Pure B-Cell Disorders

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: 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 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, then 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: Lyn, Blk, Fyn, and Lck; the second activates Bruton tyrosine kinase and Syk.

X-linked agammaglobulinemia (XLA), also known as Bruton agammaglobulinemia, results from a mutation of the BTK gene, which encodes the pre-B-cell receptor (Pre-BCR) and BCR. Pro-B cells are present in normal numbers but they are unable to mature to pre-B cells. The BTK gene is located on Xq21.3-q22, and its defect results in a deficiency of Bruton tyrosine kinase. ^[2] 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 phosphatase 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. CD22 and CD19/CD21 on the cell surface, playing the role of coreceptor-like molecules, are necessary for activating 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). ^[3] 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.  ^[4]

CVID can be described as a group of hypogammaglobulinemia syndromes. 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, including a severe reduction in switched memory B cells (CD19⁺CD27⁺IgD^–). In some cases, expansion of transitional B cells (CD19⁺CD24^hiCD38^hi), CD21^lowCD38^low B cells (the latter thought to play a role in autoimmunity), has been observed. ^[5]

The genetic basis of CVID is complex. In a minority of CVID patients, monogenic defects have been identified. If a causative mutation is identified, these conditions are reclassified as CVID-like disorders. ^[6]  Over 12 monogenic defects causing CVID-like disorders have been identified, most of which appear to impair B-cell function directly. Currently, if a single causative mutation is identified, by definition, such patients are reclassified with a specific molecular diagnosis—for example, NFκB1-deficiency (OMIM CVID12). ^[7]

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

Regulatory T-cells (Treg) have been implicated in the pathogenesis of THI. Recent data suggest that myeloid-derived suppressor cells (MDSC) in THI induce the production of Treg cells and inhibit IgG production. A higher level of Treg correlates with a delayed normalization of immunoglobulin levels. ^[8]   Helper T-lymphocyte deficiency has also 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 can synthesize and secrete 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 IgG subclass deficiency. It occurs either alone or with IgG4 or IgA deficiency. Its hallmark is the 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 eliminating 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 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 immune complexes' clearance 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 (e.g., anti-pneumococcal antibodies), and IgG3 seems to play an important role in 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.

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 an 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 widespread (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 persons in the United States have the disease, with an annual incidence of 40-50 cases per year.

Worldwide, malnutrition comprises the majority of all antibody deficiency syndromes. No racial or ethnic predilection is recognized.

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.

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 (SCID), 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. A varying age at onset characterizes CVID but the disorder usually manifests by the third decade of life.

Before the immunoglobulin era, patients with XLA died at an early age because of the complications of infections with encapsulated bacteria. The advent of intramuscular immunoglobulin brought some clinical improvement, with partial control of upper and lower respiratory tract infections, but patients still died before age 25 years. The introduction of IVIGs in the early 1980s resulted in significant improvement of infection control, with prolonged survival. With regular intravenous or subcutaneous administration of immunoglobulins and aggressive antibiotic treatment, survival approaches that of the general population. ^[5]

Most patients with XHM die in the first and second decades of life. The actuarial survival rate at 25 years is only 25%, and 80% of these patients develop liver disease by age 20 years. Patients with B-cell disorders have decreased immunoglobulin levels (hypogammaglobulinemia), resulting in 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 are also more common in this group of patients, resulting 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 (X-SCID) 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.

Complications vary among the different B-cell disorders.

X-linked agammaglobulinemia

In patients with XLA, attenuated live poliovirus vaccine may cause vaccine-associated poliomyelitis. Chronic disseminated enteroviral infection may be associated with vasculitis, pneumonitis, and hepatitis. Dermatomyositis-like syndrome, a constellation of subcutaneous tissue edema, skin rash, and muscle weakness, is unusual.

Chronic pulmonary disease (50% of patients) and chronic enteroviral meningoencephalitis remain the major complications of this disease. Very high doses of immunoglobulin (0.4 mg/kg q48h to 1 g/kg/d for 3-12 mo) have been used by Quartier et al in the treatment of 3 patients with enteroviral meningoencephalitis. ^[9]  Trough levels as high as 3100-6300 mg/dL were achieved. Two patients survived, and clinical and cerebrospinal fluid abnormalities resolved. Hearing loss due to chronic otitis media or meningoencephalitis may affect up to a third of these patients. ^[10]

Infectious complications cause death by age 20 years in approximately 15% of patients.

Common variable immunodeficiency

Spruelike syndrome with malabsorption is observed in 10% of patients with CVID. Histologically, this resembles gluten-sensitive enteropathy (except for the absence of plasma cells). Infectious enteritis may imitate ulcerative colitis or Crohn disease, and both seem to occur more commonly in these patients.

