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HGNC Approved Gene Symbol: DEFA1
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:6,977,649-6,980,092 (from NCBI)
Defensins are a group of microbicidal and cytotoxic peptides made by neutrophils. Daher et al. (1988) stated that 3 human defensins, also called human neutrophil peptide-1 (HNP1), HNP2, and HNP3 (604522), make up about 30% of the neutrophil's total granule protein. From a human promyelocytic leukemia cDNA library, Daher et al. (1988) isolated clones encoding HNP1 and HNP3. Analysis of these clones indicated that the defensins are made as 94-amino acid precursor proteins that must be cleaved to yield the mature peptides. Mature HNP1 and HNP3 contain 30 amino acids each and are identical except for the N-terminal amino acid. HNP2 may be formed by degradation or processing of HNP1 and/or HNP3, because it lacks this N-terminal amino acid and is otherwise identical to HNP1 and HNP3. Defensin mRNA was detected in normal bone marrow cells but not in peripheral blood leukocytes.
Mars et al. (1987, 1988) isolated 2 overlapping cDNA clones that represent an mRNA that is highly expressed in selected subpopulations of myeloid leukocytes. The nucleotide sequence indicated that this myeloid-related sequence (MRS) probably encodes a unique 93-amino acid protein, including a leader sequence of 18 amino acids.
Liu et al. (1997) reported that there are 7 defensins in humans: 6 alpha-defensins and a beta-defensin (DEFB1; 602056). Neutrophil alpha-defensins 1 to 4 (DEFA4; 601157) are found in the microbicidal granules of neutrophils (Ganz and Lehrer, 1995) and alpha-defensins 5 (DEFA5; 600472) and 6 (DEFA6; 600471) are located in Paneth cells of the intestinal tract. DEFB1 appears to be involved in the antimicrobial defense of the epithelia of surfaces such as those of the respiratory tract, urinary tract, and vagina.
In human airways, epithelial cells lining the lumen, and intraluminal cells (e.g., polymorphonucleus cells) participate in the innate immune response. These cells secrete or express on their surfaces arginine-specific ADP ribosyltransferases. Defensins, antimicrobial proteins secreted by immune cells, are arginine-rich, leading Paone et al. (2002) to hypothesize that ADP ribosylation could modify their biologic activities. They found that an arginine-specific ADP ribosyltransferase-1 present on airway epithelial cells modifies arg-14 of alpha-defensin-1. ADP-ribosylated defensin-1 had decreased antimicrobial and cytotoxic activities but still stimulated T-cell chemotaxis and IL8 release from A549 cells. Further, ADP-ribosylated defensin-1 inhibited cytotoxic and antimicrobial activities of unmodified defensin-1. Paone et al. (2002) identified ADP-ribosylated defensin-1 in bronchoalveolar lavage fluid from smokers but not from nonsmokers, confirming its existence in vivo. Thus, airway mono-ADP-ribosyltransferases could have an important regulatory role in the innate immune response through modification of alpha-defensin-1 and perhaps other basic molecules, with alteration of their biologic properties.
The human alpha- and beta-defensin genes cluster on 8p23, a locus that also contains the pseudogene for retrocyclin. Cole et al. (2002) reported that human bone marrow expresses mRNA that is homologous to the precursors of rhesus monkey circular minidefensins. Although a stop codon within its signal sequence suggested that the human transcript now represents an expressed pseudogene, they used its sequence and information derived from studies on rhesus monkeys to synthesize retrocyclin, the putative ancestral human circular minidefensin. Retrocyclin dramatically protected human CD4(+) cells from infection by HIV-1 in vitro, was noncytotoxic, and killed certain bacteria effectively in physiologic saline. The authors suggested that retrocyclin-like agents might be useful topically to prevent sexually acquired HIV-1 infections. Cole et al. (2002) stated that it is not possible to know whether the evolutionary loss of retrocyclin contributed to the susceptibility of humans to HIV-1 infection.
Wang et al. (2003) stated that retrocyclin is distinct from alpha- and beta-defensins and belongs to a third defensin subfamily, the theta-defensins. Biacore and glycosidase analysis showed that retrocyclin is a vertebrate lectin that binds to both O- and N-linked sugars, including CD4 and HIV gp120 glycoproteins.
