Alternative titles; symbols
HGNC Approved Gene Symbol: DEFB4A
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:7,894,677-7,896,716 (from NCBI)
Defensins are a family of small (3 to 4 kD) cationic peptides exhibiting broad spectrum antimicrobial activities against bacteria and fungi. The defensins are divided into alpha- and beta-defensins based on the sequence relationship of 6 conserved cysteine residues. The human alpha-defensins HNP1 (125220) to HNP4 are stored in the azurophil granules of phagocytic leukocytes playing a role in the killing of ingested microorganisms, whereas the alpha-defensins HD5 and HD6 are expressed in epithelial cells of the small intestine. Beta-defensin-1 (DEFB1; 602056) appears from the expression pattern of the gene to be involved in the antimicrobial defense of epithelia of surfaces such as those of the respiratory tract, urinary tract, and vagina. DEFB1 has been implicated in the pathogenesis of cystic fibrosis.
Harder et al. (1997) identified a second member of the beta-defensin family, DEFB2. It is an inducible, transcriptionally regulated antibiotic peptide expressed in the skin and respiratory tract.
Bals et al. (1998) reported the isolation and characterization of DEFB2, which they identified by homology to DEFB1. They found that DEFB2 is expressed diffusely throughout the epithelia of many organs, including the lung, where it is found in the surface epithelia and serous cells of the submucosal glands. A specific antibody made of recombinant peptide detected DEFB2 in airway surface fluid of human lung. Fully processed peptide, which is salt sensitive and synergistic with lysozyme and lactoferrin, had broad antibacterial activity against many organisms. These data suggested the existence of a family of beta-defensin molecules on mucosal surfaces that in the aggregate contribute to normal host defense.
By in situ hybridization, Liu et al. (1998) determined that expression of DEFB2 is locally regulated by inflammation.
Yang et al. (1999) showed that human beta-defensins are chemotactic for immature dendritic cells (DCs) and memory T cells. Human beta-defensin was selectively chemotactic for cells stably transfected to express human CCR6 (601835), a chemokine receptor preferentially expressed by immature DCs and memory T cells. The beta-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC (601960), the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by beta-defensin. Thus, beta-defensins may promote adaptive immune responses by recruiting DCs and T cells to the site of microbial invasion through interaction with CCR6.
Biragyn et al. (2002) showed that mouse Defb2 acts directly on immature DCs as a ligand for TLR4 (603030), thereby inducing upregulation of costimulatory molecules and DC maturation. These events triggered robust type-1 immune responses in vivo by recruiting immature DCs to the site of inflammation through CCR6. Linkage of Defb2 to nonimmunogenic tumor antigens resulted in potent antitumor activity, suggesting that DEFB2 may be a useful vaccine adjuvant (see the commentary by Ganz (2002)).
By in situ hybridization, immunocytochemical, and RT-PCR analyses, Duits et al. (2002) showed that DEFB1 and DEFB2 were expressed by monocytes and macrophages and that expression increased after activation with IFNG (147570) and/or lipopolysaccharide (LPS) in a dose- and time-dependent manner. Expression of DEFB1, but not DEFB2, was detectable in dendritic cells and increased after dendritic cell maturation.
Wang et al. (2004) showed that the active hormonal form of vitamin D, 1,25(OH)2D3, directly induced CAMP (600474) and DEFB2 expression and activity in keratinocytes, monocytes, and neutrophils through consensus vitamin D response elements in the promoters of the 2 genes. RT-PCR detected synergistic enhancement of antimicrobial peptide expression in neutrophils stimulated with 1,25(OH)2D3 and LPS.
Using RT-PCR, Starner et al. (2005) found that HBD2 was the predominant beta-defensin expressed in human neonatal lung. HBD2 expression was induced by IL1B (147720) and decreased by dexamethasone, and its expression levels were dependent on gestational age. Starner et al. (2005) proposed that lower HBD2 levels may contribute to susceptibility of premature infants to pulmonary infections.
