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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Recurrent bacterial infections, typically due to encapsulated pyogenic bacteria.
Low immunoglobulin levels.
Inability to make specific antibodies to vaccine antigens or infections.
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General Considerations
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Antibody deficiency syndromes include both congenital and acquired forms of hypogammaglobulinemia with low levels of one or more of the immunoglobulins IgM, IgG, and IgA. As a group, antibody deficiencies represent nearly half of all PIDs. They can be divided into (1) defects of B-cell development, (2) defects in Ig class switching, and (3) functional B-cell deficiency. Table 33–5 outlines primary antibody deficiency syndromes, laboratory findings, and genetic inheritance in these disorders.
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A. Symptoms and Signs
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For patients with antibody deficiency, specific infectious susceptibility and other features of immune dysregulation are dependent upon the specific cause of antibody deficiency. In isolated early B-cell development defects, such as X-linked agammaglobulinemia, infections are limited to encapsulated bacteria, mycoplasma species, and enterovirus species. In the class-switching defect caused by defective CD40L, infectious susceptibility can include Pneumocystis and Cryptosporidium, whereas class-switching defects caused by absence of AICDA or UNG can include lymphoproliferation and autoimmunity. Functional defects in B cells or B-cell activation, such as in combined immunodeficiency syndromes or common variable immunodeficiency (CVID) syndromes will include infectious susceptibility dependent on the underlying molecular defect. Antibody deficiency therefore represents a broad and somewhat heterogeneous grouping whose individual features depend on the root cause of immune abnormality.
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Independent of underlying cause, untreated antibody deficiency results in typical infections. Pulmonary infection can be severe and chronic, resulting in bronchiectasis or other permanent lung damage. Severe pulmonary infections are generally preceded by chronic, recurrent middle ear and sinus infections. Additional infections can include bacteremia, bacterial meningitis, skin infection, and joint infection. Other sites of infection can arise depending on the underlying genetic defect.
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B. Laboratory Findings
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Numerous blood tests are available for the investigation of antibody production. Serum immunoglobulin levels are routinely tested and reference values are widely accessible. Antibodies to a particular antigen are measured to ensure that antibody production is specific. For instance, the amount of antibody to tetanus toxoid is frequently measured because the tetanus toxoid vaccine is routinely administered in developed countries. Vaccine titers to pneumococcal serotypes are frequently measured following vaccination with the unconjugated polysaccharide S pneumoniae vaccine. The increase in titers represents the ability of B cells to form antibodies in the absence of T-cell costimulation. Production of allo-specific IgM to red-cell antigens is also a measure of T-cell–independent antibody formation. When abnormalities are detected in immunoglobulin levels or antibody production, lymphocyte surface phenotyping may reveal additional aspects of the underlying abnormality, such as B- or T-cell deficiency.
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The characteristic feature of antibody deficiency is the absence or severe deficiency of one of the three predominant immunoglobulins found in blood, IgG, IgA, or IgM. All three immunoglobulin isotypes are severely reduced in early B-cell development defects; although, IgG deficiency is rarely seen in children younger than 4 months due to the presence of placentally transferred maternal IgG. In class switching defects, IgM production can be normal or elevated, whereas production of IgG and IgA is deficient. In functional B-cell deficiencies, a combination of antibody production abnormalities may be detected. For instance, CVID is defined by the combination of poor vaccine response and a decrease in blood levels of IgG in conjunction with a severe decrease in levels of either IgM or IgA, or a decrease of both.
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Blood cell abnormalities also vary according to the underlying cause of antibody deficiency. Many early B-cell development defects are limited to the B-cell compartment, and as a result, B-cell numbers are severely reduced, but levels of other blood cells are usually within normal limits. In class switching defects, peripheral B-cell numbers will also approach normal levels. On the other hand, functional antibody deficiency can arise in any combination of deficiency of specific lymphocyte subsets and other blood cells. For these deficiencies, the underlying genetic abnormality is most relevant to understand the resulting hematologic abnormality.