Walker et al. (1986) described an anti-HIV factor secreted by CD8 (see 186910) T cells from certain HIV-1-infected individuals in a non-major histocompatibility complex (MHC) class I-restricted and non-cell contact-dependent manner. The factor, referred to as CAF (CD8 antiviral factor), is resistant to heat and acid and is of low molecular mass. CAF is produced at relatively higher levels by clinically stable HIV-1-infected patients, the so-called long-term nonprogressors (LTNPs), but not by progressors. Cocchi et al. (1995) determined that the beta chemokines CCL5 (187011), CCL4 (182284), and CCL3 (182283) possess CAF-like activity, but only against macrophage-tropic and not T-cell-tropic viral isolates, because of their common usage of CCR5 (601373). Using a protein chip system and mass spectrometric and protein database analyses, Zhang et al. (2002) identified a cluster of three 3.3- to 3.5-kD proteins, DEFA1, DEFA2, and DEFA3 (604522), secreted by LTNPs and most normal individuals, but not by progressors. DEFA1-, DEFA2-, and DEFA3-specific antibodies depleted antiviral activity in a dose-dependent manner, particularly against viruses using CXCR4 (162643) rather than CCR5 as a coreceptor. Addition of synthetic or purified natural defensins inhibited HIV-1 replication in vitro. Flow cytometric analysis determined that in addition to neutrophils, a small population of CD8-positive T lymphocytes harbor and secrete DEFA1, DEFA2, and DEFA3. Zhang et al. (2002) proposed that these defensins account for much of the anti-HIV-1 activity of CAF that is not attributable to beta chemokines.
Chang et al. (2003) investigated whether DEFAs, particularly DEFA1, contribute to CAF-mediated inhibition of HIV-1 transcription. They found that DEFA1 inhibited HIV-1 infection following viral entry, but that the DEFAs were not involved in the inhibition of HIV-1 gene expression and long terminal repeat activation attributed to CAF derived from herpesvirus saimiri-transformed CD8-positive cells.
Independently, Mackewicz et al. (2003) showed that DEFA1, DEFA2, and DEFA3 exhibit anti-HIV activity by directly inactivating HIV particles and by reducing the ability of CD4-positive T lymphocytes to replicate the virus. Immunocytochemical and RT-PCR analysis detected expression of DEFAs in neutrophils and monocytes, but not in CD8-positive T cells. Antibodies specific for the DEFAs did not block the antiviral activity of CAF-active CD8-positive cell culture fluids, indicating that, although DEFAs possess anti-HIV effects, they are distinct from CAF.
In a retraction based upon RT-PCR analysis and careful dissection of their cell culture system, Zhang et al. (2002) concluded that their initial interpretation of a possible CD8-positive T-lymphocyte source for DEFAs was incorrect. CAF activity from CD8-positive cells, in the absence of contaminating neutrophil feeder cells, could not be attributed to DEFAs. However, neutrophil-derived DEFAs did have potent anti-HIV-1 activity, regardless of viral strain or target cell.
Anthrax lethal toxin, a combination of the bacterium's lethal factor and protective antigen proteins, plays a major role in anthrax pathogenesis. Kim et al. (2005) showed that HNP1, HNP2, and HNP3 could neutralize anthrax lethal toxin activity and protect murine macrophages in vitro and adult mice. They proposed that these defensins have potential for immunotherapy of anthrax.
By screening for compounds that inhibited infection by human papillomavirus (HPV) using pseudoviruses capable of infecting HeLa cells, Buck et al. (2006) found that DEFA1, DEFA2, DEFA3, and DEFA5 were potent antagonists of both mucosal and cutaneous HPVs. DEFA4 was less active, and DEFA6, DEFB1, and DEFB2 (DEFB4; 602215) showed little to no activity. DEFA5 was particularly active against sexually transmitted HPV types. DEFA1 and DEFA5 also inhibited HPV-mediated transduction of other cell types. Immunofluorescent confocal microscopy revealed that inhibition occurred at the level of virion escape from endocytic vesicles, but not at virion binding or internalization, and pseudoviruses remained susceptible for many hours after initial binding to cells. Mutant DEFA2 peptides with lower antibacterial activity that wildtype DEFA2 retained anti-HPV effects, suggesting that its incorporation in a topical microbicide could augment innate defenses in the vaginal tract without disrupting the normal flora.
