CHAPTER 88 IMMUNODEFICIENCY DISEASES
CHAPTER 88 IMMUNODEFICIENCY DISEASES
FRED S. ROSEN
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
The Selective Immunoglobulin Deficiencies
Definition and History
Absence of IgA and IgG with Normal or Elevated IgM
Absence of IgA with Normal IgG and IgM
Selective IgG Subclass Deficiency
Transient Hypogammaglobulinemia of Infancy
Common Variable, Unclassifiable Immunodeficiency
Severe Combined Immunodeficiency
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
Cellular Immune Deficiency Syndromes
Congenital Thymic Aplasia (Digeorge’s Syndrome)
Combined Immunodeficiency with Defective Expression in MHC Class II Genes
The primary immunodeficiency diseases are informative about the normal functioning of the immune system. Defects in B lymphocytes lead to immunoglobulin deficiencies, which render patients susceptible to pyogenic infections. Defects in T lymphocytes lead to deficiencies in cell-mediated immunity, which render patients susceptible to opportunistic infections. Serious T cell deficiencies are life threatening and require bone marrow transplantation as the optimal therapeutic procedure, whereas the consequences of B cell deficiencies can by and large be clinically controlled with intravenous infusions of gamma globulin.
The immunodeficiency diseases are characterized by a decreased capacity to mount an immune defense against foreign antigens. The specific humoral or cellular defects of these diseases are listed in Table 88-1, and the modes of transmission, basic defects, types of infection that occur, and prognoses are summarized in Table 88-2.
Acronyms and abbreviations that appear in this chapter include: ADA, adenosine deaminase; ATM, ataxia telangiectasia mutated; CVID, common variable, unclassifiable immunodeficiency; DNFB, dinitrofluorobenzene; DPT, diphtheria-pertussis-tetanus; GM-CSF, granulocyte-monocyte colony stimulating factor; MHC, major histocompatibility complex; NP, nucleoside phosphorylase; SCID, severe combined immunodeficiency.
TABLE 88-1 CONCENTRATION OF SERUM IMMUNOGLOBULIN AND BLOOD T AND B LYMPHOCYTES IN THE IMMUNODEFICIENCY DISEASES
TABLE 88-2 INHERITANCE AND PATHOGENESIS OF PRIMARY IMMUNODEFICIENCIES
DEFINITION AND HISTORY
In 1952 Bruton reported the remarkable finding of the absence of g-globulin from the serum of an 8-year-old boy who had been well up to the age of 4 years, when septic arthritis of the left knee developed. During the next 4 years, the boy had 19 episodes of pneumococcal sepsis, repeated attacks of otitis media, and two bouts of pneumococcal pneumonia. Although these illnesses were successfully treated with antibiotics, immunization with polyvalent pneumococcal vaccines was not protective and did not lead to the appearance of serum antibodies. Further investigation demonstrated that he was unable to produce antibodies after typhoid vaccination, and a Schick test remained positive after attempted diphtheria immunization. Electrophoresis of the serum revealed normal levels of albumin and a- and b-globulins, but no g-globulin. When given intramuscular injections of g-globulin, the patient remained well.1
ETIOLOGY AND PATHOGENESIS
The study of kindred with multiple occurrences of agammaglobulinemia has shown that it is inherited as an X-linked recessive trait. In most cases no B cells are present in the blood, marrow, or lymph nodes. T-cell function is normal. Blood T lymphocytes of agammaglobulinemic children respond normally to phytohemagglutinin and to antigenic and allogenic stimuli.2 Homograft rejection is intact in the few agammaglobulinemic patients who have been studied. Normally, delayed hypersensitivity reactions of both the tuberculin and the skin-contact type can be elicited.
