The prior section covered defects that predominantly affect T lymphocyte development and/or function. This section covers primary immunodeficiencies in which abnormalities of B-cell development and/or function predominate (see Figs.1 and 2).
Fig1. GENETIC DEFECTS ASSOCIATED WITH HYPOGAMMAGLOBULINEMIA. Schematic of B-cell development in bone marrow and secondary lymphoid organs, including migration of B cells into the follicular zone where they undergo activation, class-switch recombination (CSR), and somatic hypermutation (SHM). “X” denotes maturation steps at which the genes indicated are required, resulting in a block in differentiation at that stage when the gene is deficient. ActB, Activated B cell; AID, activation-induced cytidine deaminase; BTK, Bruton’s tyrosine kinase; Foll-B, follicular B cell; HSC, hematopoietic stem cell; IGLL, immunoglobulin light-like chain; IL-21, interleukin-21; immB, immature B cell (also termed transitional B cell); memB, memory B cell; MZ-B, marginal zone B cell; PC, plasma cell; Pre-B, precursor B cell; Pre-BCR, pre–B-cell receptor; Pro-B, progenitor B cell; RAG1, recombination activating gene 1; RAG2, recombination-activating gene 2; sIgA, surface IgA; sIgD, surface IgD; sIgG, surface IgG; sIgM, surface immunoglobulin M; UNG, uracil-DNA glycosylase.
Fig2. GENETIC DEFECTS ASSOCIATED WITH COMMON VARIABLE IMMUNODEFICIENCY (CVID). Schematic of cell surface molecules expressed on B cells and their ligands, highlighting those in which defects have been shown to be associated with CVID. Ag, Antigen; APRIL, a proliferation-inducing ligand; BAFF, B-cell–activating factor; BAFFR, B-cell–activating factor receptor; BCMA, B-cell–maturation antigen; DC, dendritic cell; HSPG, heparin sulfate proteoglycan; ICOS, inducible T-cell costimulator; ICOS-L, inducible T-cell costimulator ligand; Ig, immunoglobulin; IL-4, interleukin 4; IL-10, interleukin 10; PC, plasma cell; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; TI-2, T-cell–independent type 2.
X-Linked Agammaglobulinemia
X-linked agammaglobulinemia (XLA), also known as Bruton's agammaglobulinemia, is the most common monogenic cause of failure of B-cell development. Males with XLA lack circulating B cells, caused by mutations of the Bruton’s tyrosine kinase or BTK gene, which encodes for a tyrosine kinase involved in signaling through various receptors, including the pre–B-cell receptor (pre-BCR) and the BCR. Impaired signaling through the pre-BCR causes a severe, but incomplete, block at the pre–B-cell stage in the bone marrow (see Fig. 1).
Clinical manifestations of XLA include recurrent sinopulmonary infections (pneumonia, bronchitis, sinusitis, otitis), particularly with encapsulated organisms such as pneumococcus and Haemophilus influenza, bacterial skin infections (cellulitis, impetigo, pyoderma gangrenosum, perirectal abscess), and sepsis with Pseudomonas or Staphylococcus. Symptoms typically begin after 3 to 6 months of age when maternally derived antibodies disappear. The proportion of circulating B cells is markedly reduced (typically 0.05% to 0.3% of lymphocytes) and there is profound deficiency of all immunoglobulin isotypes. Neutropenia, secondary to severe infections, is observed in approximately 10% to 25% of patients; typically, it resolves with antibiotics and immunoglobulin-replacement therapy.
In addition to bacterial infections, patients with XLA are uniquely susceptible to enteroviral infections (including chronic meningoencephalitis) caused by poliovirus, coxsackie virus, and others. However, such complications have become rare after the introduction of optimal doses of immunoglobulin-replacement therapy. Patients with XLA are also at higher risk of infections caused by Mycoplasma and Ureaplasma species, which affect the joints, prostate, or lungs; and Giardia lamblia, causing protracted diarrhea and malabsorption. An increased incidence of lymphoma, colorectal cancer, and gastric adenocarcinoma has been reported in XLA.
Therapy is based on life-long regular administration of immunoglobulins intravenously or subcutaneously, and on prompt and aggressive treatment of infections. With this regimen, survival approaches that of the general population. Antibiotic prophylaxis may be beneficial, but its role has not been firmly established. Patients on immunoglobulin-replacement therapy should be monitored for side effects and adverse reactions, and for liver and renal function.
Autosomal Recessive Agammaglobulinemia
While the majority of agammaglobulinemia cases are caused by the X-linked form, about 15% of cases are presumed to be autosomal recessive (see Fig. 1). Mutations of the immunoglobulin μ heavy chain gene (IGHM) are the second most common cause of agammaglobulinemia. Other cases are caused by defects in other components of the pre-BCR/BCR complex including the signaling moieties Igα (CD79A) and Igβ (CD79B), and λ5 (IGLL1), the surrogate light chain that pairs with Vpre-B, and the scaffold protein BLNK, which brings BTK into the signaling complex. Finally, congenital agammaglobulinemia may also be caused by mutations of the PIK3CD and PIK3R1 genes, causing complete loss of the p110α and p85α subunits, respectively, of phosphatidylinositol 3-kinase (PI3K), and to heterozygous, dominant-negative mutations of the TCF3 gene encoding for the transcription factor E47.
