Inherited Immunodeficiency Disorders

Alton L. Melton Jr.

Inherited immunodeficiency disorders represent defects in normal immune function that usually result in an increased susceptibility to infection. Many of the disorders have been traced to specific genetic mutations, in which the defective proteins have been identified. Although rare, these diseases have taught us much about normal and abnormal immune function.

Immunodeficiency is suspected in patients with unusual features of infections. These include an unusual frequency of infections (e.g., >10 bacterial ear infections per year), multiple sites of infection, unusual organisms causing infections, unusual severity of infections, and unusual manifestations or sites of infection (e.g., fungal osteomyelitis). In addition, many immunodeficiency disorders are coinherited with associated clinical disorders. Finally, the disruption of normal immune function can result in symptoms of autoimmune disease or malignancy because of a lack of proper immune surveillance.

The normal immune system consists of a complex network of cells, cytokines, and receptors, the purpose of which is to recognize foreign organisms or altered cells and eliminate them before they cause harm. B lymphocytes and T lymphocytes comprise the specific immune system. These cells have special receptors (immunoglobulin for B cells, T-cell receptors for T cells) that recognize specific peptide sequences on foreign proteins. This specific binding activates the cells to secrete factors that exert their own effects, and in turn activate the phagocytes and complement proteins that comprise the nonspecific immune system. The nonspecific immune system requires direction and activation by the specific immune system so that phagocytes and complement can carry out phagocytosis and cell lysis. Immune deficiencies have been described in each of the following four categories: B-cell or antibody deficiencies, T-cell or cell-mediated immunodeficiencies, phagocytic cell disorders, and complement protein deficiencies. Of these disorders of immunodeficiency, B-cell or immunoglobulin deficiencies are the most often encountered, and complement protein deficiencies are the least commonly encountered.

B-CELL OR IMMUNOGLOBULIN DEFICIENCIES

B lymphocytes produce immunoglobulins that serve as cell surface receptors and are also secreted into the systemic circulation. Secreted immunoglobulin performs several functions: neutralization (binding to an infectious agent to prevent mucosal penetration), opsonization (binding to an infectious agent to make phagocytosis more effective), complement fixation by immunoglobulin M (IgM) and IgG (activation of the complement protein cascade to cause cytolysis and enhance opsonization), and antibodydirected cell killing by phagocytes (via immunoglobulin receptors on phagocytes).

The five classes of immunoglobulin are IgG, IgM, IgA, IgD, and IgE. IgG has the highest concentration in the serum and provides protection from septicemia and deep tissue infections. IgG is the only immunoglobulin that crosses the placenta, so that newborns have relatively high levels of IgG. IgM is less efficiently produced than other immunoglobulin types, but it is the antibody produced during the primary immune response when an antigen is encountered for the first time. IgM can activate complement, as can IgG. IgM can combine into a pentameric
structure, connected by the J chain. IgA is the major secretory antibody and often exists as a dimer in secretions. The dimer is connected by a J chain. Secretory IgA is protected by secretory component derived from mucosal epithelial cells, and in turn it protects the mucosal surfaces of the respiratory and gastrointestinal tracts from invading organisms. IgD is present in very small quantities, and its role in the immune response is unclear. IgE is present in the lowest concentration and is responsible for allergic diseases.

Deficiencies of immunoglobulin result in recurrent sinopulmonary infections by high-grade encapsulated bacteria, usually extracellular pathogens. Intracellular pathogens, such as viruses and fungi, cause few problems with the exception of enteroviruses. Striking growth retardation is usually absent, and such children generally survive to adulthood if treated appropriately.

Specific B-cell deficiencies include X-linked agammaglobulinemia, otherwise known as Bruton’s agammaglobulinemia. In this X-linked disease, recurrent severe pyogenic infections involve the respiratory tract, skin, bloodstream, meninges, and deep tissues. The disorder usually presents at 4 to 8 months of age, after placentally acquired IgG has dissipated. Levels of all immunoglobulin types are low in this disease, and very few B cells can be identified in the bloodstream. Persons with the disease are at high risk for the development of a persistent meningoencephalitis caused by enteroviruses, including echovirus, coxsackievirus, and poliovirus. The lymphoid tissues of children with X-linked agammaglobulinemia are often sparse or absent because cortical follicles are lacking. The defect has been traced to the gene for a specific tyrosine kinase, named btk or Bruton tyrosine kinase. This disease is treated with regular intravenous (IV) administration of gamma globulin, which replaces IgG. These children should avoid daycare settings in which enterovirus transmission is common.

Common variable immunodeficiency results in a similar defect in antibody function but generally presents later in life, some even in adulthood. The usual inheritance pattern is reported to be autosomal recessive. The infections are similar to those associated with X-linked agammaglobulinemia, but the frequency and severity are more variable. The disease probably represents many different gene defects, and some element of immune dysregulation may be present in many of the patients. For this reason, the risk for the development of autoimmune diseases, such as hemolytic anemia, alopecia areata, arthritis, and pernicious anemia, is elevated. Common variable immunodeficiency is also treated with IV infusions of immunoglobulin. These must be given with caution to patients lacking IgA because cases have been reported in which IgG or IgE antibodies are directed against IgA, creating a risk for transfusion reactions or anaphylaxis during the administration of immunoglobulin containing trace amounts of IgA. Some defect in cellular immunity may also be present.