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Differential Diagnosis
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The differential diagnosis of antibody deficiency includes secondary causes of decreased amount of immunoglobulin in the peripheral blood. Several medications are known to specifically decrease immunoglobulin levels in the blood. For some of these medications, the mechanism is idiosyncratic. For others, low immunoglobulin levels result from inhibition of normal B-cell development processes, such as in chronic prednisone use, or they result from direct effects on the B-cell compartment, such as with rituximab therapy. Additional secondary causes of low immunoglobulin include protein-losing states, malnutrition, and autoimmune conditions.
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Treatment of antibody syndromes is primarily directed at preventing bacterial infection. The primary intervention in achieving this goal is replacing deficient IgG. There are no formulations of isolated IgM or IgA used in clinical practice. Some treatment centers advocate the use of prophylactic antibiotic therapy. In combined immunodeficiency or antibody deficiency syndromes with associated autoimmunity, immunosuppressive therapy or even HSCT may be required.
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Antibody Deficiency Classification
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Defective B-Cell Development
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Aborted B-cell development can occur at multiple developmental stages. Initially, B cells develop from precursors in the bone marrow in a process that is dependent on the generation of a functioning rearranged B-cell receptor. In the absence of the ability to transmit signals through a B-cell receptor, B cells do not continue development. Consistent with this model of B-cell development, congenital defects in several of the proteins essential for the formation and signaling of the B-cell receptor have been identified as causes of severe B-cell deficiency. Additional blocks in B-cell development have been identified prior to the expression of the B-cell receptor and also later in development as cells approach the naïve B-cell stage.
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Patients with defects in B-cell development are generally immunologically normal with the exception of a severe reduction of B cells in the blood and infections that result from their absence. Patients with early defects have little detectable lymphoid tissue, and upon physical examination, one may find an absence of tonsils or palpable lymph nodes. Patients with later defects may have palpable lymphoid tissue. In both groups, the spleen is generally normal in size.
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Class Switching Defects
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Normal immunoglobulin isotype class switching occurs in germinal centers in response to antigenic and T-cell costimulatory signals, and the class switching defects involve severe dysfunction of this process. Defects in either T-cell surface CD40L or B-cell surface CD40 impair the initial step in the class-switching cascade, and as a result, no class switching occurs. Further downstream, defects in either AICDA or UNG impair class switching by preventing the formation of double-stranded breaks that are essential for the genomic rearrangement required to switch isotypes. Additional defects in class switching can be seen with genetic abnormalities in the NF-κB and also PIK3D activating mutations, but in either case, the class switching phenotype can be variable. Consultation of an immunologist will help determine where the class switching defect is located and direct clinical care.
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Class switching presents with various associated features depending on the genetic cause. Defects in CD40L and CD40 can have risk of associated opportunistic infection with Pneumocystis and Cryptosporidium, the latter increasing the risk for sclerosing cholangitis, and they have hypoplastic lymphoid tissue. Patients with defective AICDA can have associated autoimmunity, including ITP, hemolytic anemia, autoimmune hepatitis, inflammatory bowel disease, arthritis, and interstitial lung disease. Both AICDA- and UNG-deficient patients suffer from lymphoid hyperplasia.
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Transient Hypogammaglobulinemia
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Serum IgG levels normally decrease during an infant’s first 4–6 months of life as maternal IgG transmitted in utero is metabolized. Transient hypogammaglobulinemia represents a delay in the onset of immunoglobulin synthesis that results in a prolonged nadir. Symptomatic patients present with recurrent infections, including upper respiratory tract infections, otitis, and sinusitis. The diagnosis is suspected in infants and young children with low levels of IgG and IgA (usually two standard deviations below normal for age), but normal levels of IgM and normal numbers of circulating B lymphocytes. Most affected children have normal specific antibody responses and T-lymphocyte function. Apart from appropriate antibiotics, no treatment is required. Infants with severe infections and hypogammaglobulinemia could be given Ig replacement, but benefits and risk must be considered and this is rarely necessary. Recovery occurs between 18 and 30 months of age, and the prognosis for affected children is excellent provided infections are treated promptly and appropriately.
