Medical Genetics 15 免疫缺陷 immunodeficiency

Medical Genetics The immune system is a network of interacting cellular and soluble components. Its function is to distinguish entities within the body as "self" or "nonself" and to eliminate those that are nonself.

Medical Genetics Microorganisms are the principal nonself entities, but neoplasms, transplants, and certain foreign substances (eg, some toxins) are also important. To accomplish its tasks, the immune system has evolved two mechanisms: nonspecific immunity and specific immunity, which are linked to and influence each other.

Medical Genetics Nonspecific (Innate) Immunity This type of immunity is older phylogenetically, is present at birth, does not require a previous encounter with the offending substance, and does not develop memory. Innate immunity includes barriers, such as the skin, and chemical protection, such as gastric acid.

Medical Genetics There are two cellular components: (1)the phagocytic system, whose function is to ingest and digest invading microorganisms, and (2) natural killer (NK) cells, whose function is to kill some tumors, microorganisms, and virally infected cells. The soluble components consist of complement proteins, acute phase reactants, and cytokines.

Medical Genetics Specific (Adaptive) Immunity Specific immunity has the hallmarks of learning, adaptability, and memory. The cellular component is the lymphocyte, and immunoglobulins (Igs) are the soluble component.

Medical Genetics Immunodeficiency diseases: A group of diverse conditions caused by one or more immune system defects and characterized clinically by increased susceptibility to infections with consequent severe, acute, recurrent, or chronic disease.

Medical Genetics An immunodeficiency disorder should be considered in anyone with infections that are unusually frequent, severe, and resistant; without a symptom-free interval; from an unusual organism; or with unexpected or severe complications.

Medical Genetics Since immunodeficiency disorders are relatively uncommon, other disorders leading to recurrent infection should be considered first. If these disorders can be excluded, a defect in host defense should be suspected.

Medical Genetics DISORDERS WITH INCREASED SUSCEPTIBILITY TO UNUSUAL INFECTIONS

Medical Genetics 1. General Immunodeficiencies may be primary or secondary. Primary immunodeficiency is classified into four main groups depending on which component of the immune system is deficient: B cells, T cells, phagocytic cells, or complement.

Medical Genetics Over 70 primary immunodeficiencies have been described, and considerable heterogeneity may exist within each disorder.

Medical Genetics CLASSIFICATION, INHERITANCE, AND ASSOCIATED FEATURES OF THE PRIMARY IMMUNODEFICIENCY DISORDERS

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2. Etiology Immunodeficiency has no common cause, although a single gene defect is often implicated.

Medical Genetics The defect can lead to a missing enzyme (eg, adenosine deaminase deficiency), a missing protein (eg, complement component deficiencies), or developmental arrest at a specific differential stage (eg, pre-B-cell arrest in X-linked agammaglobulinemia).

Medical Genetics Chromosome locations of the defective genes have been identified for many of the primary immunodeficiencies.

Medical Genetics In certain illnesses, intrauterine events may be implicated (eg, maternal alcoholism in some cases of DiGeorge anomaly); in others, drug ingestion may be implicated (eg, phenytoin in IgA deficiency). The exact biologic abnormality in most of the illnesses is unknown.

Medical Genetics 3. Symptoms and Signs Most manifestations of immunodeficiency result from frequent infections, usually beginning with recurrent respiratory infections.

Medical Genetics Infection of the skin and mucous membranes also is common. Resistant thrush may be the first sign of T-cell immunodeficiency. Oral ulcers and periodontitis also are noted, particularly in granulocytic deficiencies. Conjunctivitis occurs in many antibody-deficient adults. Pyoderma, severe warts, alopecia, eczema, and telangiectasia are common.

Medical Genetics Common symptoms include diarrhea, malabsorption, and failure to thrive. The diarrhea usually is noninfectious but may be associated with Giardia lamblia, rotavirus, cytomegalovirus, or Cryptosporidium. In some patients, the diarrhea may be exudative with loss of serum proteins and lymphocytes.

Medical Genetics Less common manifestations of immunodeficiency include hematologic abnormalities (autoimmune hemolytic anemia, leukopenia, thrombocytopenia), autoimmune phenomena (vasculitis, arthritis, endocrinopathies), and CNS problems (eg, chronic encephalitis, slow development, seizures).

Medical Genetics 4. Diagnosis A family history should be obtained. If there is a history of early death, similar disease, autoimmune illness, allergy, early malignancy, or consanguinity, then a pedigree chart will help identify a hereditary pattern.

Medical Genetics The type of infection The age of onset physical examination Laboratory Tests

Medical Genetics 6.Specific Immunodeficiencies A.Transient hypo- gammaglobulinemia of infancy A self-limited antibody deficiency of both sexes, with onset at age 3 to 6 mo, persisting usually for 6 to 18 mo.

Medical Genetics Sometimes there is an associated increased frequency of infection. The disorder results from a delay in the onset of Ig synthesis despite normal numbers of B cells. T helper cells may be reduced. Premature infants are especially at risk because of lower levels of transplacental IgG at birth. The disorder is not familial.

