Many congenital immunodeficiencies are the result of genetic abnormalities that cause blocks in the maturation of B lymphocytes, T lymphocytes, or both (Figs. 1 and 2).

Fig1. Congenital immunodeficiencies caused by genetic defects in lymphocyte maturation. Lymphocyte maturation pathways are described in Chapter 4. Janus kinase 3 (JAK3) is a kinase involved in signaling by many cytokine receptors; ARTEMIS is a protein involved in antigen receptor gene recombination; Bruton tyrosine kinase (BTK) is a kinase that delivers signals from the pre–B cell receptor (BCR) and BCR; ZAP70 is a kinase involved in TCR signaling; and TAP proteins transport peptides for presentation by class I MHC molecules. ADA, Adenosine deaminase; CLP, common lymphoid progenitor; HSC, hematopoietic stem cell; PNP, purine nucleoside phosphorylase; RAG, recombination-activating gene; TCR, T cell receptor.

Fig2. Features of congenital immunodeficiencies caused by defects in lymphocyte maturation. The figure summarizes the principal features of the most common congenital immunodeficiencies in which the genetic blocks are known. ADA, Adenosine deaminase; Ig, immunoglobulin; IL-7R, interleukin-7 receptor; PNP, purine nucleoside phosphorylase; RAG, recombination-activating gene.

Severe Combined Immunodeficiency (SCID)

 Disorders manifesting as defects in both the B cell and T cell arms of the adaptive immune system are classified as SCID. The underlying cause of SCID is a defect in T cell development or function. Several different genetic abnormalities may cause SCID.

• X-linked SCID, affecting only male children, accounts for about half of the cases of SCID. More than 99% of these cases are caused by mutations in the common γ (γc) chain signaling subunit of the receptors for several cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. (Because the γc chain was first identified as one of the three chains of the IL-2 receptor, it is also called the IL-2Rγ chain.) When the γc chain is not functional, immature lymphocytes, especially pro-T cells, cannot proliferate in response to IL-7, which is the major growth factor for these cells. Defective responses to IL-7 result in reduced survival and maturation of lymphocyte precursors. In humans, the defect affects mainly T cell maturation (whereas in mice, B cells are also reduced). The consequence of this developmental block is a profound decrease in the numbers of mature T cells, deficient cell-mediated immunity, and defective humoral immunity because of absent T cell help (even though B cells may mature almost normally). NK cells also are deficient, because the γc chain is also part of the receptor for IL-15, the major cytokine involved in NK cell proliferation and maturation. An autosomal recessive form of SCID is caused by mutations in the gene encoding a kinase called Janus kinase 3 (JAK3) that is involved in signaling by the γc cytokine receptor chain. Such mutations result in the same abnormalities as those in X-linked SCID caused by γc mutations.

• About half the cases of autosomal recessive SCID are caused by mutations in an enzyme called adenosine deaminase (ADA), which is involved in the breakdown of adenosine. Deficiency of ADA leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA—namely, proliferating cells. Lymphocytes are particularly susceptible to injury by purine metabolites because these cells undergo tremendous proliferation during their maturation. ADA deficiency results in a block in T cell maturation more than in B cell maturation; defective humoral immunity is largely a consequence of the lack of T cell helper function. A similar phenotype is seen in individuals who have a deficiency in purine nucleotide phosphorylase (PNP).

• Other, less common, causes of autosomal recessive SCID include mutations in the RAG1 or RAG2 gene, which encode the recombinase that is required for immunoglobulin (Ig) and T cell receptor (TCR) gene recombination and lymphocyte maturation. In the absence of RAG1 or RAG2, B and T cells fail to develop . Mutations in the Artemis gene, which encodes an endonuclease involved in VDJ recombination, also result in failure of B and T cell development.

• DiGeorge syndrome (also known as 22q11 syndrome) is a defect in T cell maturation. It results from a deletion on chromosome 22, which interferes with the development of the thymus (and parathyroid glands). The condition tends to improve with age, probably because the small amount of thymic tissue that does develop is able to support some T cell maturation.

With the increasing application of newborn screening to identify congenital immunodeficiencies, many other rare causes of SCID have been discovered. 

Selective B Cell Deficiency

 • The most common clinical syndrome caused by a block in B cell maturation is X-linked agammaglobulinemia (first described as Bruton agammaglobulinemia). In this disorder, pre-B cells in the bone marrow fail to expand, resulting in a marked decrease or absence of mature B lymphocytes and serum immunoglobulins. The disease is caused by mutations in the gene encoding a kinase called Bruton tyrosine kinase (BTK), resulting in defective production or function of the enzyme. The enzyme is activated by the pre-B cell receptor expressed in pre-B cells, and it delivers signals that promote the survival, proliferation, and maturation of these cells. The BTK gene is located on the X chromosome. Therefore, women who carry a mutant BTK allele on one of their X chromosomes are carriers of the disease, but male offspring who inherit the abnormal X chromosome are affected. In about a fourth of patients with X-linked agammaglobulinemia, autoimmune dis eases, notably arthritis, develop as well. A link between an immunodeficiency and autoimmunity seems paradoxical. One possible explanation for this association is that BTK contributes to B cell receptor signaling and is required for B cell tolerance, so defective BTK may result in the accumulation of autoreactive B cells.

مواضيع ذات صلة

Congenital Immunodeficiencies: Defects in Innate Immunity

Congenital (Primary) Immunodeficiencies

Neuroimmunology: Interactions Between the Immune and Nervous Systems

Disorders of Neutrophils

Cell Surface Receptors

Sepsis

Acute Inflammation

Diseases Caused by T Lymphocytes

Etiology, Examples, and Therapy of Immune Complex–Mediated Diseases

Examples and Treatment of Diseases Caused by Cell- or Tissue-Specific Antibodies

Mechanisms of Antibody-Mediated Tissue Injury and Disease

Hypersensitivity Disorders Caused by Immune Responses : Clinical Syndromes and Therapy