Page 517 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 35 Primary T-Cell Immunodeficiencies 497

in patients of Turkish or Spanish descent. Autologous T cells of this condition is poor. Although HSCT can replenish the
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have partial TCR/CD3 expression with only mild lymphocytopenia hematopoietic system, this does not solve the complex and
+ +
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(T B NK ). In vitro responses of mitogens are depressed, and fatal gastrointestinal (GI) manifestations. Combined gut and
TRECs can be reduced. Although some of these patients present bone marrow transplantation could be attempted.
as typical SCIDs or with severe colitis, other family members
with an identical mutation appear well, even into adulthood. Calcium Channel Defects (ORAI-1, STIM-1 Deficiencies)
This is an autosomal recessive disorder caused by mutations
CARD11/BCL10/MALT1 (CBM) Complex Deficiencies in ORAI-1 (OMIM *610277) and STIM-1 (OMIM *605921).
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CARD11/BCL10/MALT1 deficiencies are autosomal recessive ORAI-1 is a transmembrane protein, which at tetramer configura-
2+
immunodeficiencies caused by mutations in signaling molecules tion constitutes the pore-forming structure of a Ca channel.
upstream of the NF-κB pathway. Upon TCR or BCR stimulation, STIM-1 is a calcium sensor of the endoplasmic reticulum (ER)
2+
caspase recruitment domain family, member 11 (CARD11) is and controls calcium entry after ER store depletion. Both Ca
phosphorylated, enabling its association with BCL10–MALT1 influx into the cell as well as release from cytosolic stores are
complex, to form the CBM complex. The CBM complex allows mediated through the TCR and BCR, and are critical for down-
for activation of the NEMO–IκB kinase (IKK) complex, which stream signaling. Patients may present in infancy with recurrent
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induces phosphorylation of IκB and causes its breakdown. As a severe infections indistinguishable from SCID. Patients with
consequence, NF-κB is released and translocates into the nucleus, STIM1 deficiency can also present with autoimmune features,
where it acts as a transcription factor, controlling multiple cellular such as arthritis and cytopenia, as well as lymphoproliferative
processes, such as cell proliferation, differentiation, and survival. manifestations. Both deficiencies may present with severe eczema
Patients with CARD11 deficiency (OMIM #615206) may and syndromic features, including nail dysplasia and anhydrosis,
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present with a SCID phenotype. They also suffer gingivitis ectodermal dysplasia, and generalized myopathy. Immune evalu-
and aphthous ulcers. Patients with MALT1 deficiency (OMIM ation shows normal to elevated lymphocyte counts and TREC
#615468) present at a later age during childhood with severe levels, and responses to mitogens are depressed. Ig levels are
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enterocolitis and recurrent lung infections. Evaluation of the normal, but specific antibodies are variable. TCR-mediated
2+
immune system in CARD11 deficiency shows normal number cytosolic rise in Ca is low. HSCT can be effective in reversing
of circulating T cells, B cells, and NK cells, but regulatory T cells the immunodeficiency, but not the syndromic features.
+ +
(Tregs) are absent (T B SCID). Responses to mitogens are reduced
but not absent, and TRECs and the TCR repertoire are normal.
B cells appear immature, which explains the panhypogamma- COMBINED IMMUNODEFICIENCIES WITH
globulinemia found in these patients. Patients with MALT1 VARIABLE SEVERITY (NON-SCID)
deficiency present similarly; however, although Ig levels are normal,
antibody production is faulty. Cure can be achieved with HSCT. Combined Immunodeficiency With
Autosomal dominant CARD11 deficiency is caused by a Immune Dysregulation
dominant negative monoallelic mutation and results in combined Combined immunodeficiencies characterized by autoimmune
immunodeficiency, severe atropy and autoimmunity. manifestations are summarized in Table 35.5.
COMBINED IMMUNODEFICIENCY (SCID IL-2Rα (CD25) Deficiency
PHENOTYPE) AND SYNDROMIC FEATURES IL-2 receptor α (IL-2Rα or CD25) deficiency is a complex immune
dysregulation disorder that has an autosomal recessive pattern
TTC7A Deficiency (MIA Syndrome) of inheritance (OMIM #606367). Biallelic mutations in the CD25
+ +
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TTC7A deficiency is a rare autosomal recessive disorder in which gene result in combined immunodeficiency (T B NK ). The high
obstructions occur at various levels of the gut, hence the designa- affinity IL-2 receptor must be composed of all three components,
tion multiple intestinal atresia (MIA) syndrome (OMIM the γ chain (γc), β chain (CD122), and α chain (CD25), to be
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#243150). Patients may also have severe lung disease and functional. Although the β and γ chains are constitutively
pulmonary calcifications. Immune deficiency is commonly expressed on T cells, expression of the α chain is limited to early
associated with this syndrome and is frequently severe. Patients thymocytes, Tregs and activated T cells. The inability to form
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may present with typical SCID features, albeit with various the high affinity receptor results in faulty T-cell differentiation,
levels of autologous T cells. The disease is caused by mutations loss of central and peripheral tolerance, and failure to respond
in the TTC7A gene (OMIM *609332), which encodes a protein appropriately to infections. Affected infants present with recurrent
containing nine tetratricopeptide repeat (TPR) domains. These infections, lymphadenopathy and hepatosplenomegaly, a variety
domains are degenerate 34-amino acid repeat motifs and appear of autoimmune features, and eczematous skin lesions. Patients
to play a role in multiple cellular processes, such as transcription, may present immediately after birth with diabetes mellitus and
cell cycle, protein degradation, and trafficking. may suffer severe chronic lung disease or pulmonary bleeding.
Evaluation of the immune system in TTC7A deficiency Autoimmune lymphocytic infiltrates can be identified in multiple
reveals T-cell lymphopenia and markedly depressed responses tissues, including lung, liver, gut, and bone. Autoimmune disorders
to mitogens. The TCR repertoire is restricted, and TRECs are include primary cirrhosis, colitis, thyroiditis, or insulin-dependent
low. The thymus appears dysplastic with poor corticomedullary diabetes mellitus.
demarcation, as well as poorly developed Hassall corpuscles. Evaluation of the immune system reveals reduced numbers of
Nonimmune manifestations are striking, with intraluminal circulating T cells, which are unable to respond to mitogens or
calcifications. In some patients, atresias cannot be detected; rather, antigens, but normal B cells. The thymus appears dysplastic with
severe colitis with characteristic features of mucosal atrophy absent Hassall corpuscles and loss of corticomedullary demarca-
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and massive enterocyte apoptosis is present. The prognosis tions. Thymocytes do not express CD1 and fail to downregulate