Using ELISA to detect HBD2 (DEFBR; 152700) and HNP1 (DEFA1; 125220) in sera of SLE patients and controls, Sthoeger et al. (2009) could not detect HBD2 in serum or mRNA in cells. However, DEFA2 levels were significantly higher in all SLE patients compared to controls and, in fact, 60% of patients had very high levels. High DEFA2 levels correlated with disease activity but not with neutrophil numbers, suggesting that neutrophil degranulation may lead to alpha-defensin secretion in SLE patients. Disease improvement occurs together with a reduction in DEFA2 levels.
By fluorescence in situ hybridization, Harder et al. (1997) mapped the DEFB2 gene to chromosome 8p23.1-p22. Furthermore, they assigned it to specific CEPH YACs that indicated a narrow localization. The fact that all genes encoding defensins had been found to map to 8pter-p21 suggested the presence of a gene cluster in that region that plays a major role in antimicrobial defense. By 3-color FISH on both free chromatin fiber mapping and interphase mapping, Liu et al. (1998) mapped the DEFB2 gene to 8p23.
Hollox et al. (2003) showed that a cluster of at least 3 antimicrobial beta-defensin genes (DEFB4, DEFB103 (606611), and DEFB104) at 8p23.1 are polymorphic in copy number, with a repeat unit at least 240 kb long. Individuals have 2 to 12 copies of this repeat per diploid genome. By segregation, microsatellite dosage, and semiquantitative FISH chromosomal signal intensity ratio analyses, they deduced that individual chromosomes can have 1 to 8 copies of this repeat unit. Chromosomes with 7 or 8 copies of this repeat unit are identifiable by cytogenetic analysis as a previously described 8p23.1 euchromatic variant.
Because defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion, it has been suggested that deficient defensin expression may underlie the chronic inflammation of Crohn disease (see 266600). Furthermore, the highly polymorphic nature of the DNA copy number in the beta-defensin gene cluster on 8p23.1 within the healthy population suggests that the defective beta-defensin induction in colonic Crohn disease might be due to low beta-defensin gene copy number. Fellermann et al. (2006) tested this hypothesis by array-based comparative genomic hybridization and quantitative PCR analysis of the DEFB4 gene. They showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 (range 2-10) copies of the DEFB4 gene per genome. In a surgical cohort with ileal or colonic Crohn disease and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median copy number of 4 for the DEFB4 gene, whereas those with colonic Crohn disease had a median of only 3 copies per genome (P = 0.008 for the surgical cohort; P = 0.032 for the second cohort). Overall, the copy number distribution in colonic Crohn disease was shifted to lower numbers compared with controls. Individuals with 3 copies or fewer had a significantly higher risk of developing colonic Crohn disease than did individuals with 4 or more copies (odds ratio 3.06). A gene copy number of less than 4 for the DEFB4 gene was associated with diminished mucosal mRNA expression (P = 0.033).
Using multiplex amplifiable probe hybridization (MAPH) and paralog ratio test (PRT), Hollox et al. (2008) reported an association between increased copy number variation at the beta-defensin gene cluster and psoriasis (see 177900) among 179 Dutch patients and 272 controls (p = 7.8 x 10(-5)). A second cohort of 319 German patients and 305 controls assayed using PRT confirmed the finding (p = 2.95 x 10(-5)). Hollox et al. (2008) suggested that high levels of beta-defensins may result in an inappropriate inflammatory response after minor skin injury in patients with psoriasis.
Aldhous et al. (2010) used copy number typing based on PRT to assess beta-defensin copy number in more than 1,500 DNA samples from the U.K. that included more than 1,000 cases of Crohn disease. They found no evidence to support an association of Crohn disease with either low or high beta-defensin copy number. Aldhous et al. (2010) also compared PRT-based methods with standard real-time PCR in a subset of 625 samples and found serious shortcomings of real-time PCR for typing beta-defensin copy number variation.
