Disorders of Leukocyte Function

Disorders of Leukocyte Function HR Hill, A Kuma´novics, and KD Yang, University of Utah, Salt Lake City, UT, USA ã 2014 Elsevier Inc. All rights reserved.

Neutrophil Number Disorders Leukocyte Adhesion Deficiencies Disorders of Granulocyte Chemotaxis Disorders of Microbicidal Activity Monocyte/Macrophage Function Disorders References

1 1 2 2 2 3

Disorders of leukocyte function conventionally include the primary (or genetic) immunodeficiencies of phagocytes (granulocytes and monocytes). The first disorder of leukocyte function was described about 60 years ago by Kostmann as infantile genetic agranulocytosis (or severe congenital neutropnia, Kostmann syndrome), and since that an entire spectrum of phagocyte disorders, including adhesion, movement, ingestion, and bactericidal defects have been recognized and their genetic bases have been determined. With the exception of chronic granulomatous disease, these are individually rare diseases, but as a group they represent about 12% of all congenital immunodeficiency patients (Gathmann et al., 2009). Phagocyte progenitor cells arise from hematopoietic stem cells in the bone marrow. These precursors can give rise to mature phagocytes, including polymorphonuclear granulocytes and mononuclear phagocytes, under the influence of various colonystimulating factors and transcription factors (Friedman, 2007). Neutrophil granulocytes (or polymorphonuclear leukocytes, PMNs) are the most abundant leukocytes in the bloodstream and are critical for host defense. The cytoplasmic granules contain cytotoxic molecules that are available for immediate release. Granulocytes are short-lived, terminally differentiated cells whose numbers are maintained in a narrow range. Empirically, a blood granulocyte concentration less than 1500 mm 3 is defined as granulocytopenia, and 500 mm 3 or less is usually considered severe, life-threatening granulocytopenia. It should be noted, however, that the circulating blood granulocyte level appears to be genetically determined, and varies among various ethnic groups (Nalls et al., 2008). Circulating blood monocytes may develop into different forms of dendritic cells and macrophages, possessing diverse morphologies and functions depending on environmental and immunological factors. Mononuclear phagocytes, similar to polymorphonuclear granulocytes, can move toward foreign invaders and denatured tissues and destroy them by ingestion, degranulation, and respiratory burst activity as well as by the generation of nitric oxide from arginine. In addition, macrophages and monocyte-derived dendritic cells can also take up and present the antigens to lymphocytes for adaptive immune responses.

Neutrophil Number Disorders Patients with congenital granulocytopenia usually have recurrent infections such as omphalitis, septicemia, and abscess formation early in life. Those who survive infancy frequently show progressive periodontitis. There are now at least 15 gene defects known to cause severe congenital neutropenia (SCN), but in about 30% of cases the genetic etiology is still unknown (Bouma et al., 2010; Boztug and Klein, 2009). Congenital granulocytopenias may occur as isolated deficiencies or as part of a syndrome. The majority of autosomal dominant nonsyndromic granulocytopenias are caused by mutations in ELA2 (or ELANE) that encodes neutrophil elastase. ELA2 mutations can lead to severe congenital neutropenia or cyclic neutropenia. Cyclic neutropenia is distinguished from SCN by the regular oscillations (21 day cycles) of blood neutrophil counts. Autosomal recessive SCN can be caused by mutations in HAX1, SLC7A4, G6PC3, or GFI1. X-linked neutropenias are caused by activating mutations in Wiskott–Aldrich syndrome (WAS) protein. The unifying feature of the molecular pathogenesis of SCN is the maturation arrest of precursor cells due to increased apoptosis. Increased apoptosis might be caused by the unfolded protein response (UPR) due to accumulation of misfolded proteins (e.g. ELA2 and G6PC3), mitochondrial membrane potential (HAX1), or defective mitosis and cytokinesis (WAS). Chediak–Highasi syndrome, type 2 Hermansky–Pudlak syndrome, Griscelli syndrome, and p14/ROBLD3 deficiency all lead to neutropenia associated with pigmentation defects caused by mutations in genes encoding proteins involved in intracellular trafficking of organelles. Cohen, Cartilage Hair Dysplasia, Reticular dysgenesis, Schwachmann–Diamond, Barth, and Pearson syndromes present with neutropenia. WHIM syndrome is a chemotaxis defect (see below) that also leads to neutropenia (Bouma et al., 2010; Boztug and Klein, 2009).