The gene for X-linked agammaglobulinemia has been mapped to Xq21.3-22.3 In this region a gene encoding a unique tyrosine kinase of the src oncogene family, called btk, is mutated in affected males. The product of this gene appears to be critical for normal calcium flux in maturing pre-B cells.4,5
Male infants with X-linked agammaglobulinemia usually remain well during the first 9 months of life, probably because of the passive protection afforded by maternal g-globulin. Undue susceptibility to infection gradually develops during the second year of life, but the onset of frequent infections may depend on the environment of the child and the presence of older sibs and social contacts. Almost invariably these children contract infections from the pyogenic organisms, principally staphylococci, pneumococci, streptococci, and Haemophilus influenzae. Purulent sinusitis, pneumonia, bacteremia, meningitis, and furunculosis are most common. These types of infection usually can be controlled with antimicrobial chemotherapy, but they recur persistently until proper prophylactic therapy is undertaken.
Agammaglobulinemic children do not have increased susceptibility to the common viral diseases and exanthems of childhood. They usually overcome measles, mumps, varicella, and rubella in an ordinary fashion. When vaccinated with vaccinia virus, they generally exhibit the usual course of a primary take. They have no unusual infections with enterococci or gram-negative bacilli, nor do they have undue susceptibility to mycotic infections.
One-third to one-half of all patients with agammaglobulinemia develop a disease of the large joints that resembles rheumatoid arthritis. The joint disease may develop before susceptibility to infection leads to the establishment of the diagnosis. Joint complications disappear once replacement therapy with g-globulin is initiated.
Other collagen-vascular diseases have been observed in children with agammaglobulinemia. One of the most distressing (and ultimately fatal) is a syndrome resembling dermatomyositis. Edema, ligneous induration of the muscles, weakness, and rash over the extensor surfaces of the joints are the salient features of this complication. Biopsy and autopsy materials show lymphorrhages around the small blood vessels. Similar involvement of the central nervous system has been observed, producing a progressive and eventually fatal neurologic disease. The disease is fatal despite the use of glucocorticoids and antimetabolite therapy. Echovirus has been persistently cultured from the cerebrospinal fluid of several of these patients.6 High-dose intravenous g-globulin has been effective in controlling symptoms and halting progression of this complication.
Hemolytic anemia, drug eruptions, atopic eczema, poison ivy sensitivity, allergic rhinitis, and asthma occur frequently in agammaglobulinemic patients. Wheal-and-flare reactions cannot be elicited.
The serum contains less than 100 mg/dl of IgG. Other serum immunoglobulins, IgA, IgM, IgD, and IgE, are undetectable. Isohemagglutinin is lacking or at a low level. Immunization can be used to demonstrate the basic defect. Stimulation with diphtheria-pertussis-tetanus (DPT) or with any number of other antigens fails to elicit an antibody response. Other serum constituents involved in resistance to infection are normal. Serum complement, lysozyme, and properdin levels; phagocytosis; and interferon synthesis are within normal limits.
The basic deficiency in the disease is an absence of B cells and plasma cells from the lymph nodes, spleen, intestine, blood, and marrow. Moreover, plasma cells do not appear in lymph nodes that are stimulated with antigen. There are no normal lymph node follicles, but the thymus is normal.
THERAPY, COURSE, AND PROGNOSIS
Periodic intravenous administration of immune serum globulin is effective in preventing the severe recurrent pyogenic infections that affect these males. The optimal therapeutic dose must be determined in each case and usually is at least 400 mg/kg per month. It is best administered at more frequent intervals, divided into weekly or biweekly injections. Appropriate antibiotic therapy should be given for intercurrent infections. With this regimen of therapy the prognosis is excellent.
Inadequate treatment with immune serum globulin (g-globulin) results in chronic progressive bronchiectasis, as a result of repeated pulmonary infections, and ultimately in death from respiratory failure. The central nervous system infections with echovirus, resulting in the dermatomyositis-like syndrome (see above), also can be controlled with high-dose intravenous g-globulin. Various products should be screened for relevant antibody to the infecting virus.
