Page 348 - Clinical Immunology_ Principles and Practice ( PDFDrive )

328 Part two Host Defense Mechanisms and Inflammation

deficiencies have been described. Patients with primary MPO eosinophil-derived neurotoxin (EDN), and major basic protein
deficiency do not usually have increased infections, probably (MBP) despite the presence of messenger RNA (mRNA) tran-
because MPO-independent mechanisms compensate for the lack scripts for these proteins. Few patients have been reported to
of MPO-dependent microbicidal activity. Visceral candidiasis have survived beyond adolescence except for those with a milder
occurring with concurrent diabetes has been reported in some dominant form. Bone marrow transplantation should be con-
patients. However, the frequency of such cases is very low. Affected sidered early in the course of the disease.
individuals may develop nonfungal infections, malignancies, and
certain skin disorders. In several cohorts of patients with complete KEY CoNCEPtS
MPO deficiency, an increased incidence of solid or hematological
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tumors has been observed. MPO-deficient neutrophils have no Specific Granule Deficiency (SGD)
apparent defect in the phagocytosis of bacteria or fungi, but micro- • SGD is caused by promyelocyte–myelocyte transition block as a result
bicidal activity is slower than normal. MPO-deficient neutrophils of a mutation in the C/EBPε gene.
are severely impaired in killing Candida spp. or Aspergillus spp. • Absence of secondary granule proteins, and a selective loss of the
in vitro despite the fact that most patients with MPO deficiency primary granule defensins are the pathological findings in SGD
do not develop significant fungal infections. This suggests that granulocytes.
the mucosal barrier to fungal infection is independent of MPO • The prognosis is very poor in recessive forms of SGD.
activity and is able to prevent invasive infection.
The most common mutation is a missense replacement of CHEDIAK-HIGASHI SYNDROME
arginine 569 with tryptophan (R569W), causing maturational
arrest of the MPO precursor and preventing heme incorporation. Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive
Most patients are compound heterozygotes. The diagnosis of disorder characterized by partial oculocutaneous albinism,
MPO deficiency is made by using anti-MPO monoclonal antibod- increased susceptibility to infections, deficient NK-cell activity,
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ies (mAbs) in flow cytometric analysis of neutrophils. No MPO and abnormal giant primary granules in neutrophils. This
expression is seen in congenital deficiency, whereas near-normal immunodeficiency was first reported by Beguez-Cesar in 1943
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antigenic reactivity may be seen with the acquired form. and then further elaborated by Chediak and Higashi a decade
Maintenance antibiotic or antifungal therapy is not routinely later. The hallmark of CHS is giant abnormal granules in all
recommended. Prompt and prolonged therapy is advised in granule-containing cells, including melanocytes (melanosomes
patients with diabetes mellitus and congenital MPO deficiency, are members of the lysosomal lineage of organelles), neutrophils,
as they may develop localized or systemic infections. central and peripheral nerve tissues, fibroblasts, and hair. The
problem is the inability to form appropriate lysosomes and
Secondary or Acquired MPO Deficiency cytoplasmic granules. CHS granulocytes lack cathepsin G and
In the majority of patients, MPO deficiency is partial and elastase, but the defensin content is normal. The giant granules
transient. Secondary MPO deficiency occurs under certain clinical of CHS are derived predominantly from azurophilic granules.
conditions, such as some hematological malignancies or dis- CHS is classically described as a biphasic immunodeficiency, in
seminated cancers, exposure to cytotoxic agents or antiinflam- which susceptibility to infection marks the first phase, and an
matory medications, iron deficiency, lead intoxication, thrombotic accelerated lymphoproliferative syndrome with histiocytic
diseases, renal transplantation, and pregnancy. MPO activity in infiltration of various tissues marks the second. Rarely, the
bone marrow myeloid precursors as well as peripheral blood accelerated phase may be the initial presentation. The giant
cells may vary from cell to cell. Treatment of the underlying organelles are derived from the late compartments of the endocytic
condition typically corrects the defect. This deficiency is most pathway, affecting specifically late endosomes and lysosomes with
likely linked to somatic mutations in the case of malignancy or minimal or no effect on early endosomes. CHS1 encodes a 3801
toxic–metabolic effects on MPO activity. 41 amino acid peptide (lysosomal transporter [LYST]) that has a
vital role in lysosomal trafficking. Lysosomal exocytosis triggered
Specific Granule Deficiency by membrane wounding is impaired in Chediak-Higashi fibro-
Neutrophil-specific granule deficiency (SGD) is a rare disorder blasts. The reduced survival of fibroblasts after wounding indicates
of leukocyte maturation in which neutrophil secondary granules that impaired lysosomal exocytosis inhibits membrane resealing.
and some primary granule proteins are absent as a result of Inability of cells to repair plasma membrane lesions may con-
mutations in CCAAT/enhancer binding protein epsilon (C/EBPε, tribute to the pathology of CHS. The degree of albinism can
located at 14q11.2), a member of the leucine zipper family of vary from a slightly diluted skin pigment to hypopigmented skin
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transcription factors. SGD is characterized by frequent, severe and hair, photophobia, nystagmus, strabismus, macular hypo-
pyogenic infections, a paucity or absence of neutrophil-specific plasia, and reduced visual acuity. Skin biopsy shows large irregular
granule proteins and defensins, and atypical neutrophil nuclear melanin granules in melanocytes. Microscopic analysis of hair
structure with mostly bilobed nuclei. In vitro, these patients’ also shows poor distribution of melanin. Pancytopenia, neutro-
cells show diminished neutrophil migration, reduced staphylococ- penia, and lack of NK-cell activity result in frequent pyogenic
cal killing, reduced phagocytosis, and increased cell surface-to- infections, usually caused by staphylococci or streptococci.
volume ratio. Eosinophils and platelets are also affected in SGD. Hepatosplenomegaly and lymphadenopathy are common. A mild
Platelets lack high-molecular-weight (HMW) von Willebrand bleeding diathesis results from platelet storage pool deficiency.
factor multimers and have reduced platelet fibrinogen and Neurological dysfunction, including mental retardation, seizures,
fibronectin due to diminished platelet α granules. Bleeding cranial nerve palsies, and progressive peripheral neuropathy, has
diatheses and neutrophil phagocytosis of platelets are seen in been noted in CHS.
SGD. In addition, SGD eosinophils are deficient in the eosinophil- The lymphoma-like lymphohistiocytic accelerated phase is
specific granule proteins eosinophil cationic protein (ECP), characterized by increased hepatosplenomegaly, lymphadenopathy,