Page 499 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 479

to IL-4 induces production of IgG4 and IgE. This change in Ig frank IgG subclass deficiencies, or evidence of impairment of
isotype reflects both induction of switching and the enhanced T-cell function. Patients with IgA serum levels that fall >2 standard
survival and proliferation of the B cell. In the absence of CD154, deviations (SDs) below the mean serum level for their age are
B cells can express IgM but have difficulty switching and are considered to have partial IgA deficiency. These patients can also
likely to undergo apoptosis, rather than proliferate in response suffer from recurrent infections.
to antigen.
+
+
CD40–CD154 interactions between CD154 T cells and CD40 Clinical Manifestations
macrophages lead to enhanced production of IL-12, which then The likelihood that an individual with IgA deficiency that was
stimulates T cells to release interferon-γ (IFN-γ). Activation of identified serendipitously will require medical attention is difficult
this pathway appears necessary for the defense against P. jiroveci to assess because most studies in the literature reflect patients
and other opportunistic organisms. who were ascertained to have the condition as a result of clinical
symptoms. Among patients with IgAD referred to immunology
Treatment and Prognosis clinics, more than 85% present with recurrent infections, typically
The availability of human Ig replacement therapy has greatly with encapsulated bacteria. Among affected children, symptoms
improved the quality of life in patients with HIGM. Adequate may begin in the first year of life, although the physiological lag
replacement can result in the reduction of serum IgM concen- in serum IgA may delay the diagnosis until after the age of 2
trations, prevention of infections with encapsulated bacteria, years. In some patients, respiratory infections disappear with
resumption of growth, and the gradual resolution of splenomegaly maturity. In others, infections may persist throughout adult life.
and lymphoid hyperplasia. Autoimmune and lymphoproliferative Rarely, patients with IgAD may experience recurrent bronchitis,
complications may respond to anti-CD20 therapy (rituximab). 21 pneumonia, and even bronchiectasis. These more severely afflicted
Unfortunately, in spite of the improvement gained by Ig patients often exhibit concurrent IgG2 and IgG4 subclass deficien-
replacement, the prognosis of patients with defects in the cies. Some symptomatic patients have elevated IgE levels and
CD40–CD154 axis remains guarded. Death at a young age manifest allergic or asthmatic components to respiratory dysfunc-
continues to be common. It is primarily the result of opportunistic tion. The rise in IgE has been explained as a compensatory
infections, including Pneumocystis pneumonia, cholangitis, CMV response to the absence of IgA. This appears to be a double-edged
infection, mycobacterial infections, and cirrhosis secondary to sword because up to 20% of these patients complain of allergic
hepatitis. Prophylaxis with trimethoprim–sulfamethoxazole can rhinitis, conjunctivitis, urticaria, and atopic eczema. Allergic
significantly reduce the risk of Pneumocystis pneumonia and is reactions may be enhanced because of the lack of IgA-blocking
indicated in those with CD40L and CD40 deficiency. Regular antibodies in serum, and unusually severe asthma has also been
monitoring of GI manifestations and management of neutropenia associated with IgAD.
is mandatory. Neutropenia should be treated with a trial of Among those less common IgA-deficient patients that are
granulocyte macrophage–colony-stimulating factor (GM-CSF), truly devoid of IgA, as many as three-fifths produce IgG or IgE
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since some have responded to this therapy. Bone marrow anti-IgA antibodies. These uncommon patients are at an
transplantation is a viable option for patients that fail to respond uncertain risk for adverse reactions following transfusion with
to supportive therapy. blood products (as mentioned previously), plasma from normal
donors, or from some preparations of Ig replacement therapy,
SELECTIVE IGA DEFICIENCY which, of course, contain IgA. Patients with high anti-IgA levels
(>1 : 1 000) typically have potent antibodies directed against all
Selective IgA deficiency (IgAD), selective IgG subclass deficiencies, IgA. These patients are at risk for severe anaphylaxis. Patients
CVID, and a syndrome of recurrent sinopulmonary infections with low anti-IgA antibody titers (<1 : 256) are often multiparous
(RESPIs) with normal serum Ig levels appear to share an overlap- women or those who had received multiple transfusions. These
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ping set of gene defects. Clinically, these disorders are marked patients rarely demonstrate severe anaphylaxis after infusion
by an increased susceptibility to upper and lower respiratory with plasma or blood products but do present with hives and
infections with encapsulated bacteria. IgAD and CVID feature rashes.
similar B-cell differentiation arrests but differ in the extent of Patients with IgAD often develop autoimmune diseases. GI
Ig deficits. The correlation between serum Ig levels and severity disorders include pernicious anemia, inflammatory bowel disease,
of infection is not absolute. 23 intestinal disaccharidase deficiency, lactase deficiency, pancreatic
insufficiency, and celiac disease. The last, in particular, can be
Diagnosis difficult to diagnose without biopsy, since serological diagnosis
Approximately 1 in 600 individuals of European ancestry are often relies on detection of antitissue transglutaminase and
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unable to produce detectable quantities of IgA1 and IgA2, making antiendomysial or antigliaden IgA antibodies. Hepatobiliary
selective IgAD the most frequently recognized primary immu- disorders include chronic active hepatitis, cholelithiasis, lupoid
nodeficiency in the Americas, Australia, and Europe. The diagnosis hepatitis, and primary biliary cirrhosis. Skin disorders include
is dependent on the sensitivity of the laboratory measurement. pyoderma gangrenosum, paronychia, and vitiligo. It is unclear
The clinical laboratory typically reports serum IgA levels of less whether this autoimmune diathesis is the end result of recurrent
than 7 mg/dL, the concentration below which nephelometry infections or is the product of recurrent insult by antigens that
becomes unreliable. would otherwise be cleared by IgA, or whether the underlying
Patients with uncomplicated IgAD have normal serum levels deficit that leads to IgAD also increases the risk of developing
of IgM, have normal or elevated levels of IgG, and demonstrate an autoimmune disorder. For example, autoimmune disorders,
normal cell-mediated immunity. A minority of patients may such as insulin-dependent diabetes mellitus and celiac disease,
demonstrate additional evidence of immune dysfunction, with are associated with the same major histocompatibility complex
inability to generate appropriate IgG2 anticarbohydrate antibodies, (MHC) haplotypes (Chapter 5) as IgAD and CVID.