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Chapter 51 Congenital Disorders of Lymphocyte Function 715

signal. The serine-threonine protein kinase 4 (STK4) protein induces cells that express several HLA class I-binding molecules. HLA class I
the transcriptional coactivation of target genes involved in cell pro- molecules are assembled and loaded with peptides in the endoplasmic
liferation and survival, and is involved in the control of cell death. reticulum by transporter associated with antigen presentation (TAP)
At variance with typical forms of SCID, genetic defects of TCR proteins (TAP1 and TAP2) and the TAP binding or Tapasin protein
signaling are characterized by residual number and/or function of T (TAPBP). Mutations of TAP1, TAP2, or TAPBP cause defective
cells, consistent with partially preserved thymic architecture and expression of HLA class I molecules, which is associated with a severe
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function. Since the thymus of these patients is not empty, the use of reduction in the number of circulating CD8 TCRαβ lymphocytes.
chemotherapy is required to facilitate engraftment and T-cell differ- NK cells expressing killer inhibitory receptors may not receive HLA
entiation with donor-derived cells. The immunological phenotype of class I-dependent inhibitory signals, and hence may mount cytotoxic
ZAP-70 deficiency in humans is characterized by a virtual lack of responses to uninfected cells, causing inflammatory lesions in the
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CD8 lymphocytes; the number of CD4 cells is preserved, but they lungs and in the skin. There is no definitive treatment for this disease,
are unable to proliferate in response to mitogens and antigens. In and management is based on supportive care.
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contrast, both CD4 and CD8 lymphocytes are absent in
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Zap7 mice.
Both RHOH and STK4 deficiencies are characterized by a CD40 Ligand and CD40 Deficiencies
reduced number of naive T cells, an increased proportion of effector
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memory T cells (including CD8 cells with an “exhausted” CD40 ligand (CD40LG) is expressed by activated CD4 cells.
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CD45RA CCR7 phenotype), and defective lymphocyte prolifera- Interaction of CD40LG-expressing CD4 cells with B lymphocytes
tion. CD4 lymphopenia and low levels of CD4 and CD8 surface that constitutively express CD40 delivers a signal for B-cell prolifera-
expression have been reported in one patient with LCK deficiency. tion and class-switch recombination in the presence of appropriate
Progressive CD4 lymphopenia is also commonly seen in patients with cytokines (see Fig. 51.2). Furthermore, interaction between CD40LG-
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ITK deficiency. expressing CD4 lymphocytes and CD40 dendritic cells and mac-
All of these forms of impaired TCR signaling are inherited as rophages promotes secretion of IL-12, and thus enables the
autosomal recessive traits. Clinically, patients with impaired T-cell development of Th1 responses against intracellular pathogens.
signaling present with recurrent, often severe, infections. Cutaneous The CD40LG gene is located on the X chromosome (at Xq26).
viral infections are especially common in patients with RHOH and Males with CD40LG mutations suffer from a combined immunode-
STK4 deficiency. The clinical phenotype of ZAP-70 deficiency is ficiency characterized by recurrent infections, often caused by
often undistinguishable from SCID; in a few cases, hypomorphic opportunistic pathogens. P. jiroveci pneumonia classically occurs in
ZAP70 mutations have been associated with Omenn syndrome. the first year of life, but may occur at any age. Cryptosporidium
Severe lung disease and a high risk of EBV-driven lymphoprolifera- parvum infection may cause chronic watery diarrhea and lead to
tion are a hallmark of ITK deficiency. Autoimmune manifestations sclerozing cholangitis. Chronic or intermittent neutropenia has been
have been observed in several patients with these disorders. Preven- frequently observed. Patients with CD40LG deficiency are also
tion of infections is based on antimicrobial prophylaxis and use of uniquely prone to tumors of the liver and biliary tract.
intravenous immunoglobulins; however, ultimate treatment requires Levels of serum IgG and IgA are markedly reduced or undetect-
HCT. able; IgM may be normal or increased, and for this reason the disease
is also known as X-linked hyper-IgM syndrome. The number of
memory B cells is also markedly reduced.
Coronin-1A Deficiency In vitro activation of T cells with phorbol myristate acetate and
ionomycin fails to induce expression of CD40LG on the surface of
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Coronin-1A is involved in reorganization of the actin cytoskeleton CD4 cells, whereas other activation markers (e.g., CD69) are nor-
that allows egress of thymocytes to the periphery. While complete mally expressed.
deficiency of coronin-1A in humans is a cause of SCID, hypomorphic The prognosis is severe. Death may occur early in life secondary
mutations have been associated with severe naive T-cell lymphopenia, to infections, or during late childhood and young adulthood due to
oligoclonal expansion of activated T cells, and increased risk of EBV- severe liver disease and tumors. Clinical management consists of
driven lymphoproliferation. continuous prophylaxis of Pneumocystis infection with TMP-SMZ,
regular use of intravenous immunoglobulins, and hygiene measures
to limit the risk of exposure to Cryptosporidium. HCT is the only
HLA Class II Deficiency definitive cure, with survival of ~70% reported in Europe. Preexisting
pulmonary disease and Cryptosporidium infection are risk factors for
Expression of HLA class II molecules on the surface of thymic epi- less favorable outcome.
thelial and dendritic cells is essential to promote positive selection of CD40 deficiency is a very rare autosomal recessive disorder, whose
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CD4 lymphocytes. HLA class II deficiency includes a group of clinical and immunological phenotype is indistinguishable from
autosomal recessive disorders in which mutations in transcription CD40LG deficiency (see Fig. 51.2). The diagnosis is based on the
factors (CIITA, RFXAP, RFX5, and RFXANK) that regulate HLA lack of expression of CD40 on the surface of circulating B lympho-
class II gene expression result in profoundly reduced numbers of cytes. Management is as for CD40LG deficiency.
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CD4 lymphocytes. The clinical phenotype consists of recurrent
infections since infancy. Treatment is based on antimicrobial prophy-
laxis, regular use of immunoglobulins, and HCT. Persistence of CD4 Defects of NF-κB Signaling
lymphopenia is often observed after HCT, because transplantation of
hematopoietic stem cells does not correct defective expression of HLA The nuclear factor kappa-B (NF-κB) signaling pathway is ubiquitous
class II molecules on the surface of TECs, causing defective positive to all tissues and stages of development, playing critical roles in cell
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selection of CD4 lymphocytes. proliferation, oncogenesis, cell survival, and inflammatory responses.
Several genetic defects affecting activation of NF-κB have been
described that result in combined immune deficiency variably associ-
HLA Class I Deficiency ated with extra-immune manifestations. Hypomorphic mutations in
the IKBKG gene, which encodes for the NF-κB essential modulator
Presentation of antigens in association with MHC class I molecules (NEMO; also known as IKK-γ), the regulatory subunit of the IκB
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is important for thymic development of CD8 lymphocytes and for kinase complex, are inherited as an X-linked trait and represent
the development of antigen-specific cytotoxic T-cell responses. In the prototype of disorders of NF-κB signaling. Complete lack of
addition, HLA class I molecules also modulate the function of NK NEMO expression is embryonically lethal in males; females who are