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158 PRIMARY IMMUNODEFICIENCY DISEASES

158 PRIMARY IMMUNODEFICIENCY DISEASES
Harrison’s Manual of Medicine

158

PRIMARY IMMUNODEFICIENCY DISEASES

Definition
Classification

Severe Combined Immunodeficiency (SCID)

T Cell Immunodeficiency

Immunoglobulin Deficiency Syndromes
Miscellaneous Immunodeficiency Syndromes
Bibliography

DEFINITION
Disorders involving the cell-mediated (T cell) or antibody-mediated (B cell) pathways of the immune system; some disorders may manifest abnormalities of both pathways. Pts are prone to development of recurrent infections and, in certain disorders, lymphoproliferative neoplasms. Primary disorders may be congenital or acquired; some are familial in nature. Secondary disorders are not caused by intrinsic abnormalities of immune cells but may be due to infection (such as in AIDS; see HPIM-15, Chap. 309), treatment with cytotoxic drugs, radiation therapy, or lymphoreticular malignancies. Pts with disorders of antibody formation are chiefly prone to infection with encapsulated bacterial pathogens (e.g., streptococci, Haemophilus, meningococcus), and Giardia. Individuals with T cell defects are generally susceptible to infections with viruses, fungi, and protozoa.
CLASSIFICATION
Severe Combined Immunodeficiency (SCID)
Congenital (autosomal recessive or X-linked); affected infants rarely survive beyond 1 year without treatment. Dysfunction of both cellular and humoral immunity.
1.   Swiss-type: Autosomal recessive; severe lymphopenia involving B and T cells. Some cases due to mutations in the RAG-1 or RAG-2 genes; the combined activities of which are needed for V(D)J recombination of the T and B cell antigen receptors.
2.   Adenosine deaminase (ADA) deficiency: Autosomal recessive; has been treated with gene therapy.
3.   X-linked SCID: Characterized by an absence of peripheral T cells and natural killer (NK) cells. B lymphocytes are present in normal numbers but are functionally defective. These pts have a mutation in the gene that encodes the gamma chain common to the interleukin (IL) -2, -4, -7, -9, -15 receptors, thus disrupting the action of these important lymphokines. The same phenotype seen in X-linked SCID can be inherited as an autosomal recessive disease due to mutations in the JAK3 protein kinase gene. This enzyme associates with the common gamma chain of the receptors for IL-2, -4, -9, and -15 and is a key element in the signal transduction pathways used by these receptors.

TREATMENT
Bone marrow transplantation is useful in some SCID pts.

T Cell Immunodeficiency
1.   DiGeorge’s syndrome: Maldevelopment of organs derived embryologically from third and fourth pharyngeal pouches (including thymus); associated with congenital cardiac defects, parathyroid hypoplasia with hypocalcemic tetany, abnormal facies, thymic aplasia; serum Ig levels may be normal, but specific antibody responses are impaired.
2.   T cell receptor (TCR) complex deficiency: Immunodeficiencies due to inherited mutations of the CD3g and CD3e components of the TCR complex have been identified. CD3g mutations result in a selective defect in CD8 T cells, whereas CD3e mutations lead to a preferential reduction in CD4 T cells.
3.   MHC class II deficiency: Antigen-presenting cells from pts with this rare disorder fail to express the class II molecules DP, DQ, and DR on their surface, which results in limited development of CD4+ T cells in the thymus and defective interaction of CD4 T cells and antigen-presenting cells in the periphery. Affected pts experience recurrent bronchopulmonary infections, chronic diarrhea, and severe viral infections.
4.   Inherited deficiency of purine nucleoside phosphorylase: Functions in same salvage pathway as ADA; cellular dysfunction may be related to intracellular accumulation of purine metabolites.
5.   Ataxia-telangiectasia: Autosomal recessive; cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency; not all pts have immunodeficiency; lymphomas common; IgG subclasses may be abnormal.

TREATMENT
Treatment for T cell disorders is complex and largely investigational. Live vaccines and blood transfusions containing viable T cells should be assiduously avoided. Preventive therapy for Pneumocystis carinii pneumonia should be considered in selected pts with severe T cell deficiency.

Immunoglobulin Deficiency Syndromes
1.   X-linked agammaglobulinemia: Due to a mutation in the Bruton’s tyrosine kinase (Btk) gene. Marked deficiency of circulating B lymphocytes; all Ig classes low; recurrent sinopulmonary infections and chronic enteroviral encephalitis, including vaccine-acquired poliomyelitis infection, are common complications.
2.   Transient hypogammaglobulinemia of infancy: This occurs between 3 and 6 months of age as maternally derived IgG levels decline.
3.   Isolated IgA deficiency: Most common immunodeficiency; the majority of affected individuals do not have increased infections; antibodies against IgA may lead to anaphylaxis during transfusion of blood or plasma; may be associated with deficiencies of IgG subclasses; often familial.
4.   IgG subclass deficiencies: Total serum IgG may be normal, yet some individuals may be prone to recurrent sinopulmonary infections due to selective deficiencies of certain IgG subclasses.
5.   Common variable immunodeficiency: Heterogeneous group of syndromes characterized by panhypogammaglobulinemia, deficiency of IgG and IgA, or selective IgG deficiency and recurrent sinopulmonary infections; associated conditions include chronic giardiasis, intestinal malabsorption, atrophic gastritis with pernicious anemia, benign lymphoid hyperplasia, lymphoreticular neoplasms, arthritis, and autoimmune diseases.
6.   X-linked immunodeficiency with increased IgM: In most pts this syndrome results from genetic mutation in the gene encoding CD40 ligand, a transmembrane protein expressed by activated T cells and necessary for normal T and B cell cooperation, germinal center formation, and immunoglobulin isotype switching. Pts exhibit normal or increased serum IgM with low or absent IgG and IgA and recurrent sinopulmonary infections; pts also exhibit T lymphocyte abnormalities with increased susceptibility to infection with opportunistic pathogens (P. carinii, Cryptosporidium). Associated conditions include neutropenia and hepatobiliary tract disease.

TREATMENT
Intravenous immunoglobulin administration (only for pts who have recurrent bacterial infections and are deficient in IgG):

Table 158-1 Laboratory Work-Up for Primary Immunodeficiency

Starting dose 200–400 mg/kg given every 3–4 weeks

Adjust dose to keep trough IgG level > 500 mg/dL

Usually done in outpatient setting

Decision to treat based on severity of clinical symptoms and response to antigenic challenge

MISCELLANEOUS IMMUNODEFICIENCY SYNDROMES

Mucocutaneous candidiasis

X-linked lymphoproliferative syndrome

Immunodeficiency with thymoma

Wiskott-Aldrich syndrome

Hyper-IgE syndrome

Metabolic abnormalities associated with immunodeficiency
Bibliography

For a more detailed discussion, see Cooper MD, Schroeder HW Jr: Primary Immune Deficiency Diseases, Chap. 308, p. 1843, in HPIM-15.

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