Leukocyte Adhesion Deficiencies Leukocyte adhesion deficiency (LAD) disorders are characterized by the inability of leukocytes to emigrate from the circulation to the sites of injury. b2 integrins expressed on the leukocyte surface mediate tight binding to the endothelium (Ley and Morris, 2005).

Reference Module in Biomedical Research

http://dx.doi.org/10.1016/B978-0-12-801238-3.05554-9

1

2

Disorders of Leukocyte Function

LAD-I is caused by mutations in the gene encoding the common b-chain of the b2 integrin family (CD18). LAD-II is caused by the deficiency in fucosylation required for the function of adhesion molecules and also known as Congenital Disorder of Glycosylation, Type IIc. It is caused by mutations in the SLC35C1 gene encoding a Golgi ADP-fucose transporter (Helmus et al., 2006). LAD-III is caused by deficient cytokine activation of the adherent leukocytes leading to diminished integrin expression. LAD-III is caused by homozygous mutation in the FERMT3 (or KINDLIN3) gene (Svensson et al., 2009). Patients with LAD-I frequently have delayed separation of the umbilical cord, perirectal abscesses, and recurrent staphylococcal and gram-negative bacterial infections. Patients with LAD-II also have mental retardation, neutrophilia, recurrent infections, and periodontitis, but they do not have delayed separation of the umbilical cord. Patients with LAD-III were first described as LAD-I variants who suffered from a bleeding tendency due to platelet aggregation deficiency.

Disorders of Granulocyte Chemotaxis WHIM syndrome is an autosomal dominant disorder of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis caused by heterozygous gain-of-function mutations in the gene encoding the CXCR4 chemokine receptor (Kawai and Malech, 2009). Chemotaxis defects also include the previously mentioned deficiency of the adhesion molecules and defects associated with impaired degranulation (e.g. Che´diak–Higashi syndrome). Hyper-IgE syndrome (or Job syndrome) caused by mutations in STAT3 is usually associated with a granulocyte chemotactic defect and high levels of IgE, altered T-cell activity, and low IFN-g and IL17 production (Woellner et al., 2010).