Aldhous, M. C., Bakar, S. A., Prescott, N. J., Palla, R., Soo, K., Mansfield, J. C., Mathew, C. G., Satsangi, J., Armour, J. A. L. Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease. Hum. Molec. Genet. 19: 4930-4938, 2010. [PubMed: 20858604] [Full Text: https://doi.org/10.1093/hmg/ddq411]
Bals, R., Wang, X., Wu, Z., Freeman, T., Bafna, V., Zasloff, M., Wilson, J. M. Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J. Clin. Invest. 102: 874-880, 1998. [PubMed: 9727055] [Full Text: https://doi.org/10.1172/JCI2410]
Biragyn, A., Ruffini, P. A., Leifer, C. A., Klyushnenkova, E., Shakhov, A., Chertov, O., Shirakawa, A. K., Farber, J. M., Segal, D. M., Oppenheim, J. J., Kwak, L. W. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298: 1025-1029, 2002. [PubMed: 12411706] [Full Text: https://doi.org/10.1126/science.1075565]
Duits, L. A., Ravensbergen, B., Rademaker, M., Hiemstra, P. S., Nibbering, P. H. Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 106: 517-525, 2002. [PubMed: 12153515] [Full Text: https://doi.org/10.1046/j.1365-2567.2002.01430.x]
Fellermann, K., Stange, D. E., Schaeffeler, E., Schmalzl, H., Wehkamp, J., Bevins, C. L., Reinisch, W., Teml, A., Schwab, M., Lichter, P., Radlwimmer, B., Stange, E. F. A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am. J. Hum. Genet. 79: 439-448, 2006. [PubMed: 16909382] [Full Text: https://doi.org/10.1086/505915]
Ganz, T. Versatile defensins. Science 298: 977-979, 2002. [PubMed: 12411693] [Full Text: https://doi.org/10.1126/science.1078708]
Harder, J., Siebert, R., Zhang, Y., Matthiesen, P., Christophers, E., Schlegelberger, B., Schroder, J.-M. Mapping of the gene encoding human beta-defensin-2 (DEFB2) to chromosome region 8p22-p23.1. Genomics 46: 472-475, 1997. [PubMed: 9441752] [Full Text: https://doi.org/10.1006/geno.1997.5074]
Hollox, E. J., Armour, J. A. L., Barber, J. C. K. Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am. J. Hum. Genet. 73: 591-600, 2003. [PubMed: 12916016] [Full Text: https://doi.org/10.1086/378157]
Hollox, E. J., Huffmeier, U., Zeeuwen, P. L. J. M., Palla, R., Lascorz, J., Rodijk-Olthuis, D., van de Kerkhof, P. C. M., Traupe, H., de Jongh, G., den Heijer, M., Reis, A., Armour, J. A. L., Schalkwijk, J. Psoriasis is associated with increased beta-defensin genomic copy number. Nature Genet. 40: 23-25, 2008. [PubMed: 18059266] [Full Text: https://doi.org/10.1038/ng.2007.48]
Liu, L., Wang, L., Jia, H. P., Zhao, C., Heng, H. H. Q., Schutte, B. C., McCray, P. B., Jr., Ganz, T. Structure and mapping of the human beta-defensin HBD-2 gene and its expression at sites of inflammation. Gene 222: 237-244, 1998. [PubMed: 9831658] [Full Text: https://doi.org/10.1016/s0378-1119(98)00480-6]
Starner, T. D., Agerberth, B., Gudmundsson, G. H., McCray, P. B., Jr. Expression and activity of beta-defensins and LL-37 in the developing human lung. J. Immun. 174: 1608-1615, 2005. [PubMed: 15661923] [Full Text: https://doi.org/10.4049/jimmunol.174.3.1608]
Sthoeger, Z. M., Bezalel, S., Chapnik, N., Asher, I., Froy, O. High alpha-defensin levels in patients with systemic lupus erythematosus. Immunology 127: 116-122, 2009. [PubMed: 19191901] [Full Text: https://doi.org/10.1111/j.1365-2567.2008.02997.x]
Wang, T.-T., Nestel, F. P., Bourdeau, V., Nagai, Y., Wang, Q., Liao, J., Tavera-Mendoza, L., Lin, R., Hanrahan, J. W., Mader, S., White, J. H. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immun. 173: 2909-2912, 2004. Note: Erratum: J. Immun. 173: following 6489, 2004. [PubMed: 15322146] [Full Text: https://doi.org/10.4049/jimmunol.173.5.2909]
Yang, D., Chertov, O., Bykovskala, S. N., Chen, Q., Buffo, M. J., Shogan, J., Anderson, M., Schroder, J. M., Wang, J. M., Howard, O. M. Z., Oppenheim, J. J. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286: 525-528, 1999. [PubMed: 10521347] [Full Text: https://doi.org/10.1126/science.286.5439.525]