THE SELECTIVE IMMUNOGLOBULIN DEFICIENCIES
DEFINITION AND HISTORY
The advent of immunoelectrophoretic techniques led to a more precise definition of immunoglobulin defects that involve deficiencies in only one or two of the immunoglobulin classes. Although there are six possible combinations of deficiencies involving one or more of the three major serum immunoglobulin classes, only two have been reported repeatedly. It has been estimated that about 1 in 200 random hospital admissions has some form of selective immunoglobulin deficiency.7
ABSENCE OF IgA AND IgG WITH NORMAL OR ELEVATED IgM
One of the common partial immunoglobulin abnormalities is a deficiency of IgA and IgG with an increased or normal amount of IgM in the serum,8 commonly called the hyper-IgM syndrome or hyper-IgM immunodeficiency. IgM levels in this entity range from 150 to 1000 mg/dl, but in spite of the enormous elevation in IgM level, monoclonal components are not present. Also, the distribution of k and l light chains in the IgM appears to be normal. Some, but not all, of these patients have an elevated level of serum IgD and IgM subunits. Both hereditary and acquired forms of this defect have been observed. In addition to their undue susceptibility to pyogenic infection, and Pneumocystis carinii pneumonia, many of these patients develop thrombocytopenia, neutropenia, renal lesions, and aplastic or hemolytic anemia.9 Optimal treatment includes immune serum globulin replacement, as in patients with X-linked agammaglobulinemia, and GM-CSF for neutropenia.
The X-linked form of hyper-IgM immunodeficiency is due to a genetic defect in the CD40 ligand,10,11,12 and 13 a type II membrane glycoprotein expressed on activated T cells. In order for B lymphocytes to undergo isotype switching from IgM and IgD synthesis to IgG, IgA, or IgE synthesis, the B lymphocyte must receive two signals (see Chap. 94). The first signal is a cytokine, such as interleukin-4 for IgE synthesis or interleukin-2 or interleukin-10 for IgG or IgA synthesis. The second signal involves the physical engagement of CD40 on the B cell with the CD40 ligand expressed on activated T cells. The gene for the CD40 ligand maps to Xq26. Several mutations in the CD40 ligand gene have been found in males affected with hyper-IgM syndrome.10,11,12,13,14 and 15
ABSENCE OF IgA WITH NORMAL IgG AND IgM
The isolated absence of IgA from serum (<5 mg/dl) occurs in a small but significant proportion of the population (1 per 700). This is the most common immunodeficiency in Caucasians.16 IgA deficiency is encountered only very rarely in other populations. Most IgA-deficient individuals have no symptoms. However, there is a high incidence of lupus erythematosus, rheumatoid arthritis, and other connective tissue diseases in this group of people.17 They also have a high incidence of allergies and gastrointestinal disease, such as celiac disease and inflammatory bowel disease. About 20 percent of IgA-deficient individuals have concomitant deficiencies of IgG2 and IgG4. These patients are prone to recurrent and progressive respiratory infections and should be treated with intravenous g-globulin, as outlined above.
Approximately 80 percent of patients with hereditary ataxia-telangiectasia have IgA deficiency. This deficiency also occurs in patients treated with certain drugs, most commonly phenytoin, but also D-penicillamine, gold salts, captopril, antimalarials, and other drugs. A few patients with IgA deficiency may develop IgE antibodies to IgA, which sometimes results in severe anaphylactic reactions during blood or plasma transfusions.18
Plasma cells that secrete IgA are absent from patients with IgA deficiency, but they have B lymphocytes with surface IgA. These B cells cannot be induced to secrete IgA in vitro. There is a high familial incidence of IgA deficiency, but the inheritance pattern is complex. This deficiency frequently is associated with a limited number of extended haplotypes of the major histocompatibility complex (MHC), but the significance of this is not yet understood.19
SELECTIVE IgG SUBCLASS DEFICIENCY
Patients with recurrent pyogenic infections may have selective deficiency of IgG1, IgG2, IgG3, or IgG4 or of a combination of these subclasses.20 The basis of IgG subclass deficiency is not understood.21 As many as 10 percent of the normal population may have gene deletions in the IgG heavy-chain locus. However, this has no apparent clinical consequences for heterozygous individuals who have one normal allele. Rare cases of homozygous deletions in this area of the genome have been described, resulting in immunodeficiency.22
TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY
The human fetus is capable of forming antibodies in utero when adequately stimulated after the twentieth week of gestation. Intrauterine infection with syphilis, cytomegalovirus, rubella virus, or Toxo-plasma results in antibody synthesis. The antibodies synthesized by the human fetus are mainly IgM and at times IgA.
