Of Mice and Not Men: Differences between Mouse and Human Immunology Javier Mestas and Christopher C. W. Hughes This information is current as J Immunol 2004; 172:2731-2738; ; of September 25, 2021. doi: 10.4049/jimmunol.172.5.2731 http://www.jimmunol.org/content/172/5/2731 Downloaded from References This article cites 101 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/172/5/2731.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS Of Mice and Not Men: Differences between Mouse and Human Immunology Javier Mestas and Christopher C. W. Hughes1 Mice are the experimental tool of choice for the majority of sarily true in humans. By making such assumptions we run the immunologists and the study of their immune responses risk of overlooking aspects of human immunology that do not has yielded tremendous insight into the workings of the occur, or cannot be modeled, in mice. Included in this subset human immune system. However, as 65 million years of will be differences that may preclude a successful preclinical evolution might suggest, there are significant differences. trial in mice becoming a successful clinical trial in human. Here we outline known discrepancies in both innate and In this review our aim is not to suggest that the mouse is an adaptive immunity, including: balance of leukocyte sub- invalid model system for human biology. Clearly, with so many Downloaded from sets, defensins, Toll receptors, inducible NO synthase, the paradigms that translate well between the species, and with the NK inhibitory receptor families Ly49 and KIR, FcR, Ig relative ease with which mice can now be genetically manipu- subsets, the B cell (BLNK, Btk, and ␭5) and T cell lated, mouse models will continue to provide important infor- (ZAP70 and common ␥-chain) signaling pathway com- mation for many years to come. Rather, our aim is to sound a ␥␦ word of caution. As therapies for human diseases become ever ponents, Thy-1, T cells, cytokines and cytokine recep- http://www.jimmunol.org/ tors, Th1/Th2 differentiation, costimulatory molecule more sophisticated and specifically targeted, it becomes increas- expression and function, Ag-presenting function of endo- ingly important to understand the potential limitations of ex- thelial cells, and chemokine and chemokine receptor ex- trapolating data from mice to humans. The literature is littered with examples of therapies that work well in mice but fail to pression. We also provide examples, such as multiple scle- provide similar efficacy in humans (2–7). By focusing on some rosis and delayed-type hypersensitivity, where complex known differences between mouse and human immunology we multicomponent processes differ. Such differences should hope to spur interest in this area and encourage others to note be taken into account when using mice as preclinical mod- differences where they occur. els of human disease. The Journal of Immunology, 2004, by guest on September 25, 2021 172: 2731–2738. Structure and general characteristics ice are the mainstay of in vivo immunological ex- The overall structure of the immune system in mice and hu- perimentation and in many respects they mirror hu- mans is quite similar. As this topic has been recently reviewed in M man biology remarkably well. This conservation of depth (8), we will not go into great detail here. One difference function is reflected in recent reports on the sequencing of both worth noting is that whereas mice have significant bronchus- the human and mice genomes, which reveal that to date only associated lymphoid tissue, this is largely absent in healthy hu- 300 or so genes appear to be unique to one species or the other mans (9), possibly reflecting a higher breathable Ag load for an- (1). Despite this conservation there exist significant differences imals living so much closer to the ground. between mice and humans in immune system development, ac- The balance of lymphocytes and neutrophils in adult animals tivation, and response to challenge, in both the innate and is quite different: human blood is neutrophil rich (50–70% adaptive arms. Such differences should not be surprising as the neutrophils, 30–50% lymphocytes) whereas mouse blood has a two species diverged somewhere between 65 and 75 million strong preponderance of lymphocytes (75–90% lymphocytes, years ago, differ hugely in both size and lifespan, and have 10–25% neutrophils) (10). It is not clear what, if any, func- evolved in quite different ecological niches where widely differ- tional consequence this shift toward neutrophil-rich blood in ent pathogenic challenges need to be met—after all, most of us humans has had. do not live with our heads a half-inch off the ground. However, Tyrosine kinase receptor expression on putative hemopoietic because there are so many parallels there has been a tendency to stem cells (HSC)2 shows a reciprocal pattern, with mouse HSC Ϫ ignore differences and in many cases, perhaps, make the as- being predominantly c-kithigh, flt-3 , whereas human HSC are ϩ sumption that what is true in mice—in vivo veritas—is neces- predominantly c-kitlow, flt-3 (11). Center for Immunology and Department of Molecular Biology and Biochemistry, Uni- 1 Address correspondence and reprint requests to Dr. Christopher Hughes, Department of versity of California, Irvine, CA 92697 Molecular Biology and Biochemistry, McGaugh Hall; University of California, Irvine, CA 92697. E-mail address: [email protected]. Received for publication November 12, 2003. Accepted for publication January 23, 2004. 2 Abbreviations used in this paper: HSC, hemopoietic stem cells; iNOS, inducible NO The costs of publication of this article were defrayed in part by the payment of page charges. synthase; ␥ , common ␥-chain; DETC, dendritic epidermal T cells; MS, multiple sclerosis; This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. c DTH, delayed-type hypersensitivity; EC, endothelial cells. Section 1734 solely to indicate this fact. Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 2732 BRIEF REVIEW Innate immunity other FcR associate with ITAM-containing signal transduction One of the first lines of defense in higher organisms, and often subunits (22). the only defense in lower animals, is the growing family of an- In addition to differences in FcR there are well-known dif- timicrobial peptides, and in particular the defensins. These are ferences in expression of Ig isotypes between mice and humans, important in mucosal defense in the gut and in epithelial de- and direct correlations between subtypes within classes in each fense in skin and elsewhere (12, 13). Neutrophils are a rich species are hard to make. Mice make IgA, IgD, IgE, IgM, and source of leukocyte defensins in humans, but defensins are not four subtypes of IgG: IgG1, IgG2a, IgG2b, and IgG3. Interest- expressed by neutrophils in mice (14). In contrast, Paneth cells, ingly, in the C57BL/6, C57BL/10, SJL, and NOD strains of which are present in the crypts of the small intestine, express mice there is no expression of IgG2a, instead these mice express Ͼ20 defensins (cryptdins) in mice but only two in human, the novel IgG2c (23). Humans in contrast express two subtypes likely reflecting different evolutionary pressures related to mi- of IgA—IgA1 and IgA2—along with single forms of IgD, IgE, croorganism exposure through food intake. There are also dif- and IgM. In humans there are also four subtypes of IgG: IgG1, ferences in processing of defensins (Table I). IgG2, IgG3, and IgG4; however, these are not direct homo- The last few years have seen a renewed focus on the field of logues of the mouse proteins. While different subtypes have dif- innate immunology, spurred in large part by identification of fering abilities to bind FcR or fix complement, the differences the Toll-like family of receptors—the TLRs (15). This field is between mice and humans are not considered significant. In still relatively young and so far a limited number of differences contrast, there are differences in class switching: in mice, IL-4 have been noted between mice and humans (Table I). induces IgG1 and IgE, whereas in humans, IL-4 induces Downloaded from There has been considerable controversy as to whether hu- switching to IgG4 and IgE. In contrast, IL-13 has no effect on man macrophages express NO. Expression of functional induc- mouse B cells but induces switching to IgE in humans (24). ible NO synthase (iNOS; NOS2) in mouse macrophages has There are some interesting differences in B cell development been clearly demonstrated and iNOS mRNA is readily induced that relate to the roles of several signaling molecules. BLNK (Src by IFN-␥ and LPS (16). However, these same inflammatory homology-2 domain containing leukocyte-specific phospho- http://www.jimmunol.org/ mediators have failed to show consistent effects on human mac- protein-65) is an adapter protein that is rapidly phosphorylated rophages, hence the confusion.