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Unit Code 89009:
B-Cell CD40 Expression by Flow Cytometry, Blood

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Useful For

Evaluating patients for hyper-IgM type 3 (HIGM3) syndrome due

to defects in CD40

 

Assessing B-cell immune competence in other clinical contexts

(eg, after the use of biological therapy for autoimmune disease)

Clinical Information

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 induces 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.

 

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 can have genetic

defects, mutations in 1 of 5 known genes. 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.

 

Distinguishing between the different forms of hyper-IgM syndrome is very

important because of differing prognoses. CD40 and CD40LG deficiency

are the most severe forms, 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) To date, all

documented CD40-deficient patients have been diagnosed before age

4 (see above). Intravenous injection with IgG is the treatment of choice.

Reference Values

Present (normal)

Interpretation

This assay is qualitative; CD40 expression is reported as present

(normal) or absent (abnormal).

 

Normal patients express CD40 on the surface of B cells.

 

HIGM3 syndrome patients 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 at 800-533-1710 or 507-266-5700

for ordering assistance.

Cautions

Further genetic testing is needed to confirm the diagnosis of hyper-IgM

type 3, if other clinical features of this syndrome are present.

 

This test is not used to detect in CD40L expression (CD154), which

is responsible for X-linked hyper IgM syndrome (HIGM1); see #82964

"X-Linked Hyper IgM Syndrome Panel, Blood."

Clinical Reference

1.    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

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