In normal circumstances the full-term newborn infant is provided with maternal IgG, so that umbilical cord serum contains as much IgG as the maternal serum. Infants born of agammaglobulinemic mothers have no detectable immunoglobulin in cord serum. Virtually no maternal IgA and very little maternal IgM traverses the placenta into the fetal circulation. The cord blood contains less than 1 percent of maternal serum levels of IgA, IgD, and IgE and about 10 percent of the maternal IgM level.
The transplacental passage of IgG appears to involve an active transport system that recognizes some specific structural attribute of the Fc fragment. Studies with radioactive iodinated proteins injected into pregnant women near term confirm this conclusion.23
Newborns synthesize IgM antibodies, increasing their level of serum IgM to about 75 percent of the adult level by the end of the first year of life. The newborn infant can synthesize IgA by the third week of life. The level of this globulin tends to rise more slowly and approaches 75 percent of the normal adult level by the end of the second year. Thereafter the level rises very slowly throughout childhood. IgA appears in secretions such as tears, however, by the age of 3 weeks. The maternal IgG is slowly catabolized, so that the infant’s serum IgG level reaches its low point of approximately 300 mg/ml by the end of the second month of life. With increased synthesis of IgG by the infant, the serum level rises rapidly toward normal adult values by the age of 1 year.
In some infants, the development of immunoglobulin synthesis is abnormally delayed. The nonphysiologic event has been designated transient hypogammaglobulinemia. It occurs with equal frequency in males and females. These infants usually develop the ability to synthesize immunoglobulin between 18 and 30 months of age. Before they develop the capacity for normal immunoglobulin synthesis, however, infants with transient hypogammaglobulinemia may have undue susceptibility to infections of the skin, meninges, or respiratory tract, usually due to gram-positive organisms. Recurrent otitis media, bronchitis, and bronchiolitis are the most common types of infection in these infants. Multiple cases in a single family have been observed. Despite the presence of a normal number of B cells in the blood, lymph nodes display small or no germinal centers and few, if any, plasma cells. These infants have a transient deficiency of CD4+ T lymphocytes. As the number of CD4+ T cells returns to normal, the infant usually experiences a spontaneous recovery from the hypogammaglobulinemia.24 During the period of hypogammaglobulinemia, such infants require immune serum globulin replacement therapy as described above.
COMMON VARIABLE, UNCLASSIFIABLE IMMUNODEFICIENCY
Most patients with immunodeficiency do not fall precisely into any of the aforementioned defined syndromes. Some patients are said to have “acquired” or “late-onset” agammaglobulinemia. Deterioration of T-cell function also may be observed in some instances. The acquisition of agammaglobulinemia has been documented in several cases, but the cause for this depression of immunoglobulin synthesis is unknown.
Primary acquired agammaglobulinemia occurs with equal frequency in males and females. Although there is no defined genetic pattern in its occurrence, multiple cases have occurred in a single kindred. In addition, these patients and their relatives have a high incidence of other immunologic abnormalities, such as lupus erythematosus, immune hemolytic anemia, increased rheumatoid factor titer, and thrombocytopenic purpura.
Undue susceptibility to pyogenic infections, particularly with recurrent sinusitis and pneumonia, is the prominent clinical feature of acquired agammaglobulinemia. Patients with chronic progressive bronchiectasis should, as a routine, be evaluated for this abnormality.
A prominent and frequent complication of acquired agamma-globulinemia, which is rarely seen in the X-linked disease, is a spruelike syndrome. More than half of all adults with agammaglobulinemia have diarrhea, steatorrhea, protein-losing enteropathy, and a whole range of malabsorption difficulties. Intestinal biopsies usually appear normal, without the characteristic flattening of villi seen in nontropical sprue. Some patients are noted to have nodular lymphoid hyperplasia. Giardia lamblia infection is common. Some patients improve on a gluten-free diet, while others benefit from having milk eliminated from their diet. Treatment with metronidazole (Flagyl) is usually helpful.
