Cleavage of IgGs by proteases associated with invasive diseases: an evasion tactic against host immunity?
The effective functioning of immunoglobulins and IgG mAbs in removing pathological cells requires that the antigen binding regions and the Fc (effector) domain act in concert. The hinge region that connects these domains itself presents motifs that engage Fc receptors on immune effector cells to achieve cell lysis. In addition, sequences in the lower hinge/CH2 and further down the CH2 region are involved in C1q binding and complement-mediated cell killing. Proteolytic enzymes of little relevance to human physiology were successfully used for decades to generate fragments of IgGs for reagent and therapeutic use. It was subsequently noted that tumor-related and microbial proteases also cleaved human IgG specifically in the hinge region. We have shown previously that the "nick" of just one of the lower hinge heavy chains of IgG unexpectedly prevented many effector functions without impacting antigen binding. Of interest, related single-cleaved IgG breakdown products were detected in breast carcinoma extracts. This suggested a pathway by which tumors might avoid host immune surveillance under a cloak of proteolytically-generated, dysfunctional antibodies that block competent IgG binding. The host immune system cannot be blind to this pathway since there exists a widespread, low-titer incidence of anti-hinge (cleavage-site) antibodies in the healthy population. The prevalence of anti-hinge reactivity may reflect an ongoing immune recognition of normal IgG catabolism. Tumor growth and bacterial infections potentially generate hostile proteolytic environments that may pose harsh challenges to host immunity. Recent findings involving physiologically-relevant proteases suggest that the potential loss of key effector functions of host IgGs may result from subtle and limited proteolytic cleavage of IgGs and that such events may facilitate the incursion of invasive cells in local proteolytic settings.
Brezski
Randall J
RJ
Biologics Research, Centocor R&D Inc., Radnor, PA, USA. rbrezski@its.jnj.com
Jordan
Robert E
RE
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001424:Bacterial Infections / Q000201:enzymology* / Q000276:immunology* / Q000628:therapy; D001426:Bacterial Proteins / Q000378:metabolism; D052058:Hinge Exons / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology* / Q000628:therapy; D010447:Peptide Hydrolases / Q000378:metabolism*; D019139:Tumor Escape
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D010447:Peptide Hydrolases
J Mol Biol. 2002 May 24;319(1):9-18
12051932
J Biol Chem. 1994 May 27;269(21):15287-93
8195166
J Exp Med. 1993 Apr 1;177(4):1165-73
8459210
Infect Immun. 2001 Nov;69(11):7187-9
11598100
Nat Rev Cancer. 2001 Nov;1(2):118-29
11905803
Adv Immunol. 2006;90:1-50
16730260
Proc Natl Acad Sci U S A. 1976 Sep;73(9):3278-82
1067619
J Virol. 2001 Dec;75(24):12161-8
11711607
Adv Exp Med Biol. 1995;371A:609-11
8526000
J Clin Oncol. 2007 Aug 20;25(24):3712-8
17704420
Immunology. 1974 Apr;26(4):725-33
4212065
Biochemistry. 1998 Jun 30;37(26):9266-73
9649307
Annu Rev Cell Dev Biol. 2001;17:463-516
11687497
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17864-9
19815504
J Immunol. 2006 Sep 15;177(6):3913-9
16951354
Nature. 1958 Sep 6;182(4636):670-1
13590068
Proc Natl Acad Sci U S A. 1971 Jun;68(6):1372-5
5288389
