Degranulation abnormalities | | |
Chédiak-Higashi syndrome | Autosomal recessive; disordered coalescence of lysosomal granules; responsible gene is CHSI/LYST, which encodes a protein hypothesized to regulate granule fusion | Decreased neutrophil chemotaxis; degranulation and bactericidal activity; platelet storage pool defect; impaired NK function, failure to disperse melanosomes | Neutropenia; recurrent pyogenic infections, propensity to develop marked hepatosplenomegaly as a manifestation of the hemophagocytic syndrome |
Specific granule deficiency | Autosomal recessive; functional loss of myeloid transcription factor arising from a mutation or arising from reduced expression of Gfi-1 or C/eBpε, which regulates specific granule formation | Impaired chemotaxis and bactericidal activity; bilobed nuclei in neutrophils; defensins, gelatinase, collagenase, vitamin B12-binding protein, and lactoferrin | Recurrent deep-seated abscesses |
Adhesion abnormalities |
Leukocyte adhesion deficiency I | Autosomal recessive; absence of CD11/CD18 surface adhesive glycoproteins (β2 integrins) on leukocyte membranes most commonly arising from failure to express CD18 mRNA | Decreased binding of C3bi to neutrophils and impaired adhesion to ICAM-1 and ICAM-2 | Neutrophilia; recurrent bacterial infection associated with a lack of pus formation |
Leukocyte adhesion deficiency II | Autosomal recessive; loss of fucosylation of ligands for selectins and other glycol conjugates arising from mutations of the GDP-fucose transporter | Decreased adhesion to activated endothelium expressing ELAM | Neutrophilia; recurrent bacterial infection without pus |
Leukocyte adhesion deficiency III (LAD-I variant syndrome) | Autosomal recessive; impaired integrin function arising from mutations of FERMT3, which encodes kindlin-3 in hematopoietic cells; kindlin-3 binds to β-integrin and thereby transmits integrin activation | Impaired neutrophil adhesion and platelet activation | Recurrent infections, neutropenia, bleeding tendency |
Disorders of cell motility |
Enhanced motile responses; FMF | Autosomal recessive gene responsible for FMF on chromosome 16, which encodes for a protein called “pyrin”; pyrin regulates caspase-1 and thereby IL-1β secretion; mutated pyrin may lead to heightened sensitivity to endotoxin, excessive IL-1β production, and impaired monocyte apoptosis | Excessive accumulation of neutrophils at inflamed sites, which may be the result of excessive IL-1β production | Recurrent fever, peritonitis, pleuritis, arthritis, and amyloidosis |
Depressed motile responses |
Defects in the generation of chemotactic signals | IgG deficiencies; C3 and properdin deficiency can arise from genetic or acquired abnormalities; mannose-binding protein deficiency predominantly in neonates | Deficiency of serum chemotaxis and opsonic activities | Recurrent pyogenic infections |
Intrinsic defects of the neu-trophil (eg, leukocyte adhesion deficiency, hédiak-Higashi syndrome, specific granule deficiency, neutrophil actin dysfunction, neonatal neutrophils); direct inhibition of neutrophil mobility (eg, drugs) | In the neonatal neutrophil there is diminished ability to express β2 integrins and there is a qualitative impairment in β2-integrin function; ethanol, glucocorticoids, cyclic AMP | Diminished chemotaxis; impaired locomotion and ingestion; impaired adherence | Propensity to develop pyogenic infections; possible cause for frequent infections; neutrophilia seen with epinephrine arises from cyclic AMP release from endothelium |
Immune complexes | Bind to Fc receptors on neutrophils in patients with rheumatoid arthritis, systemic lupus erythematosus, and other inflammatory states | Impaired chemotaxis | Recurrent pyogenic infections |
Hyperimmunoglobulin-E syndrome | Autosomal dominant; responsible gene is STAT3 | Impaired chemotaxis at times; impaired regulation of cytokine production | Recurrent skin and sinopulmonary infections, eczema, mucocutaneous candidiasis, eosinophilia, retained primary teeth, minimal trauma fractures, scoliosis, and characteristic facies |
Hyperimmunoglobulin-E syndrome | Autosomal recessive; more than one gene likely contributes to its etiology | High IgE levels, impaired lymphocyte activation to staphylococcal antigens | Recurrent pneumonia without pneumatoceles sepsis, enzyme, boils, mucocutaneous candidiasis, neurologic symptoms, eosinophilia |
Microbicidal activity |
Chronic granulomatous disease | X-linked and autosomal recessive; failure to express functional gp91phox in the phagocyte membrane in p22phox (autosomal recessive); other autosomal recessive forms of CGD arise from failure to express protein p47phox or p67phox | Failure to activate neutrophil respiratory burst leading to failure to kill catalase-positive microbes | Recurrent pyogenic infections with catalase-positive microorganisms |
G6PD deficiency | Less than 5% of normal activity of G6PD | Failure to activate NADPH-de-pendent oxidase, and hemolytic anemia | Infections with catalase-positive microorganisms |
Myeloperoxidase deficiency | Autosomal recessive; failure to process modified precursor protein arising from missense mutation | H2O2-dependent antimicrobial activity not potentiated by myeloperoxidase | None |
Rac-2 deficiency | Autosomal dominant; dominant negative inhibition by mutant protein of rac-2–mediated functions | Failure of membrane receptor–mediated O2 generation and chemotaxis | Neutrophilia, recurrent bacterial infections |
Deficiencies of glutathione reductase and glutathione synthetase | Autosomal recessive; failure to detoxify H2O2 | Excessive formation of H2O2 | Minimal problems with recurrent pyogenic infections |