Another singular feature of the variable form of immunodeficiency is the frequent occurrence of noncaseating granulomas. Most frequently the lungs, spleen, skin, and liver are involved. No microorganisms have been found consistently in these lesions. Steroid therapy has been useful. Several patients have splenomegaly or hepatosplenomegaly and enlarged lymph nodes, and a few patients may develop hypersplenism. Pernicious anemia also has been reported in as many as 50 percent of patients with agammaglobulinemia.25
Patients with acquired agammaglobulinemia usually have serum IgG levels that are less than 500 mg/dl but higher than those of patients with X-linked disease. The IgG may not exhibit normal heterogeneity. Both IgA and IgM may be detected in significant quantity in the sera of these patients. Like IgA deficiency, common variable immunodeficiency (CVID) has been associated with extended haplotypes in the MHC.
The lymph nodes of patients with CVID lack plasma cells. However, in contrast to patients with X-linked agammaglobulinemia, these patients may have striking follicular hyperplasia. From in vitro and in vivo studies, it does not appear that an inhibitory factor causes this disease.
B lymphocytes with surface IgM and IgD usually are encountered in normal numbers but they fail to mature into plasma cells. The reasons for this are not understood.26 Thymomas sometimes are associated with common variable immunodeficiency, and these patients may have refractory anemia and declining T-cell function. Similar to patients with X-linked agammaglobulinemia, patients with CVID should be treated with intravenous immunoglobulin.27
SEVERE COMBINED IMMUNODEFICIENCY
DEFINITION AND HISTORY
In 1950, Glanzmann and Riniker described two unrelated infants who succumbed to overwhelming infection during the second year of life after a succession of serious infections, including intractable diarrhea, thrush, and persistent morbilliform rash.28 They noted persistent and profound lymphopenia in these two infants and designated the disease essential lymphocytophthisis. In 1958, Swiss workers pointed out that agammaglobulinemia is a prominent feature of this disease entity.28 No antibody synthesis can be detected. These infants lack B and T cells and are prey to all kinds of overwhelming infection. The immunodeficiency is uniformly fatal.
ETIOLOGY AND PATHOGENESIS
Initially, it appeared that the disease was transmitted as an autosomal recessive phenomenon, since consanguinity was demonstrated in approximately one-third of the parents of affected children. Further study of these families in America and Europe strongly suggested an additional X-linked transmission of the defect, on the basis of (1) the documentation of affected males in three generations, (2) the appearance of the disease in sons of identical-twin mothers, and (3) the appearance of the disease in sons of the same mother but different fathers. The two different modes of inheritance, autosomal and X-linked recessive, probably account for the 3:1 ratio of males and females observed in the reported cases. The X-linked form of severe combined immunodeficiency (SCID) appears distinctive in that affected males have normal numbers of circulating B cells that do not mature into plasma cells and make antibodies. This is designated T-B+ SCID. X-linked SCID has been found to result from mutations in the gene for the gamma chain of the interleukin-2 receptor.29 Because this gamma chain of the IL-2 receptor forms part of the IL-4, IL-7, IL-9, and IL-15 receptors, it is designated the gamma common (gc) chain. Engagement of the IL-7 receptor is ritual for human T-cell development. When T cells are activated the gc chain is phosphorylated by a tyrosine kinase, Jak3. Deficiency of Jak3, which is inherited as an autosomal recessive, also results in T-B+ SCID. In obligate heterozygous women who carry the gene for X-linked SCID, there is nonrandom inactivation of the X chromosome in their peripheral blood T cells. Such nonrandom X inactivation also is found in the B cells of obligate heterozygous women who carry the gene for X-linked agammaglobulinemia. As every female cell randomly inactivates one or the other X chromosome, the finding that T cells (in the case of X-linked SCID) or B cells (in the case of X-linked agammaglobulinemia) only express the normal X chromosome suggests that the defect is restricted to either the T-cell or B-cell lineage, respectively. Susceptible cells that have inactivated the normal X chromosome cannot expand and/or survive with the defective X chromosome.
