|
|
|
|
X-Linked agammaglobulinaemia (XLA) and The Hyper-IgM (HIGM) Syndrome
The primary immunodefeciency diseases are a heterogeneous group of over 50 disorders which affect the cells, tissues and proteins of the immune system. The defect in such disorders appears to be intrinsic to one or more of the four components of the immune system which are the B-cell, T-cell, phagocytic and complement systems (1). These disorders are classified according to which functional compartment of the immune system is impaired (2). Accordingly, there are disorders that affect the B cell system, the T cell system, the B and T cells systems, the phagocytic system and the complement system. They are genetically determined and they are inherited as X-linked recessive, autosomal recessive and very rarely as autosomal dominant traits (1). Previously, the primary immunodefeciency diseases were thought to be confined to young children, but with the increasing clinical knowledge and experience, they are found to be common in young and old children as well as adolescents and adults (3), therefore, early detection of the primary immunodefeciency diseases is of great importance. This group of disorders is also so common that their frequency is similar to the frequency of leukemia and more than the frequency of cystic fibrosis by four times (1). Increased susceptibility to infections is the main clinical manifestation presented by patients in addition to other non-infectious manifestations such as autoimmune and gastrointestinal diseases, which make the situation even worse (4). Eventhough effective therapies are available for such disorders, detection of the disease before damage to organs, by recurrent infections or autoimmune disease takes place, is the most important goal. It is also important to detect the underlying genetic defect so that futuristic occurrence of the same disorder in the family is interrupted, since such disorders segregate in families in X-linked recessive or autosomal recessive manners in most of the cases (5). In the following paragraphs, two disorders, which are important members of the family of primary immunodefeciency diseases, are going to be discussed. These are the X-linked agammaglobulinaemia and the Hyper IgM Syndrome which are mainly results of defective or abnormal B cells function and are associated with absent or abnormal production of antibodies.
X-linked agammaglobulinaemia: An X-linked recessive disorder due to a developmental arrest in B-cells differentiation, with males being affected and females being carriers or affected if homozygotes (4). Affected males have decreased numbers of mature B-cells in the blood with normal numbers of pre-B cells in the bone marrow; as a result, severe panhypogammaglobulinaemia is present (5). However, cell mediated immunity is normal. Development of the disease occurs mainly after the sixth month when the passive immunity provided by maternal IgGs starts to diminish leaving the child unprotected, and easily captured by several extracellular bacterial and occasionally few viral infections (6). X-linked Hyper IgM Syndrome: An X-linked recessive disorder characterized by the absence of IgG and IgA with normal or elevated levels of IgM (150-1000 mg/dL) and IgD in the serum (7). This is due to inability of isotype switching by B cells with contribution of T cells in the defect. Recurrent pyogenic infections and autoimmune diseases are the main manifestations. In addition, formation of autoantibodies against platelets, neutrophils and tissue antigens result in autoimmune disease (8). The disease may also be inherited as an autosomal recessive trait and rarely as an autosomal dominant trait or an acquired disorder with the possibility of EBV causation. It is less common than XLA (7).
