Pure B-Cell Disorders

Updated: Jan 27, 2015
  • Author: Issam Makhoul, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

B lymphocytes, named after their site of origin in the bursa of Fabricius in birds or in the bone marrow in humans, form the basis for humoral immunity by their production of immunoglobulins. B-cell disorders are divided into defects of B-cell development/immunoglobulin production (immunodeficiencies) and excessive/uncontrolled proliferation (lymphomas, leukemias).

This article reviews B-cell immunodeficiencies, with emphasis on pathophysiology, clinical presentation, laboratory evaluation, treatment, and prognosis.

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Pathophysiology

During fetal development, hematopoiesis, including lymphopoiesis, is multicentric. After birth, the bone marrow becomes the exclusive production site for lymphoid progenitors. B and T cells, type 2 dendritic cells, and natural killer (NK) cells share a common ancestor, ie, common lymphoid progenitor (CLP). CLP differentiates into 2 intermediate progenitors: early B cells and T/NK/dendritic trilineage cells. Both continue their development in the bone marrow through an antigen-independent process called primary lymphopoiesis (PL). Recognized stages of PL are pro-B cell, pre-B cell, immature B cell, and mature B cell.

Secondary B lymphopoiesis is an antigen-dependent process and occurs in the germinal center of peripheral lymphoid organs with specific antibody production. Secondary T lymphopoiesis is also an antigen-dependent process and occurs in the thymus.

Secondary lymphopoiesis (SL) begins when mature B cells enter the extrafollicular area of lymphoid tissue and differentiate into short-lived plasma cells and memory cells after first being stimulated by antigen-presenting cells. Memory cells travel to the primary follicle, where, after exposure to dendritic cells, they differentiate into centroblasts (immunoglobulin class-switch). Centroblasts progress to centrocytes with high-affinity antibody production, and then they differentiate further to long-term memory cells and plasmablasts. The latter migrate back to the bone marrow and start producing immunoglobulins.

The earlier the defect, the more devastating the effect on lymphopoiesis. Defects occurring at the CLP stage or those affecting processes common to B- and T-cell development result in combined immunodeficiency involving B, T, and NK cells (see Combined B-Cell and T-Cell Disorders).

The human immune system is capable of producing up to 109 different antibody species to interact with a wide range of antigens. Named after the heavy-chain isotype, 9 isotypes are known: immunoglobulin G (IgG) 1, IgG2, IgG3, IgG4, immunoglobulin M (IgM), immunoglobulin A (IgA) 1, IgA2, immunoglobulin D (IgD), and immunoglobulin E (IgE). Immunoglobulin gene rearrangement begins with heavy-chain gene rearrangement followed by light-chain gene rearrangement.

Following B-cell receptor activation, 2 waves of tyrosine kinase phosphorylation occur. The first wave involves the Src family of tyrosine kinases, ie, Lyn, Blk, Fyn, and Lck; the second activates Bruton tyrosine kinase and Syk.

X-linked agammaglobulinemia (XLA), also known as Bruton agammaglobulinemia, is the result of a mutation of the BTK gene. Pro-B cells are present in normal number, but they are unable to mature to pre-B cells. The BTK gene is present on Xq21.3-q22, and its defect results in deficiency of Bruton tyrosine kinase. Non-XLA is the result of mu heavy-chain gene deficiency that leads to abortive production of IgM and failure of B-cell development.

Activated tyrosine kinases generate a second wave of messengers by activating serine/threonine kinases or phosphatases pathways. Three major pathways have been identified: the inositol phospholipid hydrolysis pathway, the phosphatidyl inositol-3-kinase pathway, and the Ras pathway. These pathways converge toward the activation of transcription factors, resulting in B-cell activation and proliferation.

SL is an antigen-dependent process and requires the collaboration of antigen presenting cells (dendritic cells and macrophages), CD4+ T lymphocytes, and different cytokines. The B-cell receptor is formed from the noncovalent association between surface IgM or IgD and 2 transmembrane proteins, IgA and immunoglobulin B. The presence of CD22 and CD19/CD21 on the cell surface, playing the role of coreceptorlike molecules, is necessary for the activation of the receptor. However, a complete functional response requires the intervention of the costimulatory molecule CD40 and the action of soluble cytokines. Immunoglobulin class-switching requires the interaction of CD40 with CD40 ligand (or gp39) present on the surface of B and T lymphocytes, respectively.

X-linked immunodeficiency with hyper-IgM (XHM) is related to a deficiency in gp39 (CD40 ligand). [1] B cells can initiate the immune response by producing IgM, but they are not capable of operating the class-switching, hence the overproduction of IgM and the decrease or absence of the other immunoglobulin isotypes. Liver disease, sclerosing cholangitis, and liver/GI malignancies are common in these patients. The expression of CD40L on the surface of biliary epithelial cells has suggested a role for CD40-CD40L interaction in the pathogenesis of these complications through defective control of intracellular pathogens such as Cryptosporidium parvum, which has been recognized as an important pathogen in these patients. [2]

In common variable immunodeficiency (CVID), mature B cells are normal in number and morphology but fail to differentiate to plasma cells because of defective interaction between T and B cells, mostly caused by a T-cell defect. This defect is thought to be related to a decreased number and/or function of CD4+ T lymphocytes or, occasionally, to an increased number of CD8+ T lymphocytes. However, abnormal responses of B cells to many usual stimuli have also been identified in vitro.

