Congenital agammaglobulinemia results from defects of early B cell development

B lymphocytes develop in the bone marrow from the hematopoietic stem cell (HSC), through various stages of maturation (see Fig. 9.w1) during which time they rearrange their immunogloulin genes to generate the pre-B cell receptor (see Fig. 9.w2). Defects in the expression and/or signaling through the pre-BCR cause congenital agammaglobulinemia with lack of circulating B lymphocytes.

X-linked agammaglobulinemia (XLA) is the prototype of these disorders, and was described by Dr Bruton in 1952. Affected males suffer from recurrent pyogenic infections. They lack serum IgA, IgM, IgD and IgE, and IgG levels are extremely low, usually <100 mg/dL. Circulating B lymphocytes are absent or markedly reduced (<1% of peripheral lymphocytes). Tonsils are absent and lymph nodes are unusually small. XLA is caused by mutations of the Bruton tyrosine kinase (BTK) gene, that encodes an enzyme involved in signaling through the pre-BCR and the BCR (Fig. 16.1). BTK mutations cause an incomplete, but severe, block at the pre-B cell stage in the bone marrow (Fig. 16.2). The BTK protein is also expressed by other cells (including monocytes and megakaryocytes), but its defect does not affect development of these cell types.

Fig. 16.1 Congenital agammaglobulinemia

Congenital agammaglobulinemia results from defects of proteins that participate at signaling through the pre-B cell receptor (pre-BRC). This is composed of the μ heavy chain, the surrogate light chains V-preB and λ5, and the signal transducing molecules Igα and Igβ. Signaling through the pre-BCR triggers activation of tyrosine kinases such as Fyn, Syk, and BTK, and involves the adaptor molecule BLNK. Ultimately, these signals converge on activation of the phospholipase C-γ (PLC-γ) and induction of calcium flux. The proteins whose mutations result in a known form of congenital agammaglobulinemia in humans are boxed in red.

Fig. 16.2 B cell maturation in X-linked immunodeficiencies

In X-LA, affected male infants have no B cells and no serum immunoglobulins, except for small amounts of maternal IgG. In IgA deficiency, IgA-bearing B cells, and in some cases IgG2- and IgG4-bearing B cells, are unable to differentiate into plasma cells. People with HIgM lack IgG and IgA. In CVID, B cells of most isotypes are unable to differentiate into plasma cells. Black bars denote points of inhibition.

For the first 4–6 months of life, males with XLA are protected by the maternally-derived IgG that has crossed the placenta, but once this supply of IgG is exhausted, they develop recurrent bacterial infections. Patients with XLA are also at risk of enteroviral infections (such as Echovirus) that may cause encephalitis. If immunized with attenuated poliovirus vaccine, they may develop paralytic poliomyelitis. Treatment of XLA is based on regular administration of immunoglobulins (IgG).

More rarely, congenital agammaglobulinemia is inherited as an autosomal recessive trait, due to mutations of other genes that encode for components of the pre-BCR or of the adaptor molecule BLNK (see Fig. 16.1). In all of these cases, there is a severe block in B-cell development at the pre-B cell stage in the bone marrow. The clinical phenotype is virtually identical to that of XLA.

Defects in terminal differentiation of B cells produces selective antibody deficiencies

Terminal maturation of B lymphocytes is marked by their differentiation into antibody-secreting plasma cells. Generation of plasma cells is markedly reduced in patients with CVID (see Fig. 16.2), who typically develop progressive hypogammaglobulinemia in the second and third decades of life. CVID is the most common primary immunodeficiency (1:10 000 affected individuals in the general population), characterized by extensive clinical and immunologic heterogeneity. Some patients have a reduced number of circulating B cells, and especially of CD27⁺ memory B lymphocytes; others show impaired function of T lymphocytes. CVID is usually sporadic, and the underlying molecular defect remains unknown in most cases. However, in some families CVID is inherited as an autosomal dominant or an autosomal recessive trait. A minority of CVID patients carry mutations in genes that play a key role in T-B cell interaction and B cell signaling (Fig. 16.3).

Fig. 16.3 Mutations associated with CVID

Common variable immunodeficiency may associate with mutations of proteins involved in B cell activation. These include co-stimulatory components of the B cell receptor (CD19, CD81, CD21), ICOS ligand (ICOS-L), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and the B-cell activating factor receptor (BAFF-R). These molecules deliver survival, activation and differentiation signals in mature B lymphocytes. (APRIL, a proliferation inducing ligand; BCMA, B cell maturation antigen; HSPG, heparan sulfate proteoglycan.)

CVID is characterized by reduced levels of specific antibody isotypes

Individuals with CVID have impaired antibody production in response to immunization or to natural infections and there is a virtual absence of plasma cells in lymphoid tissues and in the bone marrow. They suffer from recurrent infections of the respiratory tract (sinusitis, otitis, bronchitis, and pneumonia) sustained by common bacteria (non typeable H. influenzae, S. pneumoniae, etc.); lack of mucosal antibodies results in increased risk of gastrointestinal infection due to Giardia lamblia (Fig. 16.4). They are also highly prone to autoimmmune manifestations (cytopenias, inflammatory bowel disease), granulomatous lesions, lymphoid hyperplasia, and tumors (especially lymphomas). Treatment is based on immunoglobulin replacement therapy and antibiotics. Immunosuppressive and anti-inflammatory drugs may be needed in patients with autoimmune or inflammatory complications.

Fig. 16.4 Giardia lamblia

Numerous Giardia lamblia parasites can be seen swarming over the mucosa of the jejunum of a patient with CVID.

Defects of class switch recombination (CSR)

Class switch recombination (CSR) is the mechanism by which the μ chain of immunoglobulins is replaced by other heavy chains, resulting in the production of IgG, IgA, and IgE. The process occurs in germinal centres and is accompanied by affinity maturation as described in Chapter 9.

Deficiency of CD40L (X-linked) or more rarely of CD40 (autosomal recessive) results in failure of CSR, with very low or undetectable levels of IgG, IgA, and IgE and normal to increased levels of serum IgM (see Fig. 16.2). In the past, this condition was also known as ‘hyper-IgM syndrome’. In the lymph nodes, primary follicles are present, but germinal centers are absent (Fig. 16.5). Binding of CD40L to CD40 is also important to promote interaction between activated T cells and dendritic cells or monocytes/macrophages. This promotes T cell priming, production of IFNγ and activation of macrophages, that are important in the immune defense against intracellular pathogens. Consistent with this, the clinical phenotype of CD40L and of CD40 deficiency is characterized not only by recurrent bacterial infections, but also by increased risk of early-onset opportunistic infections (Pneumocystis jiroveci pneumonia, cytomegalovirus infection, protracted and watery diarrhoea due to Cryptosporidium). Neutropenia and severe liver disease are frequent. Therefore, CD40L and CD40 deficiency are not pure antibody deficiency, but rather represent examples of combined immunodeficiency. Treatment of these disorders is based on administration of immunoglobulins and antibiotics, but often requires hematopoietic stem cell transplantation (HSCT).

Fig. 16.5 CD40 ligand deficiency

Lymph nodes from patients with CD40 ligand deficiency show primary follicles, but lack germinal centers.

In B cells, signaling through CD40 promotes transcription of the gene encoding for activation-induced cytidine deaminase (AID), a DNA-editing enzyme that replaces deoxycytidine residues with deoxyuracil in the DNA of the immunoglobulin heavy chain switch regions. The resulting mismatch in the DNA is recognized by the enzyme uracil N-glycosylase (UNG) that removes the deoxy-uracil residues, leaving abasic sites that are resolved by means of DNA repair mechanisms. These DNA modifications trigger both CSR and somatic hypermutation. Both AID and UNG mutations cause severe deficiency of IgG, IgA, and IgE production; furthermore, the immunoglobulins (almost entirely IgM) produced by these patients have low affinity for the antigen. Clinically, these immunodeficiency diseases are characterized by recurrent bacterial infections. Dramatic expansion of germinal centers (leading to tonsil and lymph node enlargement), and the lack of susceptibility to opportunistic infections distinguish hyper-IgM syndrome due to AID and UNG mutations from the forms due to defects of CD40L or CD40. Treatment of AID and UNG deficiency is based on administration of immunoglobulins.

Severe combined immunodeficiency (SCID) can be caused by many different genetic defects

SCID includes a heterogeneous group of genetic disorders that affect various stages of T lymphocyte development or function (Fig. 16.6). The main pathophysiology mechanisms of SCID (and the associated diseases) are:

Fig. 16.6 Gene defects causing SCID

There is a wide range of gene defects that affect T cell development or maturation and cause combined immunodeficiency in humans. Some of these defects also affect B and/or NK cell development. The diagram indicates the main stages that are affected by each deficiency. (γc, common γ chain; ADA, adenosine deaminase; AK2, adenylate kinase 2 (causing reticular dysgenesis); CORO-1A, coronon-1A; DNA-PKcs, DNA-protein kinase catalytic subunit; IL-7R, interleukin 7 receptor; JAK3, janus-associated kinase 3; LIG4, DNA ligase IV; MHC II, major histocompatibility class II antigens (due to mutation of various transcription factors); PNP, purine nucleoside phosphorylase; RAG, recombinase activating gene; STIM1, stromal interaction molecule 1.)

While severe T cell abnormalities are a hallmark of all forms of SCID, some of these diseases also involve abnormalities of B and/or NK lymphocytes. In particular, some forms of SCID are characterized by absence of T lymphocytes, but presence of B lymphocytes (T⁻B⁺ SCID), whereas others show absence of both T and B lymphocytes (T⁻B⁻ SCID). Both of these groups of SCID include forms with or without natural killer (NK) lymphocytes.

SCID has a prevalence of approximately 1:50 000 live births, and is more common in males, reflecting the existence of X-linked SCID (X-SCID), the most common form of SCID in humans. This disease is due to mutation of the gene encoding for the common gamma chain (γc), shared by several cytokine receptors, namely those for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.