J Immunol. 1976 Mar;116(3):724-30
1254951
Science. 1960 Dec 9;132(3441):1770-1
13729245
Microbes Infect. 2005 Mar;7(3):476-84
15792635
J Clin Oncol. 2009 Mar 1;27(7):1122-9
19164213
Biochemistry. 2004 Dec 14;43(49):15540-9
15581366
Eur J Cancer. 2006 Apr;42(6):728-34
16524717
J Biol Chem. 2009 Dec 18;284(51):35390-402
19850927
Mol Immunol. 1988 Nov;25(11):1175-81
2975762
Clin Cancer Res. 2007 Sep 1;13(17):5133-43
17785568
J Clin Oncol. 2003 Nov 1;21(21):3940-7
12975461
Nat Rev Immunol. 2007 Sep;7(9):715-25
17703228
Immunity. 2007 Feb;26(2):205-13
17306569
J Mol Biol. 1998 Feb 6;275(5):861-72
9480774
Nat Rev Immunol. 2008 Jan;8(1):34-47
18064051
Mol Immunol. 2002 May;38(14):1073-83
11955599
Blood. 2002 Feb 1;99(3):754-8
11806974
Infect Immun. 2005 Mar;73(3):1515-22
15731049
EMBO J. 2002 Apr 2;21(7):1607-15
11927545
J Exp Med. 1999 Mar 1;189(5):843-53
10049948
EMBO J. 2001 Jun 15;20(12):3046-55
11406581
J Clin Oncol. 2008 Apr 10;26(11):1789-96
18347005
Science. 2003 Sep 5;301(5638):1374-7
12920303
Science. 2007 Sep 14;317(5844):1554-7
17872445
Expert Opin Biol Ther. 2007 Sep;7(9):1401-13
17727329
J Rheumatol. 1995 Jun;22(6):1075-85
7674233
Mol Immunol. 1986 Mar;23(3):319-30
3487030
J Immunol. 2008 Sep 1;181(5):3183-92
18713989
Eur J Immunol. 1999 Sep;29(9):2819-25
10508256
Biochem Biophys Res Commun. 2006 Mar 17;341(3):797-803
16442075
Nature. 1970 Oct 10;228(5267):160-2
4990048
Vox Sang. 1994;66(1):37-45
7908473
J Immunol. 1973 Oct;111(4):1274-6
4199558
J Immunol. 2005 Jun 15;174(12):7792-9
15944283
MAbs. 2010 Jan-Feb;2(1):84-100
20065640
J Am Chem Soc. 2007 Jun 6;129(22):6976-7
17500521
J Immunol. 1991 Oct 15;147(8):2657-62
1833457
J Clin Invest. 1998 Aug 1;102(3):576-83
9691094
J Biol Chem. 2001 Mar 2;276(9):6591-604
11096108
J Biol Chem. 1996 Feb 16;271(7):3659-66
8631977
Eur J Immunol. 1995 Nov;25(11):3128-33
7489753
Cell Mol Biol (Noisy-le-grand). 2002 May;48(3):271-8
12030431
Infect Immun. 1988 Oct;56(10):2717-22
3166451
Biochim Biophys Acta. 2000 Mar 7;1477(1-2):35-50
10708847
Circulation. 2003 Jun 10;107(22):2829-36
12771009
Nat Rev Cancer. 2007 Oct;7(10):800-8
17851543
J Biol Chem. 1999 Jul 30;274(31):21491-4
10419448
Nature. 1991 Oct 24;353(6346):765-9
1944535
J Immunol. 1995 May 1;154(9):4404-13
7722297
Int J Pept Protein Res. 1996 Jul;48(1):48-55
8844262
Nature. 1988 Apr 21;332(6166):738-40
3258649
J Infect Dis. 1985 Apr;151(4):589-98
3919115
Thromb Haemost. 1999 Aug;82(2):846-9
10605792
J Exp Med. 1983 Apr 1;157(4):1184-96
6220107
Immunol Lett. 2002 Apr 1;81(1):41-8
11841844
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11810-3
8524854
Nature. 2007 May 24;447(7143):482-6
17495932
Nature. 1988 Apr 7;332(6164):563-4
2965792
Blood. 1995 Jan 15;85(2):548-51
7812010
Proc Natl Acad Sci U S A. 1969 May;63(1):78-85
5257969
Mol Immunol. 1995 Nov;32(16):1271-81
8559151
Mol Immunol. 2008 Apr;45(7):1837-46
18157932
APMIS. 1996 May;104(5):321-38
8703438
Curr Opin Biotechnol. 2009 Dec;20(6):685-91
19896358
J Immunol. 2000 May 15;164(10):5313-8
10799893
Int J Cancer. 1975 Sep 15;16(3):456-64
1176203
Infect Immun. 1992 Dec;60(12):5057-64
1333448
J Clin Invest. 1985 Aug;76(2):723-30
3928684
Mol Immunol. 2008 May;45(10):2951-61
18339427
Infect Immun. 2003 Jan;71(1):211-7
12496168
J Exp Med. 1991 Jun 1;173(6):1483-91
1827828
Mol Immunol. 1990 Dec;27(12):1237-40
2148808
Mol Immunol. 1986 Dec;23(12):1365-72
2434846
Cancer Res. 2008 Aug 1;68(15):6368-76
18676862