Selective IgA deficiency is the most common inherited immunodeficiency, affecting approximately 1 in 700 to 1000 persons. Most patients with low levels of IgA are asymptomatic. However, those with IgA levels <10 mg/dL are usually symptomatic and have recurrent infections. Chronic sinopulmonary infections caused by pyogenic bacteria may develop but are usually much less severe than those in X-linked agammaglobulinemia or common variable immunodeficiency. Systemic infections are rare in this setting. About 15% of patients with a selective absence of IgA have an associated lack of the IgG2 and IgG4 subclasses. Patients with IgA deficiency are at high risk for the development of anti-IgA antibodies, which can cause transfusion reactions. This disease is not amenable to replacement therapy with gamma globulin because IV immunoglobulin preparations contain only trace amounts of IgA.

IgG subclass deficiency may occur with deficiency in specific antibody production. It is known that IgG comprises four subclasses, of which IgG1 and IgG3 best respond to protein-based antigens (e.g., tetanus and diphtheria toxoid) and IgG2 and IgG4 best respond to polysaccharidebased antigens (e.g., components of the pneumococcal cell wall). Nevertheless, the overlap in function is considerable. Patients with immunodeficiency and recurrent sinopulmonary infections with low levels of IgG subclasses usually lack specific antibody titers to immunogens such as diphtheria and tetanus toxoid and pneumococcal antigens. The significance of an isolated low level of an IgG subclass without an absence of specific antibody responses is unclear. Those who do lack a response to immunogens benefit from IV immunoglobulin therapy. Some patients with recurrent infections have impaired antibody response to immunogens, despite normal immunoglobulin levels and IgG subclasses.

In X-linked hyper-IgM syndrome, normal isotype switching from a primary IgM response to a more efficient secondary IgG, IgA, or IgE response does not take place. As a result, IgM levels are elevated and levels of IgG, IgA, and IgE are low or absent. This disease has been traced to a defect in a protein on T-helper lymphocytes called CD40 ligand. Interaction between a CD40 molecule on the B cell and the CD40 ligand on the helper T cell signals the B cell to switch from producing IgM to producing other immunoglobulins. The deficiency leads to persistently inefficient antibody production and some cases may be caused by congenital rubella infection. Patients respond well to IV immunoglobulin therapy, showing a subsequent reduction of their elevated IgM levels. Because the defect is actually in the T lymphocyte, mild or later-onset infections with protozoa, viruses, or fungi may develop, notably sclerosing cholangitis with Cryptosporidium.

Transient hypogammaglobulinemia of infancy presents with low IgG concentration associated with recurrent respiratory infections often beginning in the first or second year of life. This typically resolves by age 4 to 6 years, and most have normal specific antibody responses. This likely represents a simple maturation delay.

DISORDERS OF T LYMPHOCYTES OR CELL-MEDIATED IMMUNITY

T lymphocytes perform numerous functions in the immune system. T helper cells generate factors that enhance the B cell production of immunoglobulin. T cytotoxic cells directly kill cells infected by intracellular pathogens, such as viruses or fungi. T cells also reject incompatible and grafted material and act as an immune surveillance system against malignant transformation. T lymphocytes are a major source of cytokines, which activate phagocytes and other elements of the immune system.

Cell-mediated immunodeficiency usually results in recurrent infections with intracellular pathogens that are often opportunistic in nature, such as viruses, fungi, and protozoa. Diarrhea and gastrointestinal infections are common and lead to chronic growth retardation and wasting. Because of their association with chronic infection and a lack of immune surveillance against malignancy, these diseases are not compatible with a long lifespan. In many of the disorders, a combination of defects in both T- and B-lymphocyte function causes both cell-mediated and antibody immunodeficiency. Vaccines, especially those containing live viruses, should not be administered to severely affected children. In addition, transfusion of nonirradiated blood containing donor lymphocytes carries a risk for fatal graft vs. host disease. The disorders usually present very early in life, generally within the first 3 months.

DiGeorge syndrome is caused by embryonic dysmorphogenesis of the third and fourth branchial pouches. This results in absence or hypoplasia of the thymus gland and parathyroid glands; the aortic arch and heart are also affected structurally. Patients present with:

Neonatal hypocalcemia secondary to a lack of parathyroid glands
Congenital heart disease (usually an aortic arch anomaly such as interrupted aortic arch, truncus arteriosis, or right-sided aortic arch)
Early infection, especially mucocutaneous candidiasis

The clinical severity varies depending on the amount of thymic tissue present. Although the deficiency involves almost entirely T lymphocytes, mild B-cell functional impairment with inefficient antibody production may be present. In many patients, the disorder has been traced to a deletion on chromosome 22. Patients with severe DiGeorge anomalies should undergo some form of immune reconstitution, such as bone marrow, stem cell, or possibly fetal thymus transplantation. Most patients have a partial variant that often requires careful observation but usually no specific therapy.

Only gold members can continue reading. Log In or Register to continue