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Evaluating patients for hyper-IgM type 3 (HIGM3) syndrome due to defects in CD40, typically seen in patients <10 years of age
Assessing B-cell immune competence in other clinical contexts, including autoimmunity, malignancy and transplantation
The adaptive immune response includes both cell-mediated (mediated by T cells and natural killer [NK] cells) and humoral (mediated by B cells) immunity. After antigen recognition and maturation in secondary lymphoid organs, some antigen-specific B cells terminally differentiate into antibody-secreting plasma cells. Decreased numbers or aberrant function of B cells result in humoral immune deficiency states with increased susceptibility to infections, and these may be either primary (genetic) or secondary immunodeficiencies. Secondary causes include medications, malignancies, infections, and autoimmune disorders (this does not cause immunodeficiency with increased infection).
CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells.(1) CD40 is the receptor for CD40 ligand (CD40LG), a molecule predominantly expressed by activated CD4+ T cells. CD40/CD40LG interaction is involved in the formation of memory B lymphocytes and promotes immunoglobulin (Ig) isotype switching.(1) CD40LG expression in T cells requires cellular activation, while CD40 is constitutively expressed on the surface of B cells and other antigen-presenting cells.
Hyperimmunoglobulin M (hyper-IgM or HIGM) syndrome is a rare primary immunodeficiency characterized by increased or normal levels of IgM with low IgG and/or IgA.(2) Patients with hyper-IgM syndromes may have genetic defects or mutations in 1 of several known genes. Some of these genes are CD40LG, CD40, AICDA (activation-induced cytidine deaminase), UNG (uracil DNA glycosylase), and IKBKG (inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma; also known as NEMO).(2) Not all cases of hyper-IgM syndrome fit into these known genetic defects. Mutations in CD40LG and IKBKG are inherited in an X-linked fashion, while mutations in the other 3 genes are autosomal recessive. Elevated IgM is only one of the features of NEMO deficiency and therefore, it is no longer classified exclusively with the hyper-IgM syndromes.
Distinguishing between the different forms of hyper-IgM syndrome is very important because of differing prognoses. CD40 and CD40LG deficiency are among the more severe forms, which typically manifest in infancy or early childhood, and are characterized by an increased susceptibility to opportunistic pathogens (eg, Pneumocystis carinii, Cryptosporidium, and Toxoplasma gondii).(3)
CD40 deficiency, also known as hyper-IgM type 3 (HIGM3), accounts for <1% of hyper-IgM syndromes. Flow cytometry analysis shows complete lack of CD40 expression on the B cells of these patients.(4) Intravenous injection with IgG is the treatment of choice along with immune reconstitution with hematopoietic cell transplantation. To date, all documented CD40-deficient patients have been diagnosed before age 1. Consequently, when used in the context of HIGM3, this test is only indicated in children (for diagnosis). In the case of CD40L deficiency, this test can be used for male patients or in females of child-bearing age (to identify carriers). A larger age spectrum has been reported with CD40L deficiency, ranging from infancy to early adulthood.
CD40 expression on B cells is also an indicator of immune status (eg, after the use of biological immunomodulatory therapy for autoimmune disease, cancer and transplantation).
This assay is qualitative; CD40 expression is reported as present (normal) or absent (abnormal). Normal B cells express surface CD40 on the majority of cells.
Hyper-IgM (HIGM3) syndrome patients typically do not express CD40 on the surface of B cells. Genotyping of CD40 is required for a definite diagnosis of HIGM3. Contact Mayo Medical Laboratories for ordering assistance.
For questions about appropriate test selection, contact Mayo Medical Laboratories.
This test is not used to detect in CD40L expression (CD154), which is responsible for X-linked hyper-IgM syndrome (HIGM1); see XHIM / X-Linked Hyper IgM Syndrome, Blood.
Bishop GA, Hostager BS: The CD40-CD154 interaction in B cell-T cell liaisons. Cytokine Growth Factor Rev 2003;14:297-309
2. Lee WI, Torgerson TR, Schumacher MJ, et al: Molecular analysis of a large cohort of patients with hyper immunoglobulin M (IgM) syndrome. Blood 2005;105:1881-1890
3. Kutukculer N, Moratto D, Aydinok Y, et al: Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J Pediatr 2003;142:194-196
4. Ferrari S, Giliani S, Insalaco A, et al: Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci USA 2001;98:12614-12619