Disorders of Microbicidal Activity Disorders of oxygen-dependent microbicidal activity disorders are relatively common and include chronic granulomatous disease (CGD), glucose-6-phosphate dehydrogenase (G6PD) deficiency, myeloperoxidase (MPO) deficiency, and glutathione synthetase and reductase deficiencies. Patients with defects in oxygen-dependent bactericidal activity suffer from recurrent cutaneous, organ, and tissue abscesses and recurrent sinopulmonary infections. Granulomas may form at the site of tissue infections, resulting in obstructive disorders involving the gastrointestinal and urinary systems. Infections are most often due to catalase-positive microorganisms. CGD is caused by the deficiency of the phagocyte-specific NADPH oxidase (or NOX2; (Kuhns et al., 2010)). The neutrophil NADPH oxidase is composed of two membrane and four cytosolic components. Two-thirds of CGD cases are transmitted in an X-linked recessive pattern owing to the absence of cytochrome b558 heavy chain (p91phox, encoded by CYBB). The rest are inherited by an autosomal recessive mechanism. Mutations in p47phox are found in about 30% of CGD patients. Mutations in p22phox and p67phox each are less than 5% of CGD cases. Only one CGD patient is described with mutation in NCF4 that encodes p40phox (Matute et al., 2009). Rac2 mutations have not been reported as a cause of CGD. G6PD deficiency is one of the most common enzyme deficiency in humans, with over 140 different mutations described (Beutler and Vulliamy, 2002). The most common mutations in G6PD (seen in patients with African ancestry) lead a mild to moderate enzyme deficiency (20–60% activity) and to intermittent hemolysis usually secondary to infections or drugs. Few patients with severe forms of G6PD deficiency can present with a CGD-like clinical picture, as the profound deficiency of G6PD leads to a defect in NADPH production, causing impaired respiratory burst activity. Granulocytes with glutathione reductase or glutathione synthetase deficiency have a normal early respiratory burst, whereas subsequent continuous production of toxic oxygen products, which are normally handled by glutathione, results in auto-oxidative damage and defective microbicidal activity (Njalsson et al., 2005). Both glutathione reductase and glutathione synthetase deficiencies are transmitted by autosomal recessive inheritance. Patients with these deficiencies can have hemolytic disorders in addition to the abnormal bactericidal activity. Granulocytes in MPO deficiency (MPO; (Marchetti et al., 2004)) have normal production of superoxide but defective generation of hypochlorite ion. Patients with this disorder are not uncommon (1 in 2000 to 1 in 4000 in the general population), but are frequently asymptomatic or at most have delayed granulocyte killing activity and recurrent candidal infections. Disorders of oxygen-independent microbicidal activity arise from the absence of granules or from defective degranulation. Patients with Specific Granule Deficiency have autosomal recessive inheritance caused by mutations in CCAAT/enhancer-binding protein epsilon (C/EBPE) gene (Gombart and Koeffler, 2002), whereas Hermansky–Pudlak, Chediak–Higashi and Griscelli syndromes lead to granulocyte dysfunction due to the failure of the granule constituents to fuse with the phagosome (Huizing et al., 2008).

Monocyte/Macrophage Function Disorders Monocytes/macrophages share the same ancestor cells as granulocytes, and most of the functional defects present in granulocyte function disorders also occur in monocytes/macrophages, including LAD, respiratory burst defects such as CGD, degranulation

Disorders of Leukocyte Function

3

defects such as in Chediak–Higashi syndrome, and specific granule deficiency. Primary macrophage function defects are relatively rare; most of the macrophage function defects are secondary. Monocytes, macrophages express toll-like receptors (TLRs) that are pattern-recognition receptors (PRRs). PPRs recognize microorganisms or microbial products, and mediate signals for innate immunity and adaptive T-cell differentiation. Mutations in the shared intracellular signaling molecules of TLRs (IRAK4 and MyD88) lead to recurrent pyogenic bacterial infections, including invasive pneumococcal disease (Picard et al., 2010). Macrophage phagosomes are both the site of elimination of mycobacteria and the site of mycobacterial replication (Bustamante et al., 2011; Cottle, 2011). Mendelian susceptibility to mycobacterial diseases (MSMD) and Salmonella infection are caused by deficiencies in the IL-12/IL-23/IFN-g cytokines and their signaling pathways (IFN-gR, IFN-gR2, IL-12p40, IL-12Rb1, STAT1, or NEMO deficiency). Interestingly, the autosomal recessive form of the STAT1 signaling molecule deficiency leads to susceptibility to both mycobacteria (IFN-g-mediated immunity) and viruses (IFN-a/b-mediated immunity), whereas the autosomal dominant STAT1 deficiency leads to MSMD only. NEMO deficiency is an X-linked MSDS. Tissue resident macrophages have specialized functions. The best example is in the bone. Osteopetrosis (Stark and Savarirayan, 2009) is due to dysfunction of osteoclasts (specialized macrophages), resulting in impaired resorption of mineralized cartilage and bone remodeling. Osteopetrosis, transmitted as an autosomal recessive trait, is called osteopetrosis congenita, and it occurs in infants and children. Osteopetrosis tarda is an autosomal dominant trait, which occurs in adults. Six genes are known as causative for autosomal recessive osteopetrosis (TCIRG1, ClC7, OSTM1, PLEKHM1, TNFSF11, and TNFRSF11A). A rare X-linked recessive anhidrotic ectodermal dysplasia with osteopetrosis and immunodeficiency is caused by mutations in IKBKG gene (encoding NEMO). An autosomal dominant form of anhidrotic ectodermal dysplasia with T-cell immunodeficiency is caused by gain-offunction mutation of IKBA. Another group of hereditary macrophage function defects include the metabolic storage disorders, especially those with lysosomal enzyme deficiencies (discussed elsewhere).