Using ELISA and real-time PCR, Sthoeger et al. (2009) found that HBD2 (DEFB4) was undetectable in sera from systemic lupus erythematosus (SLE; 152700) patients and that HBD2 mRNA was low in whole blood from SLE patients, similar to controls. In contrast, DEFA2 levels were significantly higher in all SLE patients compared with controls, and 60% of patients had very high serum 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. Reduction of DEFA2 levels to the normal range correlated with disease improvement.
Cryptdin is a defensin-related peptide that is expressed in epithelial cells of intestinal crypts; hence, its name. Using Southern blot analysis of DNAs from mouse/hamster somatic cell hybrids and analysis of strain distribution pattern in recombinant inbred strains, Ouellette et al. (1989) showed that the murine cryptdin locus (Defcr) is located on chromosome 8. Other genes located on human 8p are found on mouse chromosome 8.
Ouellette and Lualdi (1990) identified a related mouse locus, Crs1c (Defcr-rs1), on chromosome 8.
Sparkes et al. (1989) used a cDNA insert for defensin HNP1 to map the gene to human chromosome 8p23, using a mouse/human somatic cell hybrid panel and in situ hybridization to normal human metaphase chromosomes. Because of the close similarity between HNP1 defensin and other defensins, they suspected that 2 or more of these genes may map to the 8p23 region.
The MRS gene was localized by Mars et al. (1987, 1988) to chromosome 8 by Southern analysis of somatic cell hybrid DNAs and was regionalized to 8q21.1-q23 by in situ hybridization to metaphase chromosomes.
As the breakpoint of a reciprocal translocation involving chromosomes 8 and 21 occurs at 8q22 in the form of myeloid leukemia known as ANLL-M2, MRS may be of pathologic interest. Mars et al. (1988) found that when Southern blot hybridization is performed by using somatic cell hybrid DNAs harboring either a single 8q- or a single 21q+ chromosome from 2 different patients with M2-ANLL, a signal was detected only in the hybrid containing the 8q- chromosome. See review by Lehrer et al. (1991).
Aldred et al. (2005) identified variation in both number and position of DEFA1 and DEFA3 genes in arrays of 19-kb tandem repeats on chromosome 8p23.1, so that the DEFA1 and DEFA3 genes appeared to be interchangeable variant cassettes within tandem gene arrays. The total number of gene copies per diploid genome varied between 4 and 11 in a sample of 111 control individuals from the U.K., with approximately 10% of people lacking DEFA3 completely. DEFA1 appeared to be at high copy number in all great apes studied; at 1 variable site in the repeat unit, both variants have persisted in humans, chimpanzees, and gorillas since their divergence. Analysis of expression levels in human white blood cells showed a clear correlation between the relative proportions of DEFA1:DEFA3 mRNA and corresponding gene numbers. However, there was no relationship between total (DEFA1+DEFA3) mRNA levels and total gene copy number, suggesting the superimposed influence of trans-acting factors. Due to the persistence of DEFA1 at high copy number in other apes, Aldred et al. (2005) suggested an alternative model for the early stages of the evolution of novel genes by duplication and divergence.
