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Chapter: Medical Immunology: Primary Immunodeficiency Diseases

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X-Linked Hyper-IgM Syndrome

This syndrome is characterized by an inability of B cells to undergo immunoglobulin class switch resulting in low levels of IgG, IgA, and IgD in association to an elevation of IgM.

X-Linked Hyper-IgM Syndrome

This syndrome is characterized by an inability of B cells to undergo immunoglobulin class switch resulting in low levels of IgG, IgA, and IgD in association to an elevation of IgM. In 70% of cases the disease is X-linked. Symptoms develop during the fist 5 years of life.

1. Genetics and Physiopathology

 

The X-linked hyper-IgM syndrome usually involves a mutation of the CD40 ligand (CD40L, CD159) gene, located on Xq26-27. As a consequence, T cells do not express CD40L and the signals mediated by CD40L-CD40 interactions are not delivered. This sig-nal is essential for B-lymphocyte differentiation and switching from IgM synthesis to the synthesis of other immunoglobulin classes. In addition to the failure to switch from IgM to IgG (IgA, IgE) synthesis during an immune response, germinal centers do not differentiate in the peripheral lymphoid tissues.

Other patients with hyper-IgM syndrome do express CD40L. In those patients, the molecular defect is believed to involve the second message systems, which transduce acti-vation signals after CD40L-CD40 interaction (mediated by the JAK-STAT and by the TRAF-MAK kinase pathways).

2. Clinical Presentation

 

These patients suffer from increased frequency of pyogenic infections, similar to those af-fecting patients with infantile agammaglobulinemia. There is also an associated finding of neutropenia that increases the predisposition for pyogenic and other opportunistic infec-tions. In addition to recurrent bacterial infections, patients carry an increased risk for Pneu-mocystis carinii pneumonia, cryptosporidium-related diarrhea, and aplastic anemia sec-ondary to parvovirus B19 infection. Autoantibodies are common. Other increased risks for these patients are lymphoproliferative syndromes, cancers of the biliary system, and biliary cirrhosis.

3. Diagnosis

 

The association of normal or high IgM levels with low IgG and IgA levels is a significant diagnostic clue. The numbers of T and B cells are normal or elevated. T-cell proliferative responses after mitogenic stimulation are normal, but the activated T cells do not express CD40L. B cells also respond to mitogenic stimulation, but produce IgM only. Definitive diagnosis of X-linked hyper-IgM syndrome requires either detection of a mutation in the CD40L gene or identification of maternal male relatives with confirmed diagnosis of this immunodeficiency.

4. Therapy

 

IVIg is used to correct the antibody deficiency associated with hyper-IgM syndrome. Pa-tients should be closely monitored for the development of autoimmunity and malignancy. Neutropenia has been corrected with the use of granulocyte colony-stimulating factors (G-CSF) and with bone marrow transplantation.

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