References Beutler E and Vulliamy TJ (2002) Hematologically important mutations: Glucose-6-phosphate dehydrogenase. Blood Cells, Molecules & Diseases 28(2): 93–103. Bouma G, Ancliff PJ, Thrasher AJ, and Burns SO (2010) Recent advances in the understanding of genetic defects of neutrophil number and function. British Journal of Haematology 151(4): 312–326. Boztug K and Klein C (2009) Novel genetic etiologies of severe congenital neutropenia. Current Opinion in Immunology 21(5): 472–480. Bustamante J, Arias AA, Vogt G, Picard C, Galicia LB, Prando C, Grant AV, Marchal CC, Hubeau M, Chapgier A, et al. (2011) Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nature Immunology 12(3): 213–221. Cottle LE (2011) Mendelian susceptibility to mycobacterial disease. Clinical Genetics 79(1): 17–22. Friedman AD (2007) Transcriptional control of granulocyte and monocyte development. Oncogene 26(47): 6816–6828. Gathmann B, Grimbacher B, Beaute J, Dudoit Y, Mahlaoui N, Fischer A, Knerr V, and Kindle G (2009) The European internet-based patient and research database for primary immunodeficiencies: Results 2006–2008. Clinical and Experimental Immunology 157(Suppl. 1): 3–11. Gombart AF and Koeffler HP (2002) Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBP(epsilon). Current Opinion in Hematology 9 (1): 36–42. Helmus Y, Denecke J, Yakubenia S, Robinson P, Luhn K, Watson DL, McGrogan PJ, Vestweber D, Marquardt T, and Wild MK (2006) Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood 107(10): 3959–3966. Huizing M, Helip-Wooley A, Westbroek W, Gunay-Aygun M, and Gahl WA (2008) Disorders of lysosome-related organelle biogenesis: Clinical and molecular genetics. Annual Review of Genomics and Human Genetics 9359–9386. Kawai T and Malech HL (2009) WHIM syndrome: Congenital immune deficiency disease. Current Opinion in Hematology 16(1): 20–26. Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DA, Soule BP, et al. (2010) Residual NADPH oxidase and survival in chronic granulomatous disease. The New England Journal of Medicine 363(27): 2600–2610. Ley K and Morris M (2005) Signals for lymphocyte egress. Nature Immunology 6(12): 1215–1216. Marchetti C, Patriarca P, Solero GP, Baralle FE, and Romano M (2004) Genetic characterization of myeloperoxidase deficiency in Italy. Human Mutation 23(5): 496–505. Matute JD, Arias AA, Wright NA, Wrobel I, Waterhouse CC, Li XJ, Marchal CC, Stull ND, Lewis DB, Steele M, et al. (2009) A New genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood 114(15): 3309–3315. Nalls MA, Wilson JG, Patterson NJ, Tandon A, Zmuda JM, Huntsman S, Garcia M, Hu D, Li R, Beamer BA, et al. (2008) Admixture mapping of white cell count: Genetic locus responsible for lower white blood cell count in the health ABC and Jackson heart studies. The American Journal of Human Genetics 82(1): 81–87. Njalsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, and Norgren S (2005) Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Human Genetics 116(5): 384–389. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonald D, Geha RS, Takada H, Krause JC, et al. (2010) Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore) 89(6): 403–425. Stark Z and Savarirayan R (2009) Osteopetrosis. Orphanet Journal of Rare Diseases 4: 5. Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, et al. (2009) Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nature Medicine 15(3): 306–312. Woellner C, Gertz EM, Schaffer AA, Lagos M, Perro M, Glocker EO, Pietrogrande MC, Cossu F, Franco JL, Matamoros N, et al. (2010) Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. The Journal of Allergy and Clinical Immunology 125(2): 424–432, e8.