Most patients with CVID and primary hypogammaglobulinemia develop pulmonary complications after several years of recurrent infections, sometimes despite appropriate IVIG therapy. Although chest radiographs are useful, the criterion standard for evaluation remains high-resolution computed tomography (HRCT) scans. Using HRCT scans, 95% of patients studied by Kainulainen et al showed abnormalities. ^[11]  The most common findings were fibrosis (81%); bronchiectasis (73%); parenchymal scarring (45%); pleural thickening (36%); and, less commonly, emphysema or parenchymal nodules. Pulmonary function tests showed obstruction in 33% of patients. Follow-up using HRCT scans and pulmonary function tests revealed silent and asymptomatic deterioration despite appropriate IVIG therapy.

Cor pulmonale may ultimately result from chronic/recurrent lower respiratory tract infections.

Autoimmune diseases occur in 10-20% of patients. Autoimmune disorders at presentation are associated with increased morbidity and mortality. ^[12]

Granulomatous disease occurs in 5.4-10% of patients with CVID and is characterized by the following: 

• Noncaseating granulomas can be localized in any organ, with the lungs, liver, and lymph nodes being the most frequent sites, followed by the bone marrow and skin. Lung involvement led to restrictive lung disease and death in 4 of 17 patients studied by Mechanic et al. ^[13]  This entity should be differentiated from mycobacterial and fungal infections and sarcoidosis.

• The major distinguishing feature from idiopathic sarcoidosis is the level of immunoglobulins, which is increased in persons with sarcoidosis and decreased in those with CVID. The Kveim test is not helpful because it returns a positive finding in up to 40-50% of CVID patients. Serum angiotensin-converting enzyme (ACE) levels, a marker of macrophage activity, are elevated in approximately a third of these patients.

In vitro T-cell dysfunction in CVID patients with the granulomatous disease may explain the higher risk of autoimmune diseases in these patients than in the rest of the group. In the small subset of patients with aggressive disease, corticosteroids are the treatment of choice.

The risk of cancer in CVID patients is 5-fold higher than in matched controls. Both lymphoid and non-lymphoid (gastric) cancers are more common in these patients. A 47-fold increase in gastric cancer and a 30-fold increase in lymphoma have been reported; however, benign lymphoproliferative disorders are much more common, affecting up to 30% of patients and manifesting as splenomegaly with or without diffuse lymphadenopathy. They are distinguished from lymphomas by the presence of a mixture of B and T lymphocytes and by the absence of clonal B- and T-cell receptor rearrangement.

IgA deficiency

Complications include malabsorption, celiac disease, giardiasis, nodular lymphoid hyperplasia, pernicious anemia, primary biliary cirrhosis, and chronic hepatitis. The incidence of gastric and colon cancer is increased. Patients have anaphylactic reactions to blood products containing IgA.

Hypogammaglobulinemia

Encephalitis is a rare complication in hypogammaglobulinemic patients. It is frequently related to Enterovirus or coxsackievirus infection and, less commonly, to measles and papovavirus.

Complications related to IVIG therapy

Complications include increased serum viscosity and more frequent thromboembolic events. The risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 to 30 d post infusion) is also increased.

The most common adverse reactions are non-anaphylactic and are characterized by back and abdominal pain, nausea, vomiting, chills, fever, and myalgias. The infusion should be discontinued until the symptoms subside, then restarted at a slower rate.

True anaphylactic reactions are rare and occur seconds to hours after the infusion is started. Typical symptoms consist of flushing, facial swelling, dyspnea, and hypotension. The infusion should be stopped, and the patient should receive epinephrine, steroids, and antihistamines together.

The risk of renal tubular necrosis is increased in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease.

Hepatitis C virus (HCV) infection transmission is much less common now than in the past. Most HCV RNA–positive patients contracted their infection in the 1980s, when serologic testing of blood donors was not available for this infection. Chronic liver disease in HCV RNA–positive patients is characterized by a severe clinical course, particularly in CVID patients.

Hepatitis B and G viruses seem to play minor roles in the pathogenesis of chronic liver disease in these patients. A milder form of chronic liver disease with negative serology findings for HCV, hepatitis B virus (HBV), and hepatitis G virus (HGV) infections has been described in these patients. This form occurs an average of 36 months after the beginning of IVIG therapy and is thought to be related to immune phenomena or an as yet unidentified viral infection. A small subset of patients without HCV, HBV, or HGV infection has a particularly severe course; in most, granulomatous disease of the liver has been identified.