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The primary immunodeficiencies are congenital disorders that affect the function of the immune system. The result is an inadequate immune response to microorganisms, selfantigens, and tumor cells, which leads to increased susceptibility to infections, autoimmunity, or malignant disease. A substantial advance has been made in the understanding of the exact molecular mechanisms leading to primary immunodeficiencies; however, for some types, a specific genetic defect has not yet been determined. The life expectancy of patients with primary immunodeficiencies has increased considerably because of bone marrow transplantation and replacement therapies. Gene therapy has already been used for a particular type of immunodeficiency and is a promising alternative for the future management of many other types of primary immunodeficiencies. A better understanding of the genetic defects that lead to primary immunodeficiencies would result in the development of novel therapeutic strategies.
The primary immunodeficiencies (PIs) are rare disorders, most of which are due to genetic defects that affect cell maturation or function at different levels during hematopoiesis. The incidence of PIs, excluding asymptomatic IgA deficiency and mannose binding lectin (MBL) deficiency, is about 1 in 5,000 live births. The underlying molecular mechanism is known for some, but not all, PIs (Table 1). Currently, substantial effort is devoted to the characterization of new genetic defects involved in the pathogenesis of PIs, which will help in the development of new types of gene therapy.
Table 1Classification of Primary Immunodeficiencies
The clinical manifestations of PIs include recurrent infections, autoimmune disorders, malignant lesions, and allergic diseases. Because these manifestations can also be features of acquired or secondary immunodeficiencies, such as the acquired immunodeficiency syndrome (AIDS) or protein-losing enteropathies, secondary causes must be ruled out when an immunodeficiency is suspected. Although PIs may initially manifest with a life-threatening infection or a severe autoimmune disorder, their expression can also be relatively mild, and thus physicians must be alert to make the diagnosis. The initial manifestations usually occur within the first years of life, but, with the common variable immunodeficiency (CVID), IgG subclass deficiency, or deficiencies of the late components of complement, patients can be asymptomatic until the third or fourth decade of life.
The nature of the immunodeficiency can usually be determined by the type and the site of the infection. For example, humoral (B cell) defects lead to increased susceptibility to encapsulated bacteria (sinopulmonary infections with pyogenic bacteria), enterovirus (gastrointestinal infection), and parasites. Cellular (T cell) immunodeficiencies are characterized by opportunistic infections with viruses, Pneumocystis, and fungi. Phagocytic defects are associated with pyogenic infections, particularly sinopulmonary and abscesses that involve the skin and lymph nodes, as well as fungal infections. Patients with complement deficiencies have pyogenic infections, sepsis, or recurrent meningitis with encapsulated organisms.
Autoimmune or inflammatory manifestations may be directed at a target organ or may be systemic. They are common in certain PIs such as CVID, IgA deficiency, and deficiencies of the initial components of complement. Autoimmunity is probably due to a dysregulation of the immune system secondary to the genetic defect that caused the PI, but the mechanisms underlying these phenomena are unclear.
Allergic symptoms are common in some PIs. They include eczema in the Wiskott-Aldrich syndrome (WAS), hyper-IgE syndrome, and CVID and other manifestations of atopy such as asthma and rhinitis in selective IgA and IgG subclass deficiencies.
The risk of malignant disease, mainly of hematologic origin, is increased in ataxia-telangiectasia (AT), WAS, CVID, selective IgA and IgG subclass deficiencies, and hyper-IgM syndrome.
Early diagnosis of PIs is essential for prevention of irreversible end-organ damage from chronic infections. The initial assessment of a patient with a suspected PI includes a past medical history, family history, physical examination, chest roentgenography, and basic screening immunologic tests.
The medical history should emphasize the frequency, severity, and responsiveness to treatment of past infections, manifestations of autoimmunity, and malignant disease. A review of systems to detect any possible causes of secondary immunodeficiencies is essential. In addition, an immunization record and any complications associated with previous live virus vaccines should be noted. A complete list of current medications should be obtained because many commonly used drugs, such as corticosteroids, are immunosuppressive.
Elicitation of the family history should address any consanguinity. A detailed family tree should include the ages and gender of all affected members to determine the pattern of inheritance.
