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Chapter: Medical Immunology: Primary Immunodeficiency Diseases

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Cellular Immunodeficiencies

Are those in which cell-mediated immunity is predominantly impaired. The general char-acteristics of the common primary cellular immunodeficiencies are summarized.

CELLULAR IMMUNODEFICIENCIES

Are those in which cell-mediated immunity is predominantly impaired. The general char-acteristics of the common primary cellular immunodeficiencies are summarized in Table 29.4.



A. Congenital Thymus Aplasia (DiGeorge Syndrome)

DiGeorge syndrome can be considered as the paradigm of a pure T-cell deficiency. Al-though DiGeorge syndrome is a congenital immunodeficiency, in most cases it is not hereditarily transmitted. It is believed to be caused by an intrauterine infection prior to the 8th week of life, possibly of viral etiology.

1. Etiology and Pathogenesis

 

The underlying genetic abnormality in these patients is microdeletions of chromosomal re-gion 22q11.2. These deletions result in defective embryogenesis of the 3rd and 4th pha-ryngeal pouches at 6–8 weeks of fetal life, leading to deficient development of the thymus and parathyroids. Conotruncal cardiac defects (including truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, or aberrant right subclavian artery) and facial dysmorphy are also characteristic of the disease.

2. Clinical Presentation

 

The main clinical features include persistent hypocalcemia, often associated with neonatal tetany, abnormalities of the heart and large vessels, facial dysmorphism, mental subnor-mality, and frequent infectious episodes often involving viral or fungal agents, although bacterial and protozoan infections can also affect these patients. Most common manifesta-tions are pneumonia, chronic mucocutaneous candidiasis, diarrhea, and failure to thrive.

3. Diagnosis of Immunological Abnormalities

 

A hallmark finding is the absence or extreme reduction in size of the thymic image on a MRI. T cells are characteristically reduced in numbers (500/ µL CD3+ T cells), and there is poor to null response of peripheral blood mononuclear cells to T-cell mitogens such as PHA. However, in some patients there are residual T lymphocytes and/or partial thymus functions (partial DiGeorge syndrome). In these cases, if the patient can be kept alive for a number of years, a slow development of immune functions may take place. The numbers of B lymphocytes in peripheral blood are normal in patients with DiGeorge syndrome and humoral immunity is not severely impaired, as a rule. Some patients may have low levels of immunoglobulins and increased frequency of viral and bacterial infections, probably due to lack of T-cell help. Definitive diagnosis requires the presence of two out of three other abnormalities besides T-cell deficiency, including conotruncal cardiac defects, persistent hypocalcemia, or deletion of chromosome 22q11.2.

4. Therapy

 

Patients with residual T lymphocytes have a good chance of slow but progressive normal-ization of immune functions. These patients may only require supportive treatment.

The best treatment for complete DiGeorge syndrome is the transplantation of a fetal thymus obtained after less than 14 weeks of gestation to avoid graft-versus-host (GVH) dis-ease. Difficulties in obtaining fetal tissues have resulted in other, less satisfactory ap-proaches being more frequently used, including antibiotic prophylaxis with sulfamethoxa-zole-trimethoprim to prevent infections by Pneumocystis carinii, bone marrow transplantation (more likely to cause GVH reactions), and administration of intravenous gamma globulin if antibody deficiency is also present. If heart surgery is performed before correction of the immune deficiency, the blood used for replacement should be irradiated to eliminate heterologous lymphocytes, potentially able to cause GVH reaction in an im-mune-deficient recipient.

B. Chronic Mucocutaneous Candidiasis

Some patients with chronic infection of skin and mucosae with Candida albicans have been shown to have a selective deficiency of cell-mediated immunity. There is selective defi-ciency to Candida antigens following delayed-type hypersensitivity skin testing and in vitro lymphocyte proliferation responses. T-lymphocyte functions are otherwise normal when tested with other antigens and mitogens. The humoral response to C. albicans is also normal. Some of these patients develop endocrinopathies affecting the parathyroid glands, adrenals, thyroid, and endocrine pancreas. Alopecia aerata is also common.

Administration of oral antimycotic agents and symptomatic treatment of endocrine abnormalities are available therapies.


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