated with autoimmune diseases and lymphoproliferation (increased numbers of lymphocytes with enlarged lymphoid tissues).

Gene therapy researchers are testing new approaches to correct the variant in the CD40 ligand gene in its location on the X chromosome in order to provide normally regulated expression of CD40 ligand. The efficiency of correction in stem cells remains an obstacle currently.