Aldred, P. M. R., Hollox, E. J., Armour, J. A. L. Copy number polymorphism and expression level variation of the human alpha-defensin genes DEFA1 and DEFA3. Hum. Molec. Genet. 14: 2045-2052, 2005. [PubMed: 15944200] [Full Text: https://doi.org/10.1093/hmg/ddi209]
Buck, C. B., Day, P. M., Thompson, C. D., Lubkowski, J., Lu, W., Lowy, D. R., Schiller, J. T. Human alpha-defensins block papillomavirus infection. Proc. Nat. Acad. Sci. 103: 1516-1521, 2006. [PubMed: 16432216] [Full Text: https://doi.org/10.1073/pnas.0508033103]
Chang, T. L.-Y., Francois, F., Mosoian, A., Klotman, M. E. CAF-mediated human immunodeficiency virus (HIV) type 1 transcriptional inhibition is distinct from alpha-defensin-1 HIV inhibition. J. Virol. 77: 6777-6784, 2003. [PubMed: 12767998] [Full Text: https://doi.org/10.1128/jvi.77.12.6777-6784.2003]
Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., Lusso, P. Identification of RANTES, MIP-1-alpha and MIP-1-beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270: 1811-1815, 1995. [PubMed: 8525373] [Full Text: https://doi.org/10.1126/science.270.5243.1811]
Cole, A. M., Hong, T., Boo, L. M., Nguyen, T., Zhao, C., Bristol, G., Zack, J. A., Waring, A. J., Yang, O. O., Lehrer, R. I. Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1. Proc. Nat. Acad. Sci. 99: 1813-1818, 2002. [PubMed: 11854483] [Full Text: https://doi.org/10.1073/pnas.052706399]
Daher, K. A., Lehrer, R. I., Ganz, T., Kronenberg, M. Isolation and characterization of human defensin cDNA clones. Proc. Nat. Acad. Sci. 85: 7327-7331, 1988. Note: Erratum: Proc. Nat. Acad. Sci. 86: 342 only, 1989. [PubMed: 3174637] [Full Text: https://doi.org/10.1073/pnas.85.19.7327]
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Kim, C., Gajendran, N., Mittrucker, H.-W., Weiwad, M., Song, Y.-H., Hurwitz, R., Wilmanns, M., Fischer, G., Kaufmann, S. H. E. Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences. Proc. Nat. Acad. Sci. 102: 4830-4835, 2005. [PubMed: 15772169] [Full Text: https://doi.org/10.1073/pnas.0500508102]
Lehrer, R. I., Ganz, T., Selsted, M. E. Defensins: endogenous antibiotic peptides of animal cells. Cell 64: 229-230, 1991. [PubMed: 1988144] [Full Text: https://doi.org/10.1016/0092-8674(91)90632-9]
Liu, L., Zhao, C., Heng, H. H. Q., Ganz, T. The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics 43: 316-320, 1997. [PubMed: 9268634] [Full Text: https://doi.org/10.1006/geno.1997.4801]
Mackewicz, C. E., Yuan, J., Tran, P., Diaz, L., Mack, E., Selsted, M. E., Levy, J. A. Alpha-defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS 17: F23-F32, 2003. Note: Erratum: AIDS 17: F31 only, 2003. [PubMed: 14502030] [Full Text: https://doi.org/10.1097/00002030-200309260-00001]
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Ouellette, A. J., Lualdi, J. C. A novel mouse gene family coding for cationic, cysteine-rich peptides: regulation in small intestine and cells of myeloid origin. J. Biol. Chem. 265: 9831-9837, 1990. Note: Erratum: J. Biol. Chem. 269: 18702 only, 1994. [PubMed: 2351676]
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Paone, G., Wada, A., Stevens, L. A., Matin, A., Hirayama, T., Levine, R. L., Moss, J. ADP ribosylation of human neutrophil peptide-1 regulates its biological properties. Proc. Nat. Acad. Sci. 99: 8231-8235, 2002. [PubMed: 12060767] [Full Text: https://doi.org/10.1073/pnas.122238899]
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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]
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Wang, W., Cole, A. M., Hong, T., Waring, A. J., Lehrer, R. I. Retrocyclin, an antiretroviral theta-defensin, is a lectin. J. Immun. 170: 4708-4716, 2003. [PubMed: 12707350] [Full Text: https://doi.org/10.4049/jimmunol.170.9.4708]
Zhang, L., Yu, W., He, T., Yu, J., Caffrey, R. E., Dalmasso, E. A., Fu, S., Pham, T., Mei, J., Ho, J. J., Zhang, W., Lopez, P., Ho, D. D. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 298: 995-1000, 2002. Note: Retraction: Science 303: 467 only, 2004. [PubMed: 12351674] [Full Text: https://doi.org/10.1126/science.1076185]