During the physical examination of the patient, the clinician should note failure to thrive, weight loss, size of tonsils and lymph nodes, presence of organomegaly, dermatitis, thrush, and clubbing.
Screening diagnostic tests for suspected PIs include a complete blood cell count with differential, serum Ig quantification, delayed type hypersensitivity skin test, and total serum hemolytic complement. If the patient has had recurrent pyogenic infections, neutrophil function can be assessed with the nitroblue tetrazolium test or by chemoluminescence analysis for the diagnosis of chronic granulomatous disease (CGD). A human immunodeficiency virus (HIV) serology, as well as serum albumin and urinary protein analysis, should be done (if clinically indicated) to exclude secondary causes of immunodeficiency. If the patient has lymphopenia or if serum Ig or results of the delayed type hypersensitivity skin test are abnormal, lymphocyte surface markers (CD3, CD4, CD8, CD19, and CD16) and lymphocyte proliferation (to mitogens and antigens) can be determined. The antibody response to specific protein and polysaccharide antigens after immunization is also helpful in the evaluation of humoral immunodeficiencies. When a PI is diagnosed, the importance of screening of family members depends on the pattern of inheritance. Carriers of most X-linked PIs can be detected with Xchromosomal inactivation studies. Prenatal diagnosis for many PIs is available, and thus parents have a reproductive choice.
Cellular immunodeficiencies comprise 20% of all PIs.
They manifest with defects not only of the cellular immunity but also of the humoral response because the ability of B lymphocytes to produce antibodies is primarily dependent on T cells.
Severe Combined lmmunodeficiency
Severe combined immunodeficiency (SCID) can manifest either with severe opportunistic infections or with chronic diarrhea and failure to thrive. About half are X-linked, and half are autosomal recessive (AR). Of patients with the AR-SCID, 50% have adenosine deaminase (ADA) deficiency. Laboratory findings in patients with SCID typically demonstrate severe lymphopenia, except in those with SCID hyper-B and Omenn syndrome.
In addition to lymphocytes, other hematologic cell linages may be affected. For example, in reticular dysgenesis, development of multiple cell linages is impaired because the primary defect affects the stem cells early during hematogenesis.
In alymphocytosis, there is a defect in the T-cell receptor and Ig gene rearrangement at the JH region. This defect is due to mutations in the recombination activating genes (RAG-1 and RAG-2), resulting in failure of lymphocyte differentiation and absence of circulating T and B lymphocytes.
an important kinase protein involved in intracellular signal transduction. Patients with SCID hyper-B have normal or high numbers of B lymphocytes but have complete absence of T lymphocytes and natural killer cells because both IL-2 receptor and are ak3 are essential for their development. Children with other types of SCID may also have circulating lymphocytes of maternal origin because they are unable to reject them due to the lack of a competent immune system of their own. These children often have signs of chronic graft-versus-host disease. If this is suspected, human leukocyte antigen (HLA) typing of the peripheral blood lymphocytes is warranted.
ADA and purine nucleoside phosphorylase (PNP) deficiencies are defects in enzymes involved in the purine metabolism that result in the accumulation of toxic metabolites and death of lymphocytes.
Patients with ADA and PNP deficiencies can have a mild, fluctuating, or severe course. ADA deficiency accounts for 15% of all SCID. Patients with ADA deficiency have characteristic skeletal abnormalities, whereas those with PNP deficiency have neurologic manifestations.
The Omenn syndrome is characterized by erythrodermia, polyadenopathy, hepatosplenomegaly, severe infections, and failure to thrive. Patients with this syndrome have circulating activated T cells that infiltrate several organs, B-cell eosinophilia, and lymphocyte depletion from lymphoid organs that are infiltrated with histiocytes. A deficiency of 5′-nucleotidase has been inconsistently reported. Such patients always die within the first year of life unless they undergo a bone marrow transplantation (BMT).
The outcome of patients with SCID is always fatal if treatment is not administered, but those who undergo successful BMT can live a normal life.
Functional T-Cell Defects
Functional T-cell defects comprise a heterogeneous group of disorders in which the common feature is the inability of T cells to respond to antigens or mitogens (or both) in a lymphocyte proliferation assay. Patients with this disorder have a normal number of lymphocytes, usually of normal phenotype, and may have normal to low levels of serum Ig. The molecular defect may involve different steps in the T-cell activation pathway (Fig. 1).
