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Hyper Igm Syndromes Ramsay Fuleihan, MD, Ann & Robert H Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases Chapter 5 Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases 6th Edition The development of this publication was supported by Shire, now Takeda. 110 West Road, Suite 300 Towson, MD 21204 800.296.4433 www.primaryimmune.org [email protected] Chapter 5 Hyper IgM Syndromes Ramsay Fuleihan, MD, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA The Hyper-IgM Syndromes (HIGM) are rare inherited primary immunodeficiency diseases (PI) characterized by decreased blood levels of immunoglobulin G (IgG) and normal or elevated levels of IgM. Most individuals with HIGM are susceptible to recurrent and severe infections including opportunistic infections, which are infections by organisms that do not normally infect healthy individuals, and are susceptible to an increased risk of cancer. A number of different genetic defects can cause HIGM. The most common form is inherited as an X-linked disease affecting boys. The other forms of HIGM are inherited as autosomal recessive traits affecting both boys and girls. (See Inheritance Chapter.) Overview individuals surviving beyond the third or fourth decade of life. In recent years, hematopoietic stem When B cells, which are the cells that make cell transplantation (bone marrow, peripheral blood antibodies, develop, the first type of antibody they stem cells or umbilical cord blood stem cells) has make is IgM. IgM is responsible for the immune been performed successfully in individuals with the system’s initial response to an infection. Once X-linked form of XHIGM. (See Hematopoietic Stem healthy B cells make IgM, they can receive signals Cell Transplantation Chapter.) from T cells that tell them to switch from making IgM to IgG, IgA, or IgE depending on which type is needed to continue to fight infection. B cells from Immunobiology individuals with HIGM are unable to switch from People with HIGM have an inability to switch from the production of antibodies of the IgM type to the production of antibodies of the IgM type to antibodies of the IgG, IgA, or IgE type due to several antibodies of the IgG, IgA, or IgE types. As a different genetic defects in the signaling pathways result, individuals with this disease have absent or between T cells and B cells. As a result, people with decreased levels of IgG, IgA, and IgE but normal or this disease have decreased levels of IgG, IgA, and elevated levels of IgM in their blood. B cells, the cells IgE but normal or elevated levels of IgM in their that make antibodies, can produce IgM antibodies blood. These different types of antibodies perform on their own, but they require interactive help from different functions and are all important in fighting T cells in order to switch from IgM to IgG, IgA or infections. (See The Immune System and Primary IgE. HIGM syndromes result from a variety of genetic Immunodeficiency Diseases Chapter.) Since most defects that affect this interaction between individuals with HIGM are identified early and usually T cells and B cells, as well as cell signaling events do not have elevated IgM levels, the name HIGM that occur within B cells that are necessary for is not always accurate. Nevertheless, HIGM is used antibody switching. to denote that these diseases are characterized by the inability to switch antibody type--the B cells can The most common form of HIGM results from a only make IgM. Depending on the genetic defect defect or deficiency of a protein that is found on causing HIGM, individuals may also be susceptible the surface of activated T cells. The affected protein to opportunistic infections [such as Pneumocystic is called CD40 ligand because it binds (ligates) to jirovecii (carinii)], cryptosporidium, certain forms of a protein on B cells called CD40. The interaction cancer, and autoimmune disease. Therefore, HIGM between CD40 and CD40 ligand signals the B cell are severe immunodeficiency diseases and in the to switch from production of IgM to other types of past have a guarded long-term outcome with few antibodies like IgG or IgA. IDF Patient & Family Handbook 23 Some individuals with HIGM due to CD40 ligand Clinical Presentation deficiency have normal IgA levels, and the mechanism for this is not clear. It appears to occur Most individuals with HIGM develop clinical via a CD40 ligand independent pathway. CD40 symptoms during their first or second year of life. ligand is made by a gene on the X chromosome. The most common problem in all forms of HIGM Therefore, this form of PI is inherited as an X-linked is an increased susceptibility to infection including recessive trait. X-linked recessive trait means that recurrent upper and lower respiratory tract infections. mothers can be carriers and boys are affected if The most frequent serious infective agents are they inherit the affected X chromosome from their bacteria, but viral illnesses are also more frequent mother. (See Inheritance Chapter.) CD40 ligand is and severe. also important for other functions carried out by In people