Causes of hypogammaglobulinemia can be divided into primary causes related to genetic deficiencies and secondary causes related to malignancies or their treatment, infections, medications, and protein losing states that deplete antibody.
Secondary Causes
Before embarking on a search for a primary disorder causing hypo gammaglobulinemia, it is important to rule out secondary causes. Malnutrition, malabsorption, and any disease state in which large amounts of protein are lost, such as nephrotic range proteinuria, severe burns, lymphangiectasia, or protein-losing enteropathy, can overwhelm the capacity of the B cells to provide adequate immunoglobulin to maintain normal serum levels. Aside from chemotherapeutic agents, a number of medications can produce hypogammaglobulinemia; these include captopril, antiseizure medications (carbamazepine, phenytoin), gold salts, antimalarials, fenoclofenac, penicillamine, and sulfasalazine, as well as glucocorticoids. Infection with HIV and EBV, and congenital infection with rubella, CMV, and T. gondii can produce very low immunoglobulin levels and should be ruled out as appropriate. A host of lymphoid malignancies produce hypogammaglobulinemia, but the defect is most profound in CLL, in which up to 70% of patients are said to possess hypogammaglobulinemia even in the absence of treatment, and several studies suggest that this hypogammaglobulinemia at diagnosis is an independent predictor of poor survival.
Primary Immunodeficiencies
The International Union of Immunological Societies has classified the primary immunodeficiency diseases into nine groups, including one class called predominantly antibody deficiencies. These disorders present in both adults and children, although some are very rare. Table 1 provides a simple grouping of these antibody disorders.
Table1. Predominant Antibody Deficiencies
The first group is characterized by a severe reduction in all serum immunoglobulin isotypes, with absence or profound reduction in B cells. Patients with these disorders, particularly those with a well defined genetic basis, present with severe bacterial infections, most commonly in the respiratory tract (pneumonia, sinusitis, and otitis media), as well as diarrhea caused by bacteria, parasites, and viruses. The prototypic member of this group is X-linked agammaglobulinemia (XLA) caused by a mutation in the Bruton tyrosine kinase (Btk) gene, which produces a block in B-cell maturation. Female carriers of a Btk mutation are generally asymptomatic, but most boys with XLA come to clinical attention by the age of 1 year. In addition to low-serum immunoglobulins, a clue to the diagnosis is the absence of lymphoid tissue, including tonsils. Autosomal recessive mutations in the μ heavy chain as well as defects in λ5, Igα, Igβ, and BLNK produce a similar phenotype. Phosphatidylinositol 3-kinase deficiency (PIK3R1) and heterozygous mutation of the E47 transcription factor deficiency (TCF3) can cause severe reduction in all serum immunoglobulin isotypes. In a small percentage of patients, no clear molecular defect can be identified. Also included in this group are thymoma with immunodeficiency (Good syndrome) and myelodysplasia. Good syndrome is a poorly understood disorder that presents primarily in middle-aged adults. Immunodeficiency can precede or follow the diagnosis of thymoma and does not resolve with thymectomy. In addition to infections, patients experience autoimmune phenomena, including myasthenia gravis, immune thrombocytopenia purpura, pure red blood cell aplasia, and pernicious anemia. MDSs can also mimic XLA and generally present with low B cells and pancytopenia with monosomy 7, trisomy 8, or dyskeratosis congenita.
A second group is characterized by severe reduction of at least two serum immunoglobulin isotypes with normal or low numbers of B cells. Most patients in this group can be categorized as having common variable immune deficiency (CVID), a heterogeneous disorder characterized by recurrent infection and failure to make antibody to vaccine antigens. Both males and females are affected, and patients can have autoimmune and gastrointestinal disease as well as lymphoproliferative disorders. Autoimmune disease can precede the hypogammaglobulinemia. Approximately 10% of patients with a CVID phenotype have a family history of immunodeficiency. Homozygous or compound heterozygous mutations in ICOS (inducible costimulator), which is expressed on activated T cells and plays a role in activating T-helper cells and providing B-cell help, and CD19, a B-cell surface molecule that participates in signaling after antigen binding to the B-cell receptor, have been shown to result in recurrent infections in childhood and hypogammaglobulinemia. Mutations in TACI (transmembrane activator and CAML-interactor) and BAFF-R (B-cell–activating factor receptor) members of the tumor necrosis factor (TNF) receptor super family, which play roles in B-cell survival and antibody production, and MSH5, a mismatch repair gene, are thought to predispose to CVID and IgA deficiency but are not sufficient to independently cause their onset. X-linked lymphoproliferative syndrome caused by mutation in the signaling lymphocyte activation molecular-associated protein SAP (gene, SH2D1A) can present atypically or later in life with a CVID phenotype. Single-gene mutations of TNSF12 (TWEAK ), NFKB2, and CXCR4 have also been demonstrated to cause low levels of immunoglobulins. Autosomal dominant mutations in PTEN, NFKB1, IKZF1, and IRF2BP2, and X-lined mutations in ATP6AP1 have been shown to result in a CVID phenotype and have been added to Table 1. Unlike most primary immune deficiencies for which a single gene defect has been identified, CVID is heterogeneous and no genetic defect has been identified in 90% of CVID patients. Class-switch recombination defects encompass a third group of antibody deficiencies and result in hyper-IgM syndrome characterized by reductions in serum IgG and IgA with normal or elevated IgM. X-linked hyper-IgM syndrome due to mutations in the CD40 ligand (CD40LG ) gene are no longer included in this category because this disease has defects in cellular immunity that now place it into the category of combined immunodeficiency. Defects in the activation-induced cytidine deaminase gene (AID) produce hypogammaglobulinemia with recurrent bacterial infections and diarrhea, as well as enlarged lymphoid organs filled with proliferating B cells. A similar clinical picture is produced by homozygous defects in uracil-DNA glycosylase (UNG). AID is thought to deaminate cytosine to uracil, and UNG subsequently deglycosylates and removes the uracil residue, creating an abasic site, which allows for creation of single stranded DNA breaks. Deficiencies in these enzymes result in defective class switching and somatic hypermutation. Patients with similar phenotypes but without defects in AID or UNG have been described and include mutations in INO80, a member of the chromatin remodeling complex and MSH6 involved in both the induction and repair of DNA double-strand breaks in switch regions.
Additional groups of antibody deficiencies exist in which overall antibody levels are normal, but there are defects in specific isotypes, light chains, or specific antibodies with normal numbers of B cells; the majority of patients with these deficiencies are healthy. The most common member of these groups is selective IgA deficiency, which occurs in approximately 1 in 500 white individuals. The molecular mechanisms underlying this deficiency are unknown, but there is an association with CVID. Finally, an entity termed transient hypogammaglobulinemia of infancy has been described in which the normal decline in immunoglobulins after maternal transfer is prolonged. This entity is poorly understood and usually affects boys, who have mild infections and diarrhea. Recovery usually, but not always, occurs by 3 years of age.