About half of the infants with the autosomal recessive form have a concomitant deficiency of adenosine deaminase (ADA), the aminohydrolase that converts adenosine to inosine.30 Prenatal diagnosis is possible by finding this enzyme deficiency in cultured amnion cells.31 Another cause of defective T-cell immunity is nucleoside phosphorylase (NP) deficiency.32 In both ADA and NP deficiency the accumulation of toxic metabolites, dATP or dGTP, inhibits normal lymphocyte development33,34 (see Chap. 90). This is classified as T-B– SCID as affected infants have virtually no T or B cells. T-B– SCID may also result from mutations in the enzymes that cleave double-stranded DNA and initiate VDJ recombination in the genes encoding the T-cell antigen receptor and the immunoglobulins Rag-1 and Rag-2. Missense mutations in these genes may result in a variant of SCID called Omenn’s syndrome, characterized by marked erythrodermia, hyper IgE, eosinophilia, and oligoclonal expansion of T cells.
There is no discernible difference in the clinical course of the various genetic types. Also, they cannot be separated on the basis of the morbid anatomy of the disease. Infection starts early, between 3 and 6 months of age, and a rapid succession of debilitating infections brings about early demise. Death within the first 2 years of life is the rule. Almost all infants with this disease have chronic watery diarrhea. Stool cultures frequently reveal strains of Salmonella or of enteropathic Escherichia coli.
In addition, pulmonary infection is almost universal. Lung abscesses that contain Pseudomonas aeruginosa are a common cause of death, as is pneumonitis due to P. carinii. Extensive moniliasis of the mouth or diaper area that persists beyond the neonatal period is often the first sign of the disease. Usually this is present even before any antibiotic therapy is instituted. These infants, furthermore, are incapable of limiting or overcoming the most benign viral infections. Death has resulted from generalized chickenpox, measles with Hecht’s giant cell pneumonia, and, in a few instances, cytomegalovirus and adenovirus infection. Vaccination results in progressive, ultimately fatal vaccinia infection. BCG inoculation also has resulted in progressive BCG infection.
The lymphocyte count is usually less than 2000/µl (2 × 109/liter). The number of lymphocytes may be variable, declining from initially normal neonatal levels [n > 3000/µl (3 × 109/liter)] to profound lymphopenia. Accordingly, a single normal lymphocyte count cannot exclude this diagnosis, particularly during its early stages. Neutrophils and platelets are normal. However, leukocytosis may not occur in response to overt infection. Eosinophilia is common, and abnormal granulation of eosinophils has been reported. The number of natural killer cells in the blood may be elevated.
Marrow in normal infants contain up to 20 percent lymphocytic elements, but in SCID the marrow is uniformly deficient in plasma cells, lymphocytes, and lymphoblasts. Lymph node biopsies show complete lack of germinal elements, plasma cells, and lymphocytes. The stroma of the node may contain an occasional mast cell and eosinophils or, rarely, small collections of lymphoid cells without any apparent organization. Lymph node biopsies should not be performed to establish the diagnosis, as the biopsy site usually becomes infected or is a portal of entry for infection. The blood contains virtually no CD3+ cells of the CD4+ or CD8+ subsets. Whatever mature T cells are encountered are usually of maternal origin.35
None of the indications of delayed sensitivity can be elicited in these infants. The blood lymphocytes are unresponsive to phytohem-agglutinin or allogenic stimulation. Skin grafts are accepted without microscopic or macroscopic signs of rejection. At autopsy, no lymphoid tissue is found in the spleen, tonsils, appendix, or intestinal tract. The thymus has usually failed to descend in the normal manner into the anterior mediastinum and is found with difficulty in the neck. It ordinarily weighs less than 1 g and is composed of primordial spindle-shaped cells, occasionally forming swirls or rosettes. No Hassall’s corpuscles and few, if any, lymphocytes are present. The embryonal appearance of the thymus is the uniform characteristic of this entity. The thymus shadow is absent in a chest X-ray antemortem.
THERAPY, COURSE, AND PROGNOSIS
Death within the first 2 years of life, from infection and malnutrition, is almost invariable in this disease. Graft-versus-host disease, however, arising after marrow or whole blood transfusions, has resulted in several fatalities. This complication may result from the persistence of maternal lymphoid cells that are acquired through the placenta. The onset of graft-versus-host disease in any event is marked by the appearance of a characteristic maculopapular rash, starting on the face about 7 days after the injection of immunocompetent incompatible cells. The rash spreads rapidly, ultimately involving all skin surfaces including the palms and soles. Thrombocytopenia, leukopenia, jaundice, and anasarca follow in quick succession. Marrow aplasia leads to death from massive hemorrhage by the twelfth or fourteenth day.36
However, transplants of histocompatible marrow, usually from sibling donors but also from unrelated donors, has proved to be life-saving. It also has been possible to use parental haploidentical marrow from which T cells have been depleted to circumvent graft-versus-host disease.37 SCID due to ADA deficiency also has been corrected by gene therapy.38 The ADA gene in a retroviral vector has been inserted into patient lymphocytes in vitro and subsequently reinjected into the patients.
CELLULAR IMMUNE DEFICIENCY SYNDROMES
Hereditary ataxia-telangiectasia is transmitted as an autosomal recessive disease. Affected persons are first noted to be ataxic and to develop choreoathetoid movements and pseudopalsy of eye movements during infancy.
The telangiectasias appear later, at 5 or 6 years, or occasionally not until adolescence. They invariably involve the conjunctivae and other exposed body areas such as the face, ears, eyelids, and arms. Progressive sinopulmonary infection also appears later in the course. Death from chronic respiratory infection or lymphoreticular malignancy is common in the second or third decade of life.
About 80 percent of patients with ataxia-telangiectasia lack both serum and secretory IgA. Some patients have antibody to IgA, resulting in the rapid catabolism of injected IgA. All patients with ataxia-telangiectasia have a defect in cellular immunity. The thymus gland is dysplastic or hypoplastic, and there is depletion of thymus-dependent areas in the lymph nodes. Delayed hypersensitivity reactions, in vitro response of blood lymphocytes to phytohemagglutinin, and allograft rejection are absent.39 Immunoglobulin replacement and symptomatic measures have had limited therapeutic success.
It is estimated that 1.4 percent of the population is heterozygous for the hereditary ataxia-telangiectasia gene, and this subpopulation may have a higher incidence of cancer.40 The ataxia-telangiectasia gene maps to chromosome 11q22-23.41 It has been cloned and designated ATM (for ataxia telangiectasia mutated). The product of this gene is involved in the repair of double-stranded DNA breaks.
The Wiskott-Aldrich syndrome is characterized by eczema, thrombocytopenia, and recurrent infections. Inheritance of the syndrome is X-linked. Affected boys rarely survive beyond the first decade of life and succumb to overwhelming infection, hemorrhage, or lympho-reticular malignancy. Both gram-positive and gram-negative bacteria, as well as viruses and fungi, produce severe infections. There appears to be a progressive deterioration of thymus-dependent cellular immunity. In addition, there are concomitant changes in the lymph nodes, resulting in progressive depletion of lymphocytes from the paracortical areas. Serum IgM concentration is usually low, but IgG and IgA levels are normal or elevated. Isohemagglutinins are regularly absent from the serum. This observation suggests a specific inability to respond to polysaccharide antigens. This now has been demonstrated quite conclusively with A and B blood group substances, Salmonella Vi lipopolysaccharide, and other similar antigens. The gene for the Wiskott-Aldrich syndrome has been mapped to Xp11.22.42 The gene has been cloned and designated WASP. It encodes a protein comprised of 502 amino acid residues and is involved in cytoskeletal reorganization in a manner that has not yet been completely elucidated. By scanning electron microscopy, the platelets are small and fragmented, and the T cells are bald and lack their usual surface ruffling; these changes are pathognomonic of the disease. Surface sialoglycoproteins, CD43 of the T cells and platelets and gpIb of the platelets, are rapidly degraded on the surface of the cells for unknown reasons.43
CONGENITAL THYMIC APLASIA (DiGEORGE’S SYNDROME)
During the sixth week of embryonic life, the thymus primordium arises from the floor of the third pharyngeal pouch and, to a lesser extent, from the fourth pharyngeal pouch. The endodermal epithelial masses rapidly elongate, move down into the neck, and fuse in the midline behind the thyroid primordium in the eighth week of embryonic life. By the twelfth week, the gland comes to occupy its ultimate position in the anterior mediastinum. The epithelial cells form Hassall’s corpuscles, and the primordium is invaded by proliferating lymphoblasts.