The underlying abnormality in selective IgM deficiency is a defect of helper T-cell and excessive suppressor T-cell activity. The disorder is characterized by a low level of IgM. IgG levels are normal, but the IgG response is usually decreased.

Helper T-lymphocyte deficiency has been incriminated in the pathogenesis of transient hypogammaglobulinemia of infancy (THI) and immunodeficiency with thymoma.

The primary defect in selective IgA deficiency is related to a failure of B cells to differentiate to mature isotype-switched surface IgA-positive B cells and IgA-secreting plasma cells with appropriate stimuli. The basis for the defect is not known. B cells from patients with IgA deficiency activated via CD40 and interleukin-10 are capable of synthesizing and secreting IgA. Defective helper T-cell and excessive suppressor T-cell activities are occasionally present. Cytokine abnormalities have also been described.

IgG2 is the most common of IgG subclass deficiencies. It occurs either alone or with IgG4 or IgA deficiency. Its hallmark is an inability to generate antibodies to polysaccharides.

Primary B-cell disorders result in a complete or partial absence of one or more immunoglobulin isotypes. Regardless of the primary cause, the symptoms depend on the type and severity of the immunoglobulin deficiency and the association of cell-mediated immunodeficiency. In general, severe immunoglobulin deficiency results in recurrent infections with specific microorganisms in certain anatomical sites.

Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biological response that culminates in the elimination of the antigen. Their role in the fight against bacterial infections has been recognized for many years. Emerging evidence from animal and clinical studies suggests a more important role for humoral immunity in the response to viral infections than what was initially thought.

IgM plays a pivotal role in the primary immune response. IgG is the major component, comprising approximately 85% of serum antibodies. They mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes, by binding to the Fc receptors. IgG1 is the major component of the response to protein antigens (eg, antitetanus/diphtheria antibodies). IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies), and IgG3 seems to play an important role in the response to respiratory viruses. Complement fixation and activation are carried out by IgG1, IgG3, IgM, and, to a lesser degree, IgG2. IgA and, to a lesser extent, IgM, produced locally and secreted in the secretions of mucous membranes, are the major determinants of mucosal immunity.

IgG antibodies are the only immunoglobulin class that crosses the placenta and provides the infant with effective humoral immunity during the first 7-9 months of life.

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Epidemiology

Frequency

United States

Acquired B-cell disorders are far more common than genetic disorders affecting B cells. Antibody deficiency disorders comprise 50% of all primary immunodeficiencies. The first and second most common B-cell disorders are IgA deficiency and CVID, with incidence estimated at 1 case in 700 persons and 1 case in 53,000-100,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. Although IgG4 deficiency is very common (detected in 10-15% of the general population), its impact on carriers is not well defined. Wiskott-Aldrich syndrome (WAS) is a rare disease. Estimates indicate that 500 Americans have the disease, with an annual incidence of 40-50 cases per year.

International

Worldwide, malnutrition comprises the majority of all antibody deficiency syndromes.

Mortality/Morbidity

Patients with B-cell disorders have decreased immunoglobulin levels (hypogammaglobulinemia), with its consequence of an increased incidence of early recurrent infections, which may ultimately lead to significant damage involving different organs, particularly the respiratory system.

  • Autoimmune disorders and cancer, also more common in this group of patients, result in significant morbidity and mortality.
  • Mortality rates in infants and young children are increased, and survivors may sustain different degrees of growth retardation. For example, without allogeneic bone marrow transplantation, most patients with X-linked severe combined immunodeficiency (XSCID) die before their second year of life and those with WAS die by age 11 years. Most patients with reticular dysgenesis die in early infancy. Despite immunoglobulin therapy, 15% of patients with XLA die of infectious complications by age 20 years.
  • Therapies for these disorders (eg, intravenous immunoglobulin [IVIG], bone marrow transplantation, gene therapy) are very costly and require highly advanced facilities.

Race

No racial or ethnic predilection is recognized.

Sex

In children, primary immunodeficiencies are more common in boys than in girls (male-to-female ratio of approximately 5:1); in adults, primary immunodeficiencies are diagnosed almost equally in both sexes (male-to-female ratio of approximately 1:1.4).

  • X-linked disorders such as XLA, XHM, XSCID, and WAS affect only males. Females are carriers and thus transmit the disease to male offspring.
  • CVID and IgA deficiency have no sex predilection, but familial clustering and a frequent association with autoimmune disorders have been described.

Age

The age of patients at onset of clinical symptoms depends on several factors, including the degree of the immunoglobulin deficiency and whether the failure of the immune system is abrupt or progressive. Certain genetic disorders may not become clinically evident until late childhood or adulthood. However, most of these disorders are symptomatic by the second half of the first year of life.

  • Symptoms in XLA begin at age 7-9 months, after a significant decline of maternal antibodies occurs and in contrast to T-cell disorders and severe combined immunodeficiencies (SCIDs), in which recurrent infections start at a younger age. In XHM, symptoms begin during the first 2 years of life.
  • IgA deficiency is usually asymptomatic in childhood, and many patients are diagnosed in early adulthood.
  • Immunodeficiency with thymoma (Good syndrome) affects adults aged 40-70 years. CVID is characterized by a varying age at onset but usually manifests by the third decade of life.
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