The “bare lymphocyte syndrome” is due to a mutation in one of the genes encoding proteins that regulate transcription of the major histocompatibility complex (MHC). MHC class II deficiency results from distinct mutations in multiple trans-activating regulatory genes, whereas MHC class I deficiency is due to a mutation in the gene encoding the TAP2 transporter protein. Patients with the bare lymphocyte syndrome do not express MHC class II or class I molecules in any tissue and have multiple infections; frequently, they die at a young age.
which is involved in the regulation of transcription of multiple lymphokines (Fig. 1).
The clinical manifestations of functional T-cell defects include mild to severe infections and autoimmunity. Treatment depends on the severity of symptoms. Patients with the bare lymphocyte syndrome and with Zap-70 deficiency must undergo BMT, whereas other patients may do well with prophylactic antibiotics and intravenous (IV)-Ig replacement therapy.
PIs Associated With Defects in DNA Repair
The PIs associated with defects in DNA repair include AT, Bloom's syndrome (BS), Nijmegen syndrome (NS), and xeroderma pigmentosum. They are characterized by a defect in the DNA repair machinery that leads to chromosomal instability and hypersensitivity to agents that cause DNA strand breaks; thus, the patient is predisposed to the development of malignant disease and combined immunodeficiency with hypogammaglobulinemia and cellular anergy. A T is due to a mutation of the A TM gene, the product of which is believed to have a role in tumor suppression.
Clinically manifests AT manifests with ataxia and progressive neurologic degeneration, oculocutaneous telangiectasia, combined immunodeficiency, and a high incidence of malignant disease (l00-fold), although not all these features need to be present. Treatment is supportive. Patients are usually wheelchair-dependent by the second decade of life and die of lung infections or malignant disease before they are 30 years old. Interestingly, relatives of patients with AT also have a high incidence of malignant disease, particularly lymphoma and breast and colon cancer, and should be closely monitored. BS is due to a mutation in BLM, a gene that encodes a protein homologous to the RecQ helicases.
Patients with BS are short and have sun-sensitive facial erythema and recurrent infections. NS manifests at birth, and characteristics are short stature, birdlike facies, microcephaly, and recurrent infections. The genetic defect for NS has not been determined but has been mapped to chromosome 8q21.
WAS is characterized by the triad of thrombopathia (thrombocytopenia, small platelets, and platelet dysfunction), eczema, and combined immunodeficiency. These three components, however, occur together in only 27% of patients with WAS. About 20% of patients have thrombopathia only, and 5% have only immunodeficiency. The molecular defect is due to a mutation of the gene encoding the WAS protein (WASP), which results in the absence or aberrant expression of the WASP in lymphocytes and megakaryocytes. The exact function of the WASP is unknown, but it is thought to be an important component of the cytoskeleton through polymerization with actin.
The absence of the WASP leads to decreased platelet size, loss of T-cell surface microvilli, and defective T-cell and platelet function. The treatment of choice is BMT if an identical donor is available. Otherwise, splenectomy improves the platelet number and increases survival.
The DiGeorge syndrome is due to a deletion in chromosome 22q11, which leads to abnormal migration of the third and fourth branchial pouches during embryogenesis, with hypoplasia to aplasia of the thymus and parathyroids, truncal cardiovascular malformations, and dysmorphic facial features.
Patients have neonatal tetany due to hypocalcemia, combined immunodeficiency, and manifestations of congenital heart disease. The immunodeficiency is highly variable, depending on the degree of thymic hypoplasia. In more than 90% of patients, the immune defect is mild and can even be transient. Although thymus transplantation can be performed, BMT is still the treatment of choice for the severe types if an HLA-identical donor is available.
The hyper-IgM syndrome is characterized by normal to high levels of polyclonal IgM and IgD with decreased or absent IgO, IgA, and IgE. The molecular defect in the most common X-linked form is due to a mutation in the gene encoding CD40 ligand, with defective expression of CD40 ligand on the surface of T cells, and therefore inability of B cells to undergo Ig isotype switching.