While the thymus is forming, the parathyroid glands arise simultaneously from the third and fourth pharyngeal pouches and start their downward migration posterior and lateral to the thyroid primordium. During this same period, the nasomedial processes fuse to form the philtrum of the lip, and the ear tubercles around the hypomandibular cleft form into the external ear.
DiGeorge observed that a congenital anomaly may result from the failure of embryogenesis of the endodermal derivatives of the third and fourth pharyngeal pouches—aplasia of the parathyroid and thymus glands. This abnormality has no increased familial incidence and does not appear to be hereditary. All infants with this syndrome thus far studied have manifested neonatal tetany. The hypocalcemia tends to ameliorate with development during the first year of life. Hypertelorism; a shortened lip philtrum; low-set, notched pinnae; and nasal clefts cause these infants to resemble one another. In addition, anomalies of the great blood vessels are almost always present; tetralogy of Fallot and right-sided aortic arch are the most common defects.44
Infants with thymic aplasia who survive the neonatal period exhibit untoward susceptibility to viral, fungal, and bacterial infections that ultimately may be overwhelming. At autopsy, some parathyroid tissue and a miniature thymus gland may be found in an ectopic position by carefully sectioning the neck organs. Nephrocalcinosis has been found in over half the infants examined. The lymphoid tissue, marrow, spleen, and gastrointestinal tract contain a normal number of plasma cells, and the cortical germinal centers of the lymph nodes are normal or hyperplastic. The subcortical “thymus-dependent region” shows a moderate to severe depletion of lymphocytes, so that the reticulum cells in this area appear to be unusually prominent. The lymphoid sheaths of the spleen are also depleted of lymphocytes. Blood usually exhibits profound lymphopenia.45
Antibody responses to primary stimuli may be normal. Serum concentrations of immunoglobulins are normal. However, patients can neither manifest delayed hypersensitivity to common antigens, such as Candida or streptokinase, nor be sensitized to dinitrofluorobenzene (DNFB). Skin allograft rejection is absent or abnormally delayed. Lymphocyte transfer tests and macrophage-immobilizing factor synthesis are abnormal. The blood lymphocytes respond poorly, if at all, to in vitro stimulation by phytohemagglutinin or allogenic cells.
Transplants of fetal thymic tissue dramatically reverse all these deficits in in vitro and in vivo lymphocyte function into children with this syndrome. Increase in lymphocyte count, population of thymus-dependent areas with lymphocytes, normal skin allograft rejection, and normal responses to intradermal antigens, as well as normalization of phytohemagglutinin response in vitro, have been documented after fetal thymus transplants.46,47
COMBINED IMMUNODEFICIENCY WITH DEFECTIVE EXPRESSION IN MHC CLASS II GENES
Several children, principally of North African origin, have been described with severe and repeated opportunistic infections, frequently causing death. These children apparently have normal numbers of T and B cells, but they fail to synthesize and express the MHC class II molecules DP, DQ, and DR. The synthesis of class II molecules cannot be induced with interferon-gamma in affected patients. Because the normal ontogeny of CD4+ T lymphocytes is induced by class II MHC molecules, these children are deficient in CD4+ cells. Consequently they do not have antibody responses and are hypogammaglobulinemic. The in vitro response of their T cells in mixed lymphocyte culture and to mitogens is poor, although they respond normally to anti-CD3 and anti-CD2. Several of these children have been rescued with transplants of bone marrow. The defect does not map to the MHC but rather appears to result from the absence of a promoter binding protein required for coordinate MHC class II synthesis. The four complementation groups of this defect have been identified to result from 4 different promoter proteins.48
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn