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1216 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1217

COMMON VARIABLE IMMUNODEFICIENCY deficiency and thymoma, which is estimated to be present in 4 percent
AND SELECTIVE IMMUNOGLOBULIN A of patients with hypogammaglobulinemia. 35
DEFICIENCY Clinical Features and Treatment of Selective
Definition Immunoglobulin A Deficiency
Common variable immunodeficiency (CVID) is a clinically and molec- The incidence of selective IgA deficiency, defined as IgA less than 5
ularly heterogeneous disorder, presenting at any age, but most often to 10 mg/dL, differs greatly between ethnic groups, being highest in
36
during adulthood. CVID is characterized by recurrent bacterial infec- Scandinavia (1 in 396 in a Finnish study) and lowest in Asian popula-
37
tions, hypogammaglobulinemia, and impaired antibody responses. tions (1 in 14,000 in Japan). Because secretory IgA is considered to be
Together with selective IgA deficiency, CVID is the most common pri- most important in protecting mucus surfaces, it is surprising that most
mary immune deficiency, with an incidence of 1 in 10,000 individuals. IgA-deficient patients remain healthy. Other defense systems, for exam-
Familial inheritance is observed in approximately 20 percent of cases ple, noncirculatory IgM or neutrophils, may compensate for this defi-
and CVID and IgA deficiency may be present in the same families. In ciency. Symptomatic individuals are not only IgA deficient, but often
rare instances, patients with selective IgA deficiency may progress to have deficient antibody responses to specific antigens. IgA deficiency
CVID. Attempts have been made to associate CVID and IgA deficiency may be associated with IgG and IgG deficiency and poor responses
3
2
38
with genes located within the major histocompatibility complex (MHC) to polysaccharide antigens. Selective IgA deficiency, if associated with
region on chromosome 6; however, no specific genes within this region symptoms, often leads to recurrent sinopulmonary infections and atopic
have been identified. A small proportion of patients with CVID have symptoms including allergic conjunctivitis, rhinitis, and eczema. Food
been molecularly defined as having mutations in several genes involved allergy may be more common in IgA-deficient patients and asthma
directly or indirectly with B-cell differentiation, including ICOS, TACI, associated with IgA deficiency appears to be more refractory to therapy.
BAFF-receptor, CD19, CD20, CD21, and CD81. The recent discov- Gastrointestinal tract disorders include chronic giardiasis, malabsorp-
27
ery of CVID-like phenotypes resulting from heterozygous mutations tion, celiac disease, primary biliary cirrhosis, pernicious anemia, and
in NF-κB2 28,29 and gain-of-function mutations in PI3Kδ, and CVID nodular lymphoid hyperplasia. A number of autoimmune diseases are
30
with autosomal recessive inheritance as a result of mutations in protein associated with selective IgA deficiency, including rheumatoid arthritis,
kinase Cδ further support the idea that CVID is a heterogeneous pri- systemic lupus erythematous, thyroiditis, myasthenia gravis, and ulcer-
31
mary immune deficiency disease (PIDD) with strong genetic roots. In ative colitis.
addition, patients with mutations in BTK, CD40L, and SH2D1A have A significant proportion of IgA-deficient individuals has anti-IgA
been mistakenly diagnosed as CVID. antibodies in their serum and may react to blood products contain-
ing IgA, including IVIG preparations with low IgA content. However,
Clinical Features and Treatment of Common Variable patients with selective IgA deficiency who make normal IgG antibody
Immunodeficiency do not need IVIG therapy.
The majority of CVID patients present with recurring sinopulmo- The fundamental defect in selective IgA deficiency is the failure of
nary infections, most often bacterial pneumonia. 27,32 If the diagnosis is IgA-bearing B lymphocytes to mature into IgA-secreting plasma cells.
delayed or if treatment is inadequate, bronchiectasis and chronic lung There is no specific treatment that would correct this problem. Intermit-
disease may develop. Gastrointestinal complaints are frequent and may tent or continuous prophylactic antibiotics may be helpful in patients
be caused by chronic G. lamblia or Campylobacter infections, resem- with recurrent respiratory tract infections, who develop chronic symp-
bling chronic inflammatory bowel disease. Lymphoid hyperplasia of the toms of lung disease. On the other hand, if IgA deficiency is associated
small bowel is a frequent finding. Autoimmune disorders are common with poor antibody responses to selected antigens, for example, to poly-
and may resemble rheumatoid arthritis, dermatomyositis, or sclero- saccharides, an attempt with IVIG substitution should be made.
derma. In addition, CVID patients may develop autoimmune hemolytic
anemia, autoimmune thrombocytopenia, autoimmune neutropenia, LIPOPOLYSACCHARIDE RESPONSIVE
pernicious anemia, and chronic active hepatitis. Lymphadenopathy BEIGE-LIKE ANCHOR DEFICIENCY
and splenomegaly are common, the result of follicular hyperplasia.
Caseating granulomas of the lung, spleen, liver, skin, and other tissues Lipopolysaccharide responsive beige-like anchor (LRBA) is a broadly
may develop at any age, and a condition resembling sarcoidosis has expressed, cytosolic protein involved in endocytosis of ligand-activated
been described. The cause of this devastating granuloma formation is receptors. LRBA deficiency is inherited as an autosomal recessive trait and
unknown. A high incidence of lymphoma and gastrointestinal malig- is characterized by recurrent bacterial and viral infections, and prominent
nancies have been reported in older CVID patients, with a 438-fold autoimmune manifestations, cytopenias, and inflammatory bowel dis-
33
increase in the risk of lymphomas in affected women during the fifth ease, in particular. 39,40 Hypothyroidism and myasthenia gravis have been
and sixth decades. Despite normal numbers of blood B lymphocytes also reported. Immunologic abnormalities include progressive hypogam-
34
and the presence of lymphoid cortical follicles, CVID patients have maglobulinemia, impaired activation and decreased survival of T and B
hypogammaglobulinemia that may be as profound as in XLA (see Table lymphocytes, reduced number of marginal zone-like and switched mem-
80–2). Antibody responses to recall and to neoantigens are diminished ory B cells, and defective autophagy.
and some CVID patients have decreased numbers of memory B cells,
especially of switched memory B cells. A subset of CVID patients have
a substantial T-cell deficiency characterized by decreased expression SEVERE COMBINED
of CD40L by activated CD4 T cells (without a mutation of CD40L) IMMUNODEFICIENCIES
+
and by reversed CD4:CD8 ratio. Treatment with IVIG substitution and
prophylactic antibiotics is beneficial but often insufficient to prevent DEFINITION AND HISTORY
serious complications. Allogeneic hematopoietic stem cell transplan-
tation (HSCT) is generally not recommended, except in patients with The first description of severe combined immunodeficiencies (SCIDs)
lymphoid malignancies. There is a rare association between immune dates back to 1950, when Glanzmann and Riniker described infants

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