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1220 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1221

have been identified in several infants from Northwestern England. The Delayed-type hypersensitivity responses are absent, but in vitro prolif-
disease is characterized by severe bacterial and viral infections since erative responses to mitogens are preserved. Hypogammaglobulinemia
early in life, and an increased risk of EBV-driven non-Hodgkin lym- is common and poor antibody response to immunization antigens is
phoma. There are no extra-immune manifestations. Variable degrees of consistently observed (see Table 80–2). The diagnosis is based on
133
lymphopenia (especially of CD4 cells), increased proportion of effec- demonstrating lack of MHC class II expression on monocytes, B lym-
+
tor memory T cells and reduced in vitro proliferation to mitogens and phocytes and in vitro activated T cells. Differential diagnoses include
antigens have been reported. Immunoglobulin levels may be normal, HIV infection and idiopathic CD4 lymphopenia; however, in these con-
but specific antibody titers are reduced, and there is a low number of ditions expression of MHC class II molecules is preserved.
memory B cells. 127
Treatment and Course
MAJOR HISTOCOMPATIBILITY COMPLEX MHC class II deficiency has a poor prognosis. If untreated, most patients
die in infancy or childhood. Respiratory infections are the predominant
CLASS I DEFICIENCY cause of death. Liver failure is observed in patients who develop sclero-
Definition sing cholangitis. Antibiotic prophylaxis and immunoglobulin replace-
MHC class I deficiency is characterized by reduced expression of MHC ment therapy, with adequate nutritional support, are required. HSCT is
class I molecules at the cell surface. The disease is inherited as an auto- the only curative approach, but survival rate is lower than in other forms
somal recessive trait, and may be caused by defects in the TAP1, of CID and graft-versus-host disease is common, especially in patients
128
TAP2, or Tapasin genes. These defects interfere with intracellular with preexisting viral infections. 133
129
130
transport of peptide antigens and their loading onto MHC class I mole-
cules, and cell-surface expression of the complex. DEFECTS OF STORE-OPERATED CA ENTRY
2+
Calcium mobilization is a key event in the activation process of lympho-
Clinical and Laboratory Features cytes and nonimmune cells. Two molecules, calcium release-activated
MHC class I deficiency manifests with recurrent respiratory infections calcium channel protein 1 (ORAI1) and stromal interaction molecule 1
in childhood, and chronic inflammatory lung disease and skin lesions, (STIM1), mediate the function of Ca entry channels. ORAI1 is a ubiq-
2+
mimicking Wegener granulomatosis in patients with transporter-associ- uitously expressed protein that constitutes the pore-forming subunits
ated with antigen-processing (TAP)-1 and TAP-2 deficiencies. 131,132 of the Ca release-activated channels located in the cell membrane.
2+
Chronic lung disease is a prominent cause of death. Glomerulonephritis STIM1 senses the Ca concentration in the endoplasmic reticulum and
2+
and herpes zoster infections have been reported in Tapasin deficiency. 130 activates Ca release-activated channels. Mutations of both the ORAI1
2+
+
The number of circulating CD8 T cells is reduced, because pos- and STIM1 genes in humans result in an autosomal recessive immuno-
itive selection of CD8 lymphocytes in the thymus depends on the deficiency with increased susceptibility to severe infections, especially
+
recognition of MHC class I molecules. In vitro T-cell function is nor- from herpesviruses infections, associated with nonprogressive myopa-
mal, which facilitates differential diagnosis with ZAP-70 deficiency in thy and ectodermal dysplasia. Manifestations of immune dysregulation
patients who have significantly reduced CD8 cells. The NK cytolytic (autoimmune cytopenias, hepatosplenomegaly) are common, espe-
+
activity is usually significantly reduced (see Table 80–2). Serum immu- cially in STIM1 deficiency. 134,135 Although T-cell development is unaf-
noglobulin levels are variable.
fected, in vitro proliferation of circulating T cells to mitogens and to
a combination of phorbol ester and ionomycin is drastically reduced,
Treatment and the Ca influx following T-cell activation is absent. Lack of natu-
2+
Prophylactic measures, similar to those used in cystic fibrosis, may be ral killer T (NKT) cells and functional defects of NK lymphocytes have
beneficial. Treatment of the granulomatous lesions is based on use of been reported. In spite of hypergammaglobulinemia, specific antibody
topical antiseptics; immunosuppressive drugs may worsen symptoms responses are typically absent. Allogeneic HSCT has been used in some
and should be avoided.
patients to correct the defect. 135
MAJOR HISTOCOMPATIBILITY COMPLEX DEFECTS OF MAGNESIUM TRANSPORTER 1
CLASS II DEFICIENCY Mg is an important second messenger in the immune system. Muta-
2+
Definition tions of the X-linked magnesium transporter 1 (MAGT1) gene, that
MHC class II deficiency is defined by the lack of MHC class II expres- encodes for a protein that permits transport of Mg across the cell
2+
sion and autosomal recessive inheritance. There is a higher prevalence in membrane, cause immunodeficiency with increased susceptibility to
populations of North African origin. MHC class II deficiency is caused bacterial and viral infections, and a high risk of EBV-driven lymphop-
by mutations of transcription factors that bind to the proximal promoters roliferative disease. Patients have CD4 lymphopenia, defective lym-
136
of the MHC class II gene. Four different gene defects are known and phocyte proliferation in vitro and impaired NK cytolytic function. 137
include mutations of the CIITA, RFXANK, RFX5, and RFXAP genes. 133
Clinical and Laboratory Features DEDICATOR OF CYTOKINESIS 8 DEFICIENCY
Typically, patients present early in life with increased susceptibility to Dedicator of cytokinesis 8 (DOCK8) is an atypical guanosine triphos-
bacterial, viral, and opportunistic infections. Severe lung infections, phatase (GTPase) that regulates cytoskeleton reorganization and intra-
chronic diarrhea, and sclerosing cholangitis, often secondary to Crypto- cellular signaling. Although it is broadly expressed, it plays a critical
sporidium or CMV infection, are frequently observed. Less-severe pre- role in T, B, and NK lymphocytes. DOCK8 deficiency is inherited as an
sentations and survival into adulthood have been reported. 133 autosomal recessive trait, and is characterized by recurrent and severe
The number of circulating CD4 T cells is markedly reduced, bacterial, fungal, and viral infections, eczema and other manifestations
+
reflecting an impairment of positive selection in the thymus. of immune dysregulation, including autoimmune cytopenias. Cutaneous

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