Medical Genetics B. X-Linked agammaglobulinemia Bruton's Agammaglobulinemia Congenital Agammaglobulinemia

Medical Genetics Panhypogammaglobulinemia of male infants characterized by levels of IgG < 100 mg/dL and other Ig levels low or absent, low or absent B cells, intact cellular immunity, and onset of infections sometime after age 6 mo, when maternal antibodies disappear.

Medical Genetics These infants have recurrent pyogenic infections of the lungs, sinuses, and bones with such organisms as pneumococcus, haemophilus, and streptococcus.

Medical Genetics They also are susceptible to vaccine-induced poliovirus infection and chronic echovirus encephalitis. Some infants have arthritis that disappears with IG therapy. X-linked inheritance is proved in about 20% of cases.

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A defect of the Btk (Bruton's tyrosine kinase) gene at Xq22 prevents differentiation of pre-B cells to B cells. Different variants of the defective gene exist in each kindred.

Medical Genetics Treatment Lifelong IG given IM or IV in the lowest dose that prevents recurrent infection is essential. Prompt, adequate antibiotic administration with each infection is crucial; continuous antibiotics are sometimes indicated. Despite these measures, many patients develop persistent sinusitis, bronchitis, and bronchiectasis. Susceptibility to malignancy is increased.

Medical Genetics C. Hyper-IgM immunodeficiency A congenital, usually X-linked immunodeficiency characterized by elevated levels of IgM, decreased levels of IgG and IgA, intermittent neutropenia, normal B-cell levels, and susceptibility to infection.

Medical Genetics Lymphadenopathy and autoimmunity may be present. Susceptibility to major gram-positive pathogens and opportunistic infections is increased. Most patients (> 70%) develop chronic liver disease by age 30.

Medical Genetics This infant with X-linked immunodeficiency with hyperimmunoglobulin M (XHIM) developed severe diarrhea and hypoproteinemia.

Medical Genetics The immunologic defect in the X- linked form is a deficiency of T cell gp39, the ligand for CD40 on B cells that induces switching from IgM to IgA, IgG, and IgE. The mutated gene has been identified at Xq27.

Medical Genetics Treatment Treatment is similar to that of X- linked agammaglobulinemia. Granulocyte colony-stimulating factor can be used for neutropenia. Stem cell transplantation has been successful in a few cases.

Medical Genetics D. DiGEORGE anomaly Thymic Hypoplasia Third Pharyngeal Pouch Syndrome Fourth Pharyngeal Pouch Syndrome

Medical Genetics A congenital immunodeficiency characterized pathologically by absence or hypoplasia of the thymus and parathyroid glands and immunologically by partial or complete T-cell immunodeficiency but normal or near-normal B-cell immunity.

Medical Genetics Affected infants have low-set ears, midline facial clefts, a small receding mandible, hypertelorism, a shortened philtrum, and congenital heart disease. Tetany appears within 24 to 48 h of life. Both sexes are equally affected, and familial cases are uncommon.

Medical Genetics Abnormalities of chromosome 22q (eg, deletion or monosomy) can be identified in 90% of cases. There seems to be an interruption of normal development of pharyngeal pouch structures near the 8th wk of gestation.

Medical Genetics Treatment Bone marrow transplantation has been successful. Some success has been achieved with fetal thymus transplants. The severity of the heart disease often determines the eventual prognosis. Partial deficiency is compatible with prolonged survival.

Medical Genetics E. Combined immunodeficiency A group of disorders characterized by congenital and usually hereditary deficiency of both B- and T-cell systems, lymphoid aplasia, and thymic dysplasia.

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The combined immunodeficiencies include severe combined immunodeficiency, Swiss agammaglobulinemia, combined immunodeficiency with adenosine deaminase or nucleoside phosphorylase deficiency, and combined immunodeficiency with immunoglobulins (Nezelof syndrome).

Medical Genetics Most patients have an early onset (within 3 mo of life) of infection with thrush, pneumonia, and diarrhea. If left untreated, most die before age 2. Most patients have profound deficiency of B cells and Igs.

Medical Genetics The following are characteristic: lymphopenia, low or absent T-cell levels, poor proliferative response to mitogens, cutaneous anergy, an absent thymic shadow, and diminished lymphoid tissue. Pneumocystis pneumonia and other opportunistic infections are common.

Medical Genetics About 1/2 of patients with an autosomal recessive inheritance have adenosine deaminase (ADA) deficiency, a purine salvage pathway enzyme that converts adenosine and deoxyadenosine to inosine and deoxyinosine, respectively.

Medical Genetics ADA deficiency results in elevated quantities of deoxyadenosine triphosphate (dATP), which inhibits DNA synthesis. ADA- deficient patients may be normal at birth but develop progressive immunologic impairment as dATP accumulates.

Medical Genetics Treatment Treatment with IG and antibiotics is indicated but not curative. Treatment of choice for all variants is stem cell transplantation. Patients with ADA deficiency have been treated successfully with polyethylene glycol conjugated to bovine ADA (PEG-ADA). IL-2-deficient patients have been treated with recombinant human IL-2. Gene therapy has been used with some success in ADA deficiency.