XLA: The genetic defect that results in the occurrence of X-linked agammaglobulinaemia is concerned with a gene located in the central region of the long arm (q) of X chromosome, at the Xq21.3-Xq22 location, where near by other genetic defects resulting in a variety of immunodefeciency disorders are located (4). The gene under discussion is the gene that codes a protein tyrosine kinase known as Bruton’s Tyrosine Kinase (Btk)(5), which belongs to the src oncogene family (7). The protein is expressed in B cells as well as polymorphonuclear cells. It consists of heavy chains, surrogate light chains along with Ig? and Ig? (5). The function of the defective protein (Btk) is to couple the pre-B cell receptor to nuclear events that lead to the growth and differentiation of pre-B cells into immature B cells in the bone marrow. These events are concerned mainly with the V-J rearrangement of the light-chain genes. For the pre-B cells to mature into immature B cells, a signal is transduced by the pre-B cell receptor via the Btk protein. Transduction of the signal results in the triggering of further developmental events concerned with the V-JL rearrangement. Absence of the Btk protein results in ignorance of the signal inspite of the presence of the pre-B cell receptor, and thus, the discontinuation of B cell maturation, which stops at the pre-B-cell stage which are incapable of immunoglobulin synthesis and secretion. As a result, the number of B cells and plasma cells is severely reduced if not absent. In affected males, although the Btk protein is absent, maturation of few pre-B cells into immature B cells still takes place, and that suggests that the function of the protein is to promote rearrangement of the light chains gene, and its absence doesn’t absolutely mean complete arrest in B cell development (5). In XLA patients T cells are completely normal, but the number of primed T cells is low and that reflects the gap created by the B cells being unable to present antigens to T cells. Other studies suggest that pre-B cells contain short cytoplasmic ? chains that lack VH sequence, and no ? or ? light chains. In this case the V-D-J rearrangement is defective and therefore heavy chain production is absent in affected individuals (3). X-linked HIGM Syndrome: In X-linked Hyper IgM Syndrome, the CD40 ligand located on the surface of activated T cells is missing (5). The gene coding for the missing ligand is located on the long arm (q) of X chromosome (3). The CD40 ligand of activated T cells is needed for the activation of B cells and their proliferation as well as for their isotype switching capability by its binding to the CD40 molecule on B cells. The formation of germinal centers is also mediated by the CD40 ligand interaction with B cells’ CD40 molecule. In X-linked HIGM Syndrome engagement of activated T cell CD40 ligand to CD40 molecule on top of B cells is defective, and thus, delivery of activatory signals to B cells is defective as well (5). In addition to the need to CD40 ligand of activated T cells, B cells need IL-4 that binds IL-4 receptor on B cell surface in order to be able of isotype switching (6). Therefore the defect in X-linked HIGM Syndrome is located in T cells, but B cells are completely normal. Thymus of an affected male lacks germinal centers which are the normal result of the interaction between B and T cells (5).
XLA: The symptoms of XLA were first described in 1952 in a male child. These include severe recurrent pyogenic infections of the lungs, sinuses, and bones caused by viruses and extracellular bacteria such as staphylococcus aureus, hemophilus influenzae and streptococcus pneumoniae (2). The infections start to take place after the 6th month when the passive immunity provided by the maternal IgGs start to diminish leaving the child unprotected, the time when exposure to the environment and its pathogens increases (1). Although T cells are normal and respond well to viral infections, affected males are also susceptible to vaccine-induced poliovirus infection and chronic echovirus encephalitis (8). Some male infants have autoimmune arthritis, mycoplasma infections that disappear after treatment with Igs. Furthermore, recurrent bacterial otitis media, bronchitis, pneumonia, meningitis, dermatitis and malabsorption, all of which respond well to antibiotic therapy are present, and this occasionally delays the diagnosis of the disease (2). Infection with Pneumocystis carinii which produce a strange form of pneumonia is also common as well as infection with giardia lamblia which produces intestinal inflammation and diarrhea (4) X-linked HIGM Syndrome: The symptoms presented by X-linked HIGM patients are similar to those experienced by XLA patients, and these include recurrent pyogenic infections such as otitis media, pneumonia and septicemia (8). Recurrent neutropenia that develops as a secondary complication, hemolytic anaemia and aplastic anaemia can also occur in some cases. Furthermore, Increased risk of neoplasms at an early age is present (6).
XLA: An important clue to the diagnosis of XLA is the failure of infections to respond completely to appropriate antibiotic therapy. Furthermore, XLA patients have a history of continuos illness (3). The occurrence of the symptoms may be delayed until early childhood when they present with other complaints such as chronic conjuctivitis, abnormal dental decay and malabsorption which if severe may cause retardation of height and weight (4). Physical examination shows the results of continuos infections such as chronic conjunctivitis and eczematiod skin as well as absence of tonsils and hypotrophy of lymph nodes, which lack germinal centers. Moreover, lymph nodes are depleted in B-cell-dependent areas (2). Despite the recurrent infections, lymphadenopathy and splenomegaly are absent (6). Laboratory results reveal absence or marked deficiency of all five immunoglobulin classes. Besides, serum protein electrophoresis and immunoelectrophoresis are used to establish the diagnosis. In addition, quantitation of immunoglobulins reveals total immunoglobulin levels below 250 mg/dL, mainly composed of IgG with the other Igs (A, M, D and E) being absent (3). Failure to make antibodies after immunization should also be demonstrated (2). The diagnosis is difficult in infants below 6 months of age because of maternal IgG in the serum. Another finding is that the plasma cells are absent as well as circulating B cells which if present don’t respond to T cells which are normal in number and activity (7). Due to the intact T cell mediated immunity, allograft rejection still take place. Delayed hypersensitivity tests are usually positive (3). X-linked HIGM Syndrome: The diagnosis of X-linked HIGM is similar to that of XLA when symptoms are taken in consideration. Laboratory results reveal a marked increase in the serum IgM and IgD levels, with the absence of IgG and IgA (3). The patient may form antibodies following specific immunization (6).
alpha-globlulin therapy is effective, therefore both XLA and X-linked HIGM Syndrome patients need periodic gamma-globulin injections given life long in the lowest dose to passively protect them against common bacterial infections (1). However, treated patients are still susceptible to sinupulmonary infections because secretory IgA is not transferred by gamma-globulin injections (4). In addition, adequate antibiotic administration with each infection is crucial with continuous antibiotics being sometimes indicated. Despite these measures, certain infections will still take place such as bronchitis and sinusitis (2). Patients should be monitored at regular intervals with chest x-rays and pulmonary function tests to determine the adequacy of the treatment (7). In case of presence of chronic lung disease, pulmonary physical therapy becomes an essential part of the treatment (8). In case of presence of autoimmune disease, caution should be taken into consideration, since the use of immunosupressive agents may worsen the situation and lead to increased susceptibility to infections (3). Unfortunately, bone marrow transplantation has not yet been successfully employed to correct any of the primary antibody deficiencies in humans, therefore, until now, antibodies replacement is the most effective mode of management of XLA and X-linked HIGM (2). XLA patients usually survive to the third decade, and the development of chronic lung diseases is possible. Moreover, neurologic handicaps resulting from early meningitis and the development of leukemia or lymphoma are also predictable in patients with this disorder. Similarly, X-linked HIGM patients may develop infiltrating neoplasms of IgM-producing plasma cells (7).
Primary immunodefeciency diseases are inherited disorders of the four compartments of the immune system. X-linked agammaglobulinaemia and X-liked Hyper-IgM Syndrome are two primary immunodefeciency disorders that affect the B cell compartment, and the B cell and Tcell compartments respectively. XLA is caused by an X-linked genetic defect that result in absent expression of the Btk protein needed to promote maturation of pre-B cells into immature B cells, as a result, mature B cell population in the peripheral blood is severely reduced and the production of immunoglobulins is reduced as well. X-linked HIGM Syndrome is caused by another X-linked genetic defect resulting in absent expression of CD40 ligand on T cells, resulting in defective interaction between B and T cells which in turn results in defective isotype switch by B cells. Elevated IgM levels with reduced or absent levels of the other 4 isotypes is the clue for diagnosis. Symptoms shared between the two diseases include recurrent pyogenic infections caused by extracellular bacteria, which respond well to parentrally-administered gammaglobulins and antibiotics. Occasional viral infections do also take place. Bone marrow transplantation has not yet been the solution that will clear the problem and early neoplasms’ formation is common in both diseases.
1. Found @ http://www.ipopi.org/idf/climpres.html#theprim |
The
primary immunodefeciency diseases.