Primary B-cell immunodeficiencies
Introduction
About 20% of serum proteins are immunoglobulins, containing all the antibody species that a human needs for protection against most infections [1]. Functional antibodies are the end product of multiple steps that include continuous reconfiguration of genes for the B-cell antigen receptors (BCR) along with the elimination of perhaps 90% of poly-reactive and autoreactive B-cells during this process [2]. One of the most illuminating lessons about B-cell biology has arisen from studies of the primary immune defects that prevent normal B-cell development. While more than 300 primary immune defects are now known [3], clinically, the most common defects found in patient populations are those that impair B-cell development or function (Fig. 1).
B-cell immunodeficiencies are often distinguished from other immune defects, by age of onset, clinical parameters, severity and mode of inheritance. The types of infections that hallmark an underlying B-cell defect include recurrent infections that are typically encapsulated bacteria, distinct from patients with T-cell or combined immunodeficiencies, who are more likely to have opportunistic or severe viral or infections. B-cell defects are quite heterogeneous, and include loss of immune globulins, and/or impaired antibody production. These result from molecular defects intrinsic to B-cells, failure of required interactions between B- and T-cells, loss of appropriate bone marrow or germinal center responses, and defects of immune regulation. These defects result in a variable loss of B-cells, reduction or absence of serum immunoglobulins and/or loss of antibody function. B-cell immunodeficiencies are categorized into the following: 1) a severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells, recognized as agammaglobulinemia; 2) severe reduction in at least 2 serum immunoglobulin isotypes (typically IgG and IgA) with normal or low number of B cells (CVID phenotype); 3) severe reduction in serum IgG and IgA with normal/elevated IgM with normal numbers of B cells (Hyper IgM syndrome); 4) Isotype or light chain deficiencies with generally normal numbers of B cells (these are outlined in Table 1).
Section snippets
X-linked agammaglobulinemia (XLA)
Agammaglobulinemia is characterized by absence of circulating B-cells with severe reduction in all serum immunoglobulin levels. Clinically, this is a rare defect (1:100,000 to 1:200,000 depending on ethnicity and the specific genetic defect) [4]. Both X-linked and autosomal recessive forms of the disease have been described. The classic disorder of B-cell development is X-linked agammaglobulinemia (XLA), first described in 1952 by Ogden Bruton, who reported an eight-year-old boy with recurrent
Common variable immune deficiency (CVID)
After early B-cell development with successful generation of cells bearing a functional BCR, B-cells move from the bone marrow to the spleen and peripheral lymphoid tissues, where additional maturational events occur which lead to plasma cell development. Failing any of these steps results in varying degrees of hypogammaglobulinemia. From the clinical point of view, patients are usually given the generic label, common variable immune deficiency (CVID). One of the essential issues in CVID is
Hyper IgM syndrome: severe reduction in serum IgG and IgA with normal/elevated IgM and normal B-cell numbers.
Class-switch recombination (CSR) occurs downstream of T-cell dependent B-cell activation in germinal centers. Activated follicular B-cells receive help from cognate T follicular helper cells to undergo CSR and somatic hypermutation (SHM). Eventually, CSR and SHM result in high-affinity antibody production and the differentiation of B-cells into long-lived memory B-cells and plasma cells [71]. Immunoglobulin class switch recombination deficiencies, previously termed “hyper-IgM syndromes (HIGM)”
Selective IgA deficiency (SIGAD)
Selective IgA deficiency is the most common primary antibody deficiency, with worldwide incidence varying depending on the ethnic background (1:143 to 1:18,500) [86]. It affects males and females equally and is defined as a serum IgA level of less than 7 mg/dl and normal levels of serum IgG and IgM in a patient older than 4 years old [87]. Primary IgA deficiency must be distinguished from secondary causes due to medications such as anticonvulsants (phenytoin, carbamazepine, valproic acid),
Diagnosis
Diagnosing a primary B-cell defect relies first on clinical history and then on confirmatory laboratory evaluations. This includes a detailed family and infection history, age of onset, frequency and duration of treatments and if known, organisms that might suggest a primary B-cell defect or a combined B- and T-cell immune defect. Laboratory evaluations include complete blood counts, full lymphocyte panels for T-cell, B-cell, and NK-cell subsets, quantitative serum immunoglobulin levels (IgM,
Treatment
The management of primary B-cell immunodeficiencies focuses largely on the prevention and treatment of infections and secondarily on controlling any complications that may develop. Adequate antibody replacement therapy for those with documented loss of functional IgG is key, with intravenous or subcutaneous immune globulin formulations being the primary cornerstone in the care of patients. Microbial therapy is used as needed for acute treatment, and in some cases, chronic antibiotic
Conclusion
Murine models have illustrated the most basic principles of B-cell biology, but what is most solidly known for human B-cell immunity, has often been based on studies of primary immunodeficiencies (PID). X-linked agammaglobulinemia permitted the elucidation of cytoplasmic tyrosine kinase BTK, crucial for maturation of mature B-cells. Defects of all of the components of the BCR result in autosomal agammaglobulinemia, demonstrating that continuous BCR signals are essential for the maintenance of
Disclosure information
T. Smith and C. Cunningham-Rundles have no relevant conflicts of interest to disclose.
Acknowledgements
Funding for this study was provided by the National Institutes of Health grants, AI-061093, AI-086037, AI-48693, and David S. Gottesman Immunology Chair at the Icahn School of Medicine at Mount Sinai.
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