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Functional Antibody Deficiency
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The group of functional antibody deficiency disorders includes any disorder in which a persistent deficiency in immunoglobulin production has been identified, and the deficiency is not the result of a secondary cause. This group includes genetic syndromes, combined immunodeficiency syndromes, CVID, and monogenetic syndromes previously classified as CVID. As expected, this group contains highly variable phenotypes, in part due to the variety of associated non-B–cell immune abnormalities, and also due to modifying factors in the individual. If possible, understanding the underlying genetic defect of the individual syndrome dramatically improves the ability to anticipate additional complications and decide on treatment approaches. Even the need for immunoglobulin G replacement therapy will vary from individual to individual.
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Monogenetic Causes of Functional Antibody Deficiency
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A number of monogenetic causes of functional antibody deficiency have been identified in scattered individuals that had previously been diagnosed with CVID. These syndromes encompass the range of phenotypes conventionally included in the broad category of CVID. Severe defects in the classic B-cell coreceptor complex, including CD19, CD21, CD81, and CD225, have been identified in individuals mainly with poor antibody response and infections that would be expected to follow. These defects presumably arise from an impaired germinal center reaction to foreign antigens in lymph nodes. Similar phenotypes were shown to result both with defects in other B-cell coreceptors such as BAFFR or TACI and also with defects in molecules that signal through these receptors such as ICOS. Additional syndromes that include involvement of T-cell dysfunction as well as functional antibody deficiency have been identified in molecules that function in both cell types. These syndromes include, but are not limited to, CD27 deficiency, PIK3D gain of function, and IL-21 deficiency. Additional syndromes with predominant features outside of functional antibody deficiency are discussed later in the chapter.
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Common variable immunodeficiency is a heterogeneous category of functional antibody deficiencies in which no other more appropriate classification is available. CVID is defined by the combination of poor vaccine response and a decrease in blood levels of IgG in conjunction with a severe decrease in levels of either IgM or IgA, or a decrease of both (see Table 33–5). Associated cellular abnormalities can include reduced numbers of memory B-cell subsets in the blood, as well as T-cell lymphopenia. Patients have recurrent infections, most often of the sinus and pulmonary tract, but chronic gastrointestinal infections may manifest with recurrent diarrhea. Patients with CVID are at risk for developing bronchiectasis, autoimmune diseases (idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, rheumatoid arthritis, and inflammatory bowel disease), and malignancies (especially gastric carcinoma and lymphoma).
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Selective Immunoglobulin Deficiencies
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Deficiency of an IgA or an IgG subclass can be seen in the presence of both recurrent infections and other immune abnormalities; however, these deficiencies are often seen in the absence of any other identifiable immune abnormality. With an incidence of 1:700, isolated IgA deficiency is a common laboratory finding. The majority of patients with isolated IgA deficiency are asymptomatic, but associations also exist with inflammatory bowel disease, allergic disease, asthma, and autoimmune disorders (thyroiditis, arthritis, vitiligo, thrombocytopenia, and diabetes). Deficiency of IgG subclasses 2–4 can be identified in the absence of other laboratory immune abnormalities; whereas, severe deficiency of IgG1 universally presents with an overall decrease in total IgG levels because it makes up the majority of IgG detectable in the blood. Deficiency of IgG2 can be seen in association with decreased IgA, and in that context, it is suggestive of an underlying functional antibody deficiency with a possibly identifiable genetic cause. IgG3 and IgG4 make up the smallest fraction of the total IgG pool, and in the absence of any other immune abnormality, deficiency of either of these IgG subclasses is generally not considered to cause increased susceptibility to infection. IgG replacement is not indicated in either IgA deficiency or IgG subclass deficiency when no other quantitative or functional immune abnormality has been identified. When other immune abnormalities are seen, antibody deficiency syndromes listed elsewhere in this chapter should be considered.
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Durandy
A, Kracker
S, Fischer
A: Primary antibody deficiencies. Nat Rev Immunol 2013;13:519033
[PubMed: 23830147]
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