Common Variable Immunodeficiency
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency severe enough to require treatment, with a prevalence estimated to be 1 in 25,000 to 1 in 30,000 Caucasians, and accounting for approximately 10% to 20% of humoral immunodeficiencies. A growing number of genetic defects have been found to be associated with a CVID phenotype, but most cases remain genetically undefined. Mutations in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) can also be found in asymptomatic individuals, and more likely represents a predisposition to CVIDs than primary cause.
Mutations in CD19, CD81, and CD21, which are all components of the B-cell coreceptor, have been reported in few individuals. These defects do not affect B-cell development but impair signaling, causing hypogammaglobulinemia, low number of switched memory B cells, and poor antibody response to T-independent antigens. In addition to recurrent infections, patients with CD19 and CD81 deficiency may also develop glomerulonephritis.
CD20 is a surface molecule involved in B-cell development and plasma cell differentiation. Autosomal recessive CD20 deficiency is characterized by recurrent infections, low serum IgG, with normal or elevated IgA and/or IgM.
BAFF-R deficiency is very rare. It has a variable clinical presentation, with CVID-like features or even absence of symptoms. Laboratory findings include hypogammaglobulinemia, low numbers of circulating B cells, a defective proportion of memory B cells, and normal antibody response to T-dependent antigen but a defective response to carbohydrate antigens.
A variable clinical phenotype has been also reported in patients with haploinsufficiency of the p50 subunit of NF-κB (encoded by the NFKB1 gene), causing defective signaling through the canonical NF-κB signaling pathway. In addition to recurrent infections and progressive lung disease, patients often present with autoimmunity (hemolytic anemia, thyroiditis, alopecia) and lymphadenopathy. However, genotypically affected individuals may also remain asymptomatic even through adulthood. Heterozygous mutations of the NFKB2 gene (affecting mostly the noncanonical NF-κB signaling pathway) cause recurrent infections (especially due to HSV, varicella zoster virus [VZV], and Giardia), central adrenal insufficiency, hypopituitarism, alopecia, trachyonychia, and growth deficiency. Hypogammaglobulinemia, a low number of memory B cells, Treg lymphocytes, T follicular helper (Tfh) cells, and NK lymphocytes have been demonstrated.
Haploinsufficiency of the IKZF1 gene, causes recurrent infections and autoimmunity, associated with progressive B-cell lymphopenia and hypogammaglobulinemia. These patients are at significantly increased risk of acute lymphoblastic leukemia.
Autosomal recessive RAC2 deficiency causes recurrent infections, post-streptococcal glomerulonephritis and urticaria, along with hypo gammaglobulinemia and poor antibody production.
Diagnostic criteria for CVIDs include the presence of hypogam maglobulinemia (<2 standard deviations below the mean for age of IgG, IgA, and/or IgM) and the lack of specific antibody responses in individuals with onset of symptoms >2 years of age, for whom other causes of humoral immunodeficiency have been ruled out. The number of circulating B cells detected is variable. Specific antibody responses should be assessed for more than one antigen.
Consistent with the antibody deficiency, CVID patients have recurrent bacterial infections of the respiratory tract, sepsis with encapsulated organisms, and infections from Ureaplasma uraelyticum, Giardia species and enteroviruses. However, variable derangement of T-cell numbers and function often results in noninfectious manifestations, including autoimmunity, lymphoid infiltration or proliferation, and malignancy. In one survey only 26% of CVID patients had infections as the only manifestation of disease. Autoimmune cytopenias are quite common (~12%) and may be the presenting feature. Other autoimmune complications include rheumatoid arthritis, systemic lupus erythematosus, hypothyroidism, vitiligo, psoriasis, diabetes, and autoimmune gastritis with pernicious anemia. Polyclonal lymphocytic granulomatous infiltrates are common and may involve the lungs, liver, or gut (causing enteropathy that is resistant to gluten withdrawal). Finally, both lymphoid (non-Hodgkin lymphoma, chronic lymphocytic leukemia) and nonlymphoid (gastric cancer) malignancies, as well as nonmalignant lymphoproliferation, are more frequent in CVID, although the gastric cancers may be related to Helicobacter pylori infection.
Replacement of immunoglobulins and treatment and prevention of infection remains the mainstay of management of CVID. Immunosuppression may be needed for inflammatory and autoimmune manifestations. Disease manifestations such as autoimmunity, polyclonal lymphocytic infiltrative disease, enteropathy, and malignancy have differential and increasing impact on survival (relative risk of death 2.5, 3.0, 4.0, and 5.5, respectively), while patients with solely infectious manifestations have equivalent survival to the general population. Treatment with HCT has been performed with limited success, and often in the context of consolidative treatment for lymphoproliferation. (See box on Diagnostic and Therapeutic Approach to Defects in Humoral Immunity.)