with XHIGM and autosomal recessive T cells, so individuals with XHIGM have defective HIGM due to a CD40 defect, a variety of other cellular immunity and thus are also susceptible to microorganisms can also cause serious infections. For opportunistic infections and to some types of cancer. example, Pneumocystis jiroveci (carinii) pneumonia, Other forms of HIGM are inherited as autosomal an opportunistic infection, is relatively common recessive traits and have been observed in both during the first year of life, and its presence may be girls and boys. (See Inheritance Chapter.) One of the first clue that a child has HIGM. these forms results from a defect in CD40 and is Gastrointestinal complaints, most commonly diarrhea clinically identical to XHIGM (the disease with the and malabsorption, also occur commonly in XHIGM defect in CD40 ligand). Other autosomal recessive and CD40 deficiency. One of the major organisms forms of HIGM result from defects in proteins that causing gastrointestinal symptoms in XHIGM is are involved in antibody class switching through the Cryptosporidium. A Cryptosporidium infection may CD40 signaling pathway, these are known as Uracil- cause sclerosing cholangitis—a severe, often fatal, DNA glycosylase (UNG) deficiency and activation- disease of the liver. induced cytidine deaminase (AID) deficiency. Autosomal recessive inherited genetic defects in two Approximately half of the individuals with XHIGM other proteins involved in antibody class switching, or CD40 deficiency develop neutropenia (low count INO80 and MSH6 have also been seen in individuals of granulocyte white blood cells), either transiently with clinical HIGM. or persistently. The cause of the neutropenia is unknown, although most individuals respond to The function of these genes is limited to antibody treatment with colony stimulating factor, G-CSF. switching (after the B cell has received the signal Severe neutropenia is often associated with oral to switch from the interaction of CD40 and CD40 ulcers, inflammation, ulceration of the rectum ligand), so the other T cell functions of CD40 ligand (proctitis), and skin infections. are not affected and these patients are less likely to have opportunistic infections or cancer. Unlike Autoimmune disorders may also occur in individuals individuals with defects in CD40 or CD40 ligand with HIGM especially in those with defects whose B cells cannot receive the signal to switch in AID or UNG. Autoimmune manifestations due to faulty communication with the T cells, B cells may include chronic arthritis, low platelet from individuals with defects in AID or UNG do counts (thrombocytopenia), hemolytic anemia, receive an activating signal, and this may lead to hypothyroidism and kidney disease. the development of enlarged lymph nodes (where B cells and T cells are found). Individuals with AID or Enlargement of the lymph nodes and the spleen is UNG defects may be more susceptible to develop seen frequently in those with autosomal recessive autoimmune disease. HIGM due to defects of AID or UNG. As a result, they often have enlarged tonsils and adenoids that Finally, since switching antibody types in B cells may cause snoring and obstructive sleep apnea. involves breaks and subsequent repair in DNA, defects in genes that are important for DNA repair Finally, the risk for cancer, particularly liver cancer, may also present with HIGM. The main features of is increased in individuals with XHIGM or CD40 these diseases are related to the defect in DNA deficiency. A few individuals with HIGM have repair, but some have immunoglobulin levels developed a rapidly progressive neuroendocrine similar to HIGM. These diseases include Ataxia- carcinoma. Telangiectasia, Nijmegen breakage syndrome, and PMS2 deficiency. 24 Chapter 5: Hyper IgM Syndromes Diagnosis development of long-term consequences of serious infections. XHIGM should be considered in any boy presenting with severe recurrent respiratory infections or an opportunistic infection who has low or absent IgG Treatment and normal or elevated IgM levels with normal T cell Since individuals with all forms of HIGM have a and B cell numbers. The presence of neutropenia severe IgG deficiency, they require immunoglobulin in addition to the above features increases the (Ig) replacement therapy. The Ig replaces the missing likelihood of having XHIGM. IgG and often results in a reduction or normalization Failure to express CD40 ligand on activated T cells of the serum IgM level, if it was elevated. Ig is a characteristic finding. Some express a defective replacement therapy can be given intravenously CD40 ligand protein that may be detected by or subcutaneously. (See Immunoglobulin Therapy the antibody used in the test (falsely normal test Chapter.) result) but will not bind to a soluble form of CD40. Since individuals with XHIGM or CD40 deficiency Confirming the diagnosis of XHIGM depends on the also have a marked susceptibility to Pneumocystis identification of a mutation affecting the CD40 ligand jiroveci (carinii) pneumonia (PJP, or PCP), they gene.
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