Page 497 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 477

B-lineage cells. Individuals with XLA begin with normal numbers splicing. E12 and E47 are involved in regulation of immuno-
of early B-lineage progenitors in their bone marrow. These B-cell globulin gene expression. A mutation in the DNA-binding region
progenitors express the expected markers of B-cell differentiation, of E47 has been shown to result in agammaglobulinemia as a
including terminal deoxynucleotidyl transferase (TdT), CD19, and result of a dominant negative early block in B-cell development. 15
CD10. There is, however, a relative deficiency of cells containing
cytoplasmic µ heavy chains in bone marrow. Development of cells LRRC8
beyond the pre–B stage is even more severely impaired. Those cells An absence of B cells has also been reported in a young female
that make it through the gauntlet can produce antigen-specific patient with a truncation of leucine-rich repeat containing 8
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antibodies. Although present in low numbers, these B cells in (LRRC8, AGM5), a gene of unknown function that is expressed
lymphoid tissues enable XLA patients to express endogenous Ig, in patients with progenitor B cells.
class switch, and even suffer allergic or autoantibody-mediated
reactions. PIK3R1
Patients have been described with an X-linked recessive form A homozygous nonsense mutation in the P1K3R1 gene, encoding
of agammaglobulinemia that is associated with growth hormone the p85a subunit of phosphoinositide 3-kinase (PI3K), was found
deficiency. Genetic analysis of the BTK gene in one such patient in a 19-year-old female with agammaglobulinemia, absent B
identified a frameshift mutation leading to a premature stop cells, and inflammatory bowel disease by exome sequencing. The
codon and the loss of carboxy-terminal amino acids. 12 loss of p85a resulted in decreased pro–B cells, a contrast to the
other agammaglobulinemia defect, which is localized to the
Treatment and Prognosis pre–B-cell stage. 17
The primary goal of therapy is to prevent damage to the lungs.
Human Ig replacement therapy should be started as soon as the Diagnosis and Treatment
diagnosis is made (Chapter 84). Patients treated with sufficient Diagnosis in each of these cases requires gene mutation analysis.
quantities (0.4–0.6 g/kg every 3–4 weeks for IVIG or 100–150 mg/ Treatment follows the same guidelines given for XLA.
kg every week for subcutaneous immunoglobulin [SQIG]) suffer
few lower respiratory tract infections. However, these patients HYPER-IGM SYNDROME
remain at risk for viral infections, including enteroviral menin-
goencephalitis. Since mucosal Ig cannot be replaced, the patients Diagnosis
also remain at risk for recurrent upper respiratory infections, Patients with the HIGM syndrome exhibit markedly reduced
which may require prophylactic antibiotic therapy. Ig-treated serum concentrations of IgG, IgA, and IgE with normal to elevated
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patients may lead normal lives without concern about exposure levels of IgM and normal numbers of circulating B cells. The
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to infectious agents in childcare settings or classrooms. Immu- altered distribution of Ig isotypes reflects a block in the ability
nizations of any type are unnecessary because the monthly of B lymphocytes to switch from IgM to the other isotypes.
replacement therapy will provide passive protection. Since patients Increased IgM reflects polyclonal expansion of IgM synthesis in
are unable to mount antibody responses, vaccines, especially live response to infection. Patients with HIGM suffer from the same
vaccines, carry some risk of untoward side effects, so these vaccines infections with encapsulated bacteria common to all patients
are relatively contraindicated. with antibody deficiency. The HIGM phenotype can be inherited
A patient with XLA who develops symptoms of enteroviral as an X-linked, autosomal recessive, or autosomal dominant
central nervous system (CNS) or neuromuscular infection should trait. The phenotype can also be acquired in association with
have appropriate culture of the involved organ system. For patients neoplasia or congenital rubella.
with agammaglobulinemia who have chronic enteroviral infec-
tions, Ig therapy should be given at higher doses and maintained HIGM Syndrome Type 1: CD40L (CD154) Deficiency
until symptoms cease and the virus can no longer be detected. Class switch recombination is a multistep process that requires
exquisite coordination between the B cell and its cognate T-helper
AUTOSOMAL AGAMMAGLOBULINEMIA (Th) cell. A key step in the initiation of the process is the binding
of constitutively expressed CD40 on the B cell to its ligand,
Origin and Pathogenesis CD40L (CD154), which is expressed on activated T cells. The
The Pre–B-Cell Receptor and Signal Transduction Axis most common form of the disease, X-HIGM1, results from
Expression of the pre-BCR is a key step in the maturation of loss-of-function mutations in CD154 (Xq26).
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the pre–B cell (Chapter 7). Function-loss mutations in any one
of the genes that code for components of the pre-BCR and its HIGM Syndrome Type 2: AID Dysfunction
associated signaling complex can inhibit pre–B-cell development, Activation-induced cytidine deaminase (AID; 12p13), a member
leading to an absence of mature B cells. This phenotype is seen of the cytidine deaminase family, is required for class switch
in patients with biallelic function-loss mutations of the µheavy recombination between Ig H chain constant domains and for
chain region (µ 0 , AGM1), the λ-like surrogate light chain (IGLL1, somatic hypermutation of the Ig V domains (Chapter 4). The
AGM2), the Ig-associated α (Igα, CD79A, AGM3) and -β(Igβ, hyper-IgM phenotype (HIGM2) can result from either biallelic
CD79B, AGM6) chains, and the adaptor B-cell linker protein AID function-loss mutations or from a dominant negative
(BLNK, AGM4), which is a key cytoplasmic component of the mutation on only one of the AID alleles.
pre-BCR signaling pathway.
HIGM Syndrome Type 3: CD40 Deficiency
TCF3 The cognate partner for CD40L (CD154) is CD40, the gene for
The TCF3 gene, also called E2A, encodes 2 basic helix-loop-helix which (CD40) is located on an autosome (20q12-q13.2). Patients
(bHLH) transcription factors, E12 and E47, through alternative with HIGM3 with function-loss mutations on both alleles of