DEFICIENCIES OF THE INNATE IMMUNE SYSTEM
Account for ~10% of all primary immunodeficiencies (Table 157-1).
DEFICIENCES OF THE ADAPTIVE IMMUNE SYSTEM
T-Lymphocyte Deficiency Syndromes
Severe Combined Immunodeficiency (SCID) Group of rare primary immunodeficiencies characterized by a profound block in T-cell development as a consequence of an intrinsic deficiency. Clinical consequences occur within 3–6 months following birth. The most frequent clinical manifestations are recurrent oral candidiasis, failure to thrive, protracted diarrhea, Pneumocystis jirovecii infections. Six distinct causative mechanisms have been identified:
Cytokine signaling deficiency: Most frequent SCID accounting for 40–50% of cases with the absence of T and NK cells. These pts have a deficiency in the gamma chain receptor shared by several cytokine receptors (interleukins 2, 4, 7, 9, 15, 21). 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.
Purine metabolism deficiency: About 20% of SCID pts are deficient in adenosine deaminase (ADA) due to mutations in the ADA gene.
Defective rearrangements of T- and B-cell receptors: Account for ~20–30% of SCID cases. Main deficiencies involve recombinase activating genes (RAG-1, RAG-2) DNA-dependent protein kinase, DNA ligase 4, and Cernunnos deficiencies.
Defective (pre-) T-cell receptor signaling in the thymus: Rare deficiencies in CD3 subunits associated with the (pre) TCR and CD45.
Reticular dysgenesis: Extremely rare. Results from adenylate kinase 2 deficiency.
Defective egress of lymphocytes: Defective egress of T cells from the thymus resulting from deficiency in coronin-1A.
TREATMENT: SEVERE COMBINED IMMUNODEFICIENCY
Curative treatment relies on hematopoietic stem cell transplant (HSCT).
Other T Cell–Related Primary Immunodeficiencies
TREATMENT: OTHER T CELL–RELATED PRIMARY IMMUNODEFICIENCIES
Treatment is complex and largely investigational. HSCT plays a role in some diseases. Live vaccines and blood transfusions containing viable T cells should be strictly avoided. Prophylaxis for P. jirovecii pneumonia should be considered in selected pts with severe T-cell deficiency.
B-Lymphocyte Deficiency Syndromes
Deficiencies that affect B cells are the most common primary immunodeficiencies and account for ~60–70% of all cases. Defective antibody production predisposes to invasive pyogenic bacterial infections as well as recurrent sinus and pulmonary infections. Complete lack of antibody production (agammaglobulinemia) predisposes to disseminated enteroviral infections causing meningoencephalitis, hepatitis, and a dermatomyositis-like disease. Diagnosis relies on the determination of serum Ig level.
Agammaglobulinemia: Due to an X-linked mutation in the Bruton’s tyrosine kinase (Btk) gene in 85% of cases.
Hyper IgM: In most pts this syndrome results from an X-linked defect in the gene encoding CD40 ligand. Pts exhibit normal or increased serum IgM with low or absent IgG and IgA.
Common variable immunodeficiency (CVID): Heterogeneous group of syndromes characterized by low serum levels of one or more Ig isotypes. Prevalence estimated to be 1 in 20,000. Besides infections, pts may develop lymphoproliferation, granulomatous lesions, colitis, antibody-mediated autoimmune diseases, and lymphomas.
Isolated IgA deficiency: Most common immunodeficiency; affects 1 in 600 people. The majority of affected individuals do not have increased infections; antibodies against IgA may lead to anaphylaxis during transfusion of blood or plasma; may progress to CVID.
Selective antibody deficiency to polysaccharide antigens.
TREATMENT: B CELL/IMMUNOGLOBULIN DEFICIENCY SYNDROMES
IV immunoglobulin administration (only for pts who have recurrent bacterial infections and are deficient in IgG):
Starting dose 400–500 mg/kg given every 3–4 weeks
Adjust dose to keep trough IgG level 800 mg/dL
SC administration usually once a week can be considered in selected pts.
Rare but increasingly described primary immunodeficiencies that cause homeostatic dysregulation of the immune system either alone or in association with increased vulnerability to infection (Table 157-1).
For a more detailed discussion, see Fischer A: Primary Immune Deficiency Diseases, Chap. 374, p. 2103, in HPIM-19.