Page 503 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 483

as the main cause for KS. Similar to CVID, patients with KS
TWEAK Deficiency have recurrent infections, reduced Ig levels, and autoimmunity. 34
A patient with TNF-like weak inducer of apoptosis (TWEAK)
deficiency displayed low to normal IgG, low IgM, and low IgA Treatment and Prognosis
and had a history of pneumococcal meningitis, osteomyelitis, Therapy in CVID begins with the aggressive treatment of ongoing
thrombocytopenia, and neutropenia. The patient had an auto- infections and the institution of prophylactic measures to prevent
somal dominant mutation in TNF superfamily member 12 or ameliorate future infections. Patients suffering from moderate
(TNFSF12), which encodes TWEAK. 30 upper respiratory tract infections and bronchitis will likely benefit
from empiric therapy with agents effective against encapsulated
NF-κB1 (CVID12) and NF-κB2 (CVID10) Deficiency organisms. The concomitant inheritance of MBL protein defi-
The NF-κB1 and NF-κB2 (noncanonical) pathways are important ciency appears to further predispose to the development of
in B cell signaling, with NF-κB2 having a more limited set of bronchopulmonary complications, such as bronchiectasis, lung
3
involved receptors, such as ICOS, TACI, BAFR-R, and BCMA, fibrosis, and respiratory insufficiency. The course of treatment
whereas NF-κB1 affects T-cell and TLR signaling as well. for patients with immunodeficiency is often prolonged, and
Heterozygous mutations in NF-κB2 were identified in at intravenous administration of antibiotics may be required.
least 10 patients who presented with early-onset CVID with The most effective therapy for hypogammaglobulinemia is Ig
autoimmunity and recurrent sinopulmonary infections. Patients replacement. A number of studies have demonstrated a steadily
with NF-κB2-deficiency display panhypogammaglobulinemia, decreasing incidence of infection with increasing frequency of Ig
aberrant B-cell subsets, and some degree of T-cell and NK-cell administration. At higher doses, even patients with bronchiectasis
dysfunction. Half of these also suffer from pituitary hormone may experience improvement in pulmonary function. Each patient
deficiencies. may demonstrate his or her own individual response to therapy,
Patients with NK-KB1 autosomal dominant mutations that exhibiting dramatic differences in the frequency and severity
create an unstable and rapidly degrading protein have recurrent of infections, with moderate changes in the replacement dose.
infections, autoimmunity, benign lymphoproliferative disease, Patients suffering from a serious acute infection often benefit
and lymphoma. 30 from one-time booster doses of Ig. Ultimately, replacement
dosage must be individualized based on the response of the
PI3K Mutations patient. Adverse reactions occur most frequently at the time
Heterozygous mutations in P1K3CD, which encodes the P13K of the first administration of Ig, likely because of concurrent
catalytic subunit p110δ, have been reported in over 50 patients infection increasing the potential for generation of immune
with CVID-like disease. The mutation leads to P13K signaling complexes.
pathway overactivity. Such patients suffer from respiratory tract Some patients with CVID can sustain severe anaphylaxis when
infections, skin infections, autoimmunity, and lymphoma. The given IVIG or other blood products that contain serum or plasma.
phenotype associated with dominant gain of function P1K3CD These patients may possess anti-IgA antibodies, including IgE
7
mutations is currently referred to as activated phosphatidylinositol anti-A antibodies. For patients with a history of severe adverse
3-kinase δ syndrome (APDS). reactions, it is advisable to try batches of IVIG with the lowest
PIK3R1 encodes the P13K regulatory subunit p85α. Splice-site IgA possible and to test the patient with the different batches in
mutation of p85α results in a loss of an exon of p85α, which is an intensive care unit. Once the clinician has identified a batch
important in inhibiting the catalytic activity of p110d. This also that can be tolerated, the patient may receive therapy under
results in autosomal dominant overactive P13K signaling. A single more relaxed conditions.
patient with a homozygous P1K3R1 mutation causing complete Serum Ig concentrations in patients with CVID may change
2
loss of p85α expression has been found with agammaglobulinemia over time, with rare patients regaining normal serum IgG levels
and absence of B cells, suggesting complete absence of p85α and no longer requiring Ig therapy. Careful review of the clinical
reduces inhibiting P13K signaling. 30 history of these patients may reveal evidence of exposure to
pharmacological agents associated with the development of
Other Genes: BLK, IRF2BP2, IKAROS hypogammaglobulinemia (e.g., phenytoin). However, the over-
A heterozygous loss of function mutation in BLK has been whelming majority of patients require replacement therapy
noted in related patients with CVID. These patients have for life.
respiratory tract infections and bacterial skin infection with Although IgG can be replaced, at present IgM and IgA cannot
panhypogammaglobulinemia. be provided to patients. The absence of these multimeric proteins
A gain of function mutation in IRF2BP2 has been found in may help explain why even patients on high-dose replacement
members of a family with CVID. These patients have autoimmune therapy may continue to suffer from recurrent sinusitis or GI
35
disease and respiratory tract infections. discomfort. Recurrent sinusitis can be ameliorated with con-
Heterozygous mutation in the gene IKZF1, encoding the tinued prophylactic therapy with antibiotics. Patients with CVID
transcription factor IKAROS, was recently found in patients with also are at risk of infection by G. lamblia as well as other enteric
CVID and low B-cell numbers. These patients have progressive pathogens. Some patients develop lactose intolerance or gluten-
loss of B cells and serum Igs. 30 sensitive enteropathy. Gluten avoidance ameliorates symptoms
in only a minority of cases. A majority responds to corticosteroids
Kabuki Syndrome or anti-TNF agents. The use of these agents can be a double-edged
Kabuki syndrome (KS) is a rare but recognizable condition that sword, however, since resistance to infection will decrease in a
consists of a characteristic face, short stature, cardiac anomalies, patient who already has immune deficiency. Other patients develop
a variable degree of intellectual disability, and immunological a malabsorption syndrome that can lead to hypoalbuminemia
defects. Mutations in KMT2D and KDM6A have been identified and hypocalcemia (as a result of malabsorption of vitamin D),