A few AR forms have been reported in which the molecular is unknown. Patients have infections, autoimmunity, and increased risk of malignant disease. Treatment is supportive, but BMT has been successfully performed.
The humoral immunodeficiencies are intrinsic defects of the B lymphocytes. They account for 70% of all PIs and are manifested by decreased Ig production.
In Bruton's or Xlinked agammaglobulinemia, B lymphocytes are absent in the periphery and lymphoid organs, although pre-B cells are present in the bone marrow. This disorder is due to a mutation in the gene encoding btk (Bruton's tyrosine kinase), which arrests B-cell development in the pre-B stage.
Therefore, boys with this disorder do not produce any antibodies and are susceptible to the infections characteristic of humoral immunodeficiencies, but they do not have a higher incidence of malignant disease or autoimmunity than does the general population.
Common Variable Immunodeficiency
By contrast, patients with CVID have decreased levels of all Igs but have circulating B cells. The molecular defect of CVID is unknown, but it is believed to include a heterogeneous group of diseases, some of which affect primarily the B lymphocytes and others that are due to primarily T-cell defects; however, all cause hypogammaglobulinemia.
It is usually asymptomatic unless it is associated with an IgG subclass deficiency, but it can manifest with gastrointestinal and respiratory infections. Recognition of this deficiency is important because it can cause anaphylactic reactions in patients treated with IgA-containiog blood products due to the development of anti-IgA antibodies. Therefore, IV-Ig replacement is replacement is not indicated in patients with selective IgA deficiency.
IgG Subclass Deficiencies
The IgG IgO subclass deficiencies usually manifest with recurrent respiratory infections, but they can be associated with autoimmune disorders, allergy, and malignant disease.
The antipolysaccharide antibody deficiency is diagnosed by measuring the ratio of antibody titers before and after immunization of a patient with a polysaccharide vaccine, such as pneumococcal or meningococcal. This response in children must be interpreted cautiously, however, because the ability to mount a humoral response to polysaccharide antigens matures much later than that to protein antigens, and normal values are not standardized according to age.
The hyper-IgE syndrome is characterized by recurrent severe pyogenic infections (mostly staphylococcal abscesses) and dermatitis in children with coarse facial features. Laboratory findings demonstrate extremely high levels of serum IgE, moderate increase of serum IgD levels, eosinophilia, variable defect of cellular and humoral response to previously encountered antigens, and defective neutrophil chemotaxis in one-third of patients. A recent report indicated that a mutation in the gene encoding the a chain of the IL-4 receptor might be implicated in the pathogenesis of this disease.
Treatment of the hyper-IgE syndrome is supportive, with long-term antistaphylococcal staphylococcal antibiotic therapy.
The lymphoproliferative syndromes (LPS) are characterized by uncontrolled proliferation B lymphocytes. The X-linked LPS occur in males who are asymptomatic until they are exposed to the Epstein-Barr virus.
The genetic defect of X-linked LPS is unknown. The LPS with autoimmunity is due to a mutation of the gene encoding the surface molecule fas, which is involved in apoptosis. Lymphocytes from patients with LPS do not express fas and therefore proliferate in the lymphoid organs; the outcome is a clinical picture similar to lymphoma, which is associated with various autoimmune disorders. It seems that the fas mutation is necessary but insufficient for the development of the LPS with autoimmunity, and children with this syndrome are heterozygous at the fas locus, as well as at an unknown locus, the product of which is involved in fas-mediated apoptosis.
Phagocyte defects account for 9% of all PIs. They manifest with recurrent pyogenic and fungal infections.
Leukocyte Adhesion Deficiency
The leukocyte adhesion deficiency (LAD)-I syndrome is due to a mutation of the gene encoding CD18, the common β chain of the leukocyte adhesion proteins. Phagocytic cells are decreased to the degree that CD18 expression is absent, and they are incapable of migration into areas of infection. Patients with LAD-I have recurrent bacterial infections with no pus formation, and infants have delayed umbilical cord separation. LAD-I phenotype can be moderate to severe, depending on the level of adhesion molecule expression. BMT can be curative in children with the severe phenotype. LAD-II is due to a defect in fucose metabolism that results in the absence of sialyl Lewis x, a selectin ligand, on the surface of neutrophils. Patients with LAD-II have recurrent bacterial infections, pronounced neutrophilia, and mental retardation.
