B-Cell and T-Cell Combined Disorders

The lymphocyte component of the immune system is divided into B cells and T cells. B cells have traditionally been believed to be the lymphocytes responsible for antibody production by means of their maturation into plasma cells (ie, humoral immunity). T cells have been believed to be the lymphocytes responsible for killing other cells or organisms (ie, cellular immunity). At present, certain T lymphocytes (ie, T-helper cells) are known to be responsible for helping immature B cells develop into mature B cells. Other T lymphocytes (ie, T-suppressor or cytotoxic cells) possess the killing function and also inhibit B-cell development. Therefore, any T-cell disorder can theoretically cause defective B-cell function.

Because ataxia telangiectasia (AT) and chronic mucocutaneous candidiasis (CMC) are not discussed in separate pediatric articles, this article emphasizes their clinical presentation and management.

Pathophysiology
Because a major loss or dysfunction of T cells can cause secondary B-cell deficiency, a number of disorders show clinical manifestations of combined B- and T-cell deficiency, though the only pathology is in the T cell. In converse, some diseases appear to primarily involve the T cells and do not appear to affect antibody production. Those diseases are discussed in T-Cell Disorders.

Development of mature functioning B and T cells involves a complex series of steps, each of which may be defective, resulting in B- and T-cell deficiency. When T-cell deficiency is especially severe or involves the T-helper cell function, the deficiency causes an antibody deficiency. The most severe manifestations occur within the first 2 years of life as various types of severe combined immunodeficiency (SCID). See Omenn Syndrome and Purine Nucleoside Phosphorylase Deficiency for a discussion of other forms of SCID.

Omenn syndrome is the result of mutations in the genes coding for recombinases (recombination activating genes), ie, RAG1 and RAG2, that cause a defect in the variable diversity joining (VDJ) rearrangement needed for mature T and B cells to develop. Deficiency of purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) elevates intracellular levels of deoxyguanosine and deoxyadenosine, respectively, which are more toxic in lymphocytes than in other cell types. Deficiency of the expression of major histocompatibility complex (MHC) class I and II cellular proteins also commonly manifests in early infancy with classic symptoms of SCID. Symptoms in affected patients indicate the crucial involvement of MHC proteins in the immune recognition of self and nonself.

In other B- and T-cell disorders, additional anomalies may predominate, and clinical manifestations suggestive of immunodeficiency may occur late in life. Recognize that patients with short-limbed skeletal dysplasia with cartilage-hair hypoplasia also can have either a T-cell or combined defect. (See Cartilage-Hair Hypoplasia.)

Male patients with thrombocytopenia and eczema may have Wiskott-Aldrich syndrome with defective T-cell function and resultant recurrent infections. They have poor antibody responses to polysaccharide antigens but elevated levels of serum immunoglobulin A (IgA) and immunoglobulin E (IgE) with low levels of immunoglobulin M (IgM). (See Wiskott-Aldrich Syndrome.)

Two autosomal recessive syndromes indicate some interaction of the immune system with neurologic function. AT is a rare, autosomal recessive, neurodegenerative disorder in which the diagnosis is obvious when both ataxia and telangiectasia are present. Multisystemic manifestations of AT include motor impairments secondary to a neurodegenerative process, oculocutaneous telangiectasia, sinopulmonary infections, hypersensitivity to ionizing radiation, and a combined immunodeficiency that can be quite variable. This is discussed in additional detail in this article.

Nijmegen breakage syndrome (NBS) is also an autosomal recessive chromosomal instability syndrome. NBS is characterized by microcephaly with growth retardation, normal or impaired intelligence, birdlike facies, increased susceptibility to infection, humoral and cellular immunodeficiency, and high risk for lymphatic tumor development. Nearly all patients with NBS are homozygous for the same founder mutation, ie, deletion of 5 bp (657del5) in the NBS1 gene, which encodes the protein nibrin. Because most patients with NBS are of Slavonic origin, this frameshift mutation came to be called the Slavonic mutation.

These 2 syndromes, AT and NBS, are part of a family of mutations involving proteins involved in DNA repair. Ataxialike disorder (ATLD) syndrome involves a mutation in meiotic recombination 11 homolog (MRE11). These 3 syndromes are associated with decrease circulating levels of T cells (but circulating levels of B cells are normal) and often decreased levels of IgA, IgE, and IgG subclasses. Artemis deficiency (with mutations in the Artemis protein resulting in defective VDJ recombination) decreases both T and B cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in circulating T and B cells and serum immunoglobulins. Finally, Bloom syndrome results from a mutation in the helicase enzyme called BLM RecQ. All of these defects in DNA repair are characterized by an increased risk of malignancy and radiation sensitivity.

CMC is a complex disorder in which patients have persistent or recurrent infections of the skin, nails, and mucous membranes due to infection by Candida species. CMC can be broadly classified into familial (inherited) or nonfamilial (noninherited) forms. Familial forms are inherited as autosomal dominant or recessive and are associated with or without varying degrees of autoimmune endocrinopathy. Two other familial subtypes are an autosomal dominant form with nail candidiasis and intercellular adhesion molecule-1 (ICAM-1) deficiency and an autosomal recessive form with hyperimmunoglobulin E.

CMC is included as part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disorder, which is also known as autoimmune polyglandular syndrome type I (APS I). The genetic basis of the disease has been mapped to chromosome 21q22.3, and the gene identified is the autoimmune regulator (AIRE) gene. It appears to be involved in DNA binding. At least 45 different disease-causing mutations in AIRE have been discovered, and its role in various manifestations of CMC and APECED or APS I are being examined.

Frequency
United States
Stiehm (1996) estimated that combined cellular and antibody deficiencies account for approximately 20% of primary immunodeficiencies. AT is a rare disease with an estimated prevalence of <1 per 100,000 population; the incidence of CMC is similar at 1 per 103,000. Some report an increased frequency of approximately 1 case of AT per 40,000 births in the United States.

International
In Brazil, combined immunodeficiency defects accounted for 16 (9.6%) of 166 primary immunodeficiencies in children examined over 15 years. Spain’s Registry for Primary Immunodeficiency Diseases included 14.7% T-cell and combined deficiencies, similar to the European registry report of 20.2%. In a survey of 201 Swedish patients from 1974-1979, 20.8% had combined T- and B-cell disorders.

The birth frequency of AT in the United Kingdom is approximately 1 in 300,000. In the Slavonic population, the prevalence of AT appears higher (1:40,000-100,000) than the prevalence of NBS (1:60,000-120,000). CMC with APECED is inherited as an autosomal recessive trait and appears to be prevalent in genetically isolated populations of the Finns, the Iranian Jews, and the Sardinians (with prevalences of 1:25,000, 1:9000, and 1:14,500, respectively).