Immunodeficiencies Involving T and B Lymphocytes
Disease Genetics Pathologic Findings Clinical Findings
X-Linked Agammaglobulinemia Mutations in the Bruton tyrosine kinase (Btk) gene with failure of pre-B cells to differentiate into functional B cells Normal numbers of circulating T cells with low to absent B cells, <100 mg/dL of IgG, and absent IgA and IgM. Atrophic lymph nodes and tonsilar tissues Recurrent bacterial infections beginning in infancy when passively acquired maternal antibody diminishes. Some affected persons will eventually develop an autoimmune disease
DiGeorge Syndrome Deletions of chromosome 22q11 with failure of thymic development and lack of functional T cells but normal levels of immunoglobulin Abnormal morphogenesis of 3rd and 4th pharyngeal pouch/arch derivatives: Thymic abnormalities, great vessel and cardiac anomalies, parathyroid hypoplasia or agenesis (with hypocalcemia), and facial anomalies. Lymph nodes have follicles but decreased numbers of T cells in paracortical and mantle zones. Severe and recurrent viral and fungal infections starting in infancy
Severe Combined Immunodeficiency (SCID) Half of cases are X-linked, with most involving the IL2RG gene encoding for the common gamma chain of interleukin-2, which forms a receptor for many cytokines needed for T-cell development. Half of cases have autosomal recessive mutations, including the adenosine deaminase (ADA) gene, leading to accumulation of purine metabolites toxic to T cells Markedly decreased circulating lymphocytes (<1000/microliter), though NK cells may be normal or increased. Minimal thymic development. Lymphoid tissues are hypoplastic. Primarily involves T cells, with greater decrease in cell mediated immunity than humoral immunity. Secondary impairment of B-cell function with diminished IgG levels and no IgA or IgM, Increased susceptibility to virtually all infectious organisms. Infants develop Candida skin rashes and thrush, persistent diarrhea, severe respiratory tract infections with Pneumocystis jiroveci and Pseudomonas soon after birth, and diarrhea with failure to thrive after 3 months of age. Severe viral infections can occur
Selective IgA Deficiency Stem cell defect involving alterations in the transmembrane activator and calcium modulator cyclophilin ligand interactor gene, with failure in final differentiation of IgA-secreting B cells into plasma cells or decreased survival of plasma cells Lack of both circulating IgA (<7 mg/dL) and secretory IgA, or partial IgA deŜciency (>7 mg/dl but >2 standard deviations below normal) at >4 years of age. Normal numbers of T and B cells but absent IgA-secreting plasma cells Recurrent sinopulmonary infections and possible bronchiectasis. Atopy with asthma. Gastrointestinal infections with Giardia duodenalis, with mild diarrhea. Autoimmunity possible. Systemic anaphylaxis with blood transfusion due to circulating anti-IgA antibodies
Common Variable Immunodeficiency (CVID) Multiple abnormalities possible: selective abnormality of T-cell activation, T- and B-cell autoantibodies. Possible failure of B-cell maturation to plasma cells, excessive T-cell suppression, or defective T-helper cell function. May be linked to selective IgA deŜciency Hypogammaglobulinaemia of two or more immunoglobulin isotypes (more often IgG and IgA); recurrent sinopulmonary infections; and impaired functional antibody responses with absent isohemagglutinins, poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (pneumococcus), or both.Normal numbers of T cells are present, but NK cells are decreased Onset from mid-childhood to mid-adulthood. Pediatric manifestions most often include sinusitis, otitis media, and pneumonia. Adults most often develop recurrent bronchitis, sinusitis, otitis media, and pneumonia, but may also develop viral hepatitis, severe Herpes zoster infection, and Giardia enteritis.
Hyper IgM Syndrome (HIGM) Mutations in the CD40 ligand induce failure in class switching of B cells; unexplained neutropenia Increased IgM but hypogammaglobulinemia with low IgG, IgA, and IgE levels Onset in infancy with recurrent sinopulmonary infections complicated by bronchiectasis, sinusitis, and otitis. Bacterial, viral, and opportunistic agents. Autoimmune manifestations.