Patients with the Chediak-Higashi syndrome (CHS) have giant granules in their phagocytes, melanocytes, and other granule-forming cells and suffer from recurrent infections (due to decreased chemotaxis and bacterial killing), partial oculocutaneous albinism, peripheral neuropathy, and a recurrent, aggressive lymphoproliferative phase with diffuse organ infiltration. CHS was recently found to be due to a mutation in L a gene that encodes a protein that is thought to be important in cellular signal response coupling.
This enzyme is involved in the oxidative burst triggered by phagocytosis, and therefore children with CGD have recurrent bacterial and fungal infections due to the inability of phagocytes to kill microorganisms. The diagnostic test for con is a nitroblue tetrazolium or a chemoluminescence assay. Treatment of COD includes prophylactic antibiotics and interferon (IFN)-y, but the only curative therapy is BMT.
MBL deficiency is a common disorder of the innate immunity. MBL is involved in opsonization of bacteria, fungi, and some viruses, as well as in complement activation. Mutation of the MBL gene occurs in 16 to 29% of the population, depending on racial background, and manifests with extremely low levels of serum MBL in homozygous patients and intermediate levels in heterozygous patients.
MBL deficiency is associated with recurrent infections, especially during infancy when maternal antibodies have cleared and the newborn's own antibody repertoire has not completely developed. Thus far, MBL replacement is not available, and patients are managed with prophylactic antibiotics.
Deficiency of the IFN-γ Receptor
Another newly discovered PI is the deficiency of the IFN -γ receptor, due to a mutation of its gene.
Patients with this immunodeficiency have a defect in antigen presentation and have increased susceptibility to atypical mycobacterial infection or disseminated bacillus Calmette-Guérin infection after vaccination, both of which are invariably fatal.
Complement deficiencies, defects in all the components of complement, have been described but are extremely rare; they account for 1% of all PIs. Usually, deficiencies of components Cl to C4 clinically manifest during childhood with pyogenic infections and autoimmune disorders (usually lupuslike picture), whereas deficiencies of components C5 to C9 are associated with recurrent Neisseria meningitidis during adulthood.
Some patients with certain complement deficiencies, particularly C2, C4, and C9, can remain completely asymptomatic. Complement replacement therapy is not available, and patients are treated with prophylactic antibiotics and specific immunizations for encapsulated organisms.
Improved techniques in BMT have been a breakthrough in the treatment of PIs. These include T-cell depletion of the donor bone marrow, infection prophylaxis, improvement in pretransplantation conditioning regimens, and prevention of graft-versus-host disease. HLA-identical BMT can cure about 90% of patients with SCID, some functional T-cell deficiencies, WAS, LAD, CHS, and CGD.
Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency.
Unfortunately, HLA-identical donors are available in only 25% of cases. BMT of T-cell-depleted bone marrow from HLA-haploidentical donors is associated with a 50 to 70% chance of long-term survival. In order to improve the rate of engraftment, a conditioning regimen is usually given to the recipient before BMT.
Lifelong IV-Ig replacement therapy is necessary for patients with the humoral immunodeficiencies. The initial regimen is 300 to 400 mg/kg every 4 weeks. The dose should be adjusted according to the clinical response. Ig trough levels are also helpful in determining the optimal dosage.
Concomitant prophylactic antibiotic therapy is used for many PIs. All live vaccines are contraindicated in patients with PIs. In addition, these patients should not be in close contact with persons who have received the attenuated poliovirus vaccine because they can potentially become infected.
Other types of therapy include enzyme replacement for ADA deficiency and the use of lymphokines, such as IL-2 for CVID and IL-2 deficiency, granulocyte-macrophage colony-stimulating factor for reticular dysgenesis, and IFN-yfor CGD and the hyper-IgE syndrome. Gene therapy has been performed for the first time in patients with ADA deficiency, but it is still highly experimental. A better understanding of the molecular defects in the PIs will help in the development of new strategies for gene therapy that may revolutionize the management of these diseases in the future.
Use of recombinant human granulocyte macrophage colony simulating factor in